A Phase 1/2, Multicenter, Open-label, Study of FT-2102 as a Single Agent and in Combination with Azacitidine in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome with an IDH1 R132 Mutation

Research Summary

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Inclusion Criteria:

1. Pathologically proven acute myeloid leukemia or intermediate, high risk or very high risk MDS as defined by the World Health Organization (WHO) criteria or Revised International Prognostic Scoring System (IPSS-R) and one of the following based on enrolment stage or treatment cohort: a. Single Agent Cohorts including Phase 1 Dose-Escalation/ Dose-Expansion and Phase 2 Treatment Cohort 1: AML/MDS either relapsed or refractory to standard therapy, or for whom standard treatments are contra-indicated. b. Single Agent Phase 2 Treatment Cohort 2: AML/MDS in morphologic CR/CRi after cytotoxic-containing induction therapy (+/- consolidation) with residual IDH-R132 mutation (≥ 0.01%) detected in the bone marrow. c. Single Agent Phase 2 Treatment Cohort 3 only: AML/MDS that is either relapsed or refractory to prior IDH1 inhibitor therapy AND for whom standard treatments are contra-indicated. d. Combination (FT-2102 + azacitidine) cohorts including Phase 1 Dose-Escalation/ Dose-Expansion and Phase 2 Treatment Cohort 4 (patients must meet one of the following): i. Patients < 60 years old with AML that is either relapsed or refractory to standard therapy, or for whom standard treatments are contraindicated. ii. Patients that have MDS that is either relapsed or refractory to standard therapy, or are treatment-naïve, who are eligible for azacitidine therapy. e. Phase 2 Treatment Cohort 5 (FT-2102 + Azacitidine) only: AML/MDS that is R/R to a hypomethylating agent as their last therapy prior to study enrolment. f. Phase 2 Expansion Cohort 6 (FT-2102 + Azacitidine) only: AML/MDS that is R/R to a single agent IDH-1 inhibitor as their last therapy prior to study enrolment. 2. Patients must have documented IDH1-R132 gene-mutated disease as evaluated by the site. 3. Patients ≥ 18 years old. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see Appendix 2). 5. Signed informed consent prior to beginning study and undergoing procedures. 6. No prior solid organ allograft. 7. Acceptable liver function: a. Bilirubin ≤ 2 times upper limit of normal (ULN) b. Aspartate transaminase (AST, also referred to as SGOT), alanine transaminase (ALT, also referred to as SGPT) and alkaline phosphatase (ALP) ≤ 3 times ULN. 8. Acceptable renal function: a. Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance ≥ 50 mL/min (Cockcroft and Gault). 9. Recovery from the nonhematologic toxic effects of prior treatment to Grade ≤ 1, or baseline value according to NCI CTCAE classification (excluding infertility, alopecia, or Grade 1 neuropathy). 10. Baseline QTcF ≤ 450 msec (average of the QTcF values of screening triplicate ECGs. Note: Patients with bundle branch block must have a QTcF ≤ 480 msec. 11. Negative pregnancy test if female of childbearing potential. 12. For fertile men and women, agreement to use effective contraceptive methods for the duration of study participation and 90 days after. 13. Phase 2 Treatment Cohorts 1-6 (SA and combination) only: Pre-treatment FFPE bone marrow biopsy or aspirate for central confirmation of IDH1-R132 mutation is required. Note: central confirmation of IDH1-R132 mutation is not required for study enrolment.

Exclusion Criteria:

1. History of prior malignancy unless disease free for ≥2 years. Patients with nonmelanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses). 2. Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy. 3. Patients with previous allogeneic stem cell transplant (SCT) if they meet any of the following criteria: < 100 days from time of SCT; active acute or chronic graft vs host disease (GvHD) or receiving immunosuppressive therapy as treatment for GvHD. Note: Doses of < 20 mg methylprednisolone (or its equivalent) daily are not an exclusion criteria. 4. Treatment with radiation therapy, major surgery (requiring general anesthesia) within one month prior to study entry. 5. Treatment with small molecule anticancer therapeutic within five half-lives of the agent or within 21 days if the half-life is unknown. 6. Treatment with an anticancer therapeutic antibody less than four weeks before first dose of study drug. 7. Treatment with other experimental therapies or participation in another clinical trial within a period of time that is less than the cycle length or within 21 days prior to starting study drug, whichever is shorter. 8. Patients unable to swallow oral medications, or patients with gastrointestinal conditions (eg, malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption. 9. Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within one year prior to study entry, uncontrolled hypertension, or uncontrolled arrhythmias (see Appendix 5). 10. Patients with family history of QT prolongation, and/or new concomitant medication(s) known to prolong the QT interval initiated less than 4 weeks before first dose of study drug (see Appendix 6). 11. Concurrent treatment with chronic corticosteroids except if chronic treatment with < 20 mg of methylprednisolone daily or equivalent (pulse steroids for treatment or prophylaxis are allowed [eg, for transfusion or medication reactions]). 12. Known HIV positivity. 13. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy (Prophylactic systemic antimicrobials permitted). 14. Uncontrolled disease-related metabolic disorder (eg, hypercalcemia). 15. Pregnant or nursing women or women of childbearing potential not using adequate contraception. Male patients not using adequate contraception. NOTE: Women of child-bearing potential (see Section 5.6) and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation and 90 days after. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 16. Serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. 17. Patients with detectable IDH2 mutation (variant allele frequency of > 0.05). 18. Patients who have exhibited allergic reactions to compounds structurally similar to FT-2102. 19. Patients who have been treated with an IDH1 targeted therapy. Note: Prior IDH-1 targeted therapy is not an exclusion criteria for patients enrolling into the Phase 2 Treatment Cohort 3 and patients enrolling into the Phase 2 Treatment Cohort 6. 20. Unwillingness or inability to comply with procedures required in this protocol. 21. Medical, uncontrolled disease-related metabolic disorder, psychiatric, cognitive, or other conditions that may compromise the patient’s ability to understand the patient information, give informed consent, comply with the study protocol, or complete the study. Patients who are candidates for hematopoietic stem cell transplantation (HSCT).

Sub Specialty:

Haematological Oncology

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A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men with Metastatic Castration-resistant Prostate Cancer

Research Summary

This research study is a double-blind, phase 3 trial evaluating the efficacy and safety (including evaluating side effects) of combination of olaparib and abiraterone versus placebo and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have received no prior cytotoxic chemotherapy or new hormonal agent at mCRPC stage. Study participants will undergo screening, treatment and follow-up period. The screening period can last up to 28 days and may require several visits. Eligible participants are males at least 18 years old and who consent to participate in the study and meet the study mandatory entry criteria. Study participants will be divided into 2 groups and will receive study medications at random assigned by a computer program. Approximately 720 subjects will be randomized 1:1 (olaparib plus abiraterone: placebo plus abiraterone) into the trial. Patients will be trained on how to use an electronic device to report their pain and symptoms at various time during the study. During the treatment period, patients will be required to attend the study clinic for study visits and assessments. The follow-up period occurs once the patient's cancer has been confirmed as progressing by radiologic imaging. This study is expected to last up to 4 years.

Inclusion Criteria:

Histologically or cytologically confirmed prostate adenocarcinoma. Metastatic status defined as at least 1 documented metastatic lesion on either a bone scan or a CT/MRI scan. First-line mCRPC: - Patients must be treatment naïve at mCRPC stage, eg, patients should not have received any cytotoxic chemotherapy, NHA, or other systemic treatment (approved drugs or experimental compounds) in the mCRPC setting. ADT is an exception. - Treatment with first-generation antiandrogen agents (eg, bicalutamide, nilutamide, and flutamide) treatment before randomisation is allowed, but there must be a washout period of 4 weeks. - Docetaxel treatment is allowed during neoadjuvant/adjuvant treatment for localised prostate cancer and at mHSPC stage, as long as no signs of failure or disease progression occurred during or immediately after such treatment. - Prior to mCRPC stage, treatment with second-generation antiandrogen agents (except abiraterone) without PSA progression/clinical progression/radiographic progression during treatment is allowed, provided the treatment was stopped at least 12 months before randomisation. Ongoing androgen deprivation with gonadotropin-releasing hormone analogue or bilateral orchiectomy, with serum testosterone < 50 ng/dL (< 2.0 nmol/L) within 28 days before randomisation. Patients receiving ADT at study entry should continue to do so throughout the study. Candidate for abiraterone therapy with documented evidence of progressive disease. Progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on androgen deprivation therapy: - PSA progression defined by a minimum of two rising PSA levels with an interval of > = 1 week between each determination. The PSA value at the Screening visit should be > = 1 μg/L (1 ng/mL) (per PCWG-3 criteria); - Soft-tissue disease progression defined by RECIST 1.1; - Bone progression defined by appearance of 2 or more new lesions on a bone scan (per PCWG-3 criteria). Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined in inclusion criteria 10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks. The participant has, in the opinion of the investigator, a life expectancy of at least 6 months. Prior to randomisation, sites must confirm availability of either an archival FFPE tumour tissue sample, or a new biopsy taken during the screening window, which meets the minimum pathology and sample requirements in order to enable HRR status subgroup analysis of the primary endpoint rPFS. If there is not written confirmation of the availability of tumour tissue prior to randomisation, the patient is not eligible for the study. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib+abiraterone when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.

Exclusion Criteria:

Known additional malignancy that has had progression or has required active treatment in the last 5 years. Exceptions include basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that has undergone potentially curative therapy. Myelodyplastic Syndrome (MDS) / Acute Myeloid Leukaemia (AML) or with features suggestive of MDS/AML. Clinically significant cardiovascular disease as evidenced by myocardial infarction or arterial thrombotic events (eg, stroke) in the past 6 months, severe or unstable angina,atrial fibrillation or other cardiac arrhythmia requiring therapy, or New York Heart Association Class II-IV heart failure or cardiac ejection fraction measurement of < 50% during screening as assessed by echocardiography or multigated acquisition scan. Planned or scheduled cardiac surgery or percutaneous coronary intervention procedure. Prior revascularisation procedure (significant coronary, carotid, or peripheral artery stenosis). Uncontrolled hypertension (systolic BP > = 160 mmHg or diastolic BP > = 95 mmHg). Patients with a history of hypertension are allowed provided BP is controlled by antihypertensive treatment. History of uncontrolled pituitary or adrenal dysfunction. Active infection or other medical condition that would make prednisone/prednisolone use contraindicated. Any chronic medical condition requiring a systemic dose of corticosteroid > 10 mg prednisone/prednisolone per day. Patients who are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, active pneumonitis, extensive interstitial bilateral lung disease on high-resolution CT scan, or any psychiatric disorder that prohibits obtaining informed consent and following the study procedures. Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAEs] grade > 2) caused by previous cancer therapy, excluding alopecia. Patients with brain metastases ( a scan to confirm the absence of brain metastases is not required). Patients with spinal cord compression are excluded unless they are considered to have received definitive treatment for this and have evidence of clinically stable disease for 4 weeks. Patients who are unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria: - A bone scan referred to as a superscan showing an intense symmetric activity in the bones. - No soft tissue lesion (measurable or non-measurable) that can be assessed by RECIST. Patients who are unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus. Patients with known active hepatitis infection (ie, hepatitis B or C). Prior/concomitant therapy - Any previous treatment with PARP inhibitor, including olaparib. - Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment. Patients who receive palliative radiotherapy need to stop radiotherapy 1 week before randomisation. - Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor (eg, abiraterone, orteronel). - Concomitant use of known strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. - Concomitant use of known strong CYP3A inducers (eg, phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine or St John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz or modafinil). The required washout period prior to starting study treatment is 5 weeks for phenobarbital and enzalutamide and 3 weeks for other agents. - Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. - Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). History of hypersensitivity to olaparib or abiraterone, any of the excipients of olaparib or abiraterone, or drugs with a similar chemical structure or class to olaparib or abiraterone.

Sub Specialty:

Prostate Cancer

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VISION: An International, Prospective, Open-Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients with Progressive PSMA-Positive Metastatic Castration Resistant Prostate Cancer (mCRPC)

Research Summary

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Inclusion Criteria:

1. Patients must have the ability to understand the Participant Information Sheet and sign an approved Consent Form 2. Patients must have the ability to understand and comply with all protocol requirements. 3. Patients must be ≥ 18 years of age. 4. Patients must have an ECOG performance status of 0 to 2. 5. Patients must have a life expectancy > 6 months. 6. Patients must have histological, pathological, and/or cytological confirmation of prostate cancer. 7. Patients must have a positive 68Ga-PSMA-11 PET/CT scan, as determined by the sponsor’s central reader. 8. Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L). 9. Patients must have received at least one NAAD (such as enzalutamide and/or abiraterone). 10. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if: a. The patient is not willing to receive a second taxane regimen, or b. The patient’s physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation or intolerance). 11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria: a. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL. b. Soft-tissue progression defined as an increase ≥ 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. c. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria). 12. Patients must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to beginning study therapy. 13. Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.). 14. Patients must have adequate organ function: a. Bone marrow reserve: • White blood cell (WBC) count ≥ 2.5 ラ 109/L (2.5 × 109/L is equivalent to 2.5 × 103/μL and 2.5 × K/μL and 2.5 × 103/cumm and 2500/μL) OR absolute neutrophil count (ANC) ≥ 1.5 ラ 109/L (1.5 × 109/L is equivalent to 1.5 × 103/μL and 1.5 × K/μL and 1.5 × 103/cumm and 1500/μL) • Platelets ≥ 100 × 109/L (100 × 109/L is equivalent to 100 × 103/μL and 100 × K/μL and 100 × 103/cumm and 100,000/ μL) • Haemoglobin ≥ 9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L) b. Hepatic: • Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert’s Syndrome ≤ 3 ラ ULN is permitted • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 ラ ULN OR ≤ 5.0 × ULN for patients with liver metastases c. Renal: • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min 15. Albumin > 3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) 16. Patients on a stable bisphosphonate or denosumab regimen for ≥ 30 days prior to randomisation are eligible. 17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial. For patients who have partners of childbearing potential: 18. Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 3 months after last study drug administration.

Exclusion Criteria:

1. Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation within 6 months prior to randomisation. Previous PSMA-targeted radioligand therapy is not allowed. 2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 28 days prior to day of randomisation. 3. Any investigational agents within 28 days prior to day of randomisation. 4. Known hypersensitivity to the components of the study therapy or its analogs. 5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. 6. Transfusion within 30 days of randomisation. 7. Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast). 8. A superscan as seen in the baseline bone scan. 9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression. 10. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to,New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. 11. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Patients with adequately treated non-melanoma skin cancer, superficial bladder cancer and patients with prior history of malignancy who have been disease free for more than 3 years are eligible.

Sub Specialty:

Prostate Cancer

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A Phase 3, Randomized, Controlled, Open-Label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia

Research Summary

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Inclusion Criteria:

Male or female patients 18 years or older. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with white blood cell count < 13,000/µL) or low-blast AML based on 1 of the following: French-American-British Classifications: o Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone marrow. o CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. OR World Health Organization (WHO) Classifications: o Refractory anemia with excess blasts-1 (RAEB-1), defined as having 5% to 9% myeloblasts in the bone marrow). o Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood). o Chronic myelomonocytic leukemia-2 (CMML-2), defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. o Chronic myelomonocytic leukemia-1 (although CMML-1 is defined as having < 10% myeloblasts in the bone marrow and/or < 5% blasts in the blood, these patients may enroll only if bone marrow blasts are ≥ 5%). o WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this protocol as low-blast AML) and < 30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine-based therapy. All patients with MDS or CMML must also have one of the following Prognostic Risk Categories, based on the IPSS-R: o Very high (> 6 points). o High (> 4.5-6 points). o Intermediate (> 3-4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of ≥ 5% bone marrow myeloblasts. ECOG PS of 0, 1, or 2. Patients with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score ≥ 4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers. Calculation of TRM score: o 0 for (age < 61 years), +2 for (age 61-70 years), +4 for (age > 71 years). o + 0 for (PS= 0), +2 for (PS= 1), +4 for (PS > 1). o + 0 for (platelets < 50,000/µL), +1 for (platelets > 50,000/µL). 6. Female patients who: o Are postmenopausal for at least 1 year before the Screening visit, OR o Are surgically sterile, OR o If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR o Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Male patients, even if surgically sterilized (ie, status postvasectomy), who: o Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half-lives) after the last dose of study drug, or o Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 7. Ability to undergo the study-required bone marrow sample collection procedures. 8. Suitable venous access for the study-required blood sampling (ie, including PK and pharmacodynamic sampling). Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug): o Albumin > 2.7 g/dL. o Total bilirubin less than or equal to the upper limit of the normal range (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5ULN of the direct bilirubin. o Alanine aminotransferase and aspartate aminotransferase < 2.5 × ULN. o Creatinine clearance > 50 mL/min. o Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

Previous treatment for HR MDS or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agents such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors: o Age > 75. o Comorbidities. o Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% blasts and TRM ≥ 4). o Physician decision (eg, lack of available stem cell donor). Patients with either clinical evidence of or history of central nervous system involvement by AML. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures or could limit expected patient survival to less than 6 months. Treatment with any antileukemic/anti-MDS therapies (eg, cytarabine, anthracyclines, purine analogs) or with any investigational products within 14 days before the first dose of any study drug. Known hypersensitivity to mannitol. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. Life-threatening illness unrelated to cancer. Prothrombin time or activated partial thromboplastin time > 1.5 × ULN or active uncontrolled coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrolment. Known human immunodeficiency virus (HIV) seropositive. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Known hepatic cirrhosis or severe preexisting hepatic impairment. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure, and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion. Treatment with strong cytochrome P450 3A inducers within 14 days before the first dose of pevonedistat. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s). Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

Sub Specialty:

Haematological Oncology

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A PHASE II, RANDOMIZED, ACTIVE-CONTROLLED, MULTI-CENTER STUDY COMPARING THE EFFICACY AND SAFETY OF TARGETED THERAPY OR CANCER IMMUNOTHERAPY GUIDED BY GENOMIC PROFILING VERSUS PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH CANCER OF UNKNOWN PRIMARY SITE WHO HAVE RECEIVED THREE CYCLES OF PLATINUM DOUBLET CHEMOTHERAPY

Research Summary

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Inclusion Criteria:

Patients must meet the following main inclusion criteria for study entry: • Signed Informed Consent Form. • Able and willing to comply with the study protocol. • Age ≥ 18 years. • Histologically-confirmed metastatic or advanced unresectable CUP diagnosed according the criteria defined in the 2015 ESMO Clinical Practice Guidelines for CUP. • At least one lesion that is measurable according to RECIST v1.1. • Availability of a tumor FFPE block ≤ 3 months old at Screening that is sufficient for generation of a FoundationOne® comprehensive genomic profile at a central reference pathology laboratory. • Availability of test reports confirming local CUP diagnosis. • Each patient must provide a blood sample for FoundationACT® genomic profiling, which will be used to assign molecularly-guided therapy ONLY in those patients for whom a FoundationOne® report could not be generated. • No prior systemic therapy for the treatment of CUP. • ECOG performance status of 0 or 1. • Life expectancy ≥ 12 weeks. • Eligible for platinum-based doublet chemotherapy. • Adequate hematologic and end-organ function, defined by laboratory results obtained within 14 days prior to initiation of study treatment: • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year during the treatment period and after the last dose of study treatment for at least: - 1 month for ipatasertib and olaparib - 3 months for alectinib - 5 months for atezolizumab - 6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, paclitaxel and gemcitabine - 7 months for trastuzumab and pertuzumab - 24 months for vismodegib • For male patients: acceptance that most of the study treatments include specific reliable and effective contraception measures, as well as measures related to sperm donation - For male patients assigned to study treatment: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below, during the Treatment Period and after the last dose of study treatment for at least: • 2 weeks for erlotinib • 1 month for ipatasertib • 2 months for vismodegib • 3 months for alectinib • 6 months for cobimetinib, vemurafenib, carboplatin, cisplatin, paclitaxel and gemcitabine • 7 months for trastuzumab and pertuzumab Prior to Start of Therapy in the Treatment Period If any of the below criteria are not met, randomisation in Category 1 patients will be delayed or study treatment will be discontinued: • Adequate hematologic and end-organ function, defined by laboratory results: • Recovery from significant toxicity from platinum-doublet therapy to Grade ≤ 1, except for alopecia and for neurosensory toxicity, which must be ≤ 2 • Recovery from active infections requiring intravenous antibiotics, with antibiotic therapy ceased for ≥ 7 days prior to planned start of therapy.

Exclusion Criteria:

• Squamous cell CUP. • Patients with specific non-CUP neoplasms: Non-epithelial cancer, Extragonadal germ-cell tumour. • Any of the following subsets of CUP with favourable prognoses: - Poorly differentiated carcinoma with midline distribution - Women with papillary adenocarcinoma of the peritoneal cavity - Women with adenocarcinoma involving only the axillary lymph nodes - Squamous cell carcinoma of the cervical lymph nodes - Poorly differentiated neuroendocrine tumors - Men with blastic bone metastases and elevated PSA - Patients with a single, small, potentially resectable tumor - Colon cancer-type CUP. • Known presence of brain or spinal cord metastasis, as determined by CT or MRI during screening. • History or known presence of leptomeningeal disease. • Uncontrolled or symptomatic hypercalcemia. • Known clinically significant history of liver disease. • Known HIV infection. • Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg) at screening. • Active tuberculosis at Screening. • Significant cardiovascular disease within 3 months prior to initiation of study treatment. • Major surgical procedure, excl. for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study. • History of malignancy other than CUP within 5 years prior to screening. • Prior allogeneic stem cell or solid organ transplantation. • Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. • Treatment with investigational therapy within 28 days prior to initiation of study treatment. • Known allergy or hypersensitivity to any component of the platinum-doublet chemotherapy. • Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or for up to 24 months after the last dose of treatment. Specific to Molecularly-Guided Therapies: All Therapies: • Known allergy or hypersensitivity to any component of the molecularly-targeted agents. All Oral Therapies: • History of malabsorption syndrome, lack of physical integrity of the upper GI tract, or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills. Alectinib: • Hereditary galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption • Symptomatic bradycardia. Vismodegib: • Males unwilling to use condoms, while being treated with vismodegib, and for 2 months after the last dose. Ipatasertib: • Fasting total serum glucose > 150 mg/dL • Glycated hemoglobin (HbA1C) > 7.5% • History of Type I or Type II diabetes mellitus requiring insulin • CrCl < 50 mL/min • Ongoing chronic corticosteroid therapy of ≥ 10 mg of prednisone per day or an equivalent dose of other antiinflammatory corticosteroids or immunosuppressants for a chronic disease • Active small or large intestine inflammation • For men: non-agreement to remain abstinent or use contraceptive measures, and non-agreement to refrain from donating sperm. Atezolizumab Monotherapy or in Combination with Platinum-Doublet Chemotherapy: • Active or history of autoimmune disease or immune deficiency • History of IPF, organising pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening CT scan • Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of immunosuppressive medication during treatment with atezolizumab. Erlotinib + Bevacizumab: • Poorly controlled hypertension • History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding • Non-healing wound, active peptic ulcer or bone fracture at Cycle 3 of platinum-doublet chemotherapy • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of planned study treatment • Recent pulmonary hemorrhage/hemoptysis • Unwillingness to stop smoking. Vemurafenib + Cobimetinib: • LVEF below institutional lLN or below 50%, whichever is lower • QTc > 500 msec at Cycle 3 of platinum-doublet chemotherapy • Long QT syndrome • Uncorrectable electrolyte abnormalities • Known risk factors for ocular toxicity • Any Grade ≥ 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 • Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment • Poorly controlled hypertension • History or presence of an abnormal ECG that is clinically significant. Trastuzumab SC + Pertuzumab + Platinum-Doublet Chemotherapy: • Serious cardiac illness • Type 1 or Type 2 diabetes mellitus requiring insulin • History of IBD, active bowel inflammation • Severe dyspnea at rest or patients requiring supplementary oxygen therapy.

Sub Specialty:

Lymphoma

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A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination with Pembrolizumab Versus Treatment of Physician’s Choice in Participants with Advanced Endometrial Cancer

Research Summary

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Inclusion Criteria:

1. Histologically confirmed diagnosis of endometrial carcinoma. 2. Documented evidence of advanced, recurrent or metastatic EC. 3. Radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for recurrent, metastatic or primary unresectable disease. - Participants who progress < 1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy are eligible without further systemic treatment. - Participants who progress > = 1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy must receive 1 additional cytotoxic systemic treatment prior to enrollment in this study. 4. Available historical or fresh tumor biopsy specimen for determination of MMR status. 5. At least 1 measurable target lesion according to RECIST 1.1 and confirmed by BICR, including the following criteria: - Non-nodal lesion that measures > = 1.0 cm in the longest diameter - Lymph node (LN) lesion that measures as > = 1.5 cm in the short axis - The lesion is suitable for repeat measurement using computed tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of subsequent growth. 6. ECOG performance status of 0 or 1 within 3 days of starting study treatment. 7. Female participants age > = 18 years and considered an adult per local regulations at the time of informed consent. 8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a.) Not a WOCBP OR b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. 9. The participant provides written informed consent for the study. 10. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP < = 150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before C1D1. 11. Have adequate organ function. Specimens must be collected within 3 days prior to the start of study treatment.

Exclusion Criteria:

1. Carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas. 2. Participants with CNS metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 3. Active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas, or basal or squamous cell carcinoma of the skin) within the past 24 months. 4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. 5. Radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. 6. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug. 7. Significant cardiovascular impairment within 12 months of the first dose of study drug: such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability. 8. Active infection (any infection requiring systemic treatment). 9. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. 10. Participants known to be positive for Human Immunodeficiency Virus (HIV). No HIV testing is required unless mandated by local heath authority. 11. Known active Hepatitis B or Hepatitis C. No testing for hepatitis B or C is required unless mandated by local health authority. 12. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis. 13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 16. Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment. 17. Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 18. Greater than 1 prior systemic anticancer regimen (other than adjuvant or neoadjuvant) for advanced, recurrent, or metastatic endometrial cancer. 19. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter). All acute toxicities related to prior treatments must be resolved to Grade < = 1, except for alopecia and Grade < = 2 peripheral neuropathy. 20. Prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 21. Participants who received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor other than an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, and who discontinued from that treatment due to a Grade 3 or higher immune-related adverse event. 22. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start. 23. Received a live vaccine within 30 days of planned start of study treatment. 24. Known intolerance to study treatment (or any of the excipients). 25. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. 26. Participants with proteinuria > 1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein > = 1 g/24 h will be ineligible. 27. Prolongation of QTc interval to > 480 ms. 28. Left ventricular ejection fraction below the institutional normal range as determined by multigated acquisition scan or echocardiogram.

Sub Specialty:

Gynaecological Cancers

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A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING THE EFFICACY AND SAFETY OF POLATUZUMAB VEDOTIN IN COMBINATION WITH RITUXIMAB AND CHP (R-CHP) VERSUS RITUXIMAB AND CHOP (R-CHOP) IN PREVIOUSLY UNTREATED PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA

Research Summary

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Inclusion Criteria:

- Age 18-80 years - Previously untreated patients with CD20-positive DLBCL, including one of the following diagnoses by 2016 WHO classification of lymphoid neoplasms: o DLBCL, not otherwise specified (NOS) including germinal center B-cell type, activated B-cell type o T-cell/histiocyte-rich large B-cell lymphoma o Epstein-Barr virus-positive DLBCL, NOS o ALK-positive large B-cell lymphoma o HHV8-positive DLBCL, NOS o High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) o High-grade B-cell lymphoma, NOS - Availability of archival or freshly collected tumor tissue before study enrollment - International Prognostic Index score of 2-5 - Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2 - Life expectancy >= 12 months - At least one bi-dimensionally measurable lesion, defined as >= 1.5 cm in its longest dimension as measured by computed tomography or magnetic resonance imaging - Ability and willingness to comply with the study protocol procedures, including patient reported outcome measures - Left ventricular ejection fraction >= 50% on cardiac multiple-gated acquisition scan or cardiac echocardiogram - Adequate hematologic function - For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 12 months after the last dose of study treatment - For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing - For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm for at least 5 months after the last dose of blinded polatuzumab vedotin/placebo, 3 months after the last dose of rituximab, and for at least 6 months after the last dose of blinded vincristine/placebo and cyclophosphamide to avoid exposing the embryo for the duration of the pregnancy.

Exclusion Criteria:

- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products - Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines - Prior organ transplantation - Current Grade > 1 peripheral neuropathy by clinical examination - Demyelinating form of Charcot-Marie-Tooth disease - History of indolent lymphoma - Follicular lymphoma grade 3B - B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma) - Primary mediastinal (thymic) large B-cell lymphoma - Burkitt lymphoma - Prior treatment with cytotoxic drugs within 5 years of screening for any condition or prior use of any anti-CD20 antibody - Prior use of any monoclonal antibody within 3 months of the start of Cycle 1 - Prior therapy for DLBCL, with the exception of nodal biopsy - Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control - Patients with CNS lymphoma, primary effusion DLBCL, and primary cutaneous DLBCL - Vaccination with live vaccines and any investigational therapy within 28 days prior to the start of Cycle 1 - History of other malignancy that could affect compliance with the protocol or interpretation of results - Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease - Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis - History or presence of an abnormal electrocardiogram that is clinically significant in the investigator’s opinion - Known active bacterial, viral, fungal, mycobacterial, parasitic or other infection at study enrollment or significant infections within 2 weeks before the start of Cycle 1 - Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis - Prior radiotherapy to the mediastinal/pericardial region - Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment - Any of the abnormal laboratory values such as international normalization ratio > 1.5 x upper limit of normal (ULN) in the absence of therapeutic anticoagulation, Partial thromboplastin time or activated partial thromboplastin time > 1.5 x ULN in the absence of a lupus anticoagulant, Serum aspartate aminotransferase and alanine aminotransferase >= 2.5 x ULN, Total bilirubin >= 1.5 x ULN, Serum creatinine clearance < 40 mL/min - Patients with suspected active or latent tuberculosis - Positive test results for chronic hepatitis B infection, hepatitis C, human T-lymphotrophic 1 virus - Known history of HIV seropositive status - Patients with a history of progressive multifocal leukoencephalopathy - Pregnancy or lactation or intending to become pregnant during study - Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to Cycle 1, Day 1.

Sub Specialty:

Lymphoma

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Phase 1-2 Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX660 in Subjects with Advanced Solid Tumors and Lymphomas

Research Summary

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Inclusion Criteria:

1. Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed. 2. Men and women 18 years of age or older. 3. Subjects with histologically or cytologically confirmed advanced solid tumors or lymphoma that is metastatic or unresectable, and for whom standard life-prolonging measures are not available. Specific tumor types that will be selected for study in Phase 2 are detailed in Section 4.1 (Table 3). 4.Subjects must have measurable disease according to RECIST v1.1 or evaluable disease that can be reliably and consistently followed. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 6. Acceptable organ function, as evidenced by the following laboratory data: a) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 × upper limit of normal (ULN). b) Total serum bilirubin ≤ 1.5 × ULN. c) Absolute neutrophil count (ANC): o Phase 1 and 2 (except Phase 2 subjects with known lymphoma): ≥ 1500 cells/mm3. o Phase 2 subjects with known lymphoma: ≥ 1000 cells/mm3 (≥ 750 cells/mm3 for subjects with lymphoma in bone marrow). d) Platelet count: o Phase 1 and 2 (except Phase 2 subjects with known lymphoma): ≥ 100,000 cells/mm3. o Phase 2 subjects with known lymphoma: ≥ 50,000 cells/mm3 (≥ 25,000 cells/mm3 for subjects with lymphoma in bone marrow). e) Serum creatinine levels ≤ 1.5 × ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance ≥ 50 mL/min. f) Amylase and lipase ≤ ULN. 7. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment.

Exclusion Criteria:

1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen. 2. Poor medical risk because of systemic diseases (eg, uncontrolled infections) in addition to the qualifying disease under study. 3. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of ASTX660. 4. A history of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions: o Abnormal left ventricular ejection fraction (LVEF; < 50%) on echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA). [Applies to Phase 1 only; ECHO/MUGA scans are not performed in Phase 2.] o Congestive cardiac failure of ≥ Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest. o Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days). o History or presence of complete left bundle branch block, heart block, cardiac pacemaker or significant arrhythmia. o Concurrent treatment with any medication that prolongs QT interval and may induce torsades de pointes and which cannot be discontinued at least 2 weeks before treatment with ASTX660. (See Section 7.6.2.) [Applies to Phase 1 only.] o Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. o Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett’s correction) of ≥ 470 msec). 5. Known history of human immunodeficiency virus (HIV) infection; or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. 6. Grade 2 or greater neuropathy [Applies to Phase 1]. Grade 3 or greater neuropathy [Applies to Phase 2]. 7. Known brain metastases unless stable or previously treated. 8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments. 9. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX660), as follows: o Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. o Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. o Investigational drugs (small molecules or biologics) within the longer of 2 weeks or 5 half-lives prior to study treatment and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].

Sub Specialty:

Lymphoma

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COMBI-APlus: Open-label, phase IIIb study of dabrafenib in COMBInation with trametinib in the Adjuvant treatment of stage III BRAF V600 mutation-positive melanoma after complete resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-management algorithm (Plus)

Research Summary

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Inclusion Criteria:

1. Is 18 years of age. 2. Has signed written informed consent. 3. Completely resected histologically confirmed high-risk [Stage IIIA (LN metastasis > 1 mm), IIIB, IIIC, IIID; 8th edition of the AJCC] V600E/K mutation positive cutaneous melanoma without prior systemic anticancer treatment or radiotherapy for melanoma. 4. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. Patients with an unknown primary melanoma are not eligible. 5. Must be surgically rendered free of disease (defined as the date of the most recent surgery) no more than 12 weeks before enrolment. 6. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). 7. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 9. Must have adequate organ function, including hematologic (absolute neutrophil count ≥ 1.2 × 109/L, hemoglobin ≥ 9 g/dL, platelet count ≥ 100 × 109/L, prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × upper limit of normal), hepatic (albumin ≥ 2.5 g/dL, total bilirubin ≤ 1.5 × upper limit of normal, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × upper limit of normal), renal (≥ 1 of the following: serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min), and cardiac (left ventricular ejection fraction ≥ lower limit of normal by echocardiography) function. 10. Women of childbearing potential must have had a negative serum β-HCG pregnancy test within 7 days of the first dose of study treatment and agreed to use effective contraception from 14 days prior to enrollment, throughout the treatment period, and for 4 months after the last dose of study treatment.

Exclusion Criteria:

1. Known mucosal or ocular melanoma or the presence of un-resectable in-transit metastases. 2. Evidence of distant metastatic disease on screening evaluation. 3. Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) including radiotherapy for melanoma. Prior surgery for melanoma is allowed. 4. Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to enrollment. Current or expected use of a prohibited medications (other anticancer therapies, other investigational drugs, antiretroviral drugs, herbal remedies, and drugs that are strong inhibitors or inducers of CYP3A and CYP2C8). 5. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). 6. Patients with known Human Immunodeficiency Virus (HIV). 7. History of another malignancy (including melanoma) or a concurrent malignancy except as noted below. Patients who have previously had Stage III melanoma or any malignancy with confirmed activating RAS mutation at any time are not eligible. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility. Exceptions: • Patients with a history of any malignancy that have been disease-free for at least 5 years are eligible except those with confirmed activating RAS mutations. • Patients with a history of completely resected non-melanoma skin cancer (e.g. basal cell carcinoma, squamous cell carcinoma) are eligible irrespective of the time since the resection. • Patients with successfully treated in situ carcinoma are eligible. • Patients presenting with multiple primary melanomas are eligible only if the lesions are concurrent. Patients who have concurrent multiple primary melanomas that are “distant” are eligible provided each lesion is considered local disease or resectable regional disease. These cases should be discussed with the Medical Lead. 8. Cardiac or cardiac repolarization abnormality, including any of the following: • History or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease, including any of the following: • Recent (within last 6 months) myocardial infarction (MI) • Unstable angina (within last 6 months), • Uncontrolled congestive heart failure (CHF) • Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker). 9. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure > 21 mm Hg as measured by tonography. 11. History of clinically significant or active interstitial lung disease or pneumonitis. 12. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures. 13. Pregnant or nursing females.

Sub Specialty:

Skin Cancer

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A Phase II, Open Label, Randomized, Two-Arm Study to Investigate the Efficacy and Safety of two doses of the Antibody Drug Conjugate GSK2857916 in participants with Relapsed/Refractory Multiple Myeloma who had 3 or more prior lines of treatment, are refractory to proteasome inhibitor, and immunomodulatory agent and have failed an Anti-CD38 Antibody (DREAMM 2)

Research Summary

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Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply: 1. Provide signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 2. Male or female, 18 years or older (at the time consent is obtained). 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix 9). 4. Histologically or cytologically confirmed diagnosis of Multiple Myeloma as defined by IMWG (2014) and: a) Has undergone stem cell transplant, or is considered transplant ineligible; b) Have received at least 3 prior lines of anti-myeloma treatments that include the following, an IMID (i.e. lenalidomide or pomalidomide), proteasome inhibitor (i.e., bortezomib, ixazomib or carfilzomib), and daratumumab (or other anti CD38 antibody) alone or in combination Appendix 8). 5. Has measurable disease with at least one of the following: a) Serum M-protein 0.5 g/dL (5 g/L); b) Urine M-protein  200 mg/24h; c) Serum FLC assay: Involved FLC level  10 mg/dL ( 100 mg/L) and an abnormal serum free light chain ratio (< 0.26 or > 1.65); 6. Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a) transplant was > 100 days prior to study enrolment; b) no active infection(s); c) participant meets the remainder of the eligibility criteria outlined in this protocol. 7. Participants after prior allogeneic SCT are allowed if the allogeneic transplant was performed ≥ 2 years prior to day 1 of study treatment, and only if participant has no active graft-versus-host disease (GVHD) requiring treatment. 8. Adequate organ system functions. 9. A female participant is eligible to participate if she is of: a) Non-childbearing potential (i.e. physiologically incapable of becoming pregnant) defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/mL (< 147 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods specified if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. b) Women of childbearing potential must have a negative serum pregnancy test within 72 hours of first dose of study treatment and agree to use effective contraception, as defined in Appendix 5, during the study and for 80 days following the last dose of study treatment. 10. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Appendix 5 from the time of first dose of study until 140 days after the last dose of study treatment to allow for clearance of any altered sperm. 11. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.03 must be ≤ Grade 1 at the time of enrolment except for alopecia and Grade 2 neuropathy. 12. In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

Participants satisfying any of these criteria are not eligible for assignment to treatment: 1. Systemic anti-myeloma therapy within < 14 days, or plasmapheresis within 7 days prior to the first dose of study drug. 2. Use of an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs. Prior BCMA targeted therapy. 3. Any toxicity from previous treatments which has not recovered to < Grade 1 or to baseline with the exception of alopecia and peripheral neuropathy as described in the Inclusion Criteria 13. 4. Evidence of active mucosal or internal bleeding. 5. Any major surgery within the last four weeks. 6. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible. 7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures. 8. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria. 9. Malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (MM). 10. Evidence of cardiovascular risk including any of the following: • QTcF interval ≥ 470 msecs (the QT interval values should be corrected for heart rate by Fridericia’s formula [QTcF]). • Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block. • History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening. • Class III or IV heart failure as defined by the New York Heart Association functional classification system. • Uncontrolled hypertension. 11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2857916, or any of the components of the study treatment. 12. Pregnant or lactating female. 13. Known active infection requiring antibiotic, antiviral, or antifungal treatment. 14. Known HIV infection. 15. Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at screening or within 3 months prior to first dose of study treatment. 16. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. NOTE: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing. 17. Current corneal epithelial disease. 18. Best corrected visual acuity in the worst seeing eye worse than 20/100 (Snellen equivalent). Participants with vision worse than 20/100 due to a treatable condition (e.g. cataract) may be discussed with the medical monitor and considered on an individual case basis.

Sub Specialty:

Haematological Oncology

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An International, Phase 2, Open-Label, Randomized Study of BGB-3111 Combined with Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma

Research Summary

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Inclusion Criteria:

Each participant eligible to participate in this study must meet all of the following criteria: 1. > = 18 years of age at the time of informed consent. 2. Histologically confirmed diagnosis of B-cell follicular lymphoma (grade 1, 2 or 3a) based on the WHO 2008 classification of tumours of haematopoietic and lymphoid tissue. 3. > = 2 prior systemic treatments for follicular lymphoma. 4. Previously received an anti-CD20 antibody and an appropriate alkylator-based combination therapy (such as rituximab, cyclophosphamide, doxorubicin, and prednisolone; rituximab, cyclophosphamide, vincristine, and prednisolone; or bendamustine plus rituximab). 5. Disease progression within 12 months after completion of most recent therapy or refractory disease, defined as failure to achieve CR or PR to most recent therapy, and most recent therapy was an appropriate second-line (or later) systemic therapy for follicular lymphoma. 6. Presence of measurable disease, defined as > = 1 nodal lesion that is > 2 cm in longest diameter, or > = 1 extranodal lesion that is > 1 cm in longest diameter. 7. Availability of archival tissue confirming diagnosis of B-cell follicular lymphoma (or if archival tissue is not available, a copy of the pathology report confirming diagnosis of B-cell follicular lymphoma is required). 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 9. Life expectancy > = 6 months. 10. Adequate organ function defined as: a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor support within 7 days) b. Platelet > 50,000/mm3 (without growth factor support or transfusion within 7 days) c. Creatinine clearance > = 30 ml/min (as estimated by the Cockcroft- Gault equation or as measured by nuclear medicine scan or 24-hour urine collection) d. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase < = 3.0 × upper limit of normal (ULN) e. Serum total bilirubin < 2.0 × ULN (unless documented Gilbert's syndrome). 11. Female participants of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study medication, for the duration of the study, and for > = 90 days after the last dose of BGB- 3111, or 18 months after the last dose of obinutuzumab, whichever is longer. These methods include the following: a. Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation i. Oral, intravaginal or transdermal b. Progestogen-only hormonal contraception associated with the inhibition of ovulation i. Oral, injectable, implantable c. An intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion f. Vasectomised partner g. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study medication, for the duration of the study, and for > = 90 days after the last dose of BGB-3111, or 18 months after the last dose of obinutuzumab, whichever is longer). Total sexual abstinence should only be used as a contraceptive method if it is in line with the participants' usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product, and withdrawal are not acceptable methods of contraception. Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception and if used, this method must be used in combination with another acceptable method listed above. 12. Male participants are eligible if vasectomised or if they agree to the use of barrier contraception in combination with other methods described above during the study treatment period and for > = 90 days after the last dose of BGB-3111. 13. Ability to provide written informed consent and can understand and comply with the requirements of the study.

Exclusion Criteria:

Each participant eligible to participate in this study must NOT meet any of the following exclusion criteria: 1. Known central nervous system involvement by leukemia or lymphoma. 2. No evidence of transformation from follicular lymphoma to DLBCL or other aggressive histology (such as large cells seen on biopsy or high PET avidity in a single node seen on PET scan). 3. Allogeneic hematopoietic stem cell transplantation within 12 months of study enrollment. 4. Prior exposure to a BTK inhibitor. 5. Prior malignancy within the past 5 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localised Gleason score 6 prostate cancer. 6. Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening b. Unstable angina within 3 months before screening c. New York Heart Association class III or IV congestive heart failure (See Appendix 4) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) e. QTcF > 480 msecs based on Fredericia's formula f. History of Mobitz II second-degree or third degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at screening. 7. History of severe bleeding disorder such as haemophilia A, haemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention. 8. History of stroke or intracranial haemorrhage within 6 months before first dose of study medication. 9. Severe or debilitating pulmonary disease. 10. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 11. Active fungal, bacterial and/or viral infection requiring systemic therapy. 12. Underlying medical conditions that, in the investigator's opinion, will render the administration of study medication hazardous or obscure the interpretation of safety or efficacy results. 13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monthly monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Participants with presence of HCV antibody are eligible if HCV RNA is undetectable (< 15 IU/mL). 14. Major surgery within 4 weeks of the first dose of study medication. 15. Pregnant or lactating women. 16. Vaccination with a live vaccine within 35 days prior to the first dose of study medication. 17. Ongoing alcohol or drug addiction. 18. Hypersensitivity to BGB-3111 or obinutuzumab or any of the other ingredients of the study medications. 19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer. 20. Concurrent participation in another therapeutic clinical study.

Sub Specialty:

Lymphoma

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A Phase 3 Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Subjects with Advanced Urothelial Cancer and Selected FGFR Gene Aberrations

Research Summary

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Inclusion Criteria:

1. ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) 2. Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components (< 50% overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable 3. Stage IV disease (metastatic or surgically unresectable, cT4b, N+, or M+ cancer) 4. Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization 5. Only one line of prior systemic treatment for metastatic urothelial cancer. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression (as defined in Criterion 4 above), within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting. Cohort 1: prior chemotherapy and anti-PD(L)1 [in combination or in maintenance setting] (anti-PD(L)1 alone is allowed only for subjects with documented cisplatin ineligibility) Cohort 2: prior chemotherapy (no prior anti-PD(L)1 treatment) 6. Subjects must meet appropriate molecular eligibility criteria (as determined by central laboratory screening): Tumors must have at least 1 of the following translocations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C. 7. ECOG performance status Grade 0, 1, or 2 (Attachment 1) 8. Adequate bone marrow, liver, and renal function: a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2 weeks):  Absolute neutrophil count (ANC) > 1,500/mm3  Platelet count > 75,000/mm3 (≥ 100,000/mm3 for Cohort 1 subjects at sites choosing vinflunine chemotherapy)  Hemoglobin > 8.0 g/dL (without transfusion or demonstrate stability, ie; no significant decline in hemoglobin, for 2 weeks after transfusion) b. Liver function:  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN [≤ 1 x ULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy]  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x institutional ULN [ALT and AST both ≤ 1.5 x ULN and alkaline phosphatase ≤ 2.5 x ULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy] c. Renal function: Creatinine clearance (CrCl) > 30 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using the Cockcroft-Gault formula (Attachment 2). d. Electrolytes: Potassium within institutional normal limits. e. Phosphate: < ULN within 14 days of treatment and prior to Cycle 1 Day 1 (medical management allowed) 9. Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. 10. A woman of childbearing potential who is sexually active must have a negative pregnancy test (-human chorionic gonadotropin [hCG]) at Screening (urine or serum). 11. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies. For women of childbearing potential:  practicing a highly effective method of contraception (failure rate of < 1% per year when used consistently and correctly) Examples of highly effective contraceptives include - user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence (true abstinence when this is in line with the preferred and usual lifestyle of the subject)1 - user-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable  agrees to remain on a highly effective method throughout the study and for at least 6 months after the last dose of study drug  agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug  not breast-feeding, not planning to become pregnant within 6 months after the last dose of study drug For men who are sexually active with women of childbearing potential:  agrees to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository)  agrees to not donate sperm during the study and for at least 6 months after the last dose of study drug  not planning to father a child during the study or within 6 months after the last dose of study drug Footnote 1. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

1. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to randomization. 2. Active malignancies (ie, requiring treatment change in the last 24 months) other than urothelial cancer (except skin cancers within the last 24 months that is considered completely cured) 3. Symptomatic central nervous system metastases 4. Received prior FGFR inhibitor treatment 5. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients 6. Corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.: a. History of central serous retinopathy (CSR) or retinal vascular occlusion (RVO) b. Active wet, age-related macular degeneration (AMD) c. Diabetic retinopathy with macular edema (non-proliferative) d. Uncontrolled glaucoma (per local standard of care) e. Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration. 7. History of uncontrolled cardiovascular disease including: a. unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V (Attachment 3) within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months. b. QTc prolongation as confirmed by triplicate assessment at screening (Fridericia; QTc > 480 milliseconds). c. Pulmonary embolism or other venous thromboembolism (VTE) within the preceding 2 months 8. Known active AIDS (human immunodeficiency virus (HIV) infection), unless the subject has been on a stable anti-retroviral therapy regimen for the last 6 months or more, has had no opportunistic infections in the last 6 months, and has CD4 count > 350 9. Known active hepatitis B or C infection (subjects with history of hepatitis C infection but negative hepatitis C virus polymerase chain reaction[(PCR] test and subjects with hepatitis B with positive hepatitis B surface antibody are allowed). 10. Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, Grade 1 neuropathy, Grade 1-2 hearing loss) 11. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions 12. Major surgery within 4 weeks before randomization 13. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Examples include poorly controlled diabetes (hemoglobin A1c > 8), or ongoing active infection requiring systemic therapy. 4.2.2. Exclusion Criteria for Cohort 1 Subjects In addition to the exclusion criteria listed above, any potential subject in Cohort 1 who meets the following criterion will be excluded from participating in the study: 14. Depending on the chemotherapy regimen to be used at the participating site, has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to either docetaxel or to other drugs formulated with polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids. For sites using docetaxel, subjects with evidence of interstitial lung disease or active non-infectious pneumonitis are excluded. 4.2.3. Exclusion Criteria for Cohort 2 Subjects In addition to the exclusion criteria listed above, any potential subject in Cohort 2 who meets any of the following criteria will be excluded from participating in the study: 15. Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren's syndrome will not be excluded from the study. 16. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 17. Active infection requiring systemic therapy. 18. Evidence of interstitial lung disease or active non-infectious pneumonitis. 19. Received a live virus vaccine within 30 days of first dose. 20. Known allergies, hypersensitivity, or intolerance to pembrolizumab or its excipients.

Sub Specialty:

Bladder Cancer

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An International, Phase 3, Open-label, Randomized Study of BGB-3111 Compared with Bendamustine plus Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Research Summary

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Inclusion Criteria:

1. Unsuitable for chemoimmunotherapy with FCR in the opinion of the investigator (eg, ≥ 65 years of age, comorbidities [eg, CIRS score > 6], creatinine clearance < 70 mL/min, previous infections, etc). The CIRS calculator can be found at: http://www.crhc.pitt.edu/psf/CI/ci.aspx 2. Confirmed diagnosis of CD20-positive CLL or SLL that meets the iwCLL criteria (Hallek et al, 2008) 3. Binet Stage C disease, or Binet Stage B or A disease requiring treatment as defined by at least one of the following criteria (Hallek et al, 2008): a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia b. Massive (≥ 6 cm below left costal margin), progressive or symptomatic splenomegaly c. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte-doubling time of < 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30×109/L (30,000/μL), lymphocyte-doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection) should be excluded. e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy f. Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs: i. Unintentional weight loss of ≥ 10% within the previous 6 months ii. Significant fatigue (ie, inability to work or perform usual activities) iii. Fevers > 100.5º F or 38º C for ≥ 2 weeks without other evidence of infection iv. Night sweats for > 1 month without evidence of infection 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 5. Life expectancy ≥ 6 months 6. Adequate bone marrow function as defined by: a. Absolute neutrophil count (ANC) ≥ 1000/mm3 (growth factor use is allowed), except for patients with bone marrow involvement in which ANC must be ≥ 750/mm3 b. Platelet ≥ 75,000/mm3 (may be post-transfusion), except for patients with bone marrow involvement by CLL in which the platelet count must be ≥ 50,000/mm3 7. Patient must have adequate organ function defined as: a. Creatinine clearance ≥ 40 mL/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection) b. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal (ULN) unless due to CLL/SLL c. Serum total bilirubin < 3.0 × ULN (unless documented Gilbert’s syndrome) 8. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of BGB-3111, 3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. These methods include the following: a. Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation i. Oral, intravaginal or transdermal b. Progestogen-only hormonal contraception associated with the inhibition of ovulation i. Oral, injectable, implantable c. An intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion f. Vasectomized partner g. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of BGB-3111, 3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer). Total sexual abstinence should only be used as a contraceptive method if it is in line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product, and withdrawal are not acceptable methods of contraception. Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception and if used, this method must be used in combination with another acceptable method listed above. 9. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for ≥ 90 days after the last dose of BGB-3111 or 3 months after the last dose of bendamustine whichever is longer. 10. Ability to provide written informed consent and can understand and comply with the requirements of the study

Exclusion Criteria:

1. Previous systemic treatment for CLL/SLL (other than 1 aborted regimen < 2 weeks in duration and > 4 weeks before randomization) 2. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation 3. Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening b. Unstable angina within 3 months before screening c. New York Heart Association class III or IV congestive heart failure (see Appendix 4) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) e. QTcF > 480 msecs based on Fredericia’s formula f. History of Mobitz II second-degree or third degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at screening 4. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast 5. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention 6. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug 7. Severe or debilitating pulmonary disease 8. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 9. Active fungal, bacterial and/or viral infection requiring systemic therapy 10. Known central nervous system involvement by leukemia or lymphoma 11. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs 12. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to undergo monthly monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable. 13. Major surgery within 4 weeks of the first dose of study drug 14. Pregnant or lactating women 15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug 16. Ongoing alcohol or drug addiction 17. Hypersensitivity to BGB-3111, bendamustine, or rituximab or any of the other ingredients of the study drugs 18. Requires ongoing treatment with a strong CYP3A inhibitor or inducer (see Appendix 5) 19. Concurrent participation in another therapeutic clinical trial.

Sub Specialty:

Lymphoma

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A Phase Ia/Ib Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of RO7198457 as a Single Agent and in Combination with Atezolizumab in Patients with Locally Advanced or Metastatic Tumors.

Research Summary

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Inclusion Criteria:

- Age > = 18 - Eastern Cooperative Oncology Group performance status of 0 or 1 - Life expectancy > = 12 weeks - Adequate haematologic and end-organ function - Measured or calculated creatinine clearance > = 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation - For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study drugs - For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm during the treatment period and for at least 28 days after the last dose of study treatment Cancer-Specific Inclusion Criteria - Patients with histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognised standard of care - Patients with confirmed availability of representative tumour specimens in formalin-fixed, paraffin-embedded blocks, or sectioned tissue with an associated pathology report - Enrollment will be limited to patients with at least five identified tumour neoantigens and sufficient tumour material to manufacture vaccine, as defined by the Sponsor - Patients with measurable disease per Response Evaluation Criteria for Solid Tumors v1.1 Additional Inclusion Criteria for Patients Who Backfill Cleared Cohorts of Phase Ia and Phase Ib - Backfill cohort enrollment may be limited to patients whose tumours have programmed death-ligand 1 (PD-L1) and/or different levels of CD8 expression, as defined by the Sponsor Additional Inclusion Criteria for Patients in Each Indication-Specific Exploration/Expansion Cohort of Phase Ib - Non-small cell lung cancer (NSCLC) Cohorts (cancer immunotherapy [CIT]-Naïve): Patients with histologically confirmed incurable, advanced NSCLC not previously treated with CIT, including anti-PD−L1/PD-1 and/or anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA−4), for whom a clinical trial of an investigational agent in combination with an anti-PD−L1 antibody is considered an acceptable treatment option, if CIT is approved as treatment for NSCLC by local regulatory authorities - NSCLC Cohort (CIT-Treated): Patients with histologically confirmed incurable, advanced NSCLC previously treated with CIT including antiPD−L1/PD-1 - Triple Negative Breast Cancer (TNBC) Cohort: Patients with histologically confirmed incurable, advanced estrogen receptornegative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative adenocarcinoma of the breast (triplenegative) - Colorectal cancer (CRC) Cohort: Patients with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum - Head and Neck Squamous Cell Carcinoma (HNSCC) Cohort: Patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent HNSCC (oral cavity, oropharynx, hypopharnyx, or larynx) not amenable to curative therapy - Urothelial Carcinoma (UC) Cohort (CIT-Naïve): Patients with histologically confirmed incurable, advanced transitional cell carcinoma of the urothelium, including renal pelvis, ureters, urinary bladder, and urethra, not previously treated with CIT (investigational or approved), including anti-PD−L1/PD-1 and/or anti-CTLA−4, for whom a clinical trial of an investigational agent in combination with an anti-PD−L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD−L1/PD-1 agents) is approved as treatment for UC by local regulatory authorities - UC Cohort (CIT-Treated): Patients with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium previously treated with CIT including anti-PD−L1/PD-1 - Renal Cell Carcinoma (RCC) Cohort: Patients with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology Additional Inclusion Criteria for Patients in the Serial-Biopsy Expansion Cohort of Phase Ib - Patients must have one of the following tumor types: NSCLC, UC, HNSCC, TNBC, RCC, melanoma, cervical cancer, anal cancer, Merkel-cell carcinoma, microsatellite instability (MSI)-High tumors, squamous cell carcinoma of the skin, hepatocellular carcinoma (non-viral), and CRC including microsatellite stable and MSI-Low - Patients must have accessible lesion(s) that permit a total of two to three biopsies (pretreatment and on-treatment) or one biopsy (entreatment, if archival tissue can be submitted in place of a pre-treatment biopsy) without unacceptable risk of a significant procedural complication.

Exclusion Criteria:

- Pregnancy, breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of study treatment - Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse - Major surgical procedure within 28 days prior to Cycle (C) 1, Day (D) 1, or anticipation of need for a major surgical procedure during the course of the study - Any other diseases, metabolic dysfunction, physical examination finding, and/or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or may render the patient at high risk from treatment complications - Previous splenectomy - Known primary immunodeficiencies, either cellular or combined T- and B-cell immunodeficiencies - Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Cancer-Specific Exclusion Criteria - Any anti-cancer therapy, whether investigational or approved, including chemotherapy, hormonal therapy, and/or radiotherapy, within 3 weeks prior to initiation of study treatment - Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort for which the patient is being considered - Any history of an immune-related Grade 4 adverse event attributed to prior CIT - Any history of an immune-related Grade 3 adverse event attributed to prior CIT that resulted in permanent discontinuation of the prior immunotherapeutic agent and/or occurred < = 6 months prior to C1D1 - Adverse events from prior anti-cancer therapy that have not resolved to Grade < = 1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy - All immune-related adverse events related to prior CIT must have resolved completely to baseline - Primary central nervous system (CNS) malignancy, untreated CNS metastases, or active CNS metastases, leptomeningeal disease - Leptomeningeal disease - Uncontrolled tumour-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures and hypercalcemia - Malignancies other than disease under study within 5 years prior to C1D1, with the exception of those with a negligible risk of metastasis or death - Patient has spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > = 2 weeks prior to screening Treatment-Specific Exclusion Criteria - History of autoimmune disease - Treatment with systemic immunosuppressive medications within 2 weeks prior to C1D1 - History of idiopathic pulmonary fibrosis, pneumonitis, organising pneumonia, or evidence of active pneumonitis on screening chest computed tomography scan - Positive test for HIV infection - Active hepatitis B and C - Active tuberculosis - Severe infections within 4 weeks prior to C1D1 - Recent infections not meeting the criteria for severe infections - Prior allogeneic bone marrow transplantation or prior solid organ transplantation - Administration of a live, attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live attenuated vaccine will be required during the study - Known hypersensitivity to the active substance or to any of the excipients in the vaccine Phase Ib and crossover, only: o History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins o Known hypersensitivity to Chinese Hamster Ovary-cell products o Allergy or hypersensitivity to components of the atezolizumab formulation.

Sub Specialty:

Breast Cancer Colorectal Cancer Lung Cancer

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A Phase 2/3, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Research Summary

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Inclusion Criteria:

1. Male or female patients aged 18 years or older. 2. Must have a confirmed diagnosis of MM requiring therapy according to IMWG criteria(see Appendix D-pg104). 3. ECOG performance status of 0 to 2 (see Appendix E-pg105). 4. Must have had a relapse or PD after having received 2 or more prior lines of systemic therapy. Note: A line of therapy is defined as 1or more cycles of a planned treatment program; this may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous SCT, followed by maintenance is considered 1 line of therapy [1]. Typically each line of therapy is separated by PD. 5. Must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should have been a minimum of 10 mg. 6. Must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, and either: – Achieved at least a PR and did not have PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib, OR – Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related AEs before completion of the planned treatment course) without PD before the start of the next regimen. 7. Patients must have measurable disease defined by: – Serum M-protein ≥ 1 g/dL (≥ 10 g/L), OR – Urine M-protein ≥ 200 mg/24 hours and must have documented MM isotype by immunofixation (central laboratory). 8. Patients must meet all of the following clinical laboratory criteria: – Absolute neutrophil count (ANC) ≥ 1000/mm3 and platelet count ≥ 75,000/mm3, without growth factor or transfusion support. – Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). – Alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN. – Calculated creatinine clearance ≥ 30 mL/min (see Section 9.4.15.1). 9. Female patients who: – Are postmenopausal for at least 1 year before the Screening Visit, OR – Are surgically sterile, OR – If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, for 4 weeks before signing the informed consent through 90 days after the last dose of study therapy, OR – Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.), AND – In women of childbearing potential (if randomized to Arm B), agree to have 2 negative pregnancy tests before initiating therapy, with 1 or both being a serum test (the first test should be performed within 10-14 days before; the second, within 24 hours before); then have a negative pregnancy test weekly during the first month and monthly thereafter in women with regular menstrual cycles or every 2 weeks thereafter in women with irregular menstrual cycles; and have a negative pregnancy test 4 weeks after the last dose of study therapy. 10. Male patients, even if surgically sterilized (ie, status postvasectomy), who: – Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study therapy, OR – Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.), AND – Do not donate semen or sperm during treatment and for 90 days after the last dose of study therapy. 11. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 12. Suitable venous access for the study-required blood sampling, including PK sampling. 13. Patient is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration. 14. Recovered (ie, ≤ Grade 1 nonhematologic toxicity) from the reversible effects of prior anticancer therapy. 15. Patients must be willing and able to adhere to pomalidomide-related risk mitigation activities if randomized to the pom+dex arm (eg, REMS, pregnancy prevention programs).

Exclusion Criteria:

1. Patients must not have received prior ixazomib or pomalidomide and must not have been a participant in a previous ixazomib clinical study. 2. Prior allogenic bone marrow transplantation in any prior line of therapy or prior autologous SCT in the last prior line of therapy. 3. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. 4. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol, such as life-threatening illness unrelated to cancer. 5. Diagnosed with or treated for another malignancy within 2 years before randomization, or previously diagnosed with another malignancy and have any evidence of residual, persistent,or recurrent disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 6. Diagnosis of smoldering MM (see Appendix D), Waldenström’s macroglobulinemia, POEMS(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 7. Known allergy to any of the study medications or their analogues, or excipients in the various formulations. 8. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period. 9. Treatment with any investigational products or with chimeric or fully human monoclonal antibodies within 30 days before randomization, systemic anticancer therapy or radiotherapy within 14 days before randomization (Note: “spot” radiation for areas of pain is permitted), and major surgery within 14 days before randomization. 10. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of study therapy, including difficulty swallowing. 11. Serious infection requiring parenteral antibiotic therapy or any other serious infection within 14 days before randomization. 12. Central nervous system involvement with MM (by clinical symptoms and signs). 13. Ongoing or active systemic infection, known human immunodeficiency virus-RNA positive, known hepatitis B surface antigen seropositive, or known hepatitis C virus-RNA positive. Note: Patients who have positive hepatitis B core antibody can be enrolled but must have hepatitis B virus-DNA negative. Patients who have positive hepatitis C antibody can be enrolled but must have hepatitis C virus-RNA negative. 14. Systemic treatment with strong cytochrome P-450 3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John’s wort within 14 days before randomization. 15. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

Sub Specialty:

Haematological Oncology

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A Phase 1, Open-Label, Multicentre, Non-Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of AZD4573, a Potent and Selective CDK9 Inhibitor, in Subjects with Relapsed or Refractory Haematological Malignancies

Research Summary

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Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. 2. Men and women ≥ 18 years of age. 3. Subjects with histologically confirmed, relapsed or refractory haematological malignancies where in the opinion of the treating Investigator, a clinical trial is the best option for next treatment based on prior response and/or tolerability to standard of care, e.g., but not limited to: Arm A: o B-cell Non-Hodgkin lymphoma o T-cell Non-Hodgkin lymphoma o Small lymphocytic lymphoma (SLL) o Multiple myeloma (MM) Arm B: o CLL (chronic lymphocytic leukemia) o Richter’s syndrome o AML/secondary AML o ALL o High-risk myelodysplastic syndrome (MDS) (according to revised International prognostic scoring system IPSS-R) o CMML (chronic myelomonocytic leukaemia) NOTE: AML/ALL subjects must have pathologically confirmed first or second relapsed or primary refractory AML using the World Health Organization (WHO) definition or European LeukemiaNet (ELN) recommendations. A bone marrow blast count of > 5% will be sufficient in the appropriate setting of a subject with a prior diagnosis of AML/ALL. NOTE: AML subjects with APL (acute promyelocytic leukemia FAB subtype M3) will be excluded. NOTE: Subjects > 70 years of age with untreated AML who are considered unfit for intensive treatment or who refuse intensive treatment, may be considered eligible for the study, upon consultation and agreement between the Sponsor and the treating Investigator. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Must have received at least 2 prior lines of therapy for the treatment of current histology and a clinical trial is best option for next treatment based on prior response and/or tolerability to standard of care. Refer to National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines of each respective histology for guidance. NOTE: For some disease indications, for example Richter’s syndrome, failure of one therapy (e.g., R-CHOP) would be sufficient to consider a subject for enrollment in a study with an Investigational agent. Disease indications, where there may be no standard of care or standard of care options have been exhausted after failure of first line therapy, these subjects may be discussed and considered by Sponsor and treating Investigator on a case by case basis for enrollment into the study and decisions to enroll such subjects documented in writing. 6. Documented active disease requiring treatment per respective NCCN/ESMO guideline that is relapsed or refractory defined as: o Recurrence of disease after response to prior line(s) of therapy o or progressive disease after completion of the treatment regimen preceding entry into the study 7. Adequate hematologic function (Note: does not apply to acute leukaemias, CLL, Richter’s syndrome or high-risk MDS), defined as: o Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 109/L) o Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) or ≥ 35,000 cells/mm3 (35 x 109/L) with bone marrow involvement. NOTE: For AML/ALL/MDS/CMML/CLL/Richter’s syndrome, subjects with platelet counts < 10 x 109/L and/or neutropenia < 0.1 x 109/L may be enrolled. NOTE: For AML/CMML subjects, WBC must be < 10,000/ul. Treatment with hydroxyurea (HU) prior to study entry to achieve this level is permitted in subjects, as long as there is 8-24 hours between the start of AZD4573 and use of HU. 8. Adequate hepatic and renal function at screening defined as: o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN) o Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) o Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min as measured or calculated by Cockcroft and Gault equation [(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]) 9. Uric acid level < 5 mg/dl at the time of treatment initiation. NOTE: TLS prophylaxis/management with rasburicase, IV fluid etc. is permitted at any time during screening and treatment. 10. Lipase ≤ 1.5 x ULN and serum amylase ≤ 1.5 x ULN and no history of pancreatitis. 11. Heart function: EF > 40% by echocardiogram or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] > 40%). Appropriate correction to be used, if a MUGA is performed. 12. Women should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential by fulfilling one of the following criteria at screening: o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 13. Men should be willing to use barrier contraception (i.e., condoms) and refrain from sperm donation during and after the conduct of the trial. If not done previously, storage of sperm before receiving AZD4573 will be advised to male subjects with a desire to have children. 14. Willing and able to participate in all required evaluations and procedures in this study protocol including receiving intravenous administration of study drug and being admitted, when required, for at least 48 hours during study drug administration, and willing and able to provide mandatory baseline bone marrow biopsy/aspirate. Host genetics research study (optional): For inclusion in the optional genetic component of the study, subjects must fulfil the following additional criteria: • Provision of signed, written, and dated informed consent for genetic research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol, so long as they consented to the main study. • Whole blood transfusion given within 120 days of genetic sample collection should be leukocyte depleted. Bone marrow aspirate/tumor biopsy at progression (optional): For inclusion in the optional bone marrow aspirate / tumor biopsy component of the study, subjects must fulfil the following additional criteria: 1. Provision of signed, written, and dated informed consent for a bone marrow aspirate or tumor biopsy at disease progression. If a subject declines to participate in the bone marrow aspirate/tumor biopsy component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol, so long as they consented to the main study. 2. Presence of superficial lymphadenopathy for the lymph node biopsy (applies only to CLL, lymphoma and ALL).

Exclusion Criteria:

1. Treatment with any of the following: o Any investigational agents from a previous clinical study within 4 half-lives of said prior investigational agent(s) with regard to the first dose of study treatment on this protocol o Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the first dose of study treatment o Any hematopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating factor; G-CSF], sargramostin [granulocyte-macrophage colony-stimulating factor; GM-CSF]) within 7 days of the first dose of study drug or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first dose of study drug o Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment 2. Subjects with asecretory myeloma. 3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment. 4. Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease or spinal cord compression. 5. History of prior nonhematologic malignancy except for the following: o Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. o Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer. o Adequately treated carcinoma in situ without current evidence of disease. 6. As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses (e.g., hemophilia or von Willebrand disease) or uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug. 7. Known history of infection with human immunodeficiency virus (HIV). 8. Serologic status reflecting active hepatitis B or C infection. o Subjects who are hepatitis B core antibody positive (anti-HBc) and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive will be excluded. o Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded. 9. Active cytomegalovirus (CMV) infection (positive CMV immunoglobulin M [IgM] and/or positive PCR result). 10. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months: o coronary artery bypass graft o angioplasty o vascular stent o myocardial infarction o angina pectoris o congestive heart failure (New York Heart Association Class ≥ 2) o ventricular arrhythmias requiring continuous therapy o atrial fibrillation, which is uncontrolled o haemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding 11. Hyperuricemia > 10 mg/dL. NOTE: If hyperuricemia of any kind is present at screening, standard of care (SoC) therapy should be administered (including IV fluid, rasburicase +/- allopurinol). 12. Any of the following cardiac criteria: o Mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 electrocardiogram (ECGs). o Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block). o Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study drug and through the DLT review period. 13. History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573. 14. History of adrenal gland insufficiency or pancreatitis. 15. Judgement by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements. In addition, the following is considered a criterion for exclusion from the optional genetic research: • Previous allogeneic bone marrow transplant.

Sub Specialty:

Haematological Oncology

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A Phase 1/2 Proof-of-Concept Study Investigating AZD6738 monotherapy and Acalabrutinib in Combination with AZD6738 (ATR inhibitor) in Subjects with Relapsed or Refractory High-risk Chronic Lymphocytic Leukemia (CLL).

Research Summary

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Inclusion Criteria:

Eligible subjects will be considered for inclusion in Parts 1 and 2 of this study if they meet all of the following criteria: 1. Diagnosis of relapsed or refractory CLL that meets published diagnostic IWCLL criteria (Hallek et al 2008) and supported/ documented by medical records: a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ B-cell marker (CD19, CD20, or CD23) and CD5. b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes. c. Presence of ≥ 5 x 109 B-lymphocytes/L (5000µL) in the peripheral blood (at any point since diagnosis). 2. Provision of signed, written, and dated ICF. 3. CLL subjects must have ≥ 1 of the following high risk prognostic factors to be considered eligible for the study: a. Presence of 17p del b. Presence of TP53 mutation c. Presence of 11q del Subjects will be eligible based on local laboratory karyotyping and FISH results and these results will also be retrospectively confirmed by a central laboratory. Where testing cannot be performed locally, central laboratory results will be required to confirm eligibility prior to enrolment. Note: For Part 1 of the study, subjects must be high risk CLL, but can be relapsed or refractory to any prior therapy for their disease. Note: For Part 2 of the study, those subjects enrolled into Arm A, must be high risk R/R CLL, but will only be eligible if they have specifically failed prior treatment with Venetoclax (or any other Bcl-2 inhibitor in clinical trials tested as an experimental agent) and/or a BTKi (this can be ibrutinib or any BTKi in clinical development as an Investigational agent). Note: For Part 2 of the study, those subjects enrolled into Arm B, must be high risk R/R CLL, but will only be eligible if they have not received any prior treatment with a BTKi (ie, subjects must be BTK naive). 4. Meet the following laboratory parameters: Adequate hematologic function, independent of transfusion and growth factor support for ≥ 14 days before screening, defined as: a. AANC > 1500 cells/mm3 (1.5 x 109 /L) b. Platelet count > 75,000 cells/mm3 (75 x 109 /L) for AZD6738 monotherapy arm and > 50,000 cells/mm3 (50 x 109 /L) for AZD6738 in combination with acalabrutinib. c. Hemoglobin ≥ 9.0 g/dL Note: It is possible that some subjects will have lower hematological parameters than those outlined above due to bone marrow involvement as part of their underlying disease. Subjects with lower values than those stated above, may be eligible for the study, based upon discussion and agreement between investigator and sponsor if these lower values are clearly due to disease involvement. d. AST, serum glutamic-oxaloacetic transaminase (SGOT), ALT and sSGP) ≤ 2.5 xULN. e. Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) f. Albumin > 33 g/L. g. Alkaline phosphatase < 2.5 x ULN h. Estimated creatinine clearance using standard methodology (i.e, eGFR using Cockcroft-Gault) ≥ 45 mL/min. 5. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL and/or thrombocytopenia (Platelet count > 75,000 cells/mm3 (75 x 109 /L) for Product: Acalabrutinib and AZD6738/ATR inhibitor AZD6738 monotherapy arm and > 50,000 cells/mm3 (50 x 109 /L) for AZD6738 in combination with acalabrutinib). b. Massive (ie, ≥ 6cm below the left costal margin), progressive, or symptomatic splenomegaly. c. Massive nodes (ie, ≥ 10cm in the longest diameter), progressive, or symptomatic lymphadenopathy. d. Progressive lymphocytosis with an increase of > 50% over a 2 month period or a LDT of < 6 months. LDT may be obtained by linear regression extrapolation ofALC obtained at intervals of 2 weeks over an observation period of 2-3 months. In subjects with initial blood lymphocyte counts of < 30 x 109 /L (30,000µL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections), should be excluded. e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. f. Constitutional symptoms documented in the subjects medical records/chart with supportive objective measures, as appropriate, defined as ≥ 1of the following disease related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before screening. ii. Significant fatigue (ie, ECOG performance status 2 or worse, inability to work or perform usual activities). iii. Fevers > 100.50 F or 380 C for ≥ 2 weeks before screening without evidence of infection. iv. Night sweats > 1 month before screening without evidence of infection. 6. Must have received ≥ 1 prior therapy for treatment of their disease. For treatment Arm A, must have received venetoclax (or any other Bcl-2 inhibitor tested as an Investigational agent) and /or BTKi (this can be Ibrutinib or any other BTKi tested as an Investigational agent). Subjects may have received bcl-2 or BTKi at any point in their treatment history. For Arm B, subjects must be BTKi naïve. 7. Men and women ≥ 18 years of age. 8. ECOG performance status of ≤ 2 with an estimated life expectancy of 12 weeks. 9. Haematuria: +++ on microscopy or dipstick. 10. PT/INR < 1.5 x ULN and aPTT < 1.5 x ULN. 11. Serum potassium within normal range. 12. Women (Refer to Section 3.12.5 of the protocol), must not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation - Amenorrhoeic for 12 months and serum FSH, luteinizing hormone and plasma oestradial levels in the postmenopausal range for the Institution. Product: Acalabrutinib and AZD6738/ATR inhibitor 13. For the duration of the study and for 6 months after the last study drug administration, sexually active male subjects must be willing to use barrier contraception (ie, condoms) with all sexual partners. 14. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules or tablets without difficulty. 15. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). Host genetics research study (optional): For inclusion in the optional genetic component of the study, subjects must fulfil the following additional criteria: 16. Provision of signed, written, and dated informed consent for genetic research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol, so long as they consented to the main study. 17. Whole blood transfusion given within 120 days of genetic sample collection should be leukocyte depleted. Tumor biopsy study (optional): For inclusion in the optional tumor biopsy component of the study, subjects must fulfil the following additional criteria: 18. Provision of signed, written, and dated informed consent for fresh lymph node tumor biopsies (at baseline and on study). If a subject declines to participate in the tumor biopsy component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol, so long as they consented to the main study. 19. Presence of superficial lymphadenopathy for the lymph node biopsy.

Exclusion Criteria:

Subjects will be ineligible for this study (both parts) if they meet any of the following criteria: 1. A diagnosis of ataxia telangiectasia 2. Any prior exposure to an ATR inhibitor or known hypersensitivity to an excipient of the product. 3. History of prior malignancy except for the following: a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. b. Adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled onmelanomatous skin cancer. c. Adequately treated carcinoma in situ without current evidence of disease. 4. As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (eg, seizures, severe hepatic impairment, interstitial lung disease, COPD, active inflammatory bowel disease, or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses (eg, hemophilia or von Willebrand disease) or uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug. 5. Known history of infection with human immunodeficiency virus (HIV). 6. Serologic status reflecting active hepatitis B or C infection. a. Subjects who are hepatitis B core antibody positive (anti-HBc) and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive will be excluded. b. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded. 7. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months: a. coronary artery bypass graft b. angioplasty c. vascular stent d. myocardial infarction e. angina pectoris f. congestive heart failure (New York Heart Association [NYHA] Grade ≥ 2) g. ventricular arrhythmias requiring continuous therapy h. supraventricular arrhythmias, including atrial fibrillation, which are uncontrolled i. hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other CNS bleeding. 8. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting GI function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 9. History of CNS lymphoma, leptomeningeal disease or spinal cord compression. 10. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of hypersensitivity to active or inactive excipients of AZD6738 or acalabrutinib or drugs with a similar chemical structure or class to AZD6738 or acalabrutinib. 11. Presence of a GI ulcer diagnosed by endoscopy within 3 months before screening. 12. Any clinically significant pre-existing renal disease or high risk of developing renal impairment. 13. Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 14. Unresolved toxicities from prior anticancer therapy, ≥ Grade 2 Common Terminology criteria for Adverse Events (CTCAE), with the exception of alopecia. 15. Cytomegalovirus (CMV) positive - CMV testing at screening must include serology testing for CMV immunoglobulin (Ig) G, CMV IgM, and CMV PCR testing. 16. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 17. Cardiac dysfunction as defined as: Myocardial infarction within 6 months of study entry, NYHA class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or a history of reduced left ventricular ejection fraction (LVEF) < 55%. 18. Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF) > 470 msec obtained from 3 ECGs in 24 hours. 19. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block). 20. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age. 21. Patients at risk of brain perfusion problems, (e.g., carotid stenosis). 22. Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mm Hg. 23. Uncontrolled hypertension requiring clinical intervention. 24. Any therapeutic antibody within 4 weeks of first dose of study drugs. 25. Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study drug (not including palliative radiotherapy). Patients must have recovered from acute toxicity due to prior treatment. 26. Ongoing immunosuppressive therapy, including systemic (eg, intravenous or oral) corticosteroids for treatment of lymphoid cancer or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤ 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. 27. Receiving or having received concomitant medications, herbal supplements and/or foods that that significantly modulate cytochrome P450 (CYP3A4) or P-glycoprotein-1 (Pgp) activity (was out periods of 2 weeks, but 3 weeks for St John’s Wort). Note these include common azole antifungals, macrolide antibiotics and other medications listed in Appendix 4. 28. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. Note: Subjects enrolled into Parts 1 and 2 of the study and randomized/enrolled to treatment Arm A (AZD6738 monotherapy) may receive anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 29. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. 30. Concurrent participation in another therapeutic clinical trial. 31. Is working at or has an immediate family member (spouse or children) who works at the investigational site or is a Sponsor staff member directly involved with this trial. 32. Evidence of Richter’s Transformation (RT) – subjects with suspected or histopathologically confirmed RT prior to or during screening will not be eligible for this study.

Sub Specialty:

Haematological Oncology

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A Phase 2, Open-Label, 2-Cohort Study of INCB050465, a PI3Kδ Inhibitor, in Subjects With Relapsed or Refractory Marginal Zone Lymphoma With or Without Prior Exposure to a BTK Inhibitor.

Research Summary

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Inclusion Criteria:

• Men and women, aged 18 or older (except in South Korea, aged 19 or older). • Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥ 1 lesion that measures > 1.5 cm in the longest transverse diameter (LDi) and ≥ 1.0 cm in the longest perpendicular diameter as assessed by CT or magnetic resonance imaging (MRI). -Subjects with splenic MZL who do not meet the radiographically measurable disease criteria described herein are eligible for participation provided that bone marrow infiltration of MZL is histologically confirmed. • Subjects must be willing to undergo an incisional or excisional lymph node or tissue biopsy or provide a lymph node or tissue biopsy from the most recent available archival tissue. • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

Exclusion Criteria:

• Evidence of diffuse large B-cell transformation. • History of central nervous system lymphoma (either primary or metastatic) or leptomeningeal disease. • Prior treatment with idelalisib, other selective PI3Kδ inhibitors, or a pan-PI3K inhibitor. • Allogeneic stem cell transplant within the last 6 months, or autologous stem cell transplant within the last 3 months before the date of the first dose of study treatment. • Active graft versus host disease. • Liver disease: - Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of reactivation.

Sub Specialty:

Lymphoma

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A phase 3, randomised, multicentre study of subcutaneous vs intravenous administration of daratumumab in subjects with relapsed or refractory multiple myeloma

Research Summary

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Inclusion Criteria:

Only Key Inclusion Available: Main inclusion criteria: 1. Multiple myeloma diagnosed according to the IMWG diagnostic criteria 2. Measurable, secretory disease 3. Relapsed or refractory disease 4. Prior treatment with at least 3 prior lines of anti-myeloma therapy

Exclusion Criteria:

Only Key Exc criteria available: Main Exclusion Criteria 1. Received any anti-CD38 investigational agent or other anti-CD38 therapies, previously 2. Received anti-myeloma treatment within 2 weeks before randomization 3. Received an allogeneic stem cell transplant; or subject has received an ASCT within 12 weeks before randomization 4. History of malignancy (other than multiple myeloma) within 3 years before randomization (some exceptions may apply) 5. Exhibits clinical signs of meningeal involvement of multiple myeloma. 6. Either of the following:

Sub Specialty:

Haematological Oncology

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A PERFORMANCE EVALUATION STUDY OF ARQUER’S MCM5 ELISA TEST TO AID IN THE MONITORING OF BLADDER CANCER RECURRENCE

Research Summary

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Inclusion Criteria:

• Patients who have been diagnosed with bladder cancer in the previous 2 years and are attending the hospital urology clinic for monitoring cystoscopy. • Patients 18 years of age or older. • Patients who, in the opinion of the Investigator, are suitable for standard urological investigations as part of normal clinical practice. • Patients who are, in the opinion of the Investigator, able to understand the purpose of the study and provide a urine specimen. • Patients who are able to give voluntary, written informed consent to participate in this study and from whom consent has been obtained.

Exclusion Criteria:

• Patients with known calculi within the urino-genitary system. • Patients currently undergoing chemotherapy or radiotherapy. • Patients who have previously been diagnosed with prostate cancer, or renal cancer. • Patients who have had urological instrumentation to the urinary tract within 14 days prior to the test. • Patients whose whole urine void at the urology clinic is required for routine clinical purposes. • Male patients known to have prostatitis.

Sub Specialty:

Bladder Cancer

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A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Compared to Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Recipients

Research Summary

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Inclusion Criteria:

1. Be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures. As applicable, a parent/both parents or legally authorized representative (LAR) must provide signature of informedconsent and there must be documentation of assent by the subject before completing anystudy-related procedures. 2. Be > = 16 years of age at the time of consent. 3. Be a recipient of hematopoietic stem cell transplant. 4. Have a documented asymptomatic CMV infection, with a screening value of CMV DNA > = 2730 IU/mL to < = 273000 IU/mL in whole blood or > = 910 IU/mL to < = 91000 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to randomization with second sample obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator. 5. Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation. 6. Per investigator’s judgment, be eligible for treatment with valganciclovir. 7. Have all of the following results as part of screening laboratory assessments (results from either the central laboratory or a local laboratory can be used for qualification): a. Absolute neutrophil count > = 1000/mm3 [1.0 x 10/L] b. Platelet count > = 25,000/mm3 [25 x 109/L] c. Hemoglobin > = 8g/dL. d. Estimated creatinine clearance > = 60mL/min/1.73m2 8. Have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test at screening, if a female of child bearing potential. Urine pregnancy tests may be done per institutional requirements; however they are not sufficient for eligibility determination. Sexually active females of child bearing potential must agree to comply with any applicable contraceptive requirements of the protocol. If male, must agree to use an acceptable method of birth control, as defined in the protocol, during the study treatment administration period and for 90 days afterward the last dose of study treatment. 9. Be able to swallow tablets. 10. Have life expectancy of > = 8 weeks. 11. Weigh > = 40 kg. 12. Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol.

Exclusion Criteria:

1. Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0. 2. Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence. 3. Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a subject who had at least one previously documented episode of CMV infection posttransplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes (during active surveillance, based on same local laboratory and same sample type). The subject must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection. 4. Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] coinfection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection. 5. Be receiving leflunomide, or artesunate when study treatment is initiated. Note: Subjects who may be receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Subjects receiving artesunate must discontinue the use prior to the first dose of study treatment. 6. Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or cidofovir) for the current CMV infection for longer than 72 hours. Note: A subject who is receiving these anti-CMV agents must discontinue their use before the first dose of study treatment. A subjects who may be receiving cidofovir must discontinue this antiviral at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Note: Subjects who were administered these anti-CMV agents for prophylaxis, should have these treatments completed at least 2 weeks prior to the study entry or start of the treatment for current infection, whichever comes first and have undetectable CMV DNA (based on local laboratory) for at least two weeks between the completion of this treatment and onset of the current infection. 7. Have known hypersensitivity to the active substance or to an excipient of the study treatments. 8. Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the first dose of study treatment that would preclude administration of oral medication. 9. Require mechanical ventilation or vasopressors for hemodynamic support at the time of randomization. 10. Be female and pregnant or nursing. 11. Have previously completed, discontinued, or have been withdrawn from this study. 12. Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or CMV vaccine at any time. 13. Have received any unapproved agent or device within 30 days before initiation of study treatment. 14. Have any clinically significant medical or surgical condition that, in the investigator’s opinion, could interfere with interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the subject. 15. Have previously received maribavir. 16. Have serum aspartate aminotransferase (AST) > 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) > 5 times ULN at screening, or total bilirubin > = 3.0 x ULN at screening (except for documented Gilbert’s syndrome), as analyzed by local or central lab. 17. Have known (previously documented) positive results for human immunodeficiency virus (HIV). 18. Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Subjects who experience relapse or progression of their underlying malignancy (for which HSCT was performed), as determined by the investigator, are not to be enrolled. 19. Be undergoing treatment for acute or chronic hepatitis C.

Sub Specialty:

Haematological Oncology Haematology

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A Multicenter, Open-Label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination with Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects with Advanced Renal Cell Carcinoma (CLEAR).

Research Summary

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Inclusion Criteria:

1. Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable). 2. Documented evidence of advanced RCC. 3. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria: - Lymph node (LN) lesion that measures at least 1 dimension as > = 1.5 cm in the short Axis - Non-nodal lesion that measures > = 1.0 cm in the longest diameter - The lesion is suitable for repeat measurement using computerised tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion. 4. Male or female subjects age > = 18 years at the time of informed consent 5. Karnofsky Performance Status (KPS) of > = 70. 6. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP < = 150/90 mmHg at Screening and no change in antihypertensive medications within 1 week before the Cycle 1/Day 1. 7. Adequate renal function defined as calculated creatinine clearance > = 30 mL/min per the Cockcroft and Gault formula. 8. Adequate bone marrow function defined by: - Absolute neutrophil count (ANC) > = 1500/mm3 - Platelets > = 100,000/mm3 - Hemoglobin > = 9 g/dL. 9. Adequate blood coagulation function defined by International Normalized ratio (INR) < = 1.5 (except for participants on warfarin therapy where INR must be < = 3.0 prior to randomisation). 10. Adequate liver function defined by: - Total bilirubin < = 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome. - Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) < = 3×ULN (in the case of liver metastases < = 5×ULN), unless there are bone metastases. Participants with ALP values > 3 times the ULN and known to have bone metastases can be included. 11. Provide written informed consent. 12. Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

1. Participants who have received any systemic anticancer therapy for RCC, including anti-VEGF therapy, or any systemic investigational anticancer agent. 2. Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 3. Active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months. Participants with history of localised & low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no PSA recurrence within the past 5 years. 4. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start. 5. Participants who are using other investigational agents or who had received investigational drugs < = 4 weeks prior to study treatment start. 6. Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). 7. Participants with proteinuria > 1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. 8. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) and/or fasting triglycerides level ˃2.5 x ULN. 9. Uncontrolled diabetes as defined by fasting glucose > 1.5 times the ULN. 10. Prolongation of QTc interval to > 480 ms. 11. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. 12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib, everolimus, and sunitinib. 13. Bleeding or thrombotic disorders or participants at risk for severe haemorrhage. The degree of tumour invasion/infiltration of major blood vessels (eg, carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy. 14. Clinically significant haemoptysis or tumour bleeding within 2 weeks prior to the first dose of study drug. 15. Significant cardiovascular impairment within 6 months of the first dose of study drug 16. Active infection (any infection requiring systemic treatment). 17. Participants known to be positive for Human Immunodeficiency Virus (HIV). 18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected). 19. Known history of, or any evidence of, interstitial lung disease. 20. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis. 21. Any medical or other condition that in the opinion of the investigator(s) would preclude the Participant’s participation in a clinical study. 22. Participants with a diagnosis of immunodeficiency or who are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. 23. Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 24. Females who are breastfeeding or pregnant at Screening or 25. Females of childbearing potential* who: - do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation ie,: ◦ total abstinence (if it is their preferred and usual lifestyle) ◦ an intrauterine device (IUD) or hormone-releasing system (IUS) ◦ a contraceptive implant ◦ an oral contraceptive** (with additional barrier method) OR - do not have a vasectomised partner with confirmed azoospermia. 26. Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to use condom + spermicide OR have a female partner who does not meet the criteria above,starting with the first dose of study therapy through 120 days after the last dose of study therapy, unless sexually abstinent. 27. Known intolerance to any of the study drugs (or any of the exipients)

Sub Specialty:

Renal Cancer

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Study Title: A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Including FGFR2 Translocations Who Failed Previous Therapy

Research Summary

-

Inclusion Criteria:

A subject who meets all of the following criteria may be included in the study: 1. Men and women, aged 18 or older. 2. Histologically or cytologically confirmed cholangiocarcinoma. 3. Radiographically measurable or evaluable disease per RECIST v1.1. 4. Tumour assessment for FGF/FGFR gene alteration status completed through the central laboratory. 5. Documented disease progression after at least 1 line of prior systemic therapy. 6. Archival tumour specimen (tumour block or minimum of 15 slides) or willingness to undergo a pretreatment tumour biopsy to provide a tumour block or unstained slides. Archival tumour biopsies are acceptable and should be no more than 2 years old (preferably < 1 year old and collected since the completion of the last treatment); subjects with a sequencing report of their tumour from Foundation Medicine within 2 years are exempt from the need for tumour biopsy, but a tumour sample should be provided to the sponsor if available. 7. Life expectancy ≥ 12 weeks. 8. ECOG performance status 0 to 2. 9. Willingness to avoid pregnancy or fathering children based on the criteria below: a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea). b. Woman of childbearing potential who has a negative pregnancy test at screening and before the first dose on Day 1 and who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed. A follow-up pregnancy test will be performed at EOT visit. c. Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after last day of treatment (1 sperm cycle). Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed.

Exclusion Criteria:

A subject who meets any of the following criteria will be excluded from the study: 1. Prior receipt of selective FGFR inhibitor. 2. Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 28 days before first dose of study drug. Subjects must have recovered (Grade ≤ 1 or at pretreatment baseline) from AEs from previously administered therapies. 3. Untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases). Subjects with previously treated and clinically stable brain/CNS metastases and who are off all corticosteroids for ≥ 4 weeks are eligible. 4. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy that has undergone potentially curative therapy. 5. Are pregnant or lactating. 6. Have abnormal laboratory parameters: a. Total bilirubin ≥ 1.5 × upper limit of normal (ULN; ≥ 2.5 × ULN if Gilbert syndrome or disease involving liver). b. AST and ALT > 2.5 × ULN (AST and ALT > 5 × ULN in the presence of liver metastases). c. Creatinine clearance ≤ 30 mL/min based on Cockroft-Gault. d. Serum phosphate > institutional ULN. e. Serum calcium outside of the institutional normal range or serum albumin-correct calcium outside of the institutional normal range when serum albumin is outside of the institutional normal range. f. Potassium levels < institutional lower limit of normal; supplementation can be used to correct potassium level during the screening. 7. Known history of human immunodeficiency virus (HIV) infection or positivity on immunoassay confirmed per local standards (NOTE: HIV screening test is optional for US subjects, but subjects with known history of HIV infection will be excluded). 8. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 9. Has a history or presence of an abnormal ECG that in the investigator's opinion is clinically meaningful. Subjects with a screening QTcF interval > 450 milliseconds are excluded. 10. History of clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, or arrhythmia requiring therapy. Subjects with a pacemaker and well-controlled rhythm for at least 1 month prior to first dose will be allowed. 11. Have undergone major surgical procedure other than for diagnosis within 28 days before Cycle 1 Day 1. 12. Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy. 13. Pregnant or nursing women or subjects expecting to conceive or father children within the projected duration of the study, starting with the screening visit through completion of safety follow-up visit (90 days from date of last dose for male subjects). 14. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumour embolization). 15. Received prior radiation therapy administered within 4 weeks of first dose of study drug. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation to non-CNS disease. 16. History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification. 17. Current evidence of corneal disorder/keratopathy, including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjuctivitis, etc, confirmed by ophthalmologic examination. 18. Current use of prohibited medication 19. Use of any potent CYP3A4 inhibitors or inducers (Appendix B) within 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug. Topical ketoconazole will be allowed. 20. Known hypersensitivity or severe reaction to INCB054828 or excipients of INCB054828 study drug 21. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the investigator. 22. Inability to comprehend or unwilling to sign the informed consent form (ICF). 23. Unable or unwilling to swallow INCB054828 or significant GI disorder(s) that could interfere with the absorption, metabolism, or excretion. 24. Any condition that would in the investigator's judgment interfere with full participation in the study. 25. Subjects with history of hypovitaminosis D requiring supraphysiologic doses.

Sub Specialty:

Upper GI

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A Phase 3, Randomised, Open-Label, Multicentre Study Comparing the Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects with Waldenström’s Macroglobulinemia (WM)

Research Summary

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Inclusion Criteria:

1. Clinical and definitive histologic diagnosis of WM 2. Meeting at least one criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström’s macroglobulinemia (Dimopoulos et al 2014) 3. For subjects who have received no prior therapy for WM, they must be considered inappropriate candidates for treatment with a standard chemoimmunotherapy regimen 4. Measurable disease, as defined by serum IgM level > 0.5 g/dL 5. Age > = 18 years old 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 7. Adequate bone marrow function defined as: - Neutrophils > = 0.75 x 10 power 9/L independent of growth factor support within 7 days of study entry - Platelets > = 50 x 10 power 9/L, independent of growth factor support or transfusion within 7 days of study entry 8. Creatinine clearance of > = 30 ml/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD]) 13. Subjects may be enrolled who relapse after autologous stem cell transplant if they are at least 3 months after transplant, and after allogeneic transplant if they are at least 6 months posttransplant. To be eligible after either type of transplant, subjects should have no active related infections or in the case of allogeneic transplant relapse, no active acute graft versus host disease (GvHD) of any grade, and no chronic GvHD other than mild skin, oral, or ocular GvHD not requiring systemic immunosuppression.

Exclusion Criteria:

1. Prior exposure to a BTK inhibitor. 2. Evidence of disease transformation at the time of study entry. 3. Corticosteroids given with anti-neoplastic intent within 7 days, or chemotherapy, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapy within 4 weeks of the start of study drug. 4. Major surgery within 4 weeks of study treatment. 5. Toxicity of > = Grade 2 from prior anticancer therapy (except for alopecia, absolute neutrophil count [ANC] and platelets). For ANC and platelets, please follow inclusion criteria #7 [neutrophils] and [platelets]). 6. History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other modality) with curative intent. 7. Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening. 8. QTcF prolongation (defined as a QTcF > 450 msec) 9. Active, clinically significant Electrocardiogram (ECG) abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV block. 10. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 11. Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy that was completed < = 14 days before the first dose of study drug. 12. Known human immunodeficiency virus (HIV), or active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] detected).

Sub Specialty:

Lymphoma

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A Multicenter, Open-label Phase 2 Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer Associated with Homologous Recombination Deficiency

Research Summary

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Inclusion Criteria:

1. The participant must have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form prior to any study specific evaluation. 2. Male > = 18 years of age at the time the informed consent form is signed. 3. The participant must have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate (pure small-cell histologies or pure highgrade neuroendocrine histologies are excluded; neuroendocrine differentiation is allowed). 4. The participant must have been surgically or medically castrated, with serum testosterone levels of < = 50 ng/dL (1.73 nM). For patients currently being treated with luteinizing hormone–releasing hormone (LHRH) agonists (ie, patients who have not undergone an orchiectomy), therapy must be continued throughout the study. 5. There must be evidence of disease progression after prior therapy for mCRPC: a. Disease progression after treatment with at least 1 but no more than 2 prior next-generation AR-targeted therapies (abiraterone acetate, enzalutamide, or investigational AR-targeted agent) for castration-resistant disease (treatment with the older anti-androgen therapies such as bicalutamide, flutamide, and nilutamide are not counted toward this limit), AND b. Disease progression after treatment with 1 prior taxane-based chemotherapy for castration-resistant disease. Prior taxane therapy administered for hormone-sensitive disease is permitted and is not counted toward this limit. Disease progression after initiation of most recent therapy is based on any of the following criteria: i. Rise in PSA: a minimum of 2 consecutive rising levels, with an interval of > = 1 week between each determination. The most recent screening measurement must have been > = 2 ng/mL. ii. Transaxial imaging: new or progressive soft tissue masses on CT or MRI scans as defined by RECIST 1.1. iii. Radionuclide bone scan: at least 2 new metastatic lesions 6. Molecular evidence of mCRPC associated with HRD: a. Cohort A and B: deleterious BRCA1/2 or ATM mutation. b. Cohort C: deleterious mutation in another HR gene associated with sensitivity to PARPi (Appendix 1) Mutation status is determined by a local laboratory with the result documented in the patient's medical record, or identified by the sponsor's central laboratory via testing of plasma, archival tumor tissue or tissue biopsy performed during the Screening period. 7. Cohort A only: have measurable visceral or nodal disease per RECIST 1.1 criteria (Appendix 2). 8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 3). 9. Have adequate organ function confirmed by the following clinical laboratory values obtained within 14 days prior to the first dose of rucaparib: a. Bone Marrow Function i. Absolute neutrophil count (ANC) > = 1.5 × 109/L ii. Platelets > 100 × 109/L iii. Hemoglobin > = 10 g/dL independent of transfusion within 14 days b. Hepatic Function i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < = 3 × ULN ii. Bilirubin < = 1.5 × ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert's syndrome). c. Renal Function i. Serum creatinine < = 1.5 × ULN or estimated glomerular filtration rate (GFR) > = 45 mL/min using the Cockcroft-Gault formula. 10. Male patients with female partners of childbearing potential may be enrolled if they are: a. Documented to be surgically sterile (ie, vasectomy) b. Committed to practicing true abstinence during treatment and for 4 months after the last rucaparib dose c. Committed to using an effective method of contraception (refer to protocol) with their partner during treatment and for 4 months following the last dose of rucaparib. 11. Have a life expectancy of at least 6 months.

Exclusion Criteria:

1. Active malignancy, with the exception of curatively treated nonmelanoma skin cancer, carcinoma in situ, or superficial bladder cancer. - Patients with a history of malignancy that has been completely treated, and currently with no evidence of that cancer, are permitted to enroll in the trial provided all therapy was completed > 6 months prior and/or bone marrow transplant (BMT) > 2 years prior to first dose of rucaparib 2. Prior treatment with any PARP inhibitor, mitoxantrone, cyclophosphamide or any platinum-based chemotherapy. 3. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable (not requiring steroids for at least 4 weeks prior to first dose of rucaparib) and have had appropriate scans at screening assessment. 4. Symptomatic or impending spinal cord compression unless appropriately treated, clinically stable, and asymptomatic. 5. Pre-existing duodenal stent and/or any gastrointestinal (GI) disorder or defect that would, in the opinion of the investigator, interfere with absorption of rucaparib. 6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C. 7. Received treatment with chemotherapy, hormonal therapy (with the exception of LHRH analog), radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs within 2 weeks prior to first dose of rucaparib. 8. Adverse effect of prior therapy not resolved to CTCAE Grade 1 or below with the exception of alopecia. Ongoing Grade 2 non-hematologic toxicity related to most recent treatment regimen may be permitted with prior advanced approval from the sponsor. 9. Initiated bisphosphonate or denosumab therapy or adjusted bisphosphonate or denosumab dose/regimen within 4 weeks prior to first dose of rucaparib. Patients on a stable bisphosphonate or denosumab regimen are eligible and may continue treatment. 10. Non-study related minor surgical procedure < = 5 days, or major surgical procedure < = 21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently recovered and stable before treatment administration. 11. Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study.

Sub Specialty:

Prostate Cancer

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A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with Extensive Stage Small Cell Lung Cancer (MERU)

Research Summary

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Inclusion Criteria:

• Histologically or cytologically confirmed extensive-stage disease small cell lung cancer (ED SCLC) with ongoing clinical benefit (stable disease [SD], partial response [PR], or complete response [CR]) following completion of 4 cycles of first-line platinum-based therapy • At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based chemotherapy and randomization. • Participants with a history of central nervous system (CNS) metastases prior to the initiation of first-line platinum-based chemotherapy must have received definitive local treatment and have documentation of stable or improved CNS disease status • Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 • Participants must have adequate bone marrow, renal and hepatic function

Exclusion Criteria:

• Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any other anti-cancer therapy than that described in inclusion criteria • Any disease-directed radiotherapy (except prophylactic cranial irradiation) after last dose of first-line chemotherapy. • Prior exposure to a pyrrolobenzodiazepine (PBD)- or indolinobenzodiazepine-based drug, prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.

Sub Specialty:

Lung Cancer

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Randomized, Double-Blind Phase 2/3 Study in Subjects with Malignant Pleural Mesothelioma with Low Argininosuccinate Synthetase 1 Expression to Assess ADI-PEG 20 with Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study)

Research Summary

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Inclusion Criteria:

1. Histologically proven advanced MPM of biphasic or sarcomatoid histology. Biphasic MPM is defined using the World Health Organization’s international histological classification of tumors as containing an epithelial and a sarcomatoid component with each component comprising at least 10% of the tumor (Corson 2004, Allen 2005). 2. Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy study). 3. MPM tumor sample for determination of ASS1 status. ASS1-deficiency is not required for study entry at study start, but tumor sample for ASS1 status is required. This study will employ an adaptive biomarker-driven design with an interim analysis to be conducted at the end of the phase 2 portion. The interim analysis will evaluate the treatment effect of ADI PEG 20 in combination with pemetrexed and cisplatin on overall survival (OS) in the overall population (biphasic and sarcomatoid histology patients) and pre-defined subpopulation of biomarker-positive patients (ASS1-deficient subpopulation). Thus ASS1 deficiency may be required for the phase 3 portion of the study, pending the interim analysis. ASS1-deficiency, demonstrated on tissue specimen (cytospin samples are not acceptable), will be defined in the laboratory manual. If archived tissue is not sufficient or not available, then tissue must be obtained by biopsy. 4. Measurable disease as assessed by modified RECIST for MPM for thoracic disease (Appendix A) and RECIST 1.1 for extra-thoracic disease (Appendix B). 5. ECOG performance status of 0 – 1 (Appendix C). 6. Predicted life expectancy of at least 12 weeks. 7. Age ≥ 18 years (there is no upper age limit). 8. Fully recovered from any prior surgery and no major surgery within 4 weeks. Surgery for placement of vascular access devices is acceptable. 9. Subjects and their partners must be asked to use appropriate contraception. They must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study and for 35 days after last dose of ADI-PEG 20 or for at least six months after treatment with pemetrexed and cisplatin whichever is the longer duration. Females must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy must be performed according to GCP before this patient is claimed eligible. 10. Informed consent must be obtained prior to study initiation. 11. Hemoglobin (HB) > 9.0 g/dL. 12. Absolute neutrophil count (ANC) > 1,500/µL. 13. Platelets > 75,000/µL. 14. Either: (i) serum bilirubin ≤ 1.5 x upper limit of normal (ULN) or (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or alkaline phosphatase (ALP) ≤ 3 x (ULN) unless raised due to tumor in which case up to 5 x ULN is permissible 15. Serum uric acid ≤ 10 mg/dL (595 µmol/L) (with or without medication control). 16. Creatinine clearance ≥ 40 mL/min (estimated, using Cockcroft and Gault formula). Cisplatin dose adjustment is recommended for subjects with a creatinine clearance between 40 and 59 mL/min (Bennis 2014) as follows: reduce cisplatin dose by 25% for clearance between 50 59.9 mL/min and by 50% for clearance between 40 – 49.9 mL/min.

Exclusion Criteria:

1. Radiotherapy (except for palliative reasons) the previous two weeks before. 2. Ongoing toxic manifestations of previous treatments. 3. Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery). 4. Major thoracic or abdominal surgery from which the patient has not yet recovered. 5. Serious infection requiring treatment with intravenous antibiotics at the time of study entrance, or an infection requiring intravenous therapy within 7 days prior. 6. Known to be serologically positive for human immunodeficiency virus (HIV). Testing to determine possible infection status is not required. 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic cardiac arrhythmia, previous history of myocardial infarction (unless stable and good ejection fraction on echocardiogram) or psychiatric illness, and social situations that would limit compliance with study requirements. 8. Is a participant of, or plans to participate in, another interventional clinical study whilst taking part in this study. Participation in an observational or biomarker study would be acceptable, with prior Sponsor approval. 9. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the Investigator will not affect patient outcome. 10. Allergy to platinum salts. 11. Pregnancy or lactation. 12. Expected non-compliance. 13. Subjects who had been treated with ADI-PEG 20 previously. 14. History of seizure disorder not related to underlying cancer. 15. ECOG performance status > 2. 16. Allergy to pegylated compounds. 17. Allergy to E. coli drug products (such as GMCSF).

Sub Specialty:

Lung Cancer

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A Phase 3 Randomized Study Comparing Nivolumab and Ipilimumab Combination vs Placebo in Participants with Localized Renal Cell Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse

Research Summary

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Inclusion Criteria:

Kidney tumor has been completely resected, and the nephrectomy must occur no less than 4 weeks and 12 weeks prior to randomization. Partial nephrectomy is allowed provided all inclusion criteria are met and negative surgical margins are obtained. Post-nephrectomy tumor shows RCC with a predominately clear cell histology, including participants with sarcomatoid features. Pathological TNM staging per AJCC staging version 2010: i) pT2a, G3 or G4, N0M0 ii) pT2b, G any, N0M0 iii) pT3, G any, N0M0 iv) pT4, G any, N0M0 v) pT any, G any, N1M0 Participants must have no clinical or radiological evidence of macroscopic residual disease or distant metastases (M0) after nephrectomy as confirmed by the BICR.

Exclusion Criteria:

Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Uncontrolled adrenal insufficiency Participants with an active known or suspected autoimmune disease.

Sub Specialty:

Renal Cancer

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A randomized phase III study of pembrolizumab given concomitantly to chemoradiation and as maintenance therapy versus chemoradiation alone in patients with locally advanced squamous cell carcinoma of the head and neck

Research Summary

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Inclusion Criteria:

Patients must meet all of the criteria described below to be eligible for randomization. - Pathologically proven new diagnosis of squamous cell carcinoma of: - Oropharyngeal p16 positive  T4 (N0‐N3), M0  N3 (T1‐T4), M0; - Oropharyngeal p16 negative  any T3‐4 (N0‐N3), M0  any N2a‐3 (T1‐T4), M0; - Larynx/hypopharynx/oral cavity (independent of p16)  any T3‐4 (N0‐N3), M0  any N2a‐3 (T1‐T4), M0. Patients with oral cavity tumors need to have unresectable disease - No previous radiotherapy treatment for head and neck cancer; - Availability on site of adequate tissue in terms of quality and quantity for immunohistochemical staining for p16 to be assessed locally before inclusion - Availability on site of adequate tissue in terms of quality and quantity for further central immunohistochemical staining (i.e.PD‐L1 Immunohistochemistry (IHC) expression…). Central pathological review for p16 or PD‐L1 will not be performed before inclusion. Formalin‐fixed paraffin embedded tumor tissue sample blocks are preferred - At least 18 years old - Evaluable tumor burden (measurable and/or non‐measurable tumor lesions) assessed by CT scan or MRI, based on RECIST version 1.1, to be performed within 28 days before treatment start; - Patient eligible for definitive CRT and not considered for primary surgery based on investigator decision; - ECOG Performance score (PS) 0 or 1; - Adequate organ function performed within 10 days of treatment initiation.

Exclusion Criteria:

- No current participation or treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment; - No prior treatment with an anti‐PD‐1, anti‐PD‐L1/2, anti‐ CD137, CTLA‐4 modulators; patients receiving live vaccine within 30 days prior to the first dose of study treatment are not eligible; - No known history or current evidence of active tuberculosis (Bacillus Tuberculosis), Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA[qualitative] is detected) or Human Immunodeficiency Virus (HIV) (HIV‐1/2 antibodies); - No chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first dose of trial treatment:  -Corticosteroid use on study for management of ECIs (pembrolizumab Event of Clinical Interest), as pre‐medication for the administration of chemotherapies, and/or a premedication for IV contrast allergies/reactions is allowed;  -Daily prednisone at doses of 5‐7.5 mg is allowed as an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy; - No history of interstitial lung disease (ILD) that has required oral or IV steroids; - No history of pneumonitis (other than COPD exacerbation) that has required oral or IV steroids; - No active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed; - No history of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A T1‐2 prostatic cancer Gleason score ≤ 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible; - No previous allogeneic tissue/solid organ transplant; - No active infection requiring therapy; - Female patients must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) irrespectively of their childbearing potential. If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. Non‐childbearing potential is defined as (by other than medical reasons):  - ≥ 45 years of age and has not had menses for greater than 1 year,  - Amenorrheic for > 2 years without a hysterectomy and oophorectomy and an FSH value in the postmenopausal range upon pretrial (screening) evaluation,  - Whose status is post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the patient must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study treatment. Information must be captured appropriately within the site's source documents. - Female patients of childbearing potential (Section 5.9.2.2) must be willing to use an adequate method of contraception as outlined in Section 5.9.2.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.). - Note: Abstinence is acceptable if this is the established and preferred contraception for the patient. - Male patients of childbearing potential (Section 5.9.2.2) must agree to use an adequate method of contraception as outlined in Section 5.9.2.2 Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. - Note: Abstinence is acceptable if this is the established and preferred contraception for the patient. - Female patients who are breast feeding should discontinue nursing prior to the first dose of study medication and until 44 months after the last study treatment; - Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration; - Patient will not be eligible: if the patient is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific patient. After the enrollment step in ORTA, patients will be automatically randomized in the Interactive Voice Response System (IVRS). Important note: All eligibility criteria must be adhered to. A two days deviation rule will be allowed.

Sub Specialty:

Head and Neck Cancer

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A global, prospective, non-interventional, observational study of presentation, treatment patterns, and outcomes in multiple myeloma patients - the INSIGHT-MM study

Research Summary

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Inclusion Criteria:

Each patient must meet all of the following criteria to be included in this study: • Is 18 years of age or older. • Is experiencing one of the following: o Newly diagnosed and not yet relapsed MM with documented month and year of diagnosis, criteria met for diagnosis, stage, and MM-directed treatment history, including duration. o Relapsed/refractory MM with documented data in the medical record regarding diagnosis (month and year), prior exposure to classes of medications (e.g., proteosome inhibitors, immunomodulatory drugs), and number of previous lines of therapies. • Is willing and able to sign informed consent to participate. • Is willing and able to complete patient assessment questionnaires.

Exclusion Criteria:

Patients meeting any of the following criteria will be excluded from the study: • Patients reporting to a site in this study for a second opinion (consultation only) or patients whose frequency of consult and follow-up are not adequate for quarterly electronic case report form (eCRF) completion. • Participation in another study (observational or interventional) that prohibits participation in this study. • Unable or unwilling to complete HRQoL and PROs.

Sub Specialty:

Haematological Oncology

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A prospective, multicentre, randomised, controlled study evaluating SIR-Spheres Y-90 resin microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) chemotherapy versus CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable intrahepatic cholangiocarcinoma (SIRCCA)

Research Summary

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Inclusion Criteria:

1. Willing, able and mentally competent to provide written informed consent. 2. Aged 18 years or older. 3. Histologically or cytologically confirmed unresectable and non ablatable intrahepatic cholangiocarcinoma 4. Liver-only or liver predominant intrahepatic cholangiocarcinoma. Patients are permitted to have loco-regional lymph node involvement defined as: portal LN < = 2 cm and/or para aortic LN < = 1.5 cm in longest diameter, and/or up to 2 indeterminate lung lesions < 1 cm if these lung lesions are PET negative. 5. Chemotherapy naive. Adjuvant chemotherapy is not permitted. 6. ECOG performance status of 0 or 1. 7. Adequate haematological function defined as: - Haemoglobin > = 10g/dL - WBC > = 3.0 x 109/L - Absolute neutrophil count (ANC) > = 1.5 x 109/L - Platelet count > = 100,000/mm3 8. Adequate liver function defined as: - Total bilirubin < = 30 µmol/L (1.75mg/dL) - Albumin > = 30 g/L 9. Adequate renal function defined as: - Serum urea and serum creatinine < 1.5 times upper limit of normal (ULN) - Creatinine clearance > = 45 ml/min (calculated Cockcroft-Gault Equation). All blood tests results must be within 14 days prior to randomization. 10. Life expectancy of at least 3 months without any active treatment. 11. Female patients must either be post-menopausal, sterile (surgically or radiation- or chemically- induced), or if sexually active use an acceptable method of contraception during the study. 12. Male patients must be surgically sterile or if sexually active must use an acceptable method of contraception during the study. 13. Considered suitable to receive either treatment regimen in the clinical judgment of the treating investigator.

Exclusion Criteria:

1. Patients with only non-measurable lesions in the liver according to RECIST criteria. 2. Incomplete recovery from previous liver surgery, e.g. unresolved biliary tree obstruction or biliary sepsis or inadequate liver function. 3. Biliary stenting in-situ. 4. Main trunk Portal Vein Thrombosis (PVT). 5. Ascites, even if controlled with diuretics. (A minor peri-hepatic rim of ascites detected at imaging is acceptable). 6. Mixed HCC-ICC disease. 7. History of prior malignancy. Exceptions include in-situ carcinoma of the cervix treated by con-biopsy/resection, non-metastatic basal and/or squamous cell carcinoma of the skin, recurrent intra-hepatic cholangiocarcinoma post local treatment, or any early stage (stage I) malignancy adequately resected with curative intent at least 5 years prior to study entry. 8. Suspicion of any bone metastasis/metastases or central nervous system metastasis/metastases on clinical or imaging examination. 9. Prior internal or external radiation delivered to the liver. 10. Pregnancy; breast-feeding. 11. Participation within 28 days prior to randomisation, in an active part of another clinical study that would compromise any of the endpoints of this study. 12. Evidence of ongoing active infection that may affect treatment feasibility or outcome. 13. Prior Whipple’s procedure.

Sub Specialty:

Upper GI

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A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab Plus Ipilimumab versus Oxaliplatin Plus Fluoropyrimidine in Subjects with Previously Untreated Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Research Summary

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Inclusion Criteria:

- Male or Female at least 18 years of age; - Must have gastric cancer or gastroesophageal junction cancer that cannot be operated on and that is advanced or has spread out; - Did not receive neoadjuvant or adjuvant treatment (chemotherapy, radiotherapy, or both) for their disease within the last 6 months; - Must have full activity or, if limited, must be able to walk and carry out light activities such as light house work or office work; - Must agree to provide tumor tissue sample, either from a previous surgery or biopsy within 6 months or fresh, prior to the start of treatment in this study.

Exclusion Criteria:

- Known Her2 positive status; - Presence of tumour cells in the brain or spinal cord that have not been treated; - Active known or suspected autoimmune disease; - Any serious or uncontrolled medical disorder or active infection (HIV) or known acquired immunodeficiency syndrome (AIDS); - Any positive test result for hepatitis B or C indicating acute or chronic infection.

Sub Specialty:

Upper GI

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A Randomized, Controlled, Open-Label, Phase 3 Study of Melflufen/Dexamethasone Compared with Pomalidomide/ Dexamethasone for Patients with Relapsed Refractory Multiple Myeloma who are Refractory to Lenalidomide

Research Summary

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Inclusion Criteria:

1. Male or female, age 18 years or older 2. A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening 3. Measurable disease defined as any of the following:  Serum monoclonal protein > = 0.5 g/dL by protein electrophoresis.  > = 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis  Serum free light chain > = 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio 4. Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to lenalidomide in the last line. Refractory status to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle. 5. Life expectancy of > = 6 months 6. Eastern Cooperative Oncology Group (ECOG) performance status < = 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor) 7. Females of child bearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL completed within 10 to 14 days prior to start of treatment. All FCBP must agree to either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking treatment and as appropriate based on the treatment assignment. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a condom during sexual contact with a FCBP even if they have had a vasectomy from the time of starting study treatment through 28 days after the last dose of therapy. All patients enrolled in Canada and the USA must be willing to comply with all requirements of the Canadian or USA pomalidomide REMS (Risk Evaluation and Mitigation Strategy)™ program. All patients enrolled outside of Canada and the USA must be willing to comply with all the requirements of the pomalidomide Pregnancy Prevention Plan (PPP). (Willingness, to comply with the REMS or PPP, must be documented prior to knowledge of randomization but is only required if randomized to Arm B). 8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent. 9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of < = 470 msec. 10. The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1:  Absolute neutrophil count (ANC) > = 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days prior to first drug administration)  Platelet count > = 75,000 cells/mm3 (75 x 109/L) (without transfusions during the 10 days prior to first drug administration)  Hemoglobin > = 8.0 g/dl (red blood cell (RBC) transfusions are permitted)  Total Bilirubin < = 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome that have been reviewed and approved by the medical monitor.  Aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) < = 3.0 x ULN.  Renal function: Estimated creatinine clearance by Cockcroft-Gault formula > = 45 mL/min. 11. Must be able to take antithrombotic prophylaxis. 12. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter) (Willingness must be documented prior to randomization but insertion only required if randomized to Arm A). *(FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.

Exclusion Criteria:

1. Primary refractory disease (i.e. never responded (> = MR) to any prior therapy) 2. Evidence of mucosal or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 after a transfusion of an appropriate dose of platelets) 3. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, > = grade 3 thromboembolic event in the last 6 months), 4. Prior exposure to pomalidomide 5. Known intolerance to IMiDs. (> = Grade 3 hypersensitivity reaction or at the investigators discretion) 6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization. 7. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance. 8. Pregnant or breast-feeding females 9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation 10. Known human immunodeficiency virus or active hepatitis C viral infection 11. Active hepatitis B viral infection (defined as HBsAg+).  Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).  Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation. 12. Concurrent symptomatic amyloidosis or plasma cell leukemia 13. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) 14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. The use of live vaccines within 30 days before randomization. IMiDs, PIs and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization 15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted) 16. Prior peripheral stem cell transplant within 12 weeks of randomization 17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease). 18. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization (this does not include limited course of radiation used for management of bone pain within 7 days of randomization). 19. Known intolerance to steroid therapy

Sub Specialty:

Haematological Oncology

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A Phase III, randomized, double-blind, controlled, multicenter study of intravenous PI3K inhibitor copanlisib in combination with standard immunochemotherapy versus standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL) - CHRONOS-4

Research Summary

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Inclusion Criteria:

6.1 Inclusion criteria 1. Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure 2. Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to: • Follicular lymphoma (FL) grade 1-2-3a • Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 109/L at the time of diagnosis and at study entry • Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) • Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 3. Patients must have relapsed after at least 1 prior line of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; or radioimmunotherapy. Previous exposure to PI3K inhibitors is acceptable provided there is no resistance (treatment stopped for other reasons than progressive disease). 4. Patients must not be refractory to rituximab at any prior line of therapy (treatment-free interval of at least 6 months from the end of the last prior rituximab-containing treatment). 5. Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification (15). 6. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level = 2 x upper limit of normal (ULN). 7. Male or female patients = 18 years of age. 8. Eastern Cooperative Oncology Group (ECOG) performance status = 2. 9. Life expectancy of at least 3 months. 10. Availability of fresh tumor tissue and/or archival tumor tissue at Screening. 11. Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the informed consent form and 6 months after the last administration of study treatment. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices (hormonal or non-hormonal), bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms by patients or their partners is required unless the woman has had a hysterectomy. 12. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting the study treatment: • Total bilirubin within normal limits (< 3 x ULN for patients with Gilbert-Meulengracht syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement by lymphoma). • Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN (< 5x ULN for patients with documented liver involvement or with biliary obstruction due to lymphoma). • Lipase = 1.5 x ULN. • Glomerular filtration rate (GFR) = 40 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24 hour sampling. If the latter result is within acceptable range, it may be used to fulfill the inclusion criteria instead. • International normalized ratio (INR) and partial thromboplastin time (PTT) = 1.5 x ULN. • Platelet count = 75,000 /mm3. • Hemoglobin (Hb) = 8 g/dL. • Absolute neutrophil count (ANC) = 1,500/mm3. 13. Left ventricular ejection fraction (LVEF) = 50%.

Exclusion Criteria:

6.2 Exclusion criteria Patients who meet any of the following criteria at the time of screening will be excluded. 1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study. 2. Previous (within 28 days or 5 half-lives of the drug before start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s) 3. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site). Excluded medical conditions: 4. Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3b or transformed disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of transformed disease a fresh biopsy is recommended. 5. Rituximab refractoriness at any line of therapy (refractory defined as not responding or progressing within 6 months of the last course of a rituximab containing regimen). 6. History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator) 7. Known lymphomatous involvement of the central nervous system. 8. Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160 mg/dL at Screening. 9. Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations. 10. Hepatitis B (HBV) and C (HCV) infection. All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients with serologic markers of HBV immunization due to known vaccination (HBsAg negative, anti-HBc negative and anti-HBs positive) will be eligible. 11. Previous or concurrent history of malignancies other than indolent non-Hodgkin’s lymphoma within 5 years prior to study treatment except for curatively treated: • Cervical carcinoma in situ • Non-melanoma skin cancer • Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]) • Localized prostate cancer 12. Congestive heart failure > New York Heart Association (NYHA) class 2. 13. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of test drug. 14. History of, or actual, autoimmune disease. 15. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management). 16. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication. 17. Non-healing wound, ulcer, or bone fracture. 18. Active, clinically serious infections (> CTCAE grade 2). 19. Patients with seizure disorder requiring medication. 20. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event = CTCAE Grade 3 within 4 weeks of start of study medication. 21. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation. 22. Proteinuria of CTCAE Grade 3 or higher (estimated by urine protein : creatinine ratio > 3.5 on a random urine sample) 23. Unresolved toxicity higher than NCI-CTCAE (version 4.03) grade 1 attributed to any prior therapy/procedure excluding alopecia. 24. Concurrent diagnosis of pheochromocytoma. 25. Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment. 26. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results. 27. Any illness or medical conditions that are unstable or could jeopardize the safety of the patients and their compliance in the study. Excluded previous therapies and medications: 28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatment 29. Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors defined as: • No response (response defined as partial response [PR] or complete response [CR]) at any time during therapy, or • Progression (PD) after any response (PR/CR) or after stable disease within 6 months from the end of the therapy with a PI3K inhibitor 30. Ongoing immunosuppressive therapy. 31. Radiotherapy or immuno-/chemotherapy less than 4 weeks before start of treatment, unless evidence of progression since last treatment 32. Radioimmunotherapy or autologous transplant less than 3 months before start of treatment, unless evidence of progression since last treatment. 33. Myeloid growth factors within 14 days prior to treatment start. 34. Blood or platelet transfusion within 7 days prior to treatment start. 35. Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed. Patients may be using topical or inhaled corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before performing the screening PET-CT and/or CT/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the screening. 36. History of having received an allogeneic bone marrow or organ transplant. 37. Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of study medication, open biopsy within 7 days before start of study medication. 38. Anti-arrhythmic therapy (beta blockers or digoxin are permitted). 39. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until the safety follow-up visit. 40. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the safety follow-up visit. For prohibited concomitant therapy please refer to Section 8.1

Sub Specialty:

Lymphoma

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A Phase II Basket Study of the Oral TRK Inhibitor LOXO-101 in Subjects with NTRK Fusion-Positive Tumors

Research Summary

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Inclusion Criteria:

1. Locally-advanced or metastatic malignancy with an NTRK1, NTRK2 or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. 2. Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy. 3. Subjects must have at least one measurable lesion as defined by RECIST 1.1 (Eisenhauer 2009). Subjects without RECIST measurable disease (e.g., evaluable disease only) will be eligible for enrollment to Cohort 8, regardless of tumor type. Subjects in Cohort 7 (primary CNS tumors) should meet the following criteria: a. Have received prior treatment including radiation and/or chemotherapy, with radiation completed > 12 weeks prior to C1D1 of therapy. b. Have = 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions = 1 cm in each dimension and noted on more than one imaging slice. c. Imaging study performed within 28 days before enrollment while on stable dose steroid medication for at least 5 days immediately before and during the imaging study. 4. At least 18 years of age. 5. Eastern Cooperative Oncology Group (ECOG) score of ≤ 2 (see Appendix A). 6. Archived tumor tissue. 7. Adequate organ function as defined by the following criteria: a. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) < 2.5 'upper limit of normal (ULN), or AST and ALT < 5 ULN if liver function abnormalities are due to underlying malignancy. b. Total bilirubin < 2.0 ULN. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible. c. Serum creatinine < 2.0 'ULN OR an estimated glomerular filtration rate = 30 mL/minute using the Cockroft-Gault formula: (140 – age) x body weight (kg) 0.85 (if female) serum creatinine (mg/dL) x 72 8. Ability to swallow capsules, comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. 9. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following study completion.

Exclusion Criteria:

1. Investigational agent or anticancer therapy within 2 weeks prior to planned start of IP or 5 half-lives, whichever is shorter, and with recovery of clinically significant toxicities from that therapy. 2. Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain metastases are eligible to participate in the study). Subjects with primary CNS tumors are eligible. 3. Uncontrolled concurrent malignancy that would limit assessment of efficacy of IP. 4. Active uncontrolled systemic bacterial, viral, or fungal infection, unstable cardiovascular disease or other systemic disease that would limit compliance with study procedures. 5. Malabsorption syndrome or other condition affecting oral absorption. 6. Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer (see Appendix B) prior to start of treatment initiation. 7. Pregnancy or lactation.

Sub Specialty:

Brain Cancer Breast Cancer

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A Randomized, Multicenter, Double Blind, Phase III Study of Adjuvant Nivolumab or Placebo in Subjects with Resected Esophageal, or Gastroesophageal Junction Cancer

Research Summary

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Inclusion Criteria:

• All subjects must have Stage II or Stage III (per AJCC 7th edition) carcinoma of the esophagus or gastroesophageal junction and have histologically confirmed predominant adenocarcinoma or squamous cell carcinoma esophageal or gastroesophageal junction cancer at the time of initial diagnosis. • Subjects must complete pre-operative chemoradiotherapy followed by surgery prior to randomization. Platinum based chemotherapy should be used. Chemotherapy and radiation regimens can be followed as per local standards of care per NCCN or ESMO guidelines. • Subject must have complete resection (R0), have been surgically rendered free of disease with negative margins on resected specimens. Subject must have residual pathologic disease, i.e. non-pathologic complete response (non-pCR) of their EC or GEJ, with at least one pathological lesion with at least ypN1 or at least ypT1 in the surgically resected specimen. The pathology reports of detectable lesion(s) confirming malignancy must be reviewed, dated, and signed by the investigator prior to randomization. • Complete resection must be performed within 12 weeks prior to randomization. • ECOG performance status score of 0 or 1. • All subjects must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization. Imaging studies must include CT scan of neck, chest, abdomen, and all known sites of resected disease. • Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized, a subject must have a PD-L1 expression classification (1% or < 1%) as determined by the central lab. If insufficient tumor tissue content is provided for analysis, acquisition of additional archived tumor tissue (block and /or slides) for the biomarker analysis is required.

Exclusion Criteria:

• Subjects with cervical esophageal carcinoma. Location of tumor as it relates to eligibility can be discussed with BMS medical monitor. • Subjects who do not receive concurrent CRT prior to surgery. Subjects who only receive chemotherapy or only radiation prior to surgery are not eligible. • Subjects with Stage IV resectable disease. • Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

Sub Specialty:

Upper GI

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A Randomized, Controlled, Phase 3 Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular Melanoma

Research Summary

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Inclusion Criteria:

Patients must meet all of the following criteria for study entry: 1. Male or female patients = 18 years of age. 2. Patients must weigh = 35 kg (due to possible size limitations with respect to percutaneous catheterization of the femoral artery and vein using the Delcath Hepatic Delivery System). 3. 50% or less histologically or cytologically-proven ocular melanoma metastases in the parenchyma of the liver. 4. Disease must be measurable by computed tomography (CT) and/or MRI. 5. Evidence of limited extrahepatic disease on preoperative radiological studies is acceptable if the life treatening component of PD is in the liver. Limited extrahepatic disease is defined in this protocol as follows: metastasis in up to one other organ (bone, subcutaneous, or pulmonary), limited to up to 2 nodules and amenable to resection or radiation. The extrahepatic lesions should be no larger than 2 cm in diameter each. The rationale for permitting this limited extrahepatic disease is that these types of lesions are amenable to surgical resection or radiation. 6. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to randomization. An MRI of the liver is required at screening to validate that CT accurately reflects the extent of disease in the liver. 7. Patients must have had no chemotherapy or radiotherapy for their malignancy in the month prior to treatment and must have recovered from all side effects of therapeutic and diagnostic interventions except those listed in Appendix B of the study protocol. Patients receiving anti programmed cell death protein 1 (PD-1) immunotherapy such as pembrolizumab or nivolumab, or human cytotoxic T-lymphocyte antigen 4 blocking antibody such as ipilimumab should wait 8 weeks before Melphalan/HDS treatment. 8. Patients must have an ECOG PS of 0-1 at screening and on the day prior to treatment. 9. Patients must have adequate hepatic function as evidenced by total serum bilirubin = 1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of the upper normal limit. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) must be = 2.5 x ULN. 10. Patients must have a platelet count > 100,000/µL, hemoglobin = 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count (ANC) = 1.5 x 109/L, and a serum creatinine = 1.5 mg/dL unless the measured creatinine clearance is > 40 mL/min/1.73 m2. 11. Provided signed informed consent.

Exclusion Criteria:

Patients who meet any of following criteria will be excluded from study entry: 1. Patients with Child-Pugh Class B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies. 2. Those with New York Heart Association functional classification II, III or IV active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia. 3. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia. 4. For female patients of childbearing potential (i.e., have had a menstrual period within the past 12 months): unwilling or unable to undergo hormonal suppression to avoid menstruation during treatment. 5. For female patients of childbearing potential (i.e. have had a menstrual period within the past 12 months): a positive serum pregnancy test (ß-human chorionic gonadotropin) within 7 days prior to enrollment. 6. Sexually active females of childbearing potential and sexually active males with partners of reproductive potential: unwilling or unable to use appropriate contraception from screening until at least 30 days after last administration of study treatment. 7. Patients taking immunosuppressive drugs or who are unable to be temporarily removed from chronic anti-coagulation therapy. 8. Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate therapy. 9. Patients with severe allergic reaction to iodine contrast, which cannot be controlled by premedication with antihistamines and steroids (because a hepatic angiogram is needed for the Delcath system procedure). 10. Patients with a history of or known hypersensitivity to melphalan or the components of the Melphalan/HDS system. 11. Patients previously treated with any intra-arterial regional hepatic therapy. 12. Patients with latex allergy. 13. Patients with a history of hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia. 14. Patients with a history of bleeding disorders or evidence of intracranial abnormalities which would put them at risk for bleeding with anti-coagulation (e.g., strokes, active metastases). 15. Patients with a history of gastrinoma, hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting. 16. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer. 17. Patients with prior Whipple’s procedure. 18. Patients with brain metastases or presence of other intracranial lesions at risk for bleeding by history or baseline radiologic imaging. Active infection, including Hepatitis B and Hepatitis C infection. Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are exception(s). 19. Uncontrolled endocrine disorders including diabetes mellitus, hypothyroidism, or hyperthyroidism. 20. Received any investigational agent for any indication within 30 days prior to first treatment. 21. Not recovered from side effects of prior therapy to = Grade 1 (according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Certain side effects that are unlikely to develop into serious or life–threatening events (e.g. alopecia) are allowed at > Grade 1.

Sub Specialty:

Skin Cancer

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An Open-Label, Randomised, Multi-Drug, Biomarker-Directed,Multi-Centre, Multi-arm Phase 1b Study in patients with Muscle Invasive Bladder Cancer (MIBC) who have progressed on prior treatment (BISCAY)

Research Summary

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Inclusion Criteria:

1. Male/female 18 years+ Note: for patients receiving AZD4547 in the Module A sub-study patients must be aged 25 years or older (see the Module A specific criteria in Appendix G) 2. Histological confirmation of metastatic muscle invasive bladder cancer - Patients may be second- or third-line patients. Patients must have received 1 accepted first-line treatment (eg, methotrexate, vinblastine, doxorubicin, and cisplatin/gemcitabine). All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study. 3. Any patient who has failed adjuvant or neo-adjuvant chemotherapy within a year of Screening 4. Willingness to provide consent for biopsy samples. Tumour biopsies will be required for all patients as described in the CSP. Tumour lesions used for biopsy must not be lesions used as RECIST target lesions (TLs). Tumour sample requirements: 1. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for analysis. A copy of the pathology report related to the archival tissue must also be provided, if available.  AND 2. A recent tumour biopsy must also be provided during the Screening Period prior to the first dose for eligible patients, except if associated with unacceptable clinical risk and after discussion with the medical monitor. (Note: The tumour biopsy must be taken within the Screening Period or the 3 months prior to dosing [only acceptable if no other therapies have been received in that 3-month period].) 6. World Health Organization performance status of 0 to 1 with no deterioration between Screening and the first dose of study treatment, and a minimum life expectancy of 12 weeks 7. Females must be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing 8. Male patients must use barrier contraception (ie, condoms).

Exclusion Criteria:

Prior exposure to any of the following: 1. Any other immunotherapy (eg, a CTLA4, PD1 or PDL1 inhibitor) before the first dose of study treatment. Any other chemotherapy or anticancer agents within 4 weeks before the first dose of study treatment. Radiotherapy of the primary site with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment. Any investigational agents or study drugs from a previous clinical study within 30 days before the first dose of study treatment. 2. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment. 3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment. Any prior Grade ≥ 3 immunerelated adverse event (irAE) while receiving immunotherapy, including antiCTLA4 treatment, or any unresolved irAE > Grade 1 4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. NOTE: Local treatment of isolated lesions for palliative intent is acceptable (eg, by local surgery or radiotherapy). 5. Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent. Note: This criterion is only applicable to patients receiving treatment with MEDI4736. 6. Any of the following immune related criteria: Active or prior documented autoimmune disease within the past 2 years prior to screening. NOTE: Patients with vitiligo, Grave’s disease, Hashimoto’s disease, or psoriasis not requiring systemic treatment (within the past 2 years prior to Screening) are not excluded.  Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis)  History of primary immunodeficiency  History of organ transplant that requires use of immunosuppressives 7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 8. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. 9. Any of the following cardiac criteria:  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Friderecia’s correction  Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, first degree heart block Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval. Uncontrolled hypertension – blood pressure (BP) ≥ 150/95 mmHg despite medical therapy Uncontrolled hypotension – systolic BP < 90 mmHg and/or diastolic BP < 50 mmHg Left ventricular ejection fraction < 55% measured by echocardiography  Atrial fibrillation with a ventricular rate > 100 bpm on an ECG at rest  Symptomatic heart failure – New York Heart Association Grade II-IV  Prior or current cardiomyopathy Severe valvular heart disease Uncontrolled angina (Canadian Cardiovascular Society Grade II-IV despite medical therapy) Stroke or transient ischemic attack in the last 6 months prior to Screening Acute coronary syndrome in the last 6 months prior to Screening 10. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count < 1.5 x 109/L Platelet count < 100 x 109/L Haemoglobin < 9.0 g/dL Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases Total bilirubin > 1.5 times ULN or for patients with documented/suspected Gilbert’s disease, bilirubin ≥ 2 × ULN Creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN Corrected calcium > ULN Phosphate > ULN 11. Known history of tuberculosis 12. Receipt of any live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736. Note: Not applicable to patients not receiving MEDI4736. 13. History of hypersensitivity to active or inactive excipients of any investigational drug in the study or drugs with a similar chemical structure or class to those investigated in the study. 14. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. Genetics research study (optional) Exclusion criteria for participation in the optional (DNA) genetics research component of the study: 1. Previous allogeneic bone marrow transplant 2. Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.

Sub Specialty:

Bladder Cancer

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A PHASE 1/2, OPEN LABEL, MULTICENTER STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF DURVALUMAB (ANTI-PD-L1 ANTIBODY) AS MONOTHERAPY AND IN COMBINATION THERAPY IN SUBJECTS WITH LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA

Research Summary

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Inclusion Criteria:

Subjects with R/R lymphoma or CLL requiring therapeutic intervention must satisfy the following criteria to be enrolled in the study: APPLY to ALL TREATMENT ARMS 1. Subject is ≥ 18 years of age and ≤ 80 years of age at the time of signing the informed consent form (ICF). At the discretion of the investigator, subjects > 80 years of age may be included if their ECOG performance status is ≤ 1; each of their individual organ system scores must be ≤ 2 using the Cumulative Illness Rating Scale (CIRS) for comorbitidy (Salvi, 2008a; Salvi 2008b; Appendix J). 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 4. Subject has histologically confirmed and documented eligible histologies as listed in Table 3, Table 4, or Table 5 as assessed by the investigator and local pathologist per 2008 WHO Lymphoma Classification (Swerdlow, 2008). 5. Subject has been previously treated with at least one prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy. Note: Local involved field radiation therapy (IFRT) or antibiotic-based therapy is not deemed as systemic therapy for this study. 6. Subject with high-risk CLL/SLL is defined by the presence of at least one of the following factors: a. Complex karyotype; b. del (17p) abnormality; c. Mutated TP53; d. Ibrutinib-failure (defined as progression while on ibrutinib treatment [excluding isolated early lymphocytosis]; or an inadequate tumor response which is less than partial response [PR] [Hallek, 2008; Cheson 2012]); e. Relapsed/progressive disease within 6 months of completing their last therapy. 7. Subject is willing and able to undergo biopsy: a. Subject with lymphoma is willing and able to undergo tumor/lymph node biopsy (incisional/excisional or multiple core needle) during the Screening Period and at the time of disease progression from subjects who have achieved objective response (CR/PR) to study treatment. Exception: An archival diagnostic lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy acquired by a surgical or core needle biopsy within 18 months prior to signing informed consent may be acceptable for enrollment of a subject with poorly accessible tumor following the discussion with the sponsor’s medical monitor. b. Subject with CLL is willing and able to undergo bone marrow biopsy during the Screening and Treatment Periods. Material from a fine needle aspiration is not acceptable. 8. Subject who has documented active relapsed or refractory disease requiring therapeutic intervention. 9. Subject who has measurable disease: a. For subject with lymphoma, bi-dimensionally measurable disease on cross-sectional imaging by computed tomography (CT) with at least one nodal or extranodal lesion ≥ 2.0 cm in its longest dimension. b. For subject with CLL, in need of treatment as defined by IWCLL Guidelines for the Diagnosis and Treatment of CLL (Appendix I). 10. Subject who has performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale. 11. Subject who has life expectancy of greater than 6 months. 12. Subject who fulfills the following laboratory requirements: Table 6: Eligible Laboratory Values Laboratory Value/ Treatment Arms : ANC (cells/mm3) ≥ 1500 ≥ 1000 (NHL) Arm A ≥ 1500 Arm B ≥1000 (NHL) ≥500 (CLL) Arm C ≥ 1000 (NHL)≥ 750 CLL) Arm D ≥ 1000 Unless secondary to bone marrow involvement documented as at least ≥ 80% bone marrow infiltration of CLL cells or ≥ 50% bone marrow infiltration of lymphoma cells by pretreatment bone marrow biopsy; these subjects will be excluded from dose finding cohorts. Laboratory Value/ Treatment Arms : Platelets (cells/mm3) Arm A ≥75,000 Arm B ≥50,000 Arm C ≥ 75,000 (NHL)≥ 50,000 CLL) Arm D ≥ 50,000 Unless secondary to bone marrow involvement documented as at least ≥ 80% bone marrow infiltration of CLL cells or ≥ 50% bone marrow infiltration of lymphoma cells by pretreatment bone marrow biopsy; these subjects will be excluded from dose finding cohorts. In the case of bone marrow involvement, platelets must be > 10,000 cells/mm3 and without evidence of any bleeding. AST/ALT (ULN): For Arm A,B,C,D, ≤ 2.5 × ULN (In the case of documented liver involvement by lymphoma, the requirement is ≤ 5.0 × ULN) Total Bilirubin (mg/dL): For Arm A,B,C,D, ≤ 2.0 mg/dL (34 µmol/L) (In the case of Gilbert’s Syndrome, or documented liver or pancreatic involvement by lymphoma, the requirement is ≤ 5.0 mg/dl (86 µmol/L) Creatinine (mg/dL): For ARM A,B,C,D ≤ 2 Creatinine Clearance (mL/min) based on Cockcroft-Gault formula Arm A: ≥ 60 (eligible for all parts) ≥ 30 (ineligible for dose finding part) ARM C: ≥ 40 PT/INR (ULN) : ARM B < 1.5 × ULN PTT/aPTT (ULN): ARM B < 1.5 × ULN Abbreviations: ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST/ALT = aspartate transaminase / aspartate transaminase; CLL = chronic lymphocytic leukemia; INR = international normalized ratio; LLN = lower limit of normal; NHL = non-Hodgkin lymphoma; PTT = partial thromboplastin time; ULN = upper limit of normal. 13. Female subject of childbearing potential (FCBP1) who is sexually active with a male must: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy. They must agree to ongoing pregnancy testing during the course of the study, and after the last dose of any IP. This applies even if the subject practices complete abstinence2 from heterosexual contact. b. Use effective methods (1 highly effective and 1 additional effective [barrier] method) of contraception from 28 days prior to starting durvalumab, and must agree to continue using such precautions while taking durvalumab (including dose interruptions) and for 90 days after the last dose of durvalumab. Cessation of contraception after this point should be discussed with a responsible physician. The following are examples of highly effective and additional effective methods of contraception:  Highly effective methods (defined as one that results in a low failure rate rate [ie, less than 1% per year] when used consistently and correctly): (i) Intrauterine device (IUD) (ii) Hormonal (birth control pills, injections, implants) (iii) Tubal ligation (iv) Partner’s vasectomy  Additional effective methods: (i) Male condom (ii) Diaphragm (iii) Cervical cap True abstinence is acceptable only when this is in line with the preferred and usual lifestyle of the female subject of childbearing potential. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. c. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of durvalumab. d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab. 14. Male subject who is sexually active with a female partner of childbearing potential must: a. Use male condom plus spermicide (even if he has undergone a successful vasectomy) from starting dose of durvalumab (Cycle 1 Day 1) through 90 days after receipt of the last dose of durvalumab. True abstinence is acceptable only when this is in line with the preferred and usual lifestyle of nonsterilized male subject. b. Refrain from semen or sperm donation while taking durvalumab and for at least 90 days after the last dose of durvalumab. Inclusion numbers 15-17 APPLY to ARM A only: 15. Female subject of childbearing potential must: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy (ie, durvalumab, lenalidomide and rituximab). They must agree to ongoing pregnancy testing during the course of the study, and after last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact. b. Either commit to complete abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective (1 highly effective and 1 additional effective method) contraception without interruption, 28 days prior to starting any IP, during the IP therapy (including dose interruptions), and for 12 months after the last dose of rituximab, 90 days after the last dose of durvalumab, or 28 days after the last dose of lenalidomide, whichever is longer. c. Agree to abstain from breastfeeding during study participation and for at least 28 days after the last dose of lenalidomide or 12 months after the last dose of rituximab, whichever is longer. d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last dose of durvalumab. 16. Male subject must: a. Practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of lenalidomide, or for at least 90 days after the last dose of durvalumab, even if he has undergone a successful vasectomy, whichever is longer. b. Agree to not donate semen or sperm during the IP therapy and for 28 days after the last dose of lenalidomide or 90 days after the last dose of durvalumab, whichever is longer. 17. All subjects must: a. Have an understanding that lenalidomide could have a potential teratogenic risk. b. Agree to abstain from donating blood while taking lenalidomide therapy and for 28 days after the last dose of lenalidomide therapy or 90 days after the last dose of durvalumab, whichever is longer. c. Agree not to share lenalidomide with another person. d. Agree to be counseled about pregnancy precautions and risk of fetal exposure. Inclusion numbers 18-19 APPLY to ARM B only: 18. Female subject of childbearing potential must: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy (ie, durvalumab and ibrutinib). They must agree to ongoing pregnancy testing during the course of the study, and after last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact. b. Either commit to complete abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective (1 highly effective and 1 additional effective method) contraception without interruption, 28 days prior to starting IP therapy, during the IP therapy (including dose interruptions) and for 90 days after the last dose of IP. c. Agree to abstain from breastfeeding during study participation and for at least 90 days after last dose of IP therapy. d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last dose of durvalumab. 19. Male subject must: a. Practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and for at least 90 days following the last dose of IP, even if he has undergone a successful vasectomy, whichever is longer. b. Agree to not donate semen or sperm during the IP therapy and for 28 days after the last dose of ibrutinib or 90 days after the last dose of durvalumab, whichever is longer. Inclusion numbers 20-21 APPLY to ARM C only: 20. Female subject of childbearing potential must: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy (ie, durvalumab, bendamustine and rituximab). They must agree to ongoing pregnancy testing during the course of the study, and after last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact. b. Either commit to complete abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective (1 highly effective and 1 additional effective method) contraception without interruption, 28 days prior to starting IP therapy, during the IP therapy (including dose interruptions) and for 12 months after the last dose of rituximab or for 90 days after the last dose of the other IP (ie, bendamustine and/or durvalumab) dose, whichever is longer. c. Agree to abstain from breastfeeding during study participation and for at least 12 months after the last dose of rituximab. d. Refrain from egg cell donation while taking durvalumab and for 90 days after the last dose of durvalumab. 21. Male subject must: a. Practice complete abstinence or agree to use a condom during sexual contact with a pregnant female subject or an FCBP while participating in the study, during dose interruptions and for at least 90 days after the last dose of durvalumab or 6 months after the last dose of bendamustine, even if he has undergone a successful vasectomy, whichever is longer. b. Agree to not donate semen or sperm during the IP therapy and for at least 90 days after the last dose of durvalumab or 6 months after the last dose of bendamustine, whichever is longer.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment: APPLY to ALL TREATMENT ARMS 1. Subject has known or suspected central nervous system (CNS) or meningeal involvement by lymphoma. 2. Subject has other lymphoma histologies which are not listed on Table 3, Table 4, or Table 5 (eg, human immunodeficiency virus [HIV]-associated lymphomas, CNS lymphoma, Waldenstrom’s macroglobulinemia). a. Subject has blastoid variants of MCL or MCL with blastoid transformation. b. Dose Confirmation and Expansion Parts only: Subject has transformed lymphoma or Richter’s transformation. 3. Subject who has any histopathologic finding consistent with myelodysplastic syndrome on bone marrow studies. 4. Subject who has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 5. Subject who has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 6. Subject who has any condition that confounds the ability to interpret data from the study. 7. Subject who has any uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from durvalumab and/or other investigational treatment regimens, or compromise the ability of the subject to give written informed consent. 8. Subject who is concurrent enrolled in another clinical study, unless in a follow-up period or it is an observational study. 9. Subject who has any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. NOTE: Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. 10. Subject who has received any systemic antilymphoma/leukemia therapy, or hematopoietic growth factors, blood or platelets transfusions within 14 days prior to the first dose of IP (ie, Cycle 1 Day 1). Exception: The use of hematopoietic growth factors or blood product transfusional support for subjects with extensive marrow involvement by lymphoma or CLL may be allowed after consultation with the sponsor’s medical monitor (see Table 6). 11. Subject who has unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values listed per the exclusion criteria. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab or other investigational treatments may be included (eg, hearing loss) after consultation with the sponsor’s medical monitor. 12. Subject who received any prior mAb against PD-1 or PD-L1 and/or any prior: a. Arm A only: IMiDs (eg, lenalidomide, thalidomide); b. Arm B only: ibrutinib or other BTK inhibitor; c. Arms C only: bendamustine. 13. Subject who has history of organ transplant or allogeneic hematopoietic stem cell transplantation. 14. Subject who has taken corticosteroids during the last 1 week prior to Cycle 1 Day 1, unless administered at a dose equivalent to ≤ 10 mg/day prednisone. 15. Subject who has received live, attenuated vaccine within 30 days prior to the first dose of durvalumab (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 30 days after the last dose of durvalumab). 16. Subject who has undergone major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP (ie, Cycle 1 Day 1) or still recovering from prior surgery. 17. Subject who has active documented autoimmune disease (including, but not limited to, inflammatory bowel disease, celiac disease, Wegener syndrome, hemolytic anemia, or immune thrombocytopenic purpura) prior to first dose of durvalumab. 18. Subject who has history of primary immunodeficiency or tuberculosis. 19. Subject who has known seropositivity for or active infection for human immunodeficiency virus (HIV) or hepatitis C virus (HCV). 20. Subject who is seropositive for or active viral infection with hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg] positive and/or detectable viral DNA) Exceptions: a. Antibody to the hepatitis B surface antigen (anti-HBs) positive only with prior HBV vaccination history. b. Anti-HBs positive (no prior HBV vaccination) and/or antibody to the hepatitis B core antigen (anti-HBc) positive but viral DNA negative. 21. Female subject who is pregnant, breastfeeding, or intend to become pregnant during the participation in the study. 22. Subject who has other invasive malignancy within 2 years prior to signing the ICF except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast, or incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) that has/have been surgically cured. a. Arm A only: Subject who has history of other malignancies, unless the subject has been free of the disease for ≥ 5 years prior to signing the ICF. Exceptions: History of previously treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and related localized non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of breast, incidental histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system). 23. Subject who has known allergy or hypersensitivity to the active substance or any of the excipients, or to other humanized mAbs. Exclusion numbers 24-26 APPLY to ARM A only: 24. Subjects with CLL or SLL. 25. Subject who has peripheral neuropathy Grade 3 or 4. 26. Subject who is at risk for a thromboembolic event and is not willing to take prophylactic treatment. Exclusion numbers 27-28 APPLY ARMS A and C only: 27. Subject who does not have CD20 positive lymphoma or CLL. 28. Subject who has hypersensitivity to rituximab. Exclusion numbers 29-32 APPLY to ARM B only: 29. Subject who has transfusion-dependent thrombocytopenia or a history of bleeding disorders or clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) that may increase the risk of life-threatening bleeding when thrombocytopenic. 30. Subject who has history of stroke or intracranial hemorrhage within 6 months prior to signing the ICF. 31. Subject who receives the medications that are strong inhibitors or inducers of CYP3A (eg, itraconazole, ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and rifampin) and cannot change. 32. Subject who has received concomitant anticoagulation with warfarin, other vitamin K antagonists, or direct thrombin inhibitors (eg, dabigatran) within 7 days prior to signing the ICF and cannot change. The use of other anticoagulants (eg, heparins) and antiplatelet agents is allowed per investigator’s discretion. Investigator questions regarding this should be addressed to the sponsor’s medical monitor or the study country principal investigators. Exclusion number 33 APPLIES to ARM C only: 33. Subject who should concurrently use allopurinol, eg, because of gout, and unwilling to switch to another equivalent medication. (Subjects with gout are advised to switch to another antigout medication, because of the risk of Stevens-Johnson syndrome observed in subjects using bendamustine and allopurinol).

Sub Specialty:

Lymphoma

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A Phase III, International, Randomized, Controlled Study of Rigosertib versus Physician’s Choice of Treatment in Patients with Myelodysplastic Syndrome after Failure of a Hypomethylating Agent

Research Summary

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Inclusion Criteria:

Male and female patients with excess blasts of 5% to 30% who meet all of the following criteria are eligible for enrollment in the trial: a. 18-79 years of age b. MDS classified as follows, according to WHO criteria or modified FAB classification: • RAEB-1 (5% to 9% BM blasts) • RAEB-2 (10% to 19% BM blasts) • RAEB-t (20% to 30% BM blasts) c. Diagnosis of MDS confirmed within 8 weeks prior to the Screening Visit d. At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin [Hgb] < 10 g/dL) e. Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DEC treatment or Failure to achieve complete or partial response or HI (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DEC or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria) or Intolerance to AZA or DEC f. Duration of prior HMA therapy = 9 months g. Last dose of AZA or DEC within 6 months before the planned date of randomization; however, must be off these treatments for = 4 weeks before randomization h. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogenic stem cell transplantation i. Off all other treatments for MDS (including AZA and DEC) for = 4 weeks before randomization, with the exception that growth factors (G-CSF, erythropoietin, and thrombopoietin) are allowed before and during the study as clinically indicated j. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 k. Willing to adhere to the prohibitions and restrictions specified in this protocol l. Patient (or patient’s legally authorized representative) must signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria:

Patients with any of the following will not be enrolled in the study: a. Previous participation in a clinical study of IV or oral rigosertib; however, patients who failed screening for other rigosertib studies may be screened for participation in this study b. Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside and 2-3 days of an anthracycline, or high-dose cytarabine (HDAC) c. Eligible to receive allogeneic stem cell transplantation d. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast e. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris f. Active infection not adequately responding to appropriate therapy g. Total bilirubin = 1.5 mg/dL not related to hemolysis or Gilbert’s disease h. Alanine transaminase (ALT)/aspartate transaminase (AST) = 2.5 x upper limit of normal (ULN) i. Serum creatinine = 2.0 mg/dLj. Known HIV, hepatitis B or hepatitis C k. Uncorrected hyponatremia (defined as serum sodium level of < 130 mEq/L) l. Female patients of child-bearing potential who are breast-feeding or have a positive blood beta-human chorionic gonadotropin (ßHCG) pregnancy test at Screening m. Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements (including condom use for males with sexual partners, and for females, prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device, double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study, up to and including the 30-day non-treatment follow-up period n. Major surgery without full recovery or major surgery within 3 weeks prior to planned randomization o. Uncontrolled hypertension p. New onset seizures (within 3 months prior to planned randomization) or poorly controlled seizures q. Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions) r. Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted for the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization s. Investigational therapy within 4 weeks of planned randomization t. Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or comply with study requirements.

Sub Specialty:

Haematological Oncology

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An Open-Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B cell Lymphomas

Research Summary

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Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (except as acceptable for Inclusion Criterion #17, which is applicable only to Phase 2 Stage 2b subjects). 2. Life expectancy >/= 3 months after starting E7438. 3. Subjects with Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #6. 4. Adequate renal function defined as serum creatinine < 1.5 × ULN (or use SI units or calculated creatinine clearance = 50 mL/min per the Cockcroft and Gault formula). 5. Adequate bone marrow function: a. Absolute neutrophil count (ANC) ³ 1500/mm3 (= 1.5 × 103/mL) b. Platelets ³ 100,000/mm3 (= 100 × 109/L) c. Hemoglobin ³ 9.0 g/dL (see Inclusion Criterion #16) 6. Adequate liver function: a. Bilirubin £ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome b. Alkaline phosphatase (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) < /= 3 × ULN (< /= 5 × ULN if subject has liver metastases) 7. Left ventricular ejection fraction (LVEF) > 50% on echocardiography or multiple gate acquisition (MUGA) scan. 8. Males or females aged ³ 18 years at the time of informed consent. 9. Females must not be lactating or pregnant at screening or baseline (as documented by a negative betahuman chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ßhCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception, from the last menstrual period prior to randomization, during Treatment Cycles, and for 30 days after the final dose of study treatment, and have a male partner who uses a condom. Highly effective contraception includes: a. Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. b. Placement of an intrauterine device. c. Established hormonal contraceptive methods: oral, injectable, or implant. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. Female subjects exempt from this requirement are subjects who practice total abstinence or have a male partner who is vasectomized with confirmed azoospermia. If currently abstinent, the subject must agree to use a double barrier method as described above if they become sexually active during the Treatment Cycles, and for 30 days after study drug discontinuation 10.Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partner must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception and use a condom throughout the study period and for 30 days after study drug discontinuation). 11. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. Phase 1 only: 12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B cell lymphomas that has progressed after treatment with approved therapies or for which there are no standard therapies available. Phase 2 (EZH2-mutation positive) B cell lymphomas only: 13. Subjects must satisfy all of the following criteria: a. Have histologically confirmed DLBCL or Grade 3 follicular lymphomas with relapsed or refractory disease following: 1) HDT and ASCT or 2) at least one combination chemotherapy containing rituximab and an anthracycline (unless anthracycline-based therapy contraindicated), and are ineligible or unwilling to undergo HDT and ASCT b. Must harbor a Y641 mutation in EZH2. (At the time of protocol amendment, before initiation of Phase 2, the specific methodology for detection of EZH2 mutation will be included in the amended protocol) c. Have measurable disease as defined by International Working Group-Non-Hodgkin’s Lymphoma (IWGNHL [Cheson, 2007]) Phase 2 Stage 2b Optional E7438 Crossover Treatment: 14. Subjects with relapsed and/or refractory B cell malignancies with disease progression following Phase 2 Stage 2, after having been randomized to standard of care therapy: a. Must not be on a maintenance dose of more than 20 mg of prednisone daily; however, prednisone must be discontinued at least 1 week before study start (see Exclusion Criterion #6). Requires a stable complete blood count (CBC) as defined by hemoglobin = 9.0 g/dL, independent of peripheral red blood cell (RBC) transfusions, and an ANC = 1.2 × 103/μL growth factor support independent of white blood count (WBC) colony stimulating growth factor (CSF) b. Must harbor a Y641 mutation in EZH2 15. Must not have received a transfusion of either packed red blood cells, platelets, or granolocyte-stimulating growth factor within 2 weeks before starting the optional E7438 crossover treatment. 16. ECOG performance status of 0 to 2.

Exclusion Criteria:

1. Prior exposure to E7438 or other inhibitor(s) of EZH2 HMT. 2. Subjects with leptomeningeal metastases or brain metastases or history of previously treated brain metastases. 3. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors or substrates with narrow therapeutic indices or St. John’s Wort. 4. Subjects unwilling to exclude grapefruit juice and grapefruit from their diet. 5. Subjects taking medications that are CYP2C8, CYP2C9, and CYP2C19 substrates. 6. Subjects who have received any anticancer treatment within 3 weeks or any investigational agent within 30 days before the first dose of study drug or who have not recovered from any acute toxicity greater than Grade 0 or 1 related to previous anticancer treatment. However, subjects may receive prednisone (at doses up to 20 mg daily) until 1 week before start of study drug. 7. Major surgery within 4 weeks before the first dose of study drug. 8. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of E7438. 9. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation). 10. Prolongation of corrected QT (QTc) interval to > 480 msec when electrolytes balance is normal. 11. Active infection requiring systemic therapy. 12. Known hypersensitivity to any component of E7438. 13. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks before study drug administration. 14. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV). 15. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency. 16. Any other major illness that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study. 17. Females who are pregnant or breastfeeding. Phase 2 only: 18. Subjects with active noncutaneous malignancies other than B cell lymphomas.

Sub Specialty:

Lymphoma

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A phase I/II study of 177Lu-HH1 (Betalutin™) radioimmunotherapy for treatment of relapsed CD37+ non-Hodgkin lymphoma

Research Summary

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Inclusion Criteria:

1. Histologically confirmed (by WHO classification) relapsed incurable non-Hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA, marginal zone, small lymphocytic, lymphoplasmacytic, mantle cell. 2. Age = 18 years. 3. A pre-study WHO performance status of 0-1. 4. Life expectancy should be = 3 months. 5. < 25% tumour cells in bone marrow biopsy. 6. CD37+, re-biopsy or test on existing tumour material if not known. 7. Measurable disease by radiological methods. 8. Women of childbearing potential must: a) understand that the study medication is expected to have teratogenic risk. b) have a negative pregnancy test. b) agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 5 months after end of study drug therapy, even if she has amenorrhoea. 9. Male subjects must agree to use condoms during intercourse throughout study drug therapy and the following 5 months. 10. Patients previously treated with native rituximab are eligible. 11. The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examination. 12. The patient has been fully informed about the study and has signed the informed consent form. Concomitant Medication: ? Patients who have received murine–derived proteins before study drug must be tested for human anti-murine antibodies (HAMA). ? The hematology parameters must be evaluated if other cytotoxic drugs will be given after Betalutin administration.

Exclusion Criteria:

1. Medical contraindications, including uncontrolled infection, severe cardiac, pulmonary, neurologic, psychiatric or metabolic disease, steroid requiring asthma/allergy, known HIV positive. 2. Laboratory values within 15 days pre-registration: a. Absolute Neutrophil Counts (ANC) = 1.5 x 10 9 /l. b. Platelet count = 150 x 10 9 /l. c. Total bilirubin = 30 mmol/l. d. ALP and ALAT = 4x normal level. e. Creatinine = 110 μmol/l (men), 90 μmol/l (women). f. IgG = 3 gr/l. 3. Known CNS involvement of lymphoma. 4. Previous total body irradiation, or irradiation of > 25% of the patient’s bone marrow. 5. Known history of HAMA. 6. Chemotherapy or immunotherapy received within the last 4 weeks prior to start of study treatment. Pre-treatment with rituximab is allowed. 7. Pregnant or lactating women.

Sub Specialty:

Lymphoma

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A randomised, double-blind, parallel group, placebo-controlled, multi-centre, Phase III study to assess the efficacy and safety of olaparib versus placebo as adjuvant treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy

Research Summary

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Inclusion Criteria:

1. *Provision of informed consent prior to any study specific procedures 2. *Female or male patients must be = 18 years of age 3. Histologically confirmed non-metastatic primary triple negative invasive adenocarcinoma of the breast that is at surgery: either axillary node-positive (any tumour size) or axillary node-negative with primary tumour > 2cm for patients who received adjuvant chemotherapy or showing evidence of non pCR for patients who received neoadjuvant chemotherapy 4. Invasive TNBC defined as: - ER and PR negative (not eligible for endocrine therapy) defined as IHC nuclear staining < 1% AND - HER2 negative (not eligible for anti-HER2 therapy) defined as: o IHC 0, 1+ without ISH OR o IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR o ISH non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC) 5. Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) 6. Completed adequate breast and axilla surgery defined as: - The inked margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ with the exception of the posterior margin if this margin is the pectoralis major fascia or the anterior margin if this is the dermis. Patients with resection margins positive for lobular carcinoma in situ are eligible. - Patients with breast conservation must have adjuvant radiotherapy. Patients having mastectomy should have adjuvant radiotherapy according to international guidelines (St Gallen/ASCO/ESTRO). Adjuvant Group: - Sentinel lymph node biopsy alone if negative or if lymph node(s) only contain micrometastases (= 2.0 mm) OR positive sentinel lymph node biopsy followed by axillary node clearance or axillary nodal radiotherapy Neoadjuvant group: - If sentinel lymph node biopsy before neoadjuvant chemotherapy: sentinel lymph node biopsy alone if negative or if lymph node(s) only contain micrometastases (= 2.0 mm) OR positive sentinel lymph node biopsy followed by axillary node clearance or axillary nodal radiotherapy following completion of neoadjuvant chemotherapy - If sentinel lymph node biopsy after neoadjuvant chemotherapy: Sentinel lymph node biopsy alone if negative OR positive sentinel lymph node biopsy followed by axillary node clearance. 7. Completed at least 6 cycles neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or the combination of both. Prior platinum as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer is allowed 8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomisation as defined below: - Haemoglobin = 10.0 g/dL with no blood transfusions in the past 28 days - Absolute neutrophil count (ANC) = 1.5 x 109/L - Platelet count = 100 x 109/L - Total Bilirubin = ULN (institutional upper limit of normal) except elevated total bilirubin < 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin - AST (SGOT)/ALT (SGPT) = 2.5 x ULN - ALP = 2.5 x ULN Patients with screening ALT/AST or ALP above institutional upper limit of normal should have liver ultrasound or CT/ MRI prior to randomisation. Screening bone scan is required if ALP and/or corrected calcium level are above the institutional upper limit. (Note PET CT scan may be used as an alternative imaging techniques). 9. Serum creatinine = 1.5 x ULN 10. ECOG performance status 0-1 11. *Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days prior to randomisation Postmenopausal is defined as: - Age = 60 years - Age < 60 years and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment - Luteinising hormone (LH), follicle stimulating hormone (FSH) and plasma oestradiol levels in the postmenopausal range for women under 60 years - Radiation-induced oophorectomy with last menses > 1 year ago - Or surgical sterilisation (bilateral oophorectomy or hysterectomy) 12. *Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations 13. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumor, mandatory*. *If tumour sample is not available, approval by Study Team for patient’s entry into the trial is required

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study. 2. BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., “Variants of uncertain clinical significance” or “Variant of unknown significance” or “Variant, favour polymorphism” or “benign polymorphism” etc.). 3. *Previous randomisation in the present study. 4. *Evidence of metastatic breast cancer. Patient considered at high risk of having disseminated disease (i.e those with clinical N2-3 or pathological N1-3 or locally advanced disease) must have a CT/MRI scan of the Thorax/Abdomen/Pelvis or any other area as clinically indicated and a bone scan at any point prior to randomisation. (Note PET CT scan may be used as an alternative imaging techniques and precludes the need for bone scan) 5. *Exposure to an investigational product within 30 days or five half lives (whichever is the longer) prior to randomisation. 6. *Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersensitivity to any of the excipients of study treatment. 7. *Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for = 5 years prior to randomization. More than one course of chemotherapy for previous malignancies (e.g: breast cancer or ovarian cancer > 5 years ago treated with adjuvant chemotherapy) 8. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24-hour period or family history of long QT syndrome. If ECG demonstrates QTc > 470 msec, patient will be eligible only if repeat ECG demonstrates QTc = 470 msec. 9. Patients receiving systemic chemotherapy within 3 weeks prior to start of study treatment. 10. Patients receiving adjuvant radiotherapy within 2 weeks prior to start of study treatment 11. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. For further detail refer to Appendix I. 12. Persistent toxicities (=CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy. 13. *Patients with myelodysplastic syndrome/ treatment related acute myeloid leukaemia (t-AML). 14. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery. 15. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, extensive bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that prohibits obtaining informed consent. 16. *Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 17. Pregnant or breastfeeding women. 18. * Patients with known active Hepatitis B or C or HIV 19. *Previous allogeneic bone marrow transplant. 20. *Whole blood transfusions in the last 120 days prior to entry to the study which may interfere with gBRCA testing (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.8).

Sub Specialty:

Breast Cancer Genetics

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PHASE I-II STUDY OF VINBLASTINE IN COMBINATION WITH NILOTINIB IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH REFRACTORY OR RECURRENT LOW-GRADE GLIOMA

Research Summary

Low grade gliomas (LGG) are the most frequent brain tumour in children. More than 50% of these tumours will progress within the first 5 years and need further treatment. As most patients are young, the risks of radiotherapy to the developing brain are high, further medical treatment options are urgently needed. Vinblastine is an effective chemotherapy drug for LGG and has been shown to improve survival. Nilotinib is type of biological therapy called a tyrosine kinase inhibitor. Vinblastine and Nilotinib have different antiangiogenic mechanisms, limited and non-overlapping toxicities, and are thought to play an interesting role in the treatment of paediatric LGG. The phase I part of the trial has already been completed and identified the recommended doses (RD) of each agent when given in combination. The main objective of the phase II part is to evaluate the efficacy of vinblastine in combination with nilotinib at the RD, as compared to vinblastine alone, in children, adolescents, and young adults with refractory or recurrent LGG. This is an open label, randomised, study of the combination of nilotinib and vinblastine versus vinblastine alone 122 patients with LGG will be randomised to receive either: • Vinblastine and nilotinib OR • Vinblastine only Vinblastine will be given as an intravenous injection on days 1, 8, 15 and 22 of each 28 day cycle. Nilotinib will be taken as a capsule orally twice a day on each day of the cycle. Patients will receive up to 12 cycles of treatment in the trial as long as they are benefitting from it and are well. This trial is being funded in the UK by Cancer Research UK (including funding from the Brain Tumour Charity). Nilotinib is being provided free of charge by Novartis. This trial will open at 6 sites in the UK plus others within Europe. The Sponsor of this international study is Gustave Roussy, France.

Inclusion Criteria:

• Written informed consent signed by the patient, or parents or legal representative and assent of the minor child where appropriate. • Age: 6 months to < 21 years of age at time of study entry • Diagnosis: one of the three conditions listed below - Refractory or recurrent low-grade glioma after at least one first-line therapy with pathological documentation in non NF1 patients (no further biopsy is needed at study entry) - Refractory or recurrent low-grade glioma after at least one first-line therapy in NF1 patients, with or without pathological documentation. For patients with NF1 and optic pathway glioma, no biopsy is required to confirm the radiological diagnosis of the low grade glioma. - Low grade glioma at diagnosis in NF1 patients when the use of chemotherapy is considered for the treatment in case of threat to vision or unequivocal radiological tumor progression. Pathological documentation is advised but not mandatory. • Evaluable Disease on morphologic MRI • Karnofsky performance status score > = 70% for patients > 12 years of age, or Lansky score > = 70% for patients < = 12 years of age, including patients with motor paresis due to disease. • Life expectancy > = 3 months. • Administration of stable dose of steroids for at least one week • Adequate organ function: - Adequate hematopoietic function: neutrophils 1.0 x 109/L, platelets 100 x 109/L; hemoglobin 8 g/dL - Adequate renal function: serum creatinine < 1.5 x ULN for age - In other cases where serum creatinine > 1.5 ULN according to age, Glomerular filtration rate or creatinine clearance has to be > 70ml/min/1.73m2 or > 70% of the expected value. - Adequate electrolytes levels: potassium, magnesium, phosphor phosphate, total calcium > = Lower Limit of Normal (LLN) - Adequate hepatic function: total bilirubin < = 1.5 x ULN; AST and ALT < = 2.5 x ULN. - Absence of peripheral neuropathy > = grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0) • Adequate cardiac function: - Shortening Fraction (SF) > = 28% (35% for children < 3 years) and Left Ventricular Ejection Fraction (LVEF) > = 50% at baseline, as determined by echocardiography - Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the QTcF formula) or other clinically significant ventricular or atrial arrhythmia • Wash-out period of at least - 3 weeks in case of preliminary chemotherapy, - 6 weeks in case of nitrosourea-containing chemotherapy, - 2 weeks in the case of treatment with vincristine only - 6 weeks in case of radiation therapy • Possibility of receiving the therapeutic schedule as indicated in the protocol • Patients with reproductive potential must use effective/acceptable birth method control (as defined per CTFG guidelines) during their treatment and for up to 90 days after the last dose. Females with reproductive potential must have a negative pregnancy test < = 7 days before randomization. • Patients already treated with one of the two drugs can be enrolled in the trial provided that rechallenging them with the same drug could be considered acceptable

Exclusion Criteria:

• Concomitant anti-tumor treatment • Not recovered to < Grade 2 from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy • Known intolerance or hypersensitivity to Vinblastine • Existence of another severe systemic disease • Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines, • Any concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib. • Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors (e.g. antiepileptic drugs, see complete list in the Appendix 5). • Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (Appendix 6) • Impaired cardiac function including any one of the following: - Clinically significant resting brachycardia (< 50 beats per minute). - QTc > 450 msec on baseline ECG. If QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. - Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension). - History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT syndrome or a known family history of congenital long QT syndrome) • Positive test for Hepatitis B virus surface antigen

Sub Specialty:

Brain Cancer

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A Phase 3b, Multicenter, Open-label, PCI-32765 (Ibrutinib) Long-term Extension Study

Research Summary

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Inclusion Criteria:

1. Subjects must be currently participating in a PCI-32765 clinical study considered complete and have received at least 6 months of treatment with PCI-32765. At study entry, subjects must be actively receiving treatment with single-agent PCI-32765. 2. Investigator’s assessment that the benefit of continued PCI-32765 therapy will outweigh the risks. 3. Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (1 month after the last dose of PCI-32765 for women and 3 months after the last dose of PCI-32765 for men), consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies. Men must agree to not donate sperm during and for 3 months after receiving the last dose of PCI-32765. 4. Women of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at Screening. 5. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

1. Subjects who require anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). 2. Subjects who require treatment with strong cytochrome P450 (CYP)3A4/5 inhibitors, unless previously approved by sponsor. 3. Any condition or situation which, in the opinion of the investigator, may put the subject at significant risk, may confound the study results, or may interfere significantly with subject’s participation in the study.

Sub Specialty:

Lymphoma

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A randomized trial for adults with newly diagnosed acute lymphoblastic leukaemia

Research Summary

Aim 1B. (precursor-B lineage) To determine if the addition of monoclonal antibody (or antibodies – arms B1 to B2) to standard induction chemotherapy results in improved EFS in patients with precursor B-cell lineage ALL. Aim 1T (T lineage) To determine if the addition of nelarabine following standard induction therapy (arms T 1 and T2) improves outcome for patients with T cell ALL. Aim 2 To determine the tolerability of pegylated asparaginase in induction (for all patients) and to compare anti-asparaginase antibody levels between patients in the 2 randomisation groups from aim 1B. Aim 3 To determine whether risk-adapted introduction of unrelated donor HSCT (myeloablative conditioning in patients aged up to and including 40 years at time of study entry and non-myeloablative conditioning in patients aged greater than 40 years, ie having reached their 41st birthday at time of study entry) result in greater EFS for patients at highest risk of relapse. Aim 4 To compare 2 schedules of administration (standard P1 vs., ‘collapsed’ P2) of keratinocyte growth factor (palifermin) for efficacy in preventing the severe mucosal toxicity of etoposide/TBI HSCT conditioning regimen.

Inclusion Criteria:

a)Subjects must be aged ≥ 25 and ≤ 65 years old with acute lymphoblastic leukaemia OR ≥ 19 and ≤ 65 years old with Philadelphia Chromosome. b)Newly diagnosed, previously untreated ALL (a steroid pre-phase of 5-7 days is acceptable and can be started prior to registration) c)Written informed consent

Exclusion Criteria:

a) Known HIV infection b) Hepatitis B infection (defined as positive HBsAg and/or HBcAb). Antibodies to Hep B surface antigen only is acceptable c) Hepatitis C infection (antibodies against hepatitis C or a PCR evaluation which is positive for hepatitis C DNA) d) Pregnant or lactating women e) Blast transformation of CML f) Mature B-cell leukemia i.e. Burkitt’s disease t(8,14)(q24 ;q32) and all disorders amplification of c-myc e.g. t(2;8)(p12’q24), t(8;22)(q24;q11)

Sub Specialty:

Haematological Oncology

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Exploring the ecology of upper gastrointestinal solid tumours from the genome to the microenvironment.

Research Summary

Upper gastrointestinal tumours have some of the worst survival rates of all cancer subtypes. 85% of Gastric cancer patients will not survive for 10 years and the figure is 88 % for oesophageal cancer. Cancer research UK has identified oesophageal cancer as an unmet need and a priority for research. More recently oesophageal and stomach cancer were both included in the less survivable cancers taskforce (a collaboration between 5 charities to improve outcomes in 6 cancers that are responsible for more than 50% of cancer deaths and receive only a fifth of the funding of more survivable cancers). Our work is also supported by the leading UK charity, Heartburn Cancer UK and our Chief Investigator is a trustee of the charity. The aim of this study is to increase understanding of the biology of upper gastrointestinal tumours with the eventual hope of identifying targets for new therapies. Our focus will be on the interplay between cancer cells and the normal cells that surround them in the tumour micro-environment. The study will be run from the Southampton Cancer Research UK centre and we will recruit patients undergoing treatment for upper gastrointestinal tumours at the Southampton and Portsmouth regional referral centres. Tissue will be used to identify and create a database of all of the normal and cancerous cell types present in upper GI tumours. We will examine the interplay between them with particular emphasis on immune cells and inflammatory cells. We will identify signalling pathways and interactions that can be manipulated with new therapies with the aim of improving survival across upper gastrointestinal cancer.

Inclusion Criteria:

INCLUSION CRITERIA All patients over 18 years old with solid tumours arising from the GI tract between the pharynx and the Ampulla of Vater undergoing surgical resection. All patients over 18 years old attending for Endoscopy (OGD/EUS) for clinical, diagnostic or therapeutic reasons.

Exclusion Criteria:

EXCLUSION CRITERIA Patients younger than 18 years old. Patients unable to give informed consent

Sub Specialty:

Upper GI

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UK P3BEP - A randomised phase 3 trial of accelerated versus standard BEP chemotherapy for patients with intermediate and poor-risk metastatic germ cell tumours

Research Summary

Germ cell tumours (GCTs) account for 98% of all testicular cancers. Germ cell tumours also arise in the ovary, accounting for 1% to 2% of ovarian neoplasms. Germ cell tumours also rarely arise in the mediastinum, retroperitoneum, ovary and brain. Post-pubertal germ cell tumours represent 14% of all cancers in older adolescents. Outcomes are excellent for most patients, however over a third of patients with metastatic disease will relapse and die despite being on best available therapy. There is a need to improve 1st line therapy results for patients classified as intermediate & poor risk. Treatment currently involves the use of a chemotherapy regimen comprising of bleomycin, etoposide, & cisplatin (BEP); coupled with surgical resection of residual metastatic disease post chemotherapy. Early trials have demonstrated the safety, feasibility & tolerability of accelerated BEP for metastatic GCTs. These trials also indicated that the chemotherapy related toxicities were no worse than those expected from standard BEP regimen. This is an open-label, randomised, stratified 2-arm multicentre phase 3 clinical trial in patients with intermediate or poor risk categorised GCTs undertaken in two stages. The patients will be given either 4 x 21-day cycles of BEP or 4 x 14-day cycles of BEP, followed by 4 doses of weekly bleomycin monotherapy. The aim of the study is to determine if accelerated BEP is superior to standard BEP as a 1st line therapy for these patient groups by comparing progression-free survival in the two arms. The research team will also compare the two arms for protocol specific response, adverse events, quality of life and treatment preference, delivered dose-intensity of chemotherapy & overall survival.

Inclusion Criteria:

Patients will be eligible for inclusion into this study if they meet all of the following criteria. 1. Able and willing to provide signed, written informed consent/assent 2. Male or female 3. Aged between 11 and 45 years inclusive on the date of consent 4. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or exceptionally raised tumour markers (AFP > = 1000ng/mL and/or HCG > = 5000IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases is consistent with GCT, high tumour burden, and a need to start therapy urgently 5. Primary arising in the testis, ovary, retro-peritoneum or mediastinum 6. Metastatic disease or non-testicular primary 7. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma and inclusion of ovarian primaries). 8. Adequate bone marrow function with ANC > = 1.0 x 109/L 9. Adequate liver function where bilirubin must be < = 1.5 x ULN, - except if the elevations are due to hepatic metastases, in which case ALT and AST must be < = 5 x ULN - except participants with Gilbert’s Syndrome where bilirubin must be < = 2.0 x ULN; ALT and AST must be < = 2.5 x ULN 10. Adequate renal function with estimated creatinine clearance of > = 60 ml/min according to the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline, in the opinion of the investigator, in which case GFR should be formally measured, e.g. with EDTA scan 11. ECOG Performance Status of 0, 1, 2 or 3 12. Study treatment both planned and able to start within 14 days of randomisation 13. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments.

Exclusion Criteria:

Patients will be excluded from this study if they meet any of the following exclusion criteria; 1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumour, or other malignancy treated at least 5 years previously with no evidence of recurrence) 2. Previous chemotherapy or radiotherapy, except: - Pure seminoma relapsing after adjuvant radiotherapy of adjuvant chemotherapy with 1-2 doses of single agent carboplatin - Non-seminoma and poor prognosis by IGCCC criteria in the rare case where low-dose induction chemotherapy is given prior to registration because patient is not fit enough to receive protocol chemotherapy (e.g. organ failure, vena cava obstruction, overwhelming burden of disease). Acceptable regimens include cisplatin 20 mg/m2 days 1-2 and etoposide 100 mg/m2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m2 days 1-2; or baby-BOP.37 Patients must meet all other inclusion and exclusion criteria at the time of registration - Participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation. Such patients must be discussed with the coordinating centre prior to registration, and must be registered within 10 days of commencing study chemotherapy 3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin 4. Significant co-morbid respiratory disease that contraindicates the use of bleomycin 5. Peripheral neuropathy > = grade 2 or clinically significant sensorineural hearing loss or tinnitus 6. Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety 7. Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and 12 months post treatment. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration 8. Known allergy or hypersensitivity to any of the study drugs 9. Presence of any psychological, familial, sociological or geographical condition that in the opinion of the investigator would hamper compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse

Sub Specialty:

Gynaecological Cancers Teenage and Young Adult's Cancer Testicular Cancer

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Establishment of a UK Peripheral T-cell Lymphoma (PTCL) Biobank and Database: An Observational Study

Research Summary

Patients with PTCL have a poor outlook. Current first line treatments are inadequate and are associated with high rates of early relapse. Despite the recent introduction of novel agents for patients with relapsed disease prognosis is again very poor. There are currently no targeted treatments although monoclonal antibodies directed against Tfh surface markers including PD1 are available (Ansell et al, 2014) and have been trialled in other conditions. Similarly therapeutic anti-ICOS antibodies (MedImmune, MEDI-570) have been trialled in autoimmune conditions and a phase 1/2 trial for PTCL is about to start recruitment in Canada (Clinical Trials Identifier: NCT02520791). Over the next few years, therefore, treatment for PTCL is anticipated to change radically. A PTCL Biobank will be a valuable resource to expedite the development of diagnostic tests, based on the new genetics of these diseases and biobank samples will also be used to investigate biomarkers for response to specific therapies and the prediction of relapse.

Inclusion Criteria:

Newly diagnosed and relapsed/refractory PTCL patients including: Angioimmunoblastic T-cell lymphoma ALK+ anaplastic large-cell lymphoma ALK- anaplastic large-cell lymphoma PTCL-NOS Male or Females, aged 18 years or above. Participants willing and able to give informed consent for participation in the study. Able (in the Investigators opinion) and willing to comply with all study requirements.

Exclusion Criteria:

Male or Female patients < 18 years. Patients with NK disease, EATL and cutaneous T-cell lymphoma Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study.

Sub Specialty:

Lymphoma

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TrueNTH Global Registry- Prostate Cancer Outcomes

Research Summary

Prostate cancer is a global problem of great impact in both human and financial terms. Men diagnosed with prostate cancer are subject to large variations in quality and outcomes of care. This variation is in part due to differences in the quality and outcomes of medical care men receive for prostate cancer. Comparative effectiveness research, often using large population registries, is emerging as a potential solution to improve comparisons and optimize outcomes and quality of care. In recent years, longitudinal registries in prostate cancer and other conditions have allowed meaningful assessment of effectiveness, costs, and safety; which has, at least in some countries, led to changes in practice and more cost-efficient care. International collaboration in creating and maintaining disease registries has allowed bench marking of process measures and some high level outcomes on a large scale. At present the UK does not have a nationwide cancer registry that collates routinely collected clinical data for all men with localised prostate cancer. We hope that this study will help to establish a registry to allow comparisons of patient-relevant outcomes in order to identify novel approaches to improving quality and outcomes of care in men with localised prostate cancer. Prostate Cancer Outcomes Global Initiative to Compare and Reduce Variation (PCO-CRV) will recruit men with localised prostate cancer to capture their health outcomes through routinely collected clinical information and patient completed questionnaires. Participants will be recruited from approximately eight NHS secondary care Trusts. Questionnaires will be completed before treatment (baseline) and again at 12 months. Data from the UK NHS sites will be anonymised and transferred securely to Monash University where it will be combined with data from around the world and analysed to learn more about outcomes for prostate cancer patients.

Inclusion Criteria:

Patients will be eligible to be recruited to the PCO‐CRV if they meet the following criteria:  Diagnosed with localised or locally advanced prostate cancer disease (any T, any N and M0) after the date on which ethical approval to contribute data to the PCO‐CRV Registry has been provided;  Diagnosed or managed within a Participating Site or Local Data Centre recruiting patients which has appropriate ethical approval for the study.

Exclusion Criteria:

Patients will be excluded if they meet the following criteria:  Aged < 18 years at diagnosis  Diagnosed with advanced prostate cancer disease  The patient’s treating clinician advises that they not be included on the basis of poor mental and/or physical health  They are unable to receive information about the study in a language they understand  They decline participation.

Sub Specialty:

Prostate Cancer

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Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker to Stratify Management of Good and Poor Responders to Chemoradiotherapy: A Rectal Cancer Multicentre Randomised Control Trial

Research Summary

Approximately half of patients diagnosed with rectal cancer are offered chemotherapy and radiotherapy treatment (CRT) before surgery. There is great variability in how each tumour responds to CRT. Approximately 30% of tumours completely respond to and no cancer cells can be found in the cancer specimen. Other tumours do not respond at all or occasionally continue to grow during treatment. In many hospitals patients receive an MRI scan before and after CRT treatment. Emerging evidence suggests that by viewing the MRI scans in a smarter way by assessing ‘mrTRG’ (MRI Tumour Regression Grade) it is possible to assess how the tumour has responded to treatment. The TRIGGER Trial aims to evaluate mrTRG as a tool for stratifying patients according to their response to treatment. Patients will be randomised (1:2 ratio) to a control and intervention arm. Patients in the control arm will receive best current practice of surgery at 6-8 weeks after CRT and then a standard course of chemotherapy. Patients in the intervention arm will receive a treatment plan according to their response to CRT, assessed using the MRI tumour regression grade (mrTRG). Patients who have a good response to CRT will defer surgery until the cancer stops reducing in size or avoid surgery altogether if the cancer cannot be detected with repeat scans and assessments. Patients who have a poor response to CRT will have additional pre-operative chemotherapy. We will be able to see if this reduces the size of the tumour further, before a decision is made about proceeding to surgery, and if this lowers the risk of the tumour spreading. TRIGGER is a randomised, controlled, multicentre trial to evaluate mrTRG as an imaging biomarker for the stratified management of patients with rectal cancer. The feasibility trial will involve the recruitment of approximately 90 patients and if feasibility is demonstrated the trial will proceed to Phase III and involve ~ 630 patients.

Inclusion Criteria:

1) Have a biopsy-confirmed adenocarcinoma 0-15cm from the anal verge (on MRI or rigid sigmoidoscopy) 2) Have locally Advanced Rectal Carcinoma diagnosed by MRI (mrCRM unsafe or ≥mrT3c [> 5mm beyond muscularis propria] or mrEMVI positive disease) 3) Be deemed to require chemoradiotherapy 4) Scheduled to receive 45Gy - 55Gy long course radiotherapy 5) Be aged 18 years or over.

Exclusion Criteria:

1) Have metastatic disease (including resectable liver metastases) 2) Are contraindicated for MRI eg. non-mr compatable hip prosthesis, cardiac pacemaker 3) Are scheduled to receive less than 45Gy or more than 55Gy long course radiotherapy 4) Are contraindicated for chemoradiotherapy (CRT) or systemic chemotherapy 5) Are receiving or planned to receive treatment outside of that stipulated by the protocol,such as an alternative cytotoxic or investigational drug. 6) Are pregnant, breastfeeding or unable / unwilling to comply with pregnancy prevention guidelines 7) Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with < 5% recurrence risk

Sub Specialty:

Colorectal Cancer Colorectal Surgery

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True NTH UK – Post Surgical Follow up

Research Summary

Men who choose radical surgery for prostate cancer (radical prostatectomy) can experience side effects, including urine leakage and problems with erections. This project aims to develop a new questionnaire for measuring urinary and sexual function following radical prostatectomy in men in the UK. We hope that this will help us to: • Allow a man to track his progress over time in a way that he can share the information with his clinical team so that reassurance can be given if things are likely to get better over time, or treatments can be started if needed. • Compare outcomes from different surgeons, so that any factors associated with improved outcomes can be learnt more widely • Use the data to help inform men who are considering radical prostatectomy what their functional outcomes could be This will be done by: Developing a new questionnaire • Using a combination of the best questionnaires available to collect data on men in the UK having radical prostatectomy • Carrying out focus groups in men who are due to have, or have had radical prostatectomy, to see where the current questionnaires are helpful and where they can be improved • Using the questionnaire and focus group data to develop a new questionnaire • Using the new questionnaire in men in the UK having radical prostatectomy Comparing outcomes across groups • Collecting details of the operation • Comparing functional outcomes from the questionnaires with the operation details • Having a surgical forum to help surgeons discuss and develop the best ways to do the operation to get the best outcomes for men Using the data for men considering prostatectomy • The results of the study will be fed back to the True NTH UK Understanding consequences project which is developing a decision aid for men who need to decide between different treatment options which include surgery

Inclusion Criteria:

• A diagnosis of prostate cancer and scheduled to have radical prostatectomy. • Access to the internet. • An understanding of the English language sufficient to understand and complete on line CRFs. • An understanding of the English language sufficient to understand written and verbal information about the trial and consent process. • Signed informed consent.

Exclusion Criteria:

• Men who are unable to give informed consent.

Sub Specialty:

Prostate Cancer Surgical Urology

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TRAcking non small cell lung Cancer Evolution through therapy (Rx)

Research Summary

We are investigating why lung tumours spread and why they become resistant to cancer drugs so rapidly. Lung cancer is the most common cancer in the world with 1.61 million new cases diagnosed every year and is the most common cause of male and female deaths from cancer (http://info.cancerresearchuk.org/cancerstats). Taking a sample or biopsy from just one part of a tumour might not give a full picture of its genetic diversity and may explain why doctors, despite using genetically targeted drugs, are often unable to save patients whose cancer has spread. There may also be markers in the blood that can be used to predict outcomes. Aim of the project: Investigate the diversity within certain lung cancers and the differences between cells of the tumour that allow the selection of a single cell to grow at distant sites of the body or evade drug treatment. This will be achieved by taking samples from different regions of the primary tumour and also from associated lymph glands where the tumour has spread at different time-points (after diagnosis, and during and after treatment). Advanced sequencing machines in the laboratory can sequence all the DNA (the genome) of tumour cells and have shown that cancer cells harbour more differences compared to each other than similarities, in contrast to normal tissue where cells are identical. These differences provide the cancer with biological fitness and the capacity to evade cancer drug treatment and grow elsewhere in the body. Patient benefit: We know that tumours are a 'patchwork' of genetic faults and mapping out the genetic landscape of lung cancer will increase our understanding of the origins and the evolution of the disease. The next step will be to develop drugs that limit this diversity by targeting key driver mutations that are common throughout the tumour

Inclusion Criteria:

• Written Informed consent • Patients > 18 years of age, with early stage I-IIIA disease who are eligible for primary surgery • Histopathologically confirmed NSCLC, or a strong suspicion of cancer on lung imaging necessitating surgery (e.g. diagnosis determined from frozen section in theatre) • Primary surgery in keeping with NICE guidelines planned • Agreement to be followed up in a specialist centre • Performance status 0 or 1 • Considered sufficiently fit for platinum-based adjuvant therapy if indicated (cisplatin or carboplatin allowed)

Exclusion Criteria:

• Any other current malignancy or malignancy diagnosed or relapsed within the past 5 years (other than nonmelanomatous skin cancer and in situ cervical cancer) • Psychological condition that would preclude informed consent • Treatment with neo-adjuvant chemotherapy deemed necessary • Adjuvant chemotherapy regimen other than platinum-based chemotherapy (if a patient is deemed suitable for adjuvant chemotherapy) • Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection • Sufficient tissue is unlikely to be obtained for the study based on pre-operative imaging

Sub Specialty:

Cardiothoracic Surgery Lung Cancer

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A double blind, randomised controlled trial evaluating the safety and efficacy of Tranexamic acid in patients with haematological malignancies with severe thrombocytopenia

Research Summary

Patients with cancers of the blood often develop low blood cell counts either as a consequence of the disease or the treatment by chemotherapy or stem cell transplantation. Platelet transfusions are commonly given to raise any low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). But recent studies have indicated that many patients continue to experience bleeding, despite the use of platelet transfusions. Tranexamic acid is a type of drug that is called an antifibrinolytic. These drugs act to reduce the breakdown of clots formed in response to bleeding. These drugs have been used widely in both elective and emergency surgery and have been shown to decrease blood loss and the use of red cell transfusions. The purpose of this study is to test whether giving tranexamic acid to patients receiving treatment for blood cancers reduces the risk of bleeding or death, and the need for platelet transfusions. Patients will be randomised to receive tranexamic acid (given intravenously through a drip, or orally) or a placebo. We will measure the rates of bleeding daily using a short structured assessment of bleeding, and we will record the number of transfusions given to patients.

Inclusion Criteria:

1. At least 18 years of age 2. Confirmed diagnosis of a haematological malignancy 3. Undergoing chemotherapy or haematopoietic stem cell transplantation 4. Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count of ≤10x10 to the power of 9/L for ≥ 5 days 5. Able to comply with treatment and monitoring

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukaemia and undergoing induction chemotherapy 2. History of ITP, TTP or HUS 3. Patients receiving L-asparginase as part of their current cycle of treatment 4. Patients with a past history or current diagnosis of arterial or venous thromboembolic disease including myocardial infarction, peripheral vascular disease and retinal arterial or venous thrombosis 5. Patients with a diagnosis/previous history of veno-occlusive disease (also called sinusoidal obstruction syndrome) 6. Patients receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor VIIa or Prothrombin Complex Concentrates (PCC) within 48 hours of enrolment, or with known hypercoagulable state 7. Known inherited or acquired bleeding disorder. E.g. acquired storage pool deficiency; paraproteinaemia with platelet inhibition; known inherited or acquired prothrombotic disorders 9. Patients receiving anticoagulant therapy or anti-platelet therapy 10. Patients with overt disseminated intravascular coagulation 11. Patints with visible haematuria at time of randomisation 12. Patients requiring a platelet transfusion threshold > 10x10 to the power of 9/L at time of randomisation 13. Patients with anuria (defined as urine output < 10mls/hr over 24 hours) 14. Patients who are pregnant 15. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth factors or other pro-coagulant agents 16. Allergic to tranexamic acid or epsilon amino caproic acid 17. Previously randomised in this study at any stage of their treatment

Sub Specialty:

Haematological Oncology Haematology

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A RANDOMIZED PHASE III TRIAL COMPARING CONVENTIONAL-DOSE CHEMOTHERAPY USING PACLITAXEL, IFOSFAMIDE, AND CISPLATIN (TIP) WITH HIGH-DOSE CHEMOTHERAPY USING MOBILIZING PACLITAXEL PLUS IFOSFAMIDE FOLLOWED BY HIGH-DOSE CARBOPLATIN AND ETOPOSIDE (TI-CE) AS FIRST SALVAGE TREATMENT IN RELAPSED OR REFRACTORY GERM CELL TUMORS

Research Summary

TIGER is a multi-centre study in germ cell patients whose cancer has returned or become resistant to their initial chemotherapy. Its primary aim is to compare the overall survival in patients treated with high-dose chemotherapy, plus collection and reinfusion of the patients own stem cells, with those treated with conventional-dose chemotherapy. Germ cell tumours (GCT) represent the most common cancer affecting adolescents and young adult men in both Europe and the United States. Early stage disease, which affects the majority of GCT patients, is nearly universally curable with surgery or short-course chemotherapy therefore current efforts are focused on finding curative treatments which are less toxic. There is no international standard treatment in this setting and routine practice differs between countries. At present, the two major approaches for patients who require further treatment are high-dose chemotherapy with a stem cell transplant of the patients own cells or conventional-dose chemotherapy; due to a lack of conclusive randomised trials, it remains unclear which option represents the best treatment approach for these patients. Defining standards and optimising outcomes of salvage treatment thus represents one of the most pressing issues in the management of GCT at present

Inclusion Criteria:

- Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment. Tumour may have originated in any primary site. - Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatinbased chemotherapy, defined as meeting at least one of the following criteria: * Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study. * Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease. * Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase. - Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy. Prior POMBACE, CBOP-BEP, or GAMEC are allowed. - No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy). - Must have adequate recovery from prior surgery (e.g., healed scar, resumption of diet, etc.). - Age ≥ 14 years. - ECOG Performance Status 0 to 2. - Male gender. - Required Initial Laboratory Values: *Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 *Platelet Count ≥ 100,000/mm3 *Calc. Creatinine Clearance ≥ 50 mL/min *Bilirubin ≤ 2.0 x upper limits of normal (ULN) *AST/ALT ≤ 2.5 x upper limits of normal (ULN) unless due to hepatic metastases in which case levels of ≤ 5 x ULN are allowed. - Negative Serology (antibody test) for the following infectious diseases: a. Human Immunodeficiency Virus (HIV) type 1 and 2 b. Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe) c. Hepatitis B surface antigen d. Hepatitis C antibody - Patient must not father a baby whilst in this study. - Written informed consent must be given prior to patient randomisation.

Exclusion Criteria:

-Prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue). - Prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed. - Concurrent treatment with other cytotoxic drugs or targeted therapies. - Contraindications to the use of paclitaxel, ifosfamide, cisplatin, carboplatin and etoposide as per the summary of product characteristics (SPC). - Radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy. - Previous chemotherapy within 16 days prior to enrollment except for bleomycin which cannot have been given within 5 days prior to enrollment. - Concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia. Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed. - Late relapse with completely surgically resectable disease. Patients with late relapses (defined as relapse ≥ 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable are not eligible. Patients with late relapses who have unresectable disease are eligible. - Large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery). Treatment may begin ≥ 7 days after completion of local treatment. Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated. Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide. - Secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression. - Although they will not be considered formal eligibility (exclusion) criteria, physicians should recognise that the following may seriously increase the risk to the patient entering this protocol: *Psychiatric illness which would prevent the patient from giving informed consent *Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous to the patient *Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years *Patients who cannot swallow oral formulations of the agent(s)

Sub Specialty:

Testicular Cancer

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Tracking mutations in cell free tumour DNA to predict Relapse in eArly Colorectal Cancer

Research Summary

This study involves the collection and analysis of tumour tissue, serial blood samples and clinical data in patients with newly diagnosed stage II and III colorectal cancer (CRC). The study is planned to recruit patients from sites within (but not limited to) the London Cancer Alliance over 3 years. DNA fragments containing cancer specific markers or mutations that originate from tumour can be detected in blood. This is known as circulating cell free tumour DNA (ctDNA). In patients that have undergone potentially curative surgery, blood samples to detect and quantify ctDNA is a promising strategy for the identification of minimal residual disease(very small amounts of persisting disease) and may identify disease relapse earlier than existing methods. Part A is a feasibility study where the proportion of patients with detectable ctDNA in blood prior to surgery will be determined. Part B will assess whether detection of ctDNA in a blood sample taken 4-8 weeks after surgery, can be used to predict relapse. Levels of ctDNA at other time points such as: during chemotherapy and post-chemotherapy and the association between the level of ctDNA with disease free survival (the length of time from the removal of cancer until the cancer returns in patients that have a relapse) and overall survival will be determined. Some patients are offered chemotherapy after surgery (adjuvant chemotherapy) to reduce the risk of the cancer returning. Only a proportion of patients will benefit directly from this and it is not entirely clear which patients these will be, although there are specific risk features that are currently used to guide treatment decisions. The study may identify a subset of patients that are unlikely to benefit from adjuvant chemotherapy on the basis of ctDNA analysis and could therefore safely spare some patients from receiving chemotherapy and its associated side-effects.

Inclusion Criteria:

Inclusion criteria to be used prior to registration: -New diagnosis of histologically confirmed CRC scheduled to undergo surgery with curative intent, with no radiological evidence of metastatic disease. -Age≥18 -Ability to give informed consent -Able to adhere to follow up schedule Additional inclusion criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy -All patients proceeding to surgery Inclusion criteria at the first post-operative visit: -Stage II or III CRC based on the post-operative histopathology report -Availability of FFPE tumour tissue from surgery, for processing and analysis at the CMP

Exclusion Criteria:

Exclusion criteria to be used prior to registration: -Scheduled to have neoadjuvant chemotherapy, (neoadjuvant chemoradiotherapy for patients with rectal cancer is permitted) -Current or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix or other non-invasive malignancy. Additional exclusion criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy -Patients scheduled to have further pre-operative treatment with chemotherapy -Patients that are no longer proceeding with surgery i.e. those in whom surgery is considered too high risk -Patients that are no longer proceeding with surgery as they are proceeding with a deferral of surgery approach (NB these patients will remain in the study as an exploratory cohort and will therefore continue to have bloods taken) Exclusion criteria at the first post-operative visit: -Stage I patients based on the post-operative histopathology report should be excluded, apart from rectal patients that had undergone pre-operative chemoradiotherapy for whom their pre-chemoradiotherapy MRI staging should be used. -Scheduled to receive post-operative radiotherapy

Sub Specialty:

Colorectal Cancer Colorectal Surgery

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The young adult cancer patient journey: Experiences from the Royal Marsden Hospital

Research Summary

What is the problem? In response to research showing that the care needs of adolescents and young adults with cancer are poorly met, there has been a rapid expansion in the availability of dedicated services for teenagers and young adults (TYA; aged 15 to 24 years at diagnosis) in the United Kingdom. However, no age-specific care services are available for young adult cancer patients aged 25 to 39 years at cancer diagnosis, while this patient group also faces age-specific issues that can negatively impact health-related quality of life. The current patient care for young adults with cancer may be compromised by the lack of insight into the young adult cancer patient journey and probably inadequate care infrastructure (e.g. resource availability, lack of expertise). What are our aims? To be able to develop age-specific supportive care services for young adults with cancer, this study aims to provide insight into the young adult cancer care experience, the (unmet) supportive care needs, impact of cancer on young adults’ lives, and preferences for and expectations of age-specific cancer care. How will we do this? This study has a mixed method design. Semi-structured interviews and focus groups will be conducted with young adult cancer patients, their health care professionals and informal caregivers about the preferences and expectations of age-specific care. A survey will be administered to all alive young adult cancer patients diagnosed with cancer aged 25-39 years in the Royal Marsden Hospital in the past five years. The survey measures care experiences, supportive care needs, health-related quality of life, psychological distress, impact of cancer, illness cognitions and self-management. What can we learn? Results of the studies described above will help to design a tool or service to support young adults with cancer (and their caregivers) in the Royal Marsden Hospital.

Inclusion Criteria:

Inclusion criteria: Eligible patients are those diagnosed with any type of cancer (ICD-10 codes C00-C97) for the first time between 25 and 39 years of age who can speak and understand English, and being treated or in follow-up at the Royal Marsden Hospital at the beginning of this study. Patients need to be within 5 years after their primary cancer diagnosis.

Exclusion Criteria:

Exclusion criteria: Patients with a significant cognitive impairment or who are too ill (death is imminent), as determined by the referring health care professional, will be excluded.

Sub Specialty:

Psychosocial Oncology and Survivorship Teenage and Young Adult's Cancer

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A Phase I/II Study of Thiotepa, Ifosphamide, Etoposide and Rituximab for the treatment of relapsed or refractory primary central nervous system lymphoma

Research Summary

The phase I dose finding component is a 3+3 cohort design which will recruit up to 18 patients in order to find the MTD of thiotepa in combination with ifosphamide, etoposide and rituximab (TIER). All patients recruited into phase I at the MTD will also contribute towards phase II. The phase II study is based on an A'hern’s design design to assess the activity of thiotepa in combination with ifosphamide, etoposide and rituximab (TIER). 28 patients will be recruited in total in phase II (including some patients from phase I).

Inclusion Criteria:

Age ≥ 16 years of age • Histologically confirmed* CD20+ Diffuse Large BCell Lymphoma (DLBCL) confined to the central nervous system • Relapsed or refractory primary central nervous system lymphoma (PCNSL) according to the following definition : o one or two prior chemotherapy regimen(s), of which at least one regimen contained highdose methotrexate at a dose of > 1g/m2. o minimum of one cycle containing highdose methotrexate • ECOG performance status 0,1 or 2 (or 3 if attributed to lymphoma) Adequate organ function o Bone marrow: platelets > 80 x109/L, neutrophils > 1 x109/L, haemoglobin > 80 g/L o Hepatic: bilirubin < 1.5 x upper limit of normal (ULN) (unless isolated unconjugated hyperbilirubinaemia attributable to Gilbert’s syndrome) o Renal: eGFR ≥40ml/min (Cockcroft-Gault) o Cardiorespiratory (as judged by the Local Investigator): clinically relevant cardiac or pulmonary function tests must be performed if there is a previous history of significant cardiac or pulmonary impairment • Able to comply with the scanning requirements of the study • Valid Informed consent

Exclusion Criteria:

• Systemic involvement with lymphoma • Active infection requiring intravenous antimicrobials • Chemotherapy for lymphoma within 4 weeks registration • Wholebrain radiotherapy within 6 months of registration • Relapse within 1 year of a Thiotepabased autologous stem cell transplant • Prior therapy with the RIE (Rituximab – ifosphamide and etoposide) regimen • Evidence of HIV or Hepatitis C infection • Hepatitis B infection* • Serum albumin < 25g/l • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) • Competent pPatients and competent patients with partners of childbearing potential not willing to use effective contraception during and for 12 months after therapy

Sub Specialty:

Lymphoma

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The PROMOTE Study: Patient Reported Outcome Measures Online To Enhance Communication and Quality of Life after childhood brain tumour

Research Summary

Is it feasible to ask children with brain tumours, and their parents, about their health, well-being, and concerns, online and then discuss this information with clinicians during routine appointments in outpatient clinics with the aim of enhancing child-clinician-parent communication, the child's quality of life (QoL), and to improve follow-up treatment plans? The QoL of these children is often impaired and not assessed early. Systematic feedback of patient reports into patient care is beneficial and now easier with computer assistance but the processes linking feedback to patient benefit are complex. This three year study, funded by the Brain Tumour Charity (BTC), will focus on these processes to strengthen the links, tailor the methods of feedback to the service providing care, and thus maximise the benefits to the QoL of affected children. In the development phase of the study, we will recruit 18-20 families with children aged 5-17 years treated for a brain tumour and also clinicians from three Children's Cancer Treatment Centres (Nottingham, Great Ormond Street, and Southampton) and using qualitative methods ask them which questions should be included in an assessment of QoL using the online platform KLIK (https://www.youtube.com/watch?v= 4A2vF0k2-jM#t= 32). We will then develop KLIK and in the feasibility phase of the study, pilot it with another 45 families across the three hospitals to see which aspects of the system work well and what the barriers are to the implementation of the platform in clinical practice. Families and clinicians will work with us in a collaborative way to gradually refine the system to develop a high fidelity feedback intervention that could be scaled up and rolled out across the UK in a subsequent project.

Inclusion Criteria:

Children aged 8-17.9 years with a brain tumour diagnosed within the previous five years, off treatment but receiving outpatient care > = 6 monthly, and their parents. Also parents of children with a brain tumour who are aged less than 8 years and not younger than 5 years. Children and parents who are able to communicate in the English language at a level to enable them to participate in discussions and interviews and who are able to read questionnaires in the English language. Clinicians involved in the outpatient care of children treated for brain tumours at three Children's Cancer Treatment Centres (CCTCs): University Hospital Southampton, Great Ormond Street Children’s Hospital, and Queens Medical Centre, Nottingham. Participants who have given informed consent.

Exclusion Criteria:

Families who are not sufficiently fluent in the English language to read text and to express their views in discussions and interviews. Families who were deemed to be ineligible by their treating clinician.

Sub Specialty:

Brain Cancer Children's Cancer and Leukaemia Teenage and Young Adult's Cancer

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The COMET Trial: Concordance between MRI and Pathology in the Diagnosis of Extranodal Tumour Deposits

Research Summary

Colorectal cancer, as with other cancers, can spread to glands (lymph nodes) and this is traditionally thought to be how cancer spreads elsewhere. Research has shown that cancer also spreads directly into veins and forms deposits of tumour outside glands. As you might suspect, tumour cells in blood vessels may be more likely to spread and deposits of cancer cells may be an important sign that cancer is spreading elsewhere in the body. These deposits have a distinctive appearance on MRI scans but can be difficult to distinguish from glands by pathologists who may not appreciate that they originate from veins. Our provisional work shows that vein deposits are more frequently seen on routine pre-surgery MRI scans. We aim to prove that abnormalities seen on MRI really are tumour deposits by working closely with surgeons, radiologists and pathologists to locate and examine these. This research is completely new and is needed to prove that MRI scans can accurately diagnose patients with tumour deposits. We know these patients are at higher risk of relapse than those with tumour in glands, so if we can predict this before surgery, chemotherapy and radiotherapy may be added to cure more patients from their cancer.

Inclusion Criteria:

Patients with rectal cancer who are going to have surgery Over 18 Able to undergo an MRI

Exclusion Criteria:

Under 18 Unable to give informed consent Unable to undergo surgery Unable to undergo MRI

Sub Specialty:

Colorectal Cancer

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The MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURES) Trial: Serial Assessment of Symptomatic Response to Non Experimental Medical Therapies and/or Phlebotomy in Patients with Myeloproliferative Neoplasms

Research Summary

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Inclusion Criteria:

Patients must be 18 years or over Patients must have either essential thrombocythemia, polycythemia vera, or myelofibrosis (primary or post polycythemia vera/post essential thrombocythemia). Patients must be beginning a new, non-experimental, therapeutic intervention for their MPN either medicinal (aspirin, hydroxyurea, anagrelide, interferon, busulfan, melphalan, cladribine, thalidomide, lenalidomide, prednisone, danazol, ruxolitinib) and/or phlebotomy. Patients must be willing to fill out the diary for 7 consecutive days (with at least the first daily assessment prior to therapy initiation) and then again for 7 consecutive days after a minimum of 90 days (maximum of 6 months).

Exclusion Criteria:

Patients under the age of 18 years. Those patients who do not have the capacity to give informed consent

Sub Specialty:

Haematological Oncology

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The Causes of Clonal Blood Cell Disorders

Research Summary

-

Inclusion Criteria:

unknown

Exclusion Criteria:

unknown

Sub Specialty:

Haematological Oncology

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Tissue analysis for stratifying therapy in proliferative lung diseases

Research Summary

Lung cancer is the most common cancer worldwide and the second most common cancer in the United Kingdom. The majority of patients in the UK (69%) are diagnosed at a late stage where curative treatment is not possible. In addition to treatments for cancer like chemotherapy and radiotherapy, in recent years another type of treatment that targets the immune system (immunotherapy) has shown promising results in improving the outcome for patients with many different cancers including lung cancer. Currently less than 50% of people benefit from this approach. This is the result of large gaps in our knowledge of how immunotherapy works and how to choose the right treatment or treatment combination for a particular patient. We will be looking at tissue from patients in whom there is a possibility there might be lung cancer or lung fibrosis. Lung fibrosis is not a cancer but shares some basis characteristics with lung cancer and looking at these samples will help our understanding of these diseases. We will compare these to samples collected from patients with lung nodules, other lung diseases and healthy lungs. We hope to be able to see if there are any particular immune or genetic markers that are related to the development of lung cancer and lung fibrosis, and to see if there are any markers we can potentially target with the outcome that the cancer or fibrosis may not develop, or may be made less harmful so we might be able to improve treatment for people with these diseases.

Inclusion Criteria:

For the prospective collection of sputum, bronchoscopic lavage, lung/tissue/lymph node biopsies, peripheral blood and where possible pulmonary vein blood and bone marrow: - Suspected diagnosis of lung cancer, lung fibrosis, lung nodules, other lung diseases or healthy lungs - Patient aged 18 or over - Patients with the ability to understand the study requirements and provide written informed consent. - Patient scheduled to undergo diagnostic procedure – Bronchoscopy/EBUS/CT or ultrasound guided biopsy/Thoracic surgery - Patients with pulmonary nodules who consent to a research bronchoscopy

Exclusion Criteria:

- Patient deemed medically unfit for sample collection - Patient has contraindication for any study specific procedure - The absence/withdrawal of consent

Sub Specialty:

Cardiothoracic Surgery Lung Cancer Respiratory Disorders

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An international randomised controlled trial to compare targeted intra-operative radiotherapy boost with conventional external beam radiotherapy boost after conservative breast surgery for women with early stage breast cancer and a high risk of local recurrence

Research Summary

Despite advances in breast cancer treatments, a subgroup of patients, especially young women, remain at a significant risk of cancer returning in the breast (recurrence) after receiving the standard breast conserving surgery and post operative course of radiotherapy. In this group of patients, standard radiotherapy would have been given several months after surgery and would normally consist of a 3-5 week course of daily radiotherapy to the whole breast, as well as a shorter 5-8 day course to the tumour bed (the normal breast tissue immediately around the tumour); it is difficult to accurately aim the boost at the tumour bed. We developed a new radiotherapy technique- TARGeted Intraoperative radioTherapy (TARGIT), in 1998 and have accumulated considerable experience through worldwide collaboration in over 30 centres. With TARGIT, radiotherapy is delivered accurately to the tissues at highest risk of recurrence- the tumour bed- at the time of surgery in a single session. The long-term analysis of the first 300 patients treated with this technique found a remarkably low recurrence rate, less than half of the expected rate. Hence we have designed a randomised trial of 1796 patients to compare TARGIT boost with conventional boost to test its superiority. The research will be a global collaborative effort of over 30 centres co-ordinated from London. The primary outcome will be local recurrence of cancer at 5 years. We shall also be looking at breast appearance, patient satisfaction and quality of life, and whether or not the intervention represents good value for money to the NHS and to patients and families (cost and cost-effectiveness).

Inclusion Criteria:

Patients diagnosed with breast cancer and suitable for conserving surgery and whole breast radiotherapy, with a histological confirmation of carcinoma can be included in the study once a written informed consent is obtained. All patients should be available for regular follow-up (according to local policies) for at least ten years. At least one of these criteria must be satisfied: 1. Less than 46 years of age 2. More than 45 years of age and with one or more of the following poor prognostic factors: a) Grade 3 histology b) ER and/or PgR negative c) lobular carcinoma d) extensive intraductal component (EIC) e) lymphovascular invasion f) axillary nodal involvement g) more than one tumour in the breast but still suitable for breast conserving surgery through a single specimen h) any factor or a combination of factors that puts the patient at a higher risk of local recurrence as per the current local guidelines : e.g., those who need a tumour bed boost or those not suitable for TARGIT-Alone as standard treatment. 3. Those patients with large tumours which have responded to neo-adjuvant chemo- or hormone therapy that is given in an attempt to shrink the tumour, and are now suitable for breast conserving surgery as a result. Note. It is recommended that hormone receptor status (at least ER) is known before randomisation. Patients with either HER2 positive or HER2 negative tumours can be included.

Exclusion Criteria:

1. Bilateral breast cancer at the time of diagnosis. 2. Patients with any severe concomitant disease that may limit their life expectancy 3. Previous history of malignant disease does not preclude entry if the expectation of relapse-free survival at 10 years is 90% or greater (e.g., non-melanoma skin cancer, CIN etc.).

Sub Specialty:

Breast Cancer Radiotherapy

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Investigation of the molecular, immunological and genetic features associated with neuroendocrine tumour dissemination, progression and response to treatment

Research Summary

Neuroendocrine tumours (NETs) are rare, and there are many different subtypes. For example they can arise in bowel, pancreas or lung, but they can also be found in the skin, thymus and other sites. The prognosis of NETs is generally favourable, with a median overall survival of 75 months. However, survival is very variable. The primary treatment for Grade 1 and Grade 2 NETs is surgery, although long-acting octreotide, radiolabelled octreotide (Peptide Receptor Radionucleotide Therapy or PRRT), chemotherapy and tyrosine kinase inhibitors or mTOR inhibitors can also be considered. Unfortunately due to the rare and heterogeneous nature of this disease there aren’t any head-to-head trials comparing different treatment strategies e.g. chemotherapy vs everolimus. There are three key reasons why we are embarking on a project to improve understanding of the molecular, immunological and genetic features associated with NET dissemination, prognosis and response to treatment. 1. There has been only minimal improvement in outcomes for patients with NETs over the last 30 years. Large clinical trials have not been possible due to the rare and heterogeneous nature of the disease. Evidence to guide treatment selection for patients with NETs is urgently required. 2. We need to improve our ability to prognosticate accurately for patients with NETs. 3. A better understanding of NET biology may lead to a greater range of treatment options for patients with this rare disease, for example immunotherapy. There are two parts to the study Part A: To study archival tissue in consort with clinical data from our NET patients, to develop a molecular classification for NETs Part B: To collect fresh tissue from tumour and healthy tissue, and blood samples, to perform testing including immune profiling and single cell sequencing to further explore specific hypotheses identified from Part A.

Inclusion Criteria:

There are two parts to the research Part A: Any patient with a histologically proven neuroendocrine tumour who has given consent for their tissue to be used for research. Part B: Any patient aged over 16 with a clinical or pathological diagnosis of a neuroendocrine tumour who understands and is willing and able to comply with study procedures.

Exclusion Criteria:

Children under 16 and vulnerable groups will be excluded.

Sub Specialty:

Upper GI

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A Phase I/IIa Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis

Research Summary

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. Systemic AL amyloidosis, which is the commonest amyloid type, occurs in a small proportion of individuals with monoclonal B cell dyscrasias. AL amyloid has a lifetime incidence and is the cause of death of between 0.5-1 per thousand individuals in the UK. It occurs equally in men and women and the median age at diagnosis is 65 years. Without therapy it is inexorably progressive and until recently the median survival was just 6-15 months. This is an open labelled Phase I/IIa Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis (TRALA). There are three treatment levels with step-wise increase of the infused [90Y]- labelled anti-CD66 radiation activity which will be given prior to autologous stem cell transplantation. The total number of participants planned is twelve (12), with a maximum of 18 if all treatment levels are expanded. The objectives of the trial is to review safety and toxicity using [90Y]-anti-CD66 as the sole conditioning prior to autologous stem cell transplantation for AL-amyloidosis and disease response as determined by changes in the free light chain assay (FLCa) pre and post [90Y]-labelled anti-CD66 and post transplantation.

Inclusion Criteria:

• Aged ≥18 years. • Have a diagnosis of systemic AL-amyloidosis, either as a new diagnosis or recurrent disease. • Measurable clonal plasma cell dyscrasia. • Amyloid related organ dysfunction or organ syndrome. • Estimated life expectancy of at least 6 months (as defined at trial entry). • Sufficient stem cells for two transplant procedures . • Bone Marrow (BM) cellularity > 20%. • Eligible for ASCT in AL amyloidosis defined as fulfilling all of the following criteria : o ECOG Performance Status of 0 or 1 o Cardiac troponinT< 0.07 μg/L o NYHA heart failure class of < 3 o No more than 3 organs involved by amyloidosis by consensus guidelines. o Creatinine clearance or isotope GFR ≥30ml/min. o Bilirubin ≤1.5 times and alkaline phosphatase ≤3 x upper limit of normal. o AST or ALT < 2.5 x upper limit of normal range. o Mean left ventricular wall thicknesses of < 16mm by echocardiography. o Absence of clinically important amyloid related autonomic neuropathy . o Absence of clinically important amyloid related gastro intestinal haemorrhage. • Capable of providing written, informed consent. • Women of child bearing potential should use adequate forms of contraception. o Intrauterine Device (IUD) o Hormonal based contraception (pill, contraceptive injection etc.) o Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) o True abstinence

Exclusion Criteria:

Patients with poor performance, advanced organ involvement or significant cardiac involvement will be excluded from the study. Patients with the following characteristics are ineligible for this study: • Overt symptomatic multiple myeloma. • Amyloidosis of unknown or non AL type. • Localised AL-amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the bladder or larynx, in association with a clonal proliferative disorder within that organ). • Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome). • NYHA Class III or IV heart failure (appendix 1). • Liver involvement by amyloid causing bilirubin > 1.5 times upper limit of normal. • Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas. • Pregnant, lactating or unwilling to use adequate contraception as listed above • Intolerance / sensitivity to any of the study drugs. • Known positive Human anti-murine antibodies (HAMA). • Unable to provide written informed consent • Involved in another IMP trial

Sub Specialty:

Haematological Oncology

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A randomised phase II trial of standard versus dose escalated radiotherapy in the treatment of pain in malignant pleural mesothelioma

Research Summary

To establish whether dose escalated, hypofractionated radiotherapy (36 Gy in 6#) increases the proportion of MPM patients experiencing a clinically significant improvement in pain compared with standard radiotherapy (20 Gy in 5#)

Inclusion Criteria:

• Histological and/or MDT diagnosis of MPM • Performance status 0-2 (ECOG) • Predicted life expectancy of > 12 weeks • CT scan within 8 weeks of starting radiotherapy • Worst Pain ≥4/10 (0-10 Numerical Rating Scale) • Ability to provide written informed consent prior to participating in the trial and prior to any trial related procedures being performed • Willingness to comply with scheduled visits, treatment plans, laboratory tests and other study procedures • Patients must have a radiotherapy plan compatible with the treatment arm (30-36 Gy in 5-6 fractions).

Exclusion Criteria:

• Patients who have received anti-cancer therapy within the 4 weeks prior to study entry that is likely to alter pain at the index site during the duration of the study. • Patients who are planned to have further anti-cancer therapy within 6 weeks post radiotherapy treatment • Psychotic disorders or cognitive impairment. • Co-existing lung tumours at the time of study entry. • Pregnant or breastfeeding. • Patients of child-bearing potential, who are unwilling to use 2 effective methods of contraception during radiotherapy treatment

Sub Specialty:

Lung Cancer Supportive and Palliative Care

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Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms

Research Summary

Myeloproliferative neoplasms (MPNs) are blood cancers which affect the normal production of blood cells from the bone marrow. They are caused by changes (mutations) in blood stem cells, frequently in the genes that produce proteins called JAK2, CALR or MPL. MPNs have a risk of developing to an acute leukaemia (a more advanced stage of disease) and currently has no effective cure, apart from bone marrow transplantation which is not possible for many patients. Recent work in mouse studies has suggested that tamoxifen, a drug widely used to treatment breast cancer, may reduce the number of mutated cells by mimicking oestrogen (a female sex hormone) which has a role in the survival and production of new stem cells that give rise to blood cancers. In these studies, tamoxifen prevented the excessive production of blood cells by restoring normal levels of cell death in the mutated cells. This is a single arm, multicentre phase II trial designed to assess if adding tamoxifen to patients receiving therapy for their MPN reduces the number of mutated cells found in the blood by ≥ 50% after 24 weeks of treatment compared to the start of the study. Collection of blood and bone marrow samples will also allow laboratory researchers to study the biological effects of tamoxifen and how this correlates with the patient’s disease and response to therapy. Patients will receive treatment with 20mg once daily (oral tablet) of tamoxifen with their normal therapy for their MPN. 42 patients will be recruited from 13-15 UK centres over 12 months.

Inclusion Criteria:

• Age ≥ 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator) • Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments) • Confirmed diagnosis of JAK2-V617F or CALR positive Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) (primary or secondary) for ≥ 6 months • JAK2-V617F or CALR mutant allele burden ≥ 20% in peripheral blood granulocyte DNA at study entry (assessed via central review) • WHO performance status 0-2 • For patients with PV or ET, maintenance of at least a partial haematological response according to 2009 ELN criteria must have been achieved for the previous 6 months (prior to registration), without introduction of any new therapeutic agents for their MPN • For patients with MF, there must not have been any evidence of disease progression* for the previous 6 months (prior to registration) and no new therapeutic agents for their MPN introduced during this period. • Patients receiving cytoreductive therapy for their MPN (not solely aspirin or venesection) • Adequate hepatic function, defined as: o bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with elevated bilirubin due to Gilbert’s syndrome are eligible) o AST/ALT/ALP ≤ 2.5 x ULN • Adequate renal function (creatinine clearance > 30 mL/min) • Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment • Patient must be able to give written informed consent *Defined by IWG-MRT ELN criteria (Appendix 6). Please note no baseline bone marrow is required to confirm absence of “Leukemic transformation confirmed by a bone marrow blast count of ≥ 20%”.

Exclusion Criteria:

• Leukaemic transformation ( > 20% blasts in blood, marrow or extramedullary site). • Accelerated phase of disease as indicated by > 5% blasts in the peripheral blood • Treatment of ET, PV or MF with Interferon alpha or JAK inhibitors, such as ruxolitinib, or other investigational agents for their MPN within 6 months prior to trial entry • Any of the following previous thrombotic events at any time: o Portal or other splanchnic venous thrombosis o Vascular access complication o Ischemia cerebrovascular o Stroke o Transient Ischaemic attack o Superficial thrombophlebitis o Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT) o Peripheral vascular ischemia o Visceral arterial ischemia o Acute coronary syndrome o Myocardial infarction • Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer • Previous endometrial cancer, hyperplasia or polyps • Prior treatment with hematopoietic stem cell transplantation • Patients who do not carry any mutations in JAK2V617F or CALR or allele burden < 20% • Female patients receiving hormone replacement therapy • Hypertriglyceridemia > grade 1 • Any serious underlying medical condition (at the judgment of the Investigator), which could impair the ability of the patient to participate in the trial (e.g. liver disease, active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C), known genetic defect (apart from MPN) relating to venous thromboembolic events, or psychiatric disorder precluding understanding of trial information) • Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen • Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics • Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts)

Sub Specialty:

Haematological Oncology

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A randomised trial of non-Selective versus selective adjuvant Therapy in high risk Apparent sTage 1 Endometrial Cancer

Research Summary

In stage I endometrial cancer, the tumour appears to be confined to the uterus. Standard treatment is surgery to remove the uterus, fallopian tubes and ovaries. Approximately 85% of patients survive for at least 5 years. However, 25% of newly diagnosed stage I cases are 'high risk', with potential to relapse and spread after surgery. Traditionally, high risk status has been confirmed by using scans and a tissue sample (biopsy) to look for features that cause the cancer to behave aggressively. The vast majority of high risk patients receive chemotherapy +/- radiotherapy after surgery. The STATEC trial will compare this approach with an alternative treatment strategy: whether lymphadenectomy has an effective role to play in selecting treatment after surgery. Lymphadenectomy is the surgical removal of lymph glands (nodes) to determine whether cancer has spread there. STATEC will use lymphadenectomy to identify 'node negative' patients without cancer in their lymph nodes i.e. patients not requiring extensive further treatment. 'Node positive' patients will require chemotherapy +/- radiotherapy. This approach may achieve comparable outcomes (including survival) to giving chemotherapy +/- radiotherapy to all high risk patients, with the advantage that node negative patients are spared additional treatment and the side effects (adverse events) that come with it. The STATEC trial will randomise 2000 high risk patients from hospitals in both the UK and other countries. Arm 1: Patients will receive lymphadenectomy as part of surgery, with subsequent treatment dependent on whether the nodes are a) negative, meaning that vaginal brachytherapy (an internal radiotherapy) will be given or b) positive, meaning that treatment will be chemotherapy +/- radiotherapy. There is an optional sentinel lymph node sub-study within this arm. Arm 2: Patients will not receive lymphadenectomy and all will be given chemotherapy +/- radiotherapy after surgery. All patients will be followed up for 5 years.

Inclusion Criteria:

• Histologically confirmed high risk apparent FIGO stage I endometrial cancer according to one of the following criteria. Confirmation must be based on either diagnostic endometrial sampling OR hysterectomy and BSO specimen if randomisation occurring after hysterectomy and BSO: - FIGO grade 3 endometrioid or mucinous carcinoma - High grade serous, clear cell, undifferentiated or dedifferentiated carcinoma or mixed cell adenocarcinoma or carcinosarcoma • Surgery to be performed ≤ 5 weeks after randomisation in patients randomised prior to hysterectomy and BSO i.e. Arm 1A and Arm 2A. Patients randomised after hysterectomy and BSO i.e. Arm 1B and 2B must have undergone hysterectomy and BSO ≤ 28 days prior to randomisation. Patients randomised after hysterectomy and BSO who are allocated lymphadenectomy i.e. Arm 1B must undergo lymphadenectomy ≤ 5 weeks after randomisation • Written informed consent • No prior anticancer therapy for endometrial cancer • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 • Life expectancy > 3 months • Adequate organ and bone marrow function • Ability to undergo post-operative chemotherapy with or without radiotherapy • Adjuvant treatment to commence ≤ 8 weeks after surgery • Willingness and ability to complete Quality of Life questionnaires

Exclusion Criteria:

• Grossly enlarged node(s) of ≥ 10 mm short axis on baseline radiological imaging • Invasion of the cervical stroma on baseline radiological imaging or obvious cervical disease on clinical examination • Involvement of uterine serosa or metastatic disease seen outside the uterus on baseline radiological imaging • Small cell carcinoma with neuroendocrine differentiation • Concurrent anti-cancer therapy • Previous malignancy < 5 years prior to randomisation or concurrent malignant disease with the exception of: - carcinoma in situ of cervix - non-melanoma skin cancer - basal cell carcinoma - melanoma in situ • Women who are pregnant or lactating

Sub Specialty:

Gynaecological Cancers Gynaecological Surgery Reproductive and Sexual Medicine

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An observational study of diagnostic criteria, clinical features and management of opioid-induced constipation in patients with cancer pain

Research Summary

Opioid-induced constipation (OIC) is constipation that occurs as a side effect of taking opioids, a major group of pain-relieving medication that includes codeine and morphine. It is a very common problem, especially in cancer patients. However, it is unclear just how common OIC is, as previous studies have not used consistent criteria to diagnose it. There are a number of treatments available to manage OIC, although it is not clear which ones should be used over others in cancer patients. A treatment plan based on current guidelines has been developed to help treatment decisions but its efficacy has not yet been tested. The objectives of this study are therefore: 1. To determine exactly how common OIC is in people with cancer by using clear criteria for making the diagnosis. 2. To determine how OIC impacts people with cancer. 3. To investigate the efficacy of the treatment plan for OIC in people with cancer. The study is divided into two parts and will take place in hospitals, hospices and community healthcare settings. The first part (Study 1) consists of one visit. Participants are asked to complete a series of questionnaires and will be assessed by a palliative care specialist. Any adult cancer patient who has been taking opioid medication for cancer pain for at least one week is eligible to take part in Study 1. There will be 1000 participants. The second part (Study 2) will investigate the efficacy of the treatment plan for OIC. Participants from Study 1 identified as having OIC that is inadequately treated will be invited to take part. It will consist of four visits over four weeks. At each visit, participants will complete a short questionnaire and treatment alterations may be made based on the treatment plan. Participants will also complete a bowel diary throughout the study.

Inclusion Criteria:

Study 1: - 18 years of age or older - Diagnosis of cancer - Diagnosis of cancer pain - Taking regular opioids for at least the last one week (i.e. opioid for mild to moderate pain / “weak” opioid; or opioid for moderate to severe pain / “strong” opioid) Study 2: - As per Study 1 - Diagnosis of OIC as defined by a Rome IV criteria - Diagnosis of inadequately treated OIC as defined by a Bowel Function Index score > = 30.

Exclusion Criteria:

Study 1: - Unable to provide consent - Unable to complete questionnaire Study 2: - As per Study 1 - Prognosis of less than one month

Sub Specialty:

Supportive and Palliative Care

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SGI-110 to potentiate platinum response: A phase Ib/randomised IIa open label clinical trial combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer

Research Summary

At present bladder cancer accounts for 10,000 new diagnoses and 5,000 deaths per annum in the UK. The current standard of care is to treat with cisplatin based chemotherapy combined with gemcitabine (GC) in both newly diagnosed and advanced disease groups. Progression or relapse following cisplatin treatment is common, however new information have suggested that DNA demethylating agents could synergise with cisplatin and in turn bypass cisplatin resistance. SGI-110 is a DNA demethylating agent which will be added to the standard GC combination in this trial. This trial will take place in four NHS trusts in England and is looking to recruit a maximum of 56 patients. The dose escalation phase will follow a rolling six (3+3) design in patients with advanced disease only. There will be four dose levels of SGI-110 given with the standard dose of GC. Patients will receive up to 6 cycles (each cycle lasts 21 days) of the combination chemotherapy and SGI-110. They will remain on trial until all side effects have been resolved. Once the optimum dose has been established the trial will open in to a randomised dose expansion phase. Patients with bladder cancer who are receiving GC chemotherapy prior to planed radical cystectomy will be eligible for this part of the trial. 20 patients will be randomised to receive the combination of SGI-110 and GC or GC alone. Prior to surgery, patients will receive 3-4 cycles of GC and SGI-110 or GC alone. They will remain on trial until all side effects have been resolved. The results will be analysed to see if there is a significant difference between the two groups and if they are positive, we will potentially open in to phase III trial.

Inclusion Criteria:

All Patients: 1. ECOG performance status of 0 or 1 2. Glomerular filtration rate estimation of ≥ 60 mL/min according to either the Cockcroft and Gault formula or by Cr-51 EDTA or Tc-99m DTPA clearance 3. Adequate haematological parameters • Haemoglobin ≥ 90 g/dL • Neutrophil count ≥ 1.5 x109/L • Platelets ≥ 100 x109/L 4. Adequate biochemical parameters • Bilirubin ≤ 1.5 x ULN • ALT and ALP ≤ 2.5 x ULN (ALP ≤ 5 x ULN if caused by liver or bone metastases) 5. Aged 16 years or over 6. Life expectancy > 3 months 7. Provision of written informed consent Patients In The Dose Escalation Phase: 8. Incurable histologically or cytologically confirmed, locally advanced or metastatic, solid cancer, for which the use of gemcitabine and cisplatin is a clinically appropriate treatment in the view of the local principal investigator. Any number of previous lines of systemic chemotherapy is permitted. Patients In The Dose Expansion Phase: 9. Bladder cancer with a pure or a predominant component of transitional cell carcinoma 10. Clinical stage T2-4a N0 M0 11. Planned to commence GC for 3 or 4 cycles with neoadjuvant (i.e. curative) intent prior to a planned radical cystectomy

Exclusion Criteria:

All Patients: 1. Unresolved toxicities from prior therapy greater than CTCAE v4.03 grade 1 (with the exception of alopecia) at the time of registration 2. Prior radiotherapy to > 30% of bone marrow 3. Major surgery within 30 days 4. Any investigational medicinal product within 30 days 5. Allergy or other known intolerance to any of the proposed study drugs including supportive agents and inclusive of G-CSF and locally utilised anti-emetics 6. Previously-identified central nervous system metastases unless treated and clinically stable and not requiring steroids for at least 4 weeks prior to the start of trial treatment 7. Coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris or congestive cardiac failure (New York Heart Association ≥ grade 2) within the last 6 months 8. Women who are pregnant or breast feeding. (Women of child-bearing potential must have a negative pregnancy test performed within 7 days prior to the start of trial treatment) 9. Patients of child-bearing potential who are not using, or who are unwilling to use, a highly effective method of contraception 10. Any patient who, in the judgment of the local investigator, is unlikely to comply with trial procedures, restrictions or requirements 11. Any patient who has received a live vaccine within 4 weeks of initiation of their treatment. Patients In The Dose Expansion Phase: 12. Recent or current separate other malignancy. Current non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer is permissible. Participants with a history of a separate other malignancy having completed all active treatment 2 or more years previously may be entered

Sub Specialty:

Bladder Cancer

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Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy

Research Summary

Added as of 23/01/2013: Prostate cancers depend upon the male hormone testosterone for their growth. Lowering testosterone levels (either by removing all or part of both testes, or by giving anti-hormone treatment) slows the growth of prostate cancers. This type of treatment is called hormone treatment and is often used when prostate cancers have spread outside the prostate gland. Although hormone treatment is usually successful at stopping the cancer growing for a period of time, the cancer will begin to grow again in most men. There are increasing numbers of treatments available for advanced prostate cancer. These treatments are usually used in prostate cancer when hormone treatment is no longer effective and the cancer has started to grow again. The aim of this trial, which is called STAMPEDE, is to assess some of these treatments, given earlier in the course of the disease in combination with hormone treatment. The treatments currently assessed inthe trial are: - Radiotherapy to the prostate - Abiraterone and enzalutamide combination Treatments previously assessed but now closed to recruitment: Zoledronic acid, Docetaxel, Celecoxib and Abiraterone alone. The trial information can also be found at the following MRC CTU web page: http://http://stampedetrial.org/

Inclusion Criteria:

PATIENT INCLUSION CRITERIA Patients must fulfil both of the criteria in Section 1 or one criterion in Section 2 or at least one criteria in Section 3. Additionally, all patients must fulfil the criteria in Section 4. 1. HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE Both: - At least two of: Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10 - Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU) OR 2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE At least one of: - Stage Tany N+ M0 - Stage Tany Nany M+ OR 3 PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING1 At least one of: - PSA ≥4ng/ml and rising with doubling time less than 6 months - PSA ≥20ng/ml - N+ - M+ AND 4. FOR ALL PATIENTS I. Histologically confirmed prostate adenocarcinoma II. Intention to treat with long-term androgen deprivation therapy III. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23 IV. Have completed the appropriate investigations prior to randomisation V. Adequate haematological function: neutrophil count > 1.5x109/l and platelets > 100x109/l VI. Estimated creatinine clearance > 30ml/min VII. Serum potassium ≥3.5mmol/L VIII. Written informed consent IX. Willing and expected to comply with follow-up schedule X. Using effective contraceptive method if applicable SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE All patients meeting criteria are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this “RT to the prostate” comparison are: - Newly diagnosed prostate cancer - Demonstrable M1 disease - No contraindication to radiotherapy e.g. no previous pelvic radiotherapy, - No previous radical prostatectomy

Exclusion Criteria:

Patients must not fulfil any of the criteria, below. I. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3 II. Metastatic brain disease or leptomeningeal disease III. Abnormal liver functions consisting of any of the following:  Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl)  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN IV. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment V. Patients with contra-indications to prednisolone, including active peptic ulceration or a history of gastrointestinal bleeding VI. Patients with active inflammatory bowel disease VII. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5 VIII. Any surgery (e.g. TURP) performed within the past 4 weeks IX. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include:  Severe/unstable angina  Myocardial infarction less than 6 months prior to randomisation  Arterial thrombotic events less than 6 months prior to randomisation  Clinically significant cardiac failure requiring treatment (NYHA II-IV)6  Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation  Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg X. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 XI. Prior exposure to abiraterone XII. Prior exposure to enzalutamide XIII. Prior chemotherapy for prostate cancer XIV. Prior therapy with zoledronic acid or other bisphosphonates other than treatment for hypercalcaemia or low bone density XV. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2) XVI. History of seizure including any febrile seizure, loss of consciousness, or transient ischaemic attack within 12 months of randomisation or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization) XVII. Unexplained history of loss of consciousness within 12 months of randomisation XVIII. Operation of heavy machinery during treatment

Sub Specialty:

Prostate Cancer

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SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma

Research Summary

The Ependymoma Program is a comprehensive program to improve the accuracy of the primary diagnosis of ependymoma and explore different therapeutic strategies in children, adolescents and young adults accordingly. This program is open to all patients diagnosed with ependymoma below the age of 22 years. After surgery and central review of imaging and pathology, patients will be enrolled in one of 3 different studies according to the outcome of the initial surgical resection, their age or eligibility/suitability to receive radiotherapy.

Inclusion Criteria:

Overall program Main residence in one of the participating countries Age < 22 years old at diagnosis Newly diagnosed intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary myxopapillary, clear-cell and tanicytic or anaplastic ependymoma Delivery to national referral pathology centre of FFPE tumour tissue blocks (or charged slides with sufficient interpretable material and curls in an Eppendorf tube) Written informed consent for data and study biological samples collection All patients and / or their parents or legal guardians willing and able to comply with protocol schedule and agree to sign a written informed consent Patients must be affiliated to a Social Security System in countries where this is mandatory After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy. Patients with centrally and histologically confirmed intracranial ependymoma (histology confirmed by National Reference centre for Biology and Pathology review) meeting the following criteria will be enrolled into one of interventional strata: •Main residence in one of the participating countries, •Age below 22 years old at the diagnosis, •Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: cellular, papillary, clear-cell and tanycytic or anaplastic ependymoma. •Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial, •Males and females of reproductive age and childbearing potential with effective contraception (see section 4.1.2.4 Definition of highly effective methods of contraception) for the duration of their treatment and 6 month after the completion of their treatment, •Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure Specific inclusion criteria have been defined for each stratum of the program. Stratum 1: •Age > 12 months and < 22 years at time of study entry •No residual measurable ependymoma based on the central neuroradiological review (detailed in protocol) •Histologically confirmed WHO Grade II-III ependymoma by central pathological review •No metastasis on spinal MRI and on CSF cytology assessments •No previous radiotherapy •No previous chemotherapy (except steroids) •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry •No medical contraindication to radiotherapy and chemotherapy, •No signs of infection •Adequate bone marrow function(detailed in protocol) •Adequate liver function (detailed in protocol) •Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) Stratum 2: •Age > 1 year and < 22 years at time of entry to study •Residual non reoperable measurable ependymoma based on central neuro-radiological review (detailed in protocol) •Histologically confirmed WHO Grade II III ependymoma by central pathological review •No metastasis on spinal MRI and on CSF cytology assessments •No previous radiotherapy •No previous chemotherapy (except steroids) •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry •No medical contraindication to radiotherapy and chemotherapy, •No signs of infection •Adequate bone marrow function (detailed in protocol) •Adequate liver function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) Stratum 3 •Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician/parent decision and according to national criteria •Histologically confirmed WHO Grade II-III ependymoma by central pathological review •Adequate bone marrow function(detailed in protocol) •Adequate liver function (detailed in protocol) •Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) •No previous chemotherapy •No previous radiotherapy •No contraindication to chemotherapy Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed

Exclusion Criteria:

All interventional stata •Tumour entity other than primary intracranial ependymoma •Primary diagnosis predating the opening of SIOP Ependymoma II •Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas •Patients with spinal cord location of the primary tumour •Participation within a different trial for treatment of ependymoma •Age ≥ 22 years •Contraindication to one of the IMP used in this stratum according to the SmPC related to the products used in the country concerned. (see SmPC in appendix 4) •Concurrent treatment with any anti-tumour agents •Inability to tolerate chemotherapy •Unable to tolerate intravenous hydration •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the Investigator •Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion •Pregnancy and breast feeding Stratum 1 and 2: •Ineligible to receive radiotherapy •Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator Stratum 3: NHS R&D Form IRAS Version 3.5 12 130101/737949/14/8 •Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion •Pregnancy and breast feeding Stratum 1 and 2: •Ineligible to receive radiotherapy •Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator Stratum 3: •Pre-existing severe hepatic (liver) and/or renal (kidney) damage Family history of severe epilepsy •Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial •Elevated blood ammonium level ≥ 1.5 x upper limit of the normal •Elevated Blood lactate level ≥ 1.5 x upper limit of the normal Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator

Sub Specialty:

Brain Cancer

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SMS - Study of Somatic Mutations using Genome Sequencing

Research Summary

Disease and tissue aging are thought to be influenced by genetic changes, or mutations, acquired throughout life. These mutations provide clues regarding the genetic damage that occurred through the lifetime of the patient, and include mutations caused by environmental factors such as ultraviolet light from sunlight or tobacco smoke affecting the skin or internal tissues, respectively. Other mutations may occur due to errors in copying the genome as cells divide. Improvements in technologies that read the genetic code have made it possible for all or selected parts of the genetic code of a human being to be "sequenced", allowing mutations (changes in the genetic code) to be detected. I n our research, we will use samples of blood, skin biopsies, plucked hairs, urine, surplus tissue removed during future planned surgery, and archived samples removed in the past. We will find the order of DNA bases in the genetic code (sequencing) in the samples to help us understand how the number and type of cells with changes in their DNA is different in tissues depending on a person's age, their exposure to environmental agents, or other factors such as disease history or treatments such as radiotherapy.

Inclusion Criteria:

Controls: Healthy adults with capacity to consent - these may be patient's relatives either recruited by the research nurse or clinician, or recruited via posters put up around the hospital requesting volunteers. Patients: Adults with capacity to consent who have been highlighted by research nurse or clinician as potentially having genetic damage caused by environmental factors, such as UV light or tobacco smoke, or other factors, such as disease history or treatments, for example radiotherapy.

Exclusion Criteria:

Adults who lack capacity to consent. Children.

Sub Specialty:

Bladder Cancer Genetics

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Show RESults to Participants Engaged in Clinical Trials

Research Summary

The Show RESPECT study is trying to find practical ways to share the results of clinical trials with the people taking part in it. It is doing this by testing several different approaches within a large ovarian cancer trial (the ICON8 trial). Each site that is taking part in ICON8 in the UK will be allocated at random to share the results of the study in one or more of the following ways: - a link to a basic webpage that contains a simple summary of the results. - Ga link to an ‘enhanced’ webpage that contains a simple summary of the results, links to further information, a short video of a doctor explaining the results, and a ‘frequently asked questions’ section that answers questions people send in. - a simple printed summary of the results. - Inviting people taking part in the trial to join an email list, where a summary of results and updates will be sent out. We will collect information from people taking part in the trial on how satisfied they are with how the results were communicated to them, including whether they found out the results, how easy it was to understand, and whether it told them everything they wanted to know. We will also collect information from research nurses on how easy it was to share the results using these methods, how much time it took, and what they think of them. We will also carry out interviews with a small number of people taking part in the trial and research nurses to explore their experience and views on this in more detail.

Inclusion Criteria:

1. Participant in the ICON8 trial 2. Currently being followed up at an ICON8 trial site in England, Scotland, Wales or Northern Ireland 3. Aged 18 years or older

Exclusion Criteria:

Exclusion criteria for quantitative and qualitative research: 1.Participant has previously informed their site that they do not wish to attend any further visits in relation to the ICON8 trial, or provide any further data (sometimes referred to as ‘withdrawal of consent’); participants who previously stopped ICON8 trial treatment earlier than expected but continue in ICON8 follow-up will not be excluded, nor will participants who have reduced follow-up arrangements but still contribute data to the ICON8 trial. 2.Lost to follow-up from the ICON8 trial 3.Site staff consider the patient to be too unwell to be contacted about this study For the qualitative research further to the above exclusion criteria, participants will also be excluded if patients do not adequately understand verbal explanations.

Sub Specialty:

Psychosocial Oncology and Survivorship

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A randomized phase III trial comparing radical hysterectomy and pelvic node dissection versus simple hysterectomy and pelvic node dissection in patients with low-risk early-stage cervical cancer

Research Summary

A randomised phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low-risk early stage cervical cancer.

Inclusion Criteria:

1) Histologically confirmed adenocarcinoma, squamous, or adenosquamous cancer of the cervix. Diagnosis has been made by LEEP, cone or cervical biopsy and has been reviewed and confirmed by the local reference gynaecological pathologist. 2) Patient has been classified as low-risk early-stage cervical cancer. These patients include: FIGO Stage 1A2 [FIGO Annual Report, 2009], defined as: a) evidence of disease by microscopy; - histologic evidence of depth of stromal invasion between 3.0-5.0mm based on the local reference pathologist’s measurement of the LEEP or cone specimen (for patient who underwent a LEEP or cone); - histologic evidence of lateral extension that is not greater than 7.0 mm based on the local reference pathologist’s measurement of the LEEP or cone specimen (for patient who underwent a LEEP or cone); and - negative margins (for patients who underwent a LEEP or cone) - radiologic evidence of less than 50% stromal invasion based on pelvic MRI (for patients who underwent a cervical biopsy only) b)FIGO Stage 1B1 [FIGO Annual Report, 2009] with favorable (low risk) features, defined as: - a clinically visible lesion or a microscopically diagnosed lesion measuring > 5 mm depth of invasion or > 7 mm in lateral extension or a IA2 sized lesion with positive margins; - histologic evidence of less than 10mm stromal invasion based on the local reference pathologist’s measurement of the LEEP or cone specimen Note: this criterion will not apply to patients who underwent a cervical biopsy only; - Radiologic evidence of maximum dimension of ≤ 20 mm as seen by pelvic MRI; and - Radiologic evidence of less than 50% stromal invasion based on pelvic MRI. 3) The histologic grade of cervical cancer must be 1, 2, 3 or not assessable 4) Physical examination, rectovaginal examination and visualization of the cervix by speculum or colposcopic examination have been done after the initial diagnosis procedure (LEEP, cone or biopsy) and prior to randomisation. Staging criteria described in 2 above must be satisfied based on these examinations. 5) Chest X-Ray or CT scan of the chest AND pelvic MRI (pelvic MRI is optional if the patient has stage 1A2 disease and underwent and LEEP or cone) done after initial diagnostic procedure (LEEP, cone or biopsy) and prior to randomisation. Staging criteria described in 2 above must be satisfied based on these examinations. The CT should be a 16 slice (or higher) helical scanner. Oral and intravenous contracts are preferred (unless there is a contraindication to the use of contrast) with scan obtained in the portal phase at a slice thickness of 5mm or lower. Pelvic MRI should be performed on a 1.5 or 3 Tesla magnet with pelvic phased-array coils. The MR pulse sequences will consist of T1 gradient echo in the axial plane at 5mm slice thickness and fast spin echo in the axial, sagittal, and coronal planes at 4mm slice thickness. The short axis (perpendicular to the tumour's long axis) with a 3mm slice thickness is required in the best plane to show the maximum thickness of stromal invasion. Use of an anti-peristaltic agent is mandatory while intravenous use of gadolinium or diffusion-weighted imaging (DWI) is optional. 6) After consideration of a patient's medical history, physical examination and laboratory testing, patients must be suitable candidates for surgery as defined by the attending physician / investigator. 7) Patients must have no desire to preserve fertility. 8) Patients must be willing to complete the Quality of Life Questionnaire. The baseline assessments must be completed within 6 weeks prior to randomisation. Inability (illiteracy in English, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. Patients fluent in English or French who reside in Canada and the United Kingdom must agree to participate in the economic evaluation component of this trial and complete the Health Economics Questionnaires. 9) Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. 10) Patient must be accessible for treatment and follow up. Investigator must assure themselves the patients randomised on this trial will be available for complete documentation of the treatment, adverse events and follow up. 11) Surgery is to be done within 20 weeks of initial diagnosis (no exceptions). The 20-week period includes time required for diagnosis, referral, diagnostic staging, randomisation and scheduling of the surgical procedure. 12) Patients must be 18 years or older.

Exclusion Criteria:

1) Patients with FIGO 1A1 disease 2) History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours, Hodgkin's lymphoma or non-Hodgkin's lymphoma curatively treated with no evidence of disease for > 5 years 3) Patients with evidence of lymph node metastasis on preoperative imaging or histology 4) Patients who have had or will receive neoadjuvant chemotherapy

Sub Specialty:

General Surgery Gynaecological Cancers Reproductive and Sexual Medicine

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A randomised Phase II/III trial to study radiotherapy dose escalation in patients with oesophageal cancer treated with definitive chemoradiation with an embedded Phase II trial for patients with a poor early response using positron emission tomography (PET)

Research Summary

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Inclusion Criteria:

1.17 years of age or older. 2.Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT. 3.Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma. 4.Tumours of the cervical, thoracic oesophagus, or gastrooesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm aboral and distal extent of primary tumour no more than 2 cm beyond the GOJ. 5. Tumours staged with spiral CT scan, PETCT with/without endoscopic ultrasound (EUS), to be T14, N/+ (provided total tumour length including nodes is ≤10). To be eligible for PET randomisation, the PETCT must be within 4 weeks of start date of treatment. 6. Total contiguous disease length ≤10cm defined by CT, EUS and/or PET. This includes ≤8cm primary tumour plus nodes within 2cm. 7. WHO performance status 0 or 1. 8. Adequate haematological, renal, respiratory, cardiac and hepatic function, and are fit to receive all protocol treatment. 9. Patients with reproductive potential (male or female), who are sexually active during the duration of the trial, should be prepared to use a highly effective method of contraception preferably with low user dependency for at least six months after the last dose of chemoradiotherapy. 10. Patients who have provided written informed consent prior to randomisation. Additional inclusion criteria for patient eligibility for PET randomisation: 11.Baseline SUVmax ≥ 5. 12.PET scan 14 days after start of chemo (2/+3 days from this date is acceptable) 13.Not responding to early cis/cape chemotherapy (< 35% reduction in SUVmax) 14.For diabetics, fasting Blood glucose ≤12 mmol/L.

Exclusion Criteria:

1. Patients who have had previous treatment for invasive oesophageal carcinoma or gastrooesophageal junction carcinoma 2. Patients with metastatic disease 3. Patients with other active malignancy or past malignancy in remission for less than 3 years except patients that have been curatively treated from the following conditions; basal cell carcinoma, Carcinomainsitu breast and carcinomainsitu cervix 4. Patients with > 2cm mucosal extension of tumour into the stomach or where the superior extent is proximal to 15 cm ab oral. 5. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease. 6. Patients who need continued treatment with a contraindicated concomitant medication or therapy. 7. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. 8. Patients with hearing impairment or sensorymotor neuropathy of WHO grade ≥2. 9. Known hypersensitivity to IMPs. 10. Women who are pregnant or breastfeeding.. 11. Oesophageal stent (Patients requiring a PEG/RIG/feeding jejunostomy for nutritional purposes are eligible). 12. Any other situation, which in the opinion of the local PI, makes the patient an unsuitable candidate for this trial (eg with profusely bleeding tumours where the PI has concerns about randomisation to paclitaxel/carboplatin arm where there is risk of aggravation of bleeding due to higher risk of thrombocytopenia)

Sub Specialty:

Upper GI

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A population based study of genetic predispositions and gene-environment interactions in cancer

Research Summary

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Inclusion Criteria:

Breast, Colorectal, Melanoma, Bladder, Brain, Kidney, NonHodgkins, Oesophageal, Pancreatic: men and women diagnosed at age 18-69 years Endometrial, Ovarian: women diagnosed at age 18-69 years Prostate: men diagnosed at age 18-69 years

Exclusion Criteria:

not specified

Sub Specialty:

Breast Cancer Cancer Primary Care

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SERENADE: Screening for synchronous metastases in colorectal cancer using Hepatic Diffusion weighted MRI.

Research Summary

Contrast enhanced CT is the standard imaging modality for the diagnosis of liver metastases in patients with colorectal cancer, but patients in the SERENADE trial will receive an additional Diffusion Weighted MRI (DW-MRI) scan of the liver which may identify more patients with synchronous liver metastases. Identification of liver metastases in an accurate and timely fashion allows the early identification of patients for surgical metastectomy and neoadjuvant therapy, or may possibly identify more patients who are suitable for trials of the treatment of metastatic disease.

Inclusion Criteria:

1. High risk primary colorectal cancer (as determined by CT or MRI). 2. CT which is negative for, or no confirmatory evidence of, metastatic disease . 3. Patient aged over 18 years

Exclusion Criteria:

1. Patients who are unable to give consent, who withhold consent or who withdraw consent will be excluded. 2. Patient is undergoing active treatment or follow-up for another malignancy (excluding basal cell carcinoma). 3. Patient has a contraindication to CT or MRI (e.g. intraocular metal fragments, pacemaker, severe claustrophobia), iodine or gadolinum based contrast agents (documented allergy to iodine, renal impairment with GFR < 30mL/min) 4. Patients who are pregnant or breast feeding. 5. Patients who have received systemic treatment for colorectal cancer. 6. Patients with any metastatic disease.

Sub Specialty:

Colorectal Cancer Other

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Response to Optimal Selection of neo-adjuvant Chemotherapy in Operable breast cancer: A randomised phase III, stratified biomarker trial of neo­adjuvant 5-Fluorouracil, Epirubicin and Cyclophosphamide vs Docetaxel and Cyclophosphamide chemotherapy

Research Summary

Neoadjuvant chemotherapy (NAC), for early breast cancer reduces the amount of surgical treatment required, often avoiding the need for mastectomy. A pathological complete response (pCR) is generally associated with excellent prognosis and no pCR is associated with poor outcomes. To maximise pCR patients are treated with both epirubicin and docetaxel containing combinations increasing toxicity due to exposure to both drugs. Retrospective analysis of adjuvant chemotherapy trials strongly suggests that a combination of two genetic markers (CEP17 and TOP2A) predict for epirubicin sensitivity. It may be unnecessary to treat all patients with both epirubicin and docetaxel. Current standard of care in patients with involved axillary nodes before chemotherapy is an axillary dissection. When there is no residual cancer this becomes an unnecessary procedure. The data on the use of sentinel lymph node biopsy post NAC is controversial. In ROSCO 1056 patients with early breast cancer will be randomised from hospitals around the UK to initial chemotherapy with either epirubicin based or docetaxel based chemotherapy. They will be stratification by CEP17 and TOP2A status. On completion of 4 cycles of chemotherapy patients will undergo surgery and pCR assessment. Where pCR is not achieved patients will receive the alternative chemotherapy as adjuvant treatment. The aim is to determine if CEP17 and TOP2A status can be used to select the appropriate chemotherapy, resulting in higher pCR rates and a requirement for less chemotherapy. Patients with axillary node involvement prechemotherapy will undergo a post NAC, sentinel node biopsy (SLNB) and axillary clearance as a single procedure to determine if post NAC SLNB is sufficiently accurate to be used as a routine staging tool in this context. Patients will be followed up for 5 years.

Inclusion Criteria:

ROSCO Main Trial • Patient with histological diagnosis of invasive breast cancer • Suitable for neo­adjuvant chemotherapy in opinion of investigator • Unifocal tumour: - Radiological size greater than or equal to (≥) 20 mm by ultrasound (or in some cases Magnetic Resonance Imaging (MRI) is allowed) ­ -T4 tumour of any size with direct extension to (a) chest wall or (b) skin or both - ­ Inflammatory carcinoma with tumour of any size OR Multifocal tumour: ­ The sum of each tumour’s maximum diameter must be ≥20 mm (total sum of multifocal deposits ≥20 mm by ultrasound) OR Other locally advanced disease ­ Biopsy confirmed axillary lymph node involvement or large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes and primary breast tumour of any diameter ­ Involvement of large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes without a primary breast tumour identified: in this case the presence of breast cancer in a lymph node must be histopathologically confirmed by lymph node biopsy (trucut or whole lymph node) • Patients with bilateral disease are eligible to enter the trial, if one of the criteria above is met for disease in at least one breast • Any HER2 status • Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician. The following recommendations must be taken into account when making this assessment: ­ Patients with HER2 positive disease must not have clinically significant cardiac abnormalities. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of Left Ventricular Ejection Fraction (LVEF) by Multi Gated Acquisition (MUGA) scan or echocardiogram (ECHO). LVEF must be within the normal range as defined locally by the treating hospital ­ Patients must have adequate bone marrow, hepatic, renal and haematological function • Eastern Co­operative Oncology Group (ECOG) performance status of 0 or 1 • Women of child­bearing potential, or men in a relationship with a woman of child­bearing age, prepared to adopt adequate contraceptive measures if sexually active • 18 years or older • Male or female • Written informed consent for the trial • Availability of embedded paraffin tumour blocks from pre­chemotherapy biopsy is required • Willing and able to comply with scheduled visits, treatment plan and other study procedures Sentinel Lymph Node Biopsy Study (in addition to above) • Biopsy/fine needle aspiration proven involved ipsilateral axillary lymph nodes at diagnosis

Exclusion Criteria:

ROSCO Main Trial • Tumours of low or intermediate grade (Grade 1 or 2) which are also Oestrogen Receptor (ER) rich and Progesterone Receptor (PgR) rich or PgR unknown, whatever the size or nodal status • Previous invasive breast cancer • Unequivocal evidence of metastatic disease • Previous diagnosis of other malignancy unless: ­ Disease­free for 5 years; or ­ Previous basal cell carcinoma, cervical carcinoma in situ, superficial bladder tumour; or ­ Contralateral or ipsilateral DCIS of the breast treated by surgery alone • Previous chemotherapy • Prior extensive radiotherapy (as judged by the investigator) to bone marrow • Previous neo­adjuvant endocrine therapy (unless less than 6 weeks duration) • Concomitant hormonal therapies/chemotherapy or any other medical treatment in relation to treating the breast cancer • In HER2 positive patients risk factors precluding co­administration of trastuzumab and FEC75 ­ Previous myocardial infarction during the 6 months prior to recruitment ­ LVEF below institutional lower limit of normal and no echocardiographic evidence of heamodynamically ­ Significant valvular heart disease or ventricular contractility • Prior diagnosis of cardiac failure • Uncontrolled hypertension, coronary heart disease other significant cardiac abnormality • Bleeding diathesis • Presence of active uncontrolled infection • Any evidence of other disease which in the opinion of the investigator places the patient at high risk of treatment related complication • Pregnant (female patients of child bearing potential should have a urine or blood Human Chorionic Gonadotropin test performed to rule out pregnancy prior to trial entry) • Lactating females • Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent completion of treatment or follow­up Sentinel Lymph Node Biopsy Study (in addition to above) • Negative nodes at diagnosis • SLNB at diagnosis • Allergy to patent blue dye

Sub Specialty:

Breast Cancer Breast Surgery

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Stereotactic ablative radiotherapy for oligometastatic non-small cell lung cancer. A randomised phase III trial.

Research Summary

The SARON trial is a phase III trial looking to see if adding radiotherapy (conventional, stereotactic radiotherapy and / or stereotactic radiosurgery (give to the brain)) to standard chemotherapy can improve overall survival in non-­small cell lung cancer (NSCLC) patients with 1- ­3 metastases. The target accrual is 340 patients. The trial is funded by Cancer Research UK and sponsored by University College London. The trial will be coordinated by the CR UK & UCL Cancer Trials Centre. • All patients in the trial will receive 4 cycles of standard doublet-platinum chemotherapy. • After two cycles of chemotherapy, patients will be assessed for progression. Those that have not progressed, have a performance status of 0, 1 or 2 and continue to meet eligibility will be randomised. • Patients randomised to the control group (chemotherapy only) will receive 2 more cycles of chemotherapy. • Patients randomised to the investigational group (chemotherapy plus radiotherapy) will receive 2 more cycles of chemotherapy followed by radiotherapy to all sites of disease. • All patients will be followed up for 3 years after completing trial treatment or until death. A safety sub­study will look at the first 20 patients receiving conventional radiotherapy to the primary and stereotactic radiotherapy to thoracic metastases to assess the level of lung inflammation within the first 3 months after the end of treatment. A feasibility sub­study will make an assessment after the first 50 patients have been randomised. This will review the practicality of achieving recruitment targets, assess the logistics of delivering the radiotherapy treatment, and the potential for patients seeking stereotactic radiotherapy off study if randomised to the control group. Primary Endpoint: Main trial ­ Overall survival Sub­Studies: Feasibility Sub­ Study • Recruitment rate • Logistical practicalities • Assess if patients seek stereotactic radiotherapy outside of the trial. Safety Sub­ Study Grade 3-­5 lung inflammation Secondary Endpoint: Main trial: • Progression­free survival • Local control of lung tumour and all metastases • New distant metastases

Inclusion Criteria:

1) Histologically or cytologically confirmed NSCLC. 2) Negative or unknown EGFR and ALK mutation status EGFR testing is mandatory and ALK testing to be performed if part of local policy. 3) Staging with FDG PET­CT whole body scan and MRI brain or CT brain with IV contrast within 42 days prior to registration. 4) ECOG performance status 0 to 1 at time of registration. 5) Patient presenting with synchronous primary disease and oligometastatic disease. 6) Patient is fit to receive four cycles of platinum­based doublet chemotherapy, cisplatin or carboplatin, according to local guidelines and assessment. 7) Primary tumour and nodes included in the radical RT volume must suitable for radical RT (either conventional RT or SABR). Conventional RT fields do not need to be contiguous. 8) Patient is deemed fit to receive conventional RT and SABR/SRS according to local guidelines and assessment. 9) Between one and three metastatic lesions, assessable according to RECIST v1.1 and suitable for SABR/SRS (only one site of metastases OR the primary tumour needs to be measurable according to RECIST v1.1) i. Nodes included in the radical RT volume will not count towards the number of sites of metastases ii. Nodes not treated in the radical RT volume are counted as metastases. The patient, though, must have stage IV disease. The same RT dose constraint eligibility criteria will apply to these nodes as to other metastases. iii. Only station 1 neck nodes (Foundation system) are considered N3. Higher neck nodes are considered as metastases. Note: If brain metastasis present, at the time of randomisation, the largest lesion must be no more than 3cm in maximum diameter. A second lesion must be no more than 2cm maximum in diameter. 10) Acceptable lung function for radical lung radiotherapy. 11) No relevant co­morbidities, including pulmonary fibrosis and connective tissue disorders.

Exclusion Criteria:

1) Patient has had palliative radiotherapy to any tumour site prior to registration or requires palliative radiotherapy prior to randomisation. 2) One or more metastases previously treated with alternative ablative treatment, e.g. RFA or surgery 3) Patient has received any previous treatment for this NSCLC malignancy 4) Patients who present with brain metastasis only and no sites of extra cranial metastatic disease i.e. the presence of more than 2 brain metastases is an exclusion criteria. 5) Metastasis in sites where normal radiotherapy constraints cannot be met 6) Brain metastasis within the brainstem 7) Patients who have more than three metastases prior to trial registration. 8) Primary tumour or metastases causing direct invasion or high clinical suspicion of direct invasion of the wall of a major blood vessel. 9) Malignant pleural or pericardial effusion 10) Patients with bilateral adrenal metastases 11) History of prior malignant tumour likely to interfere with the protocol treatment or comparisons, unless the patient has been without evidence of disease for at least 3 years or the tumour was a non­melanoma skin tumour or early cervical cancer 12) Women who are pregnant or breast feeding 13) Stage III disease even with extensive nodal disease or the tumour was a non­melanoma skin tumour or early cervical cancer 14) Leptomeningeal disease

Sub Specialty:

Lung Cancer

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Phase I/II study to determine the maximum tolerated dose and activity of the combination of romidepsin and carfilzomib in relapsed or refractory peripheral T-cell lymphoma

Research Summary

RomiCar is a prospective, single arm, multicentre phase I/II clinical trial for patients with relapsed or refractory peripheral T-cell lymphoma. The following designs will be used in each phase: Phase I: Continual Reassessment Method (CRM) to determine the Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib. Phase II: A’Hern’s single stage design to assess the activity (best overall response rate (PR + CR)) of the combination of romidepsin and carfilzomib over 8 cycles of treatment.

Inclusion Criteria:

• Age ≥ 16 years of age • Life expectancy > 12 weeks • ECOG performance status ≤ 2 • Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma, extranodal NK/T-cell lymphoma, transformed mycosis fungoides, hepatosplenic T-cell lymphoma • Failed at least 1 prior therapy (but no upper limit of prior regimens) • Patients MAY have had a prior allogeneic stem cell transplant but must not require systemic immunosuppression for graft-versus-host disease (local treatments are permitted) • Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x10^9/l and platelets ≥ 100x10^9/l or ≥ 75x10^9/l if marrow involvement documented) • Adequate liver function (bilirubin ≤ 1.5 x ULN, AST / ALT ≤ 2x ULN) • Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) • Serum potassium ≥ 3.8 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ LLN prior to trial entry • CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in craniocaudal length attributable to relapsed lymphoma • Ability to give informed consent * For all relapsed patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 6 months and preferably to confirm refractory disease.

Exclusion Criteria:

• Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2 • Previous treatment with histone deactylase inhibitor or proteasome inhibitor • Need for any other concurrent anticancer drug (apart from corticosteroids at a dose equivalent to prednisolone ≤ 7.5mg daily). A steroid prephase may be used but should be stopped by the first day of cycle 1. • Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant • Previous systemic malignancy within the last 3 years unless treated with curative intent with no sign of recurrence. Other exceptions include non-melanotic skin cancer or carcinoma in-situ of the uterine cervix • Coexisting active infection requiring parenteral antibiotics • Patients unable to swallow oral medication • Active infection with HIV, hepatitis B or hepatitis C • Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigational agents within 28 days prior to trial entry (or a longer period depending on the defined characteristics of the agents used, please contact the trials office for confirmation). *Limited field radiotherapy to an isolated lesion in bone or soft tissue must be completed 2 weeks prior to trial entry • Major surgery within 4 weeks of trial entry • Patients with proven CNS involvement • QTc interval of ≥ 450ms or patients taking medications that significantly prolong the QT interval • Patients taking any inhibitors or strong inducers of CYP3A4, with the exception of dexamethasone. • Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry and within 7 days prior to the start of treatment. Postmenopausal females (> 45 years old and without menstruation for > 1 year) and surgically sterilised females are exempt from a pregnancy test) • Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy • Concurrent Pulmonary Hypertension • Left Ventricular Ejection Fraction (LVEF) of< 40%

Sub Specialty:

Lymphoma

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ROMIO: RCT of minimally invasive or open oesophagectomy

Research Summary

Oesophageal cancer is relatively common in the UK. If detected early, it may be cured with surgery (oesophagectomy). The operation to remove the cancer is complex with large incisions made to the abdomen, chest and, sometimes, neck. 30% of patients experience complications, and about 3% of patients die soon afterwards. Surgery improves survival rates but there is a reduction in quality of life. The limited available data suggest that minimally invasive ‘keyhole’ surgery for oesophageal cancer may achieve the same survival benefit as open surgery, but with better recovery. It is possible that the improved recovery seen in these studies may be due the selection of fitter patients for the minimally invasive procedure. A pilot study has enabled us to refine the trial methodology for a robust RCT, designed to detect clinically important improvements in recovery with minimally invasive surgery at in 406 patients at 7 UK centres. Patients with localised oesophageal cancer, referred for surgery by their multi-disciplinary cancer care team, will be invited to join the study. Patients will be excluded if they have previous surgery or cancer that would make the oesophagectomy more difficult or are pregnant. Following informed consent, patients will be randomly allocated to open oesophagectomy (OO) or “laparoscopically-assisted” oesophagectomy (LAO). The abdominal surgery in the LAO group will use minimally invasive methods. The primary outcome will be a validated measure of physical function. Data will also be collected on survival, days in hospital, complications, pathological specimen quality, health-related quality of life and resource use data. Follow-up is for at least two years post-randomisation. A sub-study at two centres will also randomly allocate patients to a fully minimally invasive oesophagectomy, this will provide unbiased early information on this novel approach.

Inclusion Criteria:

Participants may enter study if ALL of the following apply: 1. 18 years of age or above 2. Referred for primary oesophagectomy by the multi-disciplinary team (MDT) or oesophagectomy following re-staging after neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (N.B, in this any type of neoadjuvant treatment may be used) 3. Confirmed MDT evidence of at least adenocarcinoma or at least squamous cell cancer of the oesophagus or oesophago-gastric junction 4. Fit for pre-operative anaesthesia and surgery, assessed by the MDT 5. Able to provide written informed consent. 6. Measurement (endoscopic or otherwise) that the tumour starts more than 5cm below crico-pharyngeus 7. Measurement (endoscopic or otherwise) that the tumour involves less than 4 cm of the gastric wall 8. The final pre-treatment tumour stage is between T1N0M0 and T4aN1M0, i.e. including all stages (T1N0M0, T1N1M0, T1N2M0, T2N0M0, T2N1M0, T2N2M0, T3N0M0, T3N1M0, T3N2M0, T4aN0M0 and T4aN1M0) in which T4a is a resectable tumour invading pleura, pericardium, or diaphragm.

Exclusion Criteria:

Participants may not enter study if ANY of the following apply 1. Patients with high grade dysplasia (squamous cell or adenocarcinoma) 2. Stage 4 disease 3. Type 3 tumours of the oesophago-gastric junction that are scheduled for total gastrectomy 4. Patients with squamous cell cancer of the oesophagus who the MDT recommends or who individually elect to undergo definitive chemoradiotherapy 5. Evidence of previous complex thoracotomies or laparotomies that preclude a minimal access approach 6. Evidence of previous/concomitant malignancy that would interfere with this treatment protocol 7. Pregnancy 8. Patients participating in other trials that would interfere with the implementation of this protocol at a particular site.

Sub Specialty:

Upper GI Upper GI Surgery

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An Evaluation Of The Impact Of Mode Of Surgery On Patient Centered Outcomes In Gynaecological Cancer

Research Summary

The aim of this study is to investigate patient recovery after surgery for gynaecological cancer. Patients will complete health-related quality-of-life questionnaires following open, Key hole (laparoscopic) and robotic surgery. In addition they will complete a walking test. These investigations will be administered before the operation and at fortnightly intervals in the six weeks following the operation. The theory being tested is that patients undergoing robotic surgery will have a better rate of recovery compared to the other surgical approaches.

Inclusion Criteria:

All women undergoing surgery to treat a gynaecological cancer, including cancer of the uterus, cancer of the cervix, cancer of the fallopian tubes/ovaries.

Exclusion Criteria:

Individuals will be excluded if they are aged < 16 years, are unfit for surgery, have a benign diagnosis, if surgery is possible only by an open approach, if surgery is anticipated to require a midline laparotomy incision beyond 4 cm above the umbilicus, if the patient is being treated for a large ovarian tumour, if the patient requires radical de-bulking surgery, if the patient requires more than hysterectomy and oophorectomy (e.g. bowel resection) or if they are unable to complete the outcome measures due to cognitive impairments or an inability to speak or understand English due to the requirement to complete the questionnaires.

Sub Specialty:

Gynaecological Cancers Gynaecological Surgery

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Refining Ovarian Cancer Test Accuracy Scores: A test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

Research Summary

The ROCkeTS project aims to derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This project will be conducted in four interlinked Phases 1. Phase 1 will be to undertake systematic reviews of the accuracy of tests and risk prediction models used for identifying OC in women with suspected OC. 2. Simultaneously, in Phase 2 we will undertake refinement of an existing risk prediction model based on additional predictions within existing large datasets. For Phase 2, we have identified 3 datasets UKCTOCS, UKOPS and InternationalOvarian Tumour Analysis (IOTA) that are relevant to primary care and secondary care settings in post and premenopausal women. 3. Phase 3 Prospective study, based on the evidence from Phases 1 and 2 , the most promising tests and risk prediction models for post and menopausal women will be externally validated, in a prospective study comprising newly presenting premenopausal and postmenopausal patients. In order to conduct this complex project as effectively as possible, we will start recruitment to the Phase 3 study and banking of samples from patients concomitant with Phases 1 and 2. 4. In Phase 4, we will develop models of pathways and cost comparisons of alternative testing. Pathways will incorporate the differences in patient management guided by different thresholds of the risk prediction models, that inform the minimum predicted probability that flags a diagnosis of OC.

Inclusion Criteria:

Pre and postmenopausal women with symptoms of suspected OC and either raised Ca125 or abnormal USG.

Exclusion Criteria:

USG reveals nonovarian pathology e.g. fibroids or simple ovarian cysts < 5cm in size (very low risk of malignancy). Patients with normal pelvis USG. Patients who decline transvaginal scan. Patients unable to provide informed consent.

Sub Specialty:

General Surgery Gynaecological Cancers Reproductive and Sexual Medicine

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International randomised controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma

Research Summary

rEECur is a randomised study to compare four chemotherapy regimens to see which is the best at treating recurrent or refractory Ewing sarcoma. Ewing sarcoma is a type of bone cancer. Recurrent Ewing sarcoma means Ewing sarcoma that has come back after being treated. Refractory Ewing sarcoma means Ewing sarcoma that has grown or progressed while being treated. Ewing sarcoma is rare and running a study such as this requires funding and collaboration across many different treatment centres and countries. The logistics behind running such a study are not trivial and as a result rEECur is the first study to directly compare different chemotherapy regimens in this disease setting. Most doctors treat recurrent and refractory Ewing sarcoma with chemotherapy. However, although several chemotherapy regimens are available to treat this disease, we do not know which is the best regimen to use. We are primarily interested in finding out which regimen is most effective at making tumour deposits shrink and, in the longer term, at curing the disease or providing prolonged disease control. We will also determine which regimen has the most side effects, which is associated with the most time spent in hospital and which has the greatest effect on quality of life. The results will help us to know which chemotherapy regimen is the best to use for patients with this disease. It will also allow us to inform patients about the relative burden of side effects associated with each regimen, allowing individual patients and/or parents to make an informed choice about how to be treated.

Inclusion Criteria:

1. Histologically confirmed Ewing sarcoma. 2. Disease recurrence or progression after completion of first line treatment OR Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on Response Evaluation Criteria In Solid Tumors (RECIST). The appearance of new bone lesions on bone scan will require confirmation with crosssectional imaging. 3. Soft tissue disease component evaluable by crosssectional imaging. Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure. 4. Age ≥4 years and < 50 years. 5. Patient assessed as medically fit to receive cytotoxic chemotherapy. 6. Documented negative pregnancy test fr female patients of childbearing potential. 7. Patient agrees to use effective contraception during therapy and for 12 months. after last trial treatment (females) or 5 months after last trial treatment (males), where applicable. 8. Written informed consent from the patient and/or legal guardian.

Exclusion Criteria:

1.Bone marrow infiltration resulting in absolute neutrophil count (ANC) < 1.0 x 109/l or platelets < 75 x 109/l 2.Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previosu two weeks. 3.Myeloablative therapy within previous eight weeks. 4.Radiotherapy to target lesion within previous six weeks. 5.Pregnant or breastfeeding women. 6.Followup not possible due to social, geographic or psychological reasons.

Sub Specialty:

Sarcoma

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Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART): An international investigator-led phase III multi-arm multi-stage randomised controlled platform trial of adjuvant therapy in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

Research Summary

Renal cell carcinoma is a type of kidney cancer that starts from the kidneys. It is the 8th most common cancer in the UK and an increase of new cases of 2% has been seen in the last twenty years. About half of the new cases of kidney cancer are among people aged 70 and above. Patients whose disease has not spread outside the kidneys typically have surgery to remove a part or all of their kidney (called a partial or radical nephrectomy). After surgery, patients are seen by their doctor with regular check-ups to look for signs of the cancer coming back or spreading to other parts of the body; this is generally called ‘active monitoring’ or ‘active surveillance’. Unfortunately, it is estimated that the cancer will return in 30-40% of the patients who have undergone surgery. Many clinical studies have been carried out to find if a new treatment after surgery might slow the cancer coming back or prevent it from coming back altogether. However, to date no treatment is available. Immunotherapy is a type of cancer treatment that ‘wakes up’ the patient’s own immune system so it can fight the cancer. New drugs which act in this way have worked well in patients with skin cancer (melanoma), lung cancer and in patients with kidney cancer that has spread outside the kidney. RAMPART is a study looking at two new immunotherapy treatments. We aim to find out whether taking one drug (durvalumab) or a combination of two drugs (durvalumab and tremelimumab) for one year can prevent or delay kidney cancer from coming back compared to the current standard of care (active monitoring after surgery). Durvalumab is sometimes referred to as an anti-PDL1 drug, and it is currently being tested (alone or in combination with other drugs) in many types of cancer. Tremelimumab is sometimes called anti-CTLA4 drug. It is also being tested in different types of cancer. Like all drugs, these treatments have side effects and patients will have regular blood tests, scans and appointments with their study doctor and nurse. Around 1,750 patients from the UK, Australia, France and the US will join the study. It will take approximately 5.5 years to reach this number. The first results from the study are expected 6.5 years after the study starts, with more results following later. If positive, the results of the study will change the current standard of care for the treatment of kidney cancer after surgery.

Inclusion Criteria:

1.Histologically proven RCC (all cell types of RCC are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); no evidence of residual macroscopic disease on post-operative CT scan after resection of RCC. Patients with treated bilateral synchronous RCCs are eligible. 2.At the start of recruitment patients with Leibovich score 3-11 will be eligible for randomisation. MRC CTU will monitor accrual and stop recruiting intermediate risk patients (Leibovich Score 3-5) after three years or when intermediate risk patients contribute 25% of the total accrual target, whichever is earlier. Recruitment of patients with Leibovich Score 6 11 will continue until the accrual target is reached. 3.Patients should have had surgery at least 28 days but no more than 91 days prior to randomisation date. 4. Post-operative scans should be performed within 28 days prior to randomisation 5.WHO Performance Status 0 or 1. 6.Patient has archival FFPE pathology tissue available, and agrees to provide at least one sample (FFPE tumour block from nephrectomy, or a minimum of 10 unstained slides), as well as a baseline EDTA blood sample for future translational research 7.Adequate normal organ and marrow function a.Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks of randomisation in order to achieve the entry criteria). b.Absolute neutrophil count (ANC) > = 1.5 x 109/L (> = 1500 per mm3). c.Platelet count > = 100 x 109 (> = 100,000 per mm3). d.Bilirubin < = 1.5 x ULN (This will not apply to subjects with confirmed Gilbert’s syndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician). e.AST/ALT < = 2.5 x ULN. f.Calculated Creatinine Clearance level > 40mL/min by Cockcroft Gault formula 8.12-lead ECG on which QTcF must be < 470 ms. In case of clinically significant ECG abnormalities, including a QTcF value > = 470 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. 9. Patient must weight > = 30Kg at the time of randomisation 10.Subjects must be > = 18 years in age. 11.Written Informed Consent obtained from the patient 12.Both men and women enrolled in this trial must use adequate contraception during the treatment phase of the study and for 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided. 13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age specific requirements apply: a. Women < 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy). b. Women > = 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy induced menopause with last menses > 1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

Exclusion Criteria:

1.Previous diagnosis of RCC. 2.Metastatic or macroscopic residual disease. 3.Patients with a single pulmonary nodule > = 5mm diameter are not eligible unless the nodule has had a definite benign diagnosis. Patients with multiple small, less than 5 mm nodules may be eligible if nodules have been shown to be radiologically stable for at least 8 weeks. 4.Prior anticancer treatment (other than nephrectomy) for RCC. 5. Any unresolved toxicity NCI CTCAE Grade > = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria a. Patients with Grade > = 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician. 6. History of another primary malignancy except for: a) Malignancy treated with curative intent and with no known active disease > = 5 years before the first dose of IP and of low potential risk for recurrence. b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c) Adequately treated carcinoma in situ without evidence of disease. 7. History of leptomeningeal carcinomatosis. 8. Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow up period of an interventional study. 9. Major surgical procedure (as defined by the Investigator) within 28 days prior to the start of treatment. Local surgery of isolated lesions for palliative intent is acceptable. 10. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years may be included but only after consultation with the RAMPART Trial Management Team e. Patients with coeliac disease controlled by diet alone 12. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty. 13. History of allogeneic organ transplant. 14. Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection b. Symptomatic congestive heart failure c. Uncontrolled hypertension d. Unstable angina pectoris e. Uncontrolled cardiac arrhythmia f. Active peptic ulcer disease or gastritis g. Active bleeding diatheses h. Psychiatric illness or social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. 15.Active infection including a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) b. Hepatitis B (known positive HBV surface antigen (HBsAg) result) c. Hepatitis C d. Human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti HBc] and absence of HBsAg) are eligible. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 16. Receipt of live attenuated vaccine within 30 days prior to the start of treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving investigational medicinal product and up to 30 days after the last dose of investigational medicinal product. 17. Pregnant or breastfeeding patients. 18. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 19. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients. 20. Previous investigational medicinal product assignment in the present study.

Sub Specialty:

Renal Cancer

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A phase IIa study of Rituximab and Varlilumab in relapsed or refractory B-cell malignancies

Research Summary

Each year, 12,000 people in the UK are diagnosed with B-cell malignancies. B-cell cancers can be divided into high grade or low grade based on how quickly the cancer grows. Although high grade lymphomas (e.g. diffuse large B-cell lymphoma (DLBCL)) are potentially curable, approximately 30% of patients will relapse after frontline therapy. There is no established standard for second line therapy but consolidation therapy with autologous stem cell transplant is undertaken if a patient is fit enough. Even with transplantation, only 50% of patients will achieve durable remissions. Thus the great majority of patients with relapsed DLBCL will eventually succumb to the disease. Whilst low grade diseases lead a less aggressive course, successive remissions become increasingly shorter, necessitating different therapies with each relapse. Thus there is a clear clinical need for more novel therapeutic agents in B-cell lymphoma. In this trial, patients with high grade or low grade B-cell lymphoma whose cancer has come back after initial response or has not responded to treatment will be treated with rituximab and varlilumab. Varlilumab is an immunostimulatory antibody. It binds to the normal immune cells and enhances their anti-tumour effect. Rituximab is an antibody that targets the tumour cells directly. It binds to the CD20 molecule that is present on the surface of normal and malignant B-cells and engages the immune effector cells, leading to killing of the tumour cell. Our hypothesis is that varlilumab enhances rituximab-mediated killing of tumour cells by increasing the number of immune effector cells. Patients will receive 6 cycles of treatment, with administration of rituximab on day 1 of each cycle and of varlilumab on day 2 of cycles 1, 3 and 5. Each cycle is 2 weeks long. Patients will be followed up 2 weeks after they complete the trial treatment and then every 2 months for one year.

Inclusion Criteria:

1. Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). • High grade subgroup: Diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL) grade 3b, transformed Follicular Lymphoma • Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL, e.g. Mantle cell lymphoma (MCL), Lymphoplasmacytic lymphoma (LPL) and Follicular Lymphoma (FL) grade 1, 2 and 3a 2. Disease must be recurrent or treatment refractory, and received at least one line of treatment. Rituximab-refractory patients are eligible for entry into the study. 3. At least one measurable lesion by CT scan (defined as > 1.5 cm in one axis) that is also easily accessible for biopsy. 4. Histological confirmation of relapse within 12 months of treatment. 5. 16 years of age or older. 6. Haematological and biochemical indices with the ranges shown below: • Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible) • Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (or ≥0.5 x 10^9/L if bone marrow involvement) G-CSF support is not permissible at screening • Platelet count ≥75 x 10^9/L (or ≥30 x 10/L if bone marrow involvement) • Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert’s syndrome in which case up to 3 x ULN is permissible • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to hepatic involvement • Calculated creatinine clearance (Cockroft-Gault formula) ≥30 ml/min (uncorrected value) 7. Ability to understand the purpose and risks of the study and provide written informed consent. 8. Willing and able to participate in all required evaluations and procedures in this study protocol. 9. Women of childbearing potential, must be willing to participate in appropriate pregnancy prevention measures: a. Female patients who have a negative serum or urine pregnancy test during screening (within 14 days prior to the start of trial treatment) and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible. b. Male patients with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception and condom; an intrauterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible. Male subjects must also refrain from donating sperm during this period. c. Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 10. Life expectancy ≥ 12 weeks. 11. ECOG performance status 0-2.

Exclusion Criteria:

1. Known central nervous system involvement by lymphoma, that is not in remission, are excluded from the study. 2. History of other malignancy within the last 2 years except for: • Noninvasive malignancies such as adequately treated ductal carcinoma in situ of the breast, non-melanoma skin cancer or lentigo maligna, cervical carcinoma in situ and urothelial papillary noninvasive carcinoma or carcinoma in situ, and • Prostate intraepithelial neoplasia without evidence of prostate cancer. 3. Receiving treatment (or within a month of) with chemotherapy, immunotherapy or immunosuppressive agents. This includes any systemic steroids at dose exceeding 10 mg prednisolone (or other steroid equivalent) within 2 weeks prior to first dose of varlilumab. 4. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study. 5. Active and documented autoimmune disease (including, but not limited to, inflammatory bowel disease, coeliac disease, haemolytic anaemia, or immune thrombocytopenic purpura) prior to first dose of varlilumab. 6. Active infection requiring systemic therapy. 7. Women who are pregnant or lactating. 8. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, the results of hepatitis serology should be known prior to commencement of immunochemotherapy. • Positive test results for chronic HBV infection (defined as positive HBsAg serology and positive HBcAb) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. • Positive test results for hepatitis C (HCV antibody serology testing) will not be eligible. 9. Previous recipient of an allogeneic bone marrow transplant at any time. 10. Autologous bone marrow transplant within 100 days of first dosing. 11. Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks prior to first dosing. 12. Subjects known or suspected of being unable to comply with the protocol. 13. Ongoing toxic manifestations of previous treatments. Exceptions are to this are alopecia or certain Grade 1-toxicities, which in the opinion of the Investigator should not exclude the patient. 14. Uncontrolled congestive cardiac failure, cardiac ischaemia or cardiac arrhythmia. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV). 15. Subjects with a known hypersensitivity to rituximab (≥Grade 3) or murine proteins, or any other excipients used in the formulation of rituximab.

Sub Specialty:

Lymphoma

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Radiogenomics: assessment of polymorphisms for predicting the effects of radiotherapy

Research Summary

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Inclusion Criteria:

Patients will either be involved in a collaborating national trial: including but not limited to RT01, CHHIP, PIVOTAL or ART-DECO. Alternatively, patients may be enrolled in a single centre Royal Marsden study (e.g. Pelvic IMRT), single centre Addenbrookes study (Cambridge breast IMRT) or be recruited prospectively with breast, prostate or gynaecological cancer (N.B. sites undertaking prospective recruitment is strictly limited). Must be over 18 years of age and give written informed consent to be involved and gift a blood sample.

Exclusion Criteria:

Volunteers from the above trials/ studies who are in poor health due to cancer or non-cancer related conditions or who are unable to give informed consent or a blood sample.

Sub Specialty:

Breast Cancer Prostate Cancer

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A randomised Phase II study of Enzalutamide (MDV3100) in combination with AZD5363 in Patients with Metastatic Castration Resistant Prostate Cancer

Research Summary

Prostate cancer is the most common male cancer in the UK with more than 11,000 deaths every year. The two most common genetic defects in this disease are androgen receptor (AR) driven rearranged oncogenes and PI3K/AKT pathway activation. Currently in the UK docetaxel followed by abiraterone is the standard of care for patients with advanced prostate cancer (APC). For patients with disease progression after treatment with abiraterone and docetaxel, options are cabazitaxel, participation in clinical trials or supportive care. About 50% of post-chemotherapy patients with APC will be eligible for REAKT; a trial of enzalutamide with the novel AKT inhibitor AZD5363. Enzalutamide is an antiandrogen with distinct properties that blocks testosterone binding to the AR, impacts AR transport into the nucleus and inhibits binding of the AR to DNA. AZD5363 inhibits the AKT protein which helps cancer cells grow, multiply and spread.. By combining enzalutamide and AZD5363 it is hoped the cancer cells stop growing and the growth and spread of those that do is slowed. REAKT has three parts;Phase I safety run-in phase to determine the dose of AZD5363 to use; Phase II randomised, double blind trial to measure how effective the combination treatment is; Single stage phase II expansion cohort where AZD5363 is added to enzaluatmaide at progression to explore whether AZD5363 can reverse resistance to enzalutamide. Enzalutamide and AZD5363 are taken orally and are taken as long as they are helping to prevent the cancer getting worse. Participants will have regular checkups at the hospital. Participants will be asked to donate blood, urine, tumour, hair, buccal (cheek) swab and saliva samples during the study to see if there are any drug to drug interactions and to see if there is anything that will predict who this combination treatment will work best for.

Inclusion Criteria:

1)Written informed consent. 2)Histological diagnosis of adenocarcinoma of the prostate and with archival tumour tissue 3)Metastatic CastrationResistant Prostate Cancer (mCRPC). 4)Progressed after 1 or 2 lines of taxane based chemotherapy. 5)Progressed after at least 12 weeks of abiraterone 6)Age 18 years or above. 7)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 02. 8)PSA greater than or equal to 10ng/ml. 9)Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment 10)Documented ongoing castrate serum testosterone < 50 ng/dL (< 2.0 nM). 11)Received prior castration by orchiectomy and/or ongoing Luteinizing HormoneReleasing Hormone (LHRH) agonist treatment. 12)Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria; a.disease progression as defined by at least 2 new lesions on bone scan. b.Soft tissue disease progression defined by modified RECIST 1.1. c.Clinical progression (worsening pain & the need for palliative radiotherapy). PHASE I SAFETY RUN IN and EXPANSION COHORT inclusion criteria: 13)Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment. SINGLE STAGE PHASE II EXPANSION COHORT ONLY inclusion criteria: 14)Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression 15)Archival tumour tissue available for the analysis of PTEN loss by the central laboratory

Exclusion Criteria:

1)Prior treatment with enzalutamide (not applicable for the phase I safety run in or for the single stage phase II expansion cohort). 2)Prior treatment with PI3K, AKT, TOR kinase or mTOR inhibitors 3)Surgery, chemotherapy, or other anticancer therapy within 4 weeks prior to trial entry / randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug. 4)Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation. 5)Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry / randomisation. 6)History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism. 7)History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry / randomisation. 8)Known brain or leptomeningeal involvement. 9)Use of potent inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 2 weeks before trial entry / randomisation (3 weeks for St John¡¯s Wort) must be avoided. 10)Clinically significant abnormalities of glucose metabolism as defined by any of the following: a.Diagnosis of diabetes mellitus type I or II b.Glycosylated haemoglobin (HbA1C) ≥8.0% at screening c.Fasting Plasma Glucose ≥8.9mmol/L at screening. 11)Inadequate organ and bone marrow function as evidenced by: a.Haemoglobin < 8.5 g/dL b.Absolute neutrophil count < 1.0 x 109/L c.Platelet count < 75 x 109/L d.Albumin ≤25 g/dL. e.AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥5 x ULN if liver metastases) f.Total bilirubin ≥ 1.5 x ULN (except for patient with Gilbert's disease) g.Serum Creatinine > 1.5 x ULN 12)Inability or unwillingness to swallow oral medication. 13)Malabsorption syndrome or other condition that would interfere with enteral absorption. 14)Any of the following cardiac criteria; a.Mean resting corrected QT interval (QTcF) > 470msec obtained triplicate ECGs b.Clinically important abnormalities(rhythm/conduction/morphology)resting ECG c.Factors that increase risk of QTc prolongation or risk of arrhythmic events d.Experience of any of the following in the preceding six months: coronary artery bypass graft angioplasty vascular stent myocardial infarction angina pectoris congestive heart failure NYHA ≥ Grade2 e.Uncontrolled hypotension 15)Clinically significant history of liver disease consistent with ChildPugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis. 16)Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications. 17)Need for chronic corticosteroid therapy of > 10 mg of prednisolone or > 0.5mg of dexamethasone per day or an equivalent dose of other anti inflammatory corticosteroid. 18)Malignancies other than prostate cancer within 5 years prior to trial entry / randomisation, except for adequately treated basal or squamous cell skin cancer. 19)Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy. 20)Inability to comply with study and follow up procedures.

Sub Specialty:

Prostate Cancer

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A Randomised phase II trial of Adaptive Image guided standard or Dose Escalated tumour boost Radiotherapy in the treatment of transitional cell carcinoma of the bladder

Research Summary

RAIDER is a multicentre two stage randomised phase II trial investigating Dose escalated Adaptive tumour boost radiotherapy (DART) for patients with muscle invasive bladder cancer. Participants will be randomised between standard whole bladder radiotherapy (WBRT), Standard dose Adaptive tumour focused radiotherapy (SART) and DART. Stage I will establish the feasibility of delivering DART in a multi-centre setting, and stage II will establish the toxicity of DART. Participants will be permitted to receive concomitant chemotherapy. 72 patients will be recruited in stage II, with an additional 168 patients in stage II. Both fractionation regimens in standard use in UK are included – 32f and 20f. 120 participants will be recruited per fractionation cohort. Primary endpoints will be assessed in each fractionation cohort separately with the flexibility to drop either a fractionation cohort or an experimental treatment group (on advice of Independent Data Monitoring Committee) following completion of stage I.

Inclusion Criteria:

1. Written informed consent 2. Age ≥16 years 3. Histologically or cytologically confirmed transitional cell carcinoma (TCC) of the bladder 4. Unifocal bladder TCC staged T2-T4a N0 M0 5. Fit to receive a radical course of radiotherapy 6. WHO performance status 0-2 7. Willing and able to comply with study procedures and follow up schedule

Exclusion Criteria:

1. Nodal or metastatic disease 2. Widespread carcinoma in situ (CIS) or CIS remote from muscle invasive tumour or multifocal invasive disease 3. Simultaneous TCC in upper tract or urethra 4. Pregnancy 5. Active malignancy within 2 years of randomisation (not including non melanomatous skin carcinoma, previous non muscle invasive bladder tumours, NCCN low risk prostate cancer (T1/T2a, Gleason 6 PSA < 10), in situ carcinoma of any site) 6. Any other conditions that in the Principal Investigator’s opinion would be a contra-indication to radiotherapy (e.g. previous pelvic radiotherapy / inflammatory bowel disease)

Sub Specialty:

Bladder Cancer

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Rare Neoplasms of Gynaecological Origin

Research Summary

We are asking patients with a rare gynaecological cancer if they would like to take part in the RaNGO study. We are researching how these cancers are currently diagnosed, treated and managed. By definition, numbers of women being diagnosed with rare cancers are very small – about 50 in the UK each year. It is therefore very difficult for individual clinicians or even Cancer Centres to build up a knowledge base on how best to treat these patients. We will not be able to improve the outlook in the UK unless we can collect such information together in one place over a number of years and then review the results of the different treatments . We hope to encourage all UK gynaecological cancer centres to join the study. Patients will continue to be treated there as usual, any of their tissue samples etc being kept in local laboratories as at present. However during the study these samples, along with the patients’ anonymised details, including treatments and outcomes, will be virtually recorded on a central index as well. If one of these rare cancers recur, we would also like patients to consider giving permission for more blood and / or fluid samples, biopsies or tissue to be taken for this study. The plan is that in 5-10 years’ time, we will have collected enough information in some of these rare gynaecological cancers to give us a clearer idea of which treatments are useful. The information collected will enable us to provide more information to individual patients and perhaps to consider starting clinical trials of new agents for these rare cancers. For laboratory work we will have information about the location of the rare tissue and blood / fluid samples for important scientific evaluation.

Inclusion Criteria:

Inclusion criteria Queries about the eligibility criteria should be addressed prior to registration. Patients are eligible for trial if all the inclusion criteria are met and none of the exclusion criteria applies: 1. Patients > = 16 years with one (or more) of the specified rare gynaecological cancers listed in Appendix 1 of the study protocol 2. Patients (or in rare circumstances any guardian or next of kin) must be able to give adequate informed consent agreeing to the collection and retention of anonymised data about their rare gynaecological cancer to RaNGO 3. Patients must provide informed consent to the exchange/release of their data from all relevant National Cancer Registries and other National Organisations, now and in the future, to allow comparison with data that are held on RaNGO, and to update information as it becomes available through these agencies. 4. Formalin-fixed, paraffin-embedded tissue taken at the time of original diagnosis of the specific rare gynaecological cancer (Appendix 1) must be available for inclusion in a virtual tissue bank for legitimate use in research and trials in the future. The tissue may have originated from a range of surgical procedures, including biopsies. For those patients with only a biopsy at the time of primary diagnosis, availability of tissue from specimens taken at interval debulking surgery and repeat biopsies at relapse or maintained remission is desirable. Laboratory accession numbers and block keys must be available at registration.

Exclusion Criteria:

Exclusion criteria 1. Rare gynaecological cancers that are not listed in Appendix 1of the study protocol 2. Diagnosis of a rare gynaecological cancer listed in Appendix 1 made on cytology only, AND no subsequent formalin-fixed paraffin embedded tissue available to confirm the diagnosis. 3. Absence of consent to inclusion of data on RaNGO or specific consent to access information from National Cancer Registries or Databases

Sub Specialty:

Gynaecological Cancers

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Proxy decision making for older women with cognitive impairments and breast cancer

Research Summary

The UK’s ageing population is growing rapidly; 1 in 6 people are now aged over 65 (ONS 2013) and over a third of all breast cancers in England are diagnosed in women over the age of 70 (Public Health England, 2014). Within this demographic, the prevalence of dementia is around 10.5% (Knapp et al. 2007), meaning that approximately 1260 women with cognitive impairment each year are likely to present with breast cancer. This is an important area of research as studies have found that older women with breast cancer are generally treated less aggressively than younger women (Malik et al. 2013, Lavelle et al. 2014) and are less likely to receive gold standard care for their cancer (surgical intervention, chemotherapy, radiotherapy) (Harder et al. 2013). Older women with late stage dementia are also more likely to lack mental capacity to make decisions regarding their breast cancer treatment, and subsequently treatment decisions may rely on a proxy (i.e. their formal or informal carer making a decision on the patient’s behalf). Little is known about how decisions are made for this sub¬population of older women with co¬existent dementia, and there are few decision¬making recommendations tailored specifically towards older women with dementia and a breast cancer diagnosis. This study will use a pragmatic mixed method approach to explore the experiences of caregivers who are involved in making a proxy treatment decision for an older adult with dementia and breast cancer. The purpose of this study will be to understand how proxy decisions are made and the psychosocial factors that impact on carers during this process. The results from this study will contribute to the wider literature addressing the needs of caregivers and guide best practice towards proxy decision¬making in breast cancer care.

Inclusion Criteria:

Inclusion Criteria 1) An individual who is an adult caregiver with the following characteristics: a. Aged 18 years and over b. A formal or informal carer for an older woman (> 70 years) with cognitive impairment c. Capable of giving informed consent d. No known cognitive impairment 2)An individual who is a caregiver for a patient with the following characteristics: a. Female b. Aged over 70 years of age at the time of diagnosis of cancer c. Primary operable (TNM categories: T1, T2, T3, N0, N1, M0; please refer to appendix for details) invasive breast cancer. d. Formal diagnosis of cognitive impairment (ICD¬10 categories: F00.0¬F00.9, F01.0¬F01.9, F02.0¬F02.8, F03; please refer to appendix for details) or an MMSE score indicating severe cognitive impairment. e. Incapable of giving informed consent to their breast cancer treatment 3) An individual who is involved in the treatment decision¬making for a person with mild/moderate/severe cognitive impairment. 4) An individual who is able to complete a questionnaire in english language.

Exclusion Criteria:

1) An individual who is a not a formal or informal caregiver for a women > 70 years with primary operable breast cancer and a diagnosis of cognitive impairment. 2) A carer who themselves has a severe cognitive impairment and is unable to give informed consent to take part in the study. 3) Individuals who cannot complete a questionnaire in english language.

Sub Specialty:

Ageing Breast Cancer Dementia

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Radiation versus Observation following surgical resection of Atypical Meningioma: a randomised controlled trial (The ROAM trial)

Research Summary

Atypical meningioma is an intermediate grade brain tumour that arises from the linings of the brain. These are very rare tumours and there are approximately 150 new cases per year in the UK, and tend to affect adults with a peak incidence at age 40-­60 years. The 5­-year tumour recurrence rates are reported as between 39 and 58%. The primary treatment for atypical meningioma is surgery and in patients with residual solid tumour, radiotherapy is administered to reduce the risk of recurrence. In patients with complete resection of the tumour, some clinicians give early radiotherapy, whilst others advise active monitoring with radiotherapy given only at recurrence. Whilst radiotherapy has been shown to be an effective adjuvant treatment in some studies but not others, there is no consensus as to which of these approaches is best. Following resection surgery for atypical meningioma, eligible patients will be randomised to receive either radiotherapy or active monitoring. Patients in both arms will typically have an early postoperative follow-up within 2 weeks of resection surgery to discuss the histopathology results and assess wounds and clinical status. Follow-up thereafter would be at 6 months, 12 months and annually until tumour recurrence or trial closure. EORTC C30 and BN20 quality of life, EQ­5D health outcome, and resource use questionnaires will be administered at each follow up visit. All participants will be followed up for a minimum of 5 years post-­surgery.

Inclusion Criteria:

a) Histologically confirmed newly diagnosed solitary atypical meningioma (WHO grade II) based on the 2016 WHO criteria [1] b) Age >/= 16 years c) All anatomical locations allowed except optic nerve sheath tumour d) Complete resection (Simpson 1, 2 or 3) as assessed by the surgeon e) Able to commence radiotherapy between within 12 weeks of surgery (ideally 8-12 weeks) f) WHO performance status 0, 1 or 2 (Appendix 1) g) Women of reproductive potential must use effective contraception for the whole duration of the treatment h) Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion Criteria:

a) Neurofibromatosis type II (NF-2) b) Optic nerve sheath tumours c) Multiple meningiomas d) Radiation-induced meningioma e) Clinical evidence of second malignancy, except for cervix carcinoma in situ or basal cell carcinoma, and history of invasive malignancy unless treated with curative intent and the patient has been disease free for the last five years f) Previous intracranial tumour in the last 10 years treated with radiotherapy or chemotherapy g) Pregnant or lactating women.

Sub Specialty:

Brain Cancer Neurosurgery

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Multicenter Observational Prospective Study For The Identification Of Prognostic Factors In Patients With Mycosis Fungoides/Sezary Syndrome: Proposal For An International Prognostic Index For Cutaneous Lymphoma

Research Summary

A study of prognostic factors in cutaneous lymphoma with the aim of developing a prognostic index to identify high risk patients

Inclusion Criteria:

All patients within 6 months of a new diagnosis of MF/SS

Exclusion Criteria:

Patients diagnosed with MF/SS more than 6 months prior to assessment. Patients unable to give informed consent.

Sub Specialty:

Lymphoma

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Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal

Research Summary

Ovarian cancer is the leading cause of deaths from gynaecological cancers. Despite massive funding in drugs and new treatment strategies, survival rates remain poor. Only 3 in 10 women are alive at 10years. Women with a > 10% risk of getting ovarian cancer are considered high-risk. 10% ovarian cancers are familial. The commonest cause is a fault/alteration in BRCA1/BRCA2 genes. BRCA1/BRCA2 carriers have a 17-44% risk of developing ovarian cancer and 69-72% risk of developing breast cancer. There is currently no NHS screening programme for ovarian cancer. Best current practice is to offer women at increased-risk, an operation to remove their fallopian tubes and ovaries on completing their family. This significantly reduces the risk of ovarian cancer by 90% but leads to early menopause. Early menopause has serious implications including, hot flushes, sweats, mood changes and pain during intercourse. Additionally, it increases the risk of thinning of the bones, heart disease, stroke and dementia. Many women avoid/delay prevention due to this. However, a significant number of ovarian cancers actually start in the fallopian-tube. This has led to an attractive alternative ‘two-stage’ proposal to prevent ovarian cancer. The first-stage involves removing the fallopian-tubes (earlysalpingectomy) alone. This is followed by a second-operation (delayed oophorectomy) to remove the ovaries after they have gone through the menopause. This offers protection against ovarian cancer in younger women whilst avoiding the negative health consequences of early menopause. However, long term consequences of this new approach have not been adequately studied. Our UK-wide study compares old and new strategies for ovarian cancer prevention. The study evaluates the impact on sexual function, endocrine function, quality-of-life and cost-effectiveness of this new strategy in high-risk women by comparing it to the traditional strategy of removing both tubes and ovaries as well as outcomes in women who don’t have an operation (controls). Women entering the study can choose whichever strategy they prefer.

Inclusion Criteria:

1. Women at high-risk of ovarian cancer (BRCA1/BRCA2 mutation carriers, or deemed to be at increased risk from a strong family history of breast and/or ovarian cancer or RAD51C/ RAD51D/ BRIP1 mutation carriers. 2. Premenopausal ≥30years. 3. Completed family (for early surgical arms only).

Exclusion Criteria:

1. Previous bilateral-salpingectomy or bilateral-oophorectomy. 2. Postmenopausal (amenorrhoea ≥1year (uterus insitu) / FSH > 40). 3. Previous tubal/ ovarian/ peritoneal malignancy. 4. < 12 months post cancer treatment. 5. Pregnancy** 6. Clinical suspicion of tubal/OC at baseline. 7. Inability to provide informed consent.

Sub Specialty:

Gynaecological Cancers

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Post-operative avoidance of radiotherapy: biomarker selection of women categorised to be in a very low risk group by IHC4+C

Research Summary

Some breast cancers are considered low risk. Low risk means there is a small chance of the breast cancer returning after it has been removed during surgery. Currently, patients with low risk breast cancer have radiotherapy after surgery, followed by drug treatment (hormone therapy tablets) for 5 years. Radiotherapy reduces the risk of cancer returning in the breast (local recurrence). However for patients with a low risk breast cancer, the risk of radiotherapy side effects may start to outweigh its benefit. The PRIMETIME study aims to identify a group of women who can safely avoid radiotherapy because the risk of their cancer returning is so low. A research calculation called IHC4+C will be used to calculate a woman's risk of cancer returning 10 years after surgery. 'Very low' risk patients are those where the chance of their cancer returning 10 years after surgery is less than 5%. This means that out of 100 women with 'very low' risk breast cancer, cancer will return in less than five women. In the PRIMETIME study women with 'very low' risk breast cancer can avoid having radiotherapy. All other women will be recommended to have radiotherapy according to standard care. Patients who are eligible to take part are those with a small, slow growing breast cancer which has not spread beyond the breast. Patients will be 60 years or over, have had surgery to remove their cancer with a plan to receive at least 5 years of drug treatment (hormone therapy) for their cancer. The study will be conducted in NHS hospitals in the UK. Participating patients will be followed up by their treating hospital for 10 years following surgery.

Inclusion Criteria:

1.Provision of written informed consent to participate in the PRIMETIME study 2.Provision of slides for research testing and availability of Ki67 result (contact ICR-CTSU to confirm Ki67 result is available) 3.Women aged ≥ 60 years (younger patients are eligible if they are post-menopausal and have co-morbidities that imply a high risk of radiotherapy toxicity (e.g. significant cardiovascular disease with left sided breast cancer); 4.Women having had breast conserving surgery with complete resection of tumour tissue (≥1 mm microscopic, circumferential margins of normal tissue from invasive cancer and DCIS); 5.AJCC staging of pT1/pN0/M0 (DCIS is allowed in combination with invasive breast cancer, providing whole tumour size (in-situ and invasive ≤2cm); isolated tumour cells in axillary nodes are allowed); 6.Histological confirmation of grade 1 or 2 invasive breast cancer; 7.Oestrogen receptor (ER) positive according to local practice. The H score must be available; 8.Progesterone receptor (PR) positive according to local practice. The percentage positivity must be available; 9.Human epidermal growth factor receptor (HER2) negative according to local practice; 10.Patients must be recommended for ≥5 years adjuvant endocrine therapy according to local policy, they must also be willing to start endocrine therapy and in the investigator’s opinion, deemed able to comply with the duration of treatment.

Exclusion Criteria:

1.Patients known to have lymphovascular space invasion and/or axillary nodal micrometastases or macrometastases. 2.Patients with a past history of malignancy except (i)basal cell skin cancer and CIN cervix uteri or (ii)treated, localised squamous cell carcinoma of the skin or (iii)malignancies treated with curative intent and the patient has been disease free ≥5 years; 3.Patients who have had an ipsilateral mastectomy; 4.Patients who have received neoadjuvant therapy (endocrine or cytotoxic chemotherapy with therapeutic intent) or who are deemed by the MDT to require adjuvant cytotoxic chemotherapy. NB. In most instances treatment within a window of opportunity study is not considered of therapeutic intent and will therefore be allowed: please check with the PRIMETIME trial manager if a patient has participated in a window of opportunity study. 5.Patients with mammographically occult breast cancers, ie. present with lump, but not visible on mammogram

Sub Specialty:

Breast Cancer

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PRIMUS 001 - An adaptive phase II study of FOLFOX-A (FOLFOX and nab-paclitaxel) versus AG (nab-paclitaxel and gemcitabine) in patients with metastatic pancreatic cancer, with integrated biomarker evaluation

Research Summary

An adaptive phase II study of FOLFOX-A (FOLFOX and nab-paclitaxel) versus AG (nab-paclitaxel and gemcitabine) in patients with metastatic pancreatic cancer, with integrated biomarker evaluation

Inclusion Criteria:

1 Patient has been enrolled in the Precision Panc Master Protocol and their tissue has been deemed suitable for NGS analysis 2 Patient has provided signed information consent for the PRIMUS 001 study 3 Age ≥ 16 years 4 Histologically-confirmed metastatic pancreatic ductal adenocarcinoma and its varients, with measurable metastatic lesion(s) according to RECIST 1.1. 5 Eastern Cooperative Oncology Group (ECOG) 0-1 with life expectation of no less than 12 weeks. 6 Patients must have received no previous chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with a fluoropyrimidine and/or gemcitabine administered in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no ongoing toxicities are present. 7 Adequate liver/bone marrow function as defined by: a. Neutrophils (ANC) ≥ 1.5 x 109/l b. Platelets ≥ 100 x 109/l c. Haemoglobin ≥ 9.0 g/dL d. WBC ≥ 3 x 109/l e. Total bilirubin ≤ 1.5 x institutional ULN unless bilirubin rise is due to Gilbert’s syndrome f. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (and < 5 ULN in the presence of liver metastases) g. Estimated creatinine clearance ≥ 60 mL/min (as calculated by Cockcroft and Gault or Wright formula or measured by EDTA clearance) NHS R&D Form IRAS Version 5.5.1 10 221370/1121060/14/694 8 Negative serum Human Chorionic Gonadotropin (HCG) test for females with child bearing potential. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential 9 Woman of child bearing potential, and men with female partners of child bearing potential, must agree to use adequate contraceptive measures (see section 8.1.8.1) for the duration of the study and for up to 6 months after the completion of study treatment. 10 Compliant, and can be followed up regularly The following additional inclusion criteria is ONLY required if recommended by the independent Data Monitoring Committee after interim review of study data (sites will have been informed by the CRUK CTU if this is the case) 11 Patient must be biomarker positive as fed back after central Precision-PANC diagnostic testing

Exclusion Criteria:

1 Prior treatment with nab-paclitaxel or oxaliplatin 2 Prior chemotherapy for metastatic pancreatic cancer 3 Known hypersensitivity for any component of any study drug 4 Active infection including Herpes Zoster and chickenpox 5 Current neuropathy ≥ grade 2 6 Uncontrolled brain metastatsis or mental illness 7 Uncontrolled congestive heart failure (CHF), or history of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months. 8 Uncontrolled serious contraindicated medical condition or illness 9 Known or suspected dihydropyrimidine (DPD) deficiency 10 Pregnant of breastfeeding 11 History of physical or psychiatric disorder that would prevent informed consent and compliance with protocol 12 Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, of receiving the first dose of trial treatment 13 Any systemic anti-cancer therapy, or major surgery within 28 days of randomisation 14 Any minor surgery or radiotherapy within 7 days of randomisation 15 Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial protocol and follow up schedule. 16 Any patients receiving treatment with brivudin, sorivudin and analogues 17 History of another malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated earlystage cervical cancer or treated/bio 18 chemically-stable, organ-confined prostate cancer). 19 Any patient with severe diarrhoea (defined as ≥grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection

Sub Specialty:

Upper GI

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POSNOC - POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy. A randomised controlled trial of axillary treatment in women with early stage breast cancer who have metastases in one or two sentinel nodes.

Research Summary

Each year more than 48,000 women are diagnosed with breast cancer in the UK. Currently women having surgery to treat their cancer undergo removal of the first one or two lymph glands (called sentinel nodes) from the armpit (axilla) to check if the cancer has spread to these. This procedure is called sentinel node biopsy. For about a quarter of women, this test shows that the breast cancer has spread to their sentinel nodes. These women then undergo treatment to their armpit (axillary treatment). This is either a second operation to remove all the lymph glands in the armpit (axillary node clearance) or radiotherapy to the armpit (axillary radiotherapy) depending on their hospital practice. After recovery from this treatment, they have chemotherapy and/or endocrine therapy. Some women may also have radiotherapy to their breast or chest wall. This chemotherapy, endocrine therapy, breast and chest wall radiotherapy is called adjuvant therapy. We now know that adjuvant therapy is very good at preventing the cancer from coming back. So, armpit treatment may no longer be needed. Armpit treatment damages the drainage channels of the lymphatic system. Fluid called lymph begins to collect in the arm and doesn't drain. The arm and hand swell and this swelling is called lymphoedema. One in 5 women will get lymphoedema in the arm after armpit treatment. Lymphoedema can be painful and make it difficult to move the arm. It cannot be completely cured, and without treatment it may get worse. Also, 1 in 3 people will have numbness or pain after armpit treatment and 1 in 5 may experience shoulder stiffness. These problems can be upsetting and difficult to cope with. If armpit treatment is no longer needed, it would be important to know this. We could then spare women unnecessary treatment, and avoid the long term problems it causes.

Inclusion Criteria:

Women will be eligible for inclusion only if ALL of the following criteria apply: • 18 years or older • Unifocal or multi-focal invasive tumour with lesion ≤5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound (tumour size should be based only on the single largest tumour; do not add the sizes together from the multiple foci) • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit > 2.0mm in largest dimension or defined as macrometastasis on molecular assay) • Fit for axillary treatment and adjuvant therapy • Have given written informed consent

Exclusion Criteria:

Women will be excluded if they have: • bilateral breast cancer • more than 2 nodes with macrometastases • neoadjuvant therapy for breast cancer • previous axillary surgery on the same body side as the scheduled sentinel node biopsy • not receiving adjuvant systemic therapy • previous cancer less than 5 years previously or concomitant malignancy except o adequately treated basal or squamous cell carcinoma of the skin o adequately treated in situ carcinoma of the cervix o adequately treated in situ melanoma o contra- or ipsilateral in situ breast cancer

Sub Specialty:

Breast Cancer Breast Surgery

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PRECISION-Panc: Advancing personalised medicine treatment strategies for pancreatic cancer.

Research Summary

Throughout the 20th century, the global incidence of pancreatic cancer has steadily increased. It is currently the 4th most common cause of cancer death in Western societies. In the period 1930-1970, the rate of mortality associated with pancreatic cancer doubled in the UK and, as the incidence of the disease continues to rise, it is expected to become the 2nd most common cause of cancer death within a decade. Pancreatic cancer is often diagnosed late and therapy options for patients are limited. This means that exceedingly poor patient outcomes remain the norm for people affected by pancreatic cancer. To put this into numbers: of the people diagnosed with pancreatic cancer in 1970, only 3% survived for five years or more. Forty years later, that figure remains more or less unchanged. Shockingly, this means that of the ~9,000 people who will be diagnosed with pancreatic cancer in the UK this year, only around 270 people are expected to survive for more than five years. Despite some incremental advances, we have not shifted the outlook for pancreatic cancer in any significant way. Due to its aggressive nature, and the lack of efficacy of chemotherapy (with combination regimens associated with more toxicity) only about 50% of patients with advanced pancreatic cancer receive any therapy. Of those that receive therapy,few benefit in any significant way, and at best, only half of them are well enough to receive a second line of treatment. Less than 5% of patients receive a third treatment. It is reasonable to argue that due to the lack of tissue for research purposes and lack of efficacy of current therapies,there is no “standard-of-care” for pancreatic cancer, and if it is to be called that, then the standard is very poor. The lack of effective therapies and bleak outlook for patient survival makes this particular cancer type an ideal target for the exploration of models of molecular phenotype guided cancer care. Precision-Panc aims to identify, test and implement tailored therapeutic approaches for individuals affected by pancreatic cancer by using a master protocol approach to obtain tissues for study. A range of clinical trials (PRIMUS) will be linked to the master protocol so that each and every patient will have real options. The goal is to “find the trial for the patient” rather than “the patient for the trial”. Patients will be profiled using state of the art molecular phenotyping approaches. We aim to offer patients, and their doctors, the ability to identify therapeutic opportunities that have a real chance of increasing the patient's survival time. We will achieve this through the use of experiments (genome/DNA sequencing approaches) to identify changes (mutations) present within the tumour of patient that could be targeted by known drugs. If such changes are identified as drug targets, patients will then be given information about any relevant clinical trials for them (should they, following discussions with their oncologist, wish to pursue that option).

Inclusion Criteria:

Patients with a suspected or confirmed diagnosis of pancreatic ductal adenocarcinoma and its variants who consent to additional biopsies to obtain tissue for next generation sequencing analyses will be included in this study. Patients will also be deemed suitable for chemotherapy and/or chemoratiotherpay, and/or surgery pending on the disease clinical stage

Exclusion Criteria:

Participants without a confirmed diagnosis of pancreatic ductal adenocarcinoma will not be eligible for this study. Patients who do not consent to additional biopsy to obtain tissue for research purposes will be excluded. Pregnant or breast-feeding individuals will also be excluded. Patients deemed to be unsuitable or too frail for chemotherapy or targeted therapy will also be excluded.

Sub Specialty:

Upper GI

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Supportive Exercise Programmes for Accelerating Recovery after major Abdominal Cancer surgery (PREPARE-ABC)

Research Summary

This trial is designed to look at whether an exercise intervention would be beneficial to patients pre and post hospital discharge when undergoing curative colorectal surgery. The trial is multi-centre, single blind (assessors only), 3-arm, randomised, controlled, recruiting colorectal cancer patients at point of diagnosis, within colorectal units in UK hospitals. Colorectal cancer is the fourth commonest cancer in the UK, with 40,000 patients diagnosed per year. The current standard and best-proven treatment for this patient group is a surgical resection, with around 25,000 patients undergoing this procedure per year. A colorectal resection, while offering the best chance of survival, results in significant post operative morbidities (POMs). POMs have psychological and health burdens for patients, but also impact greatly on healthcare resources and costs. Cost estimates show that post-surgical complications from colorectal surgery at least double the cost of post-operative care. Therefore interventions to reduce POMs could provide health benefits to patients and significant cost savings to the NHS. The Improving Surgery Outcomes Group (ISOG) have reported a correlation between patient's level of fitness and post-operative outcomes. Literature also reports that exercise training may improve fitness to a significant level even in the short period available between diagnosis and surgery. The role of pre and post-operative exercise hasn't been extensively investigated, nor has the effectiveness of professionally supervised versus home based exercise programmes. Exercise advice is not yet routinely given to cancer patients. This trial will compare standard care alone versus standard care plus supervised hospital based exercise and standard care plus supported home based exercise, undertaken 4 weeks pre-surgery and resuming 6 weeks post-surgery.

Inclusion Criteria:

1. Male and female participants ≥ 18 years old 2. Awaiting a curative elective colorectal resection for cancer 3. American Society of Anaesthesiologists physical status I-III (ASA, 2014) 4. Able and willing to provide informed consent 5. Understand verbal and written instructions in English 6. Patients who are already participating (or have participated) in other trials may be eligible, but this must be agreed in advance by the relevant trial teams.

Exclusion Criteria:

1. Contra-indications to exercise (lower limb amputation without prosthesis, orthopaedic disorder exacerbated by exercise, chronic lung disease causing desaturation with exercise or shortness of breath at rest, severe psychiatric health problems) 2. Cardiovascular contraindications (unstable angina, acute left ventricular failure, uncontrolled cardiac arrhythmias, uncontrolled hypertension, cardiac event in the previous 6 weeks, cerebral vascular disease resulting in transient ischaemic attacks) 3. Participation in other treatment trials, where this has not been agreed in advance with both trial teams

Sub Specialty:

Anaesthesia Cardiothoracic Surgery Colorectal Cancer Colorectal Surgery Perioperative Medicine and Pain Management

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Phase II Trial of Pembrolizumab and Radiotherapy in Cutaneous T cell lymphoma

Research Summary

Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects the network of vessels and glands spreading throughout the body, mainly the skin (Mycosis Fungoides [MF]), though it can also affect the blood, lymph nodes and other internal organs (Sezary Syndrome [SS]). It is caused by white blood cells, called T cells, growing in an uncontrollable way within the body. There are a number of standard treatments that are currently used in treating CTCL, depending on the stage of disease. Though the cancer often responds to these current treatments, there are instances where the cancer does not respond or where it returns. There is, therefore, a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. PORT study will investigate whether radiotherapy in addition to pembrolizumab, a type of immunotherapy designed to ‘re-awaken’ the immune system, will improve response to treatment. In this study, 46 adult (aged > = 18 years) patients with CTCL, whose disease has either come back or not responded to treatment, will be given pembrolizumab with radiotherapy. Pembrolizumab will be given every 3 weeks for a maximum of 2 years. patients will also receive radiotherapy at week 12. Patients will be seen regularly during treatment and then yearly until the last patient entering the study completes their 2 year 5 months follow-up. The study will be conducted at NHS hospitals and is expected to last 5 years and 5 months.

Inclusion Criteria:

-Age > = 18 years -Diagnosis of Stage IB-IVB CTCL mycosis fungoides (MF)/Sézary Syndrome (SS) -Have relapsed, are refractory or progressed after at least 1 systemic therapy -Skin biopsy at the time of or within 6 months prior to study entry -Have at least 1 cutaneous lesion suitable for palliative radiotherapy -Have in addition at least 1 measurable lesion with a minimum mSWAT score of 10, or 2 or more cutaneous tumours, which will not be irradiated but must be measurable to assess the abscopal effect of the treatment -Have a minimum wash-out and adverse event (AE) recovery period from previous treatments (e.g. topical therapy, phototherapy, local radiotherapy, monoclonal antibody, systemic cytotoxic anticancer treatment or other novel agents) prior to the first dose of pembrolizumab, as detailed in section 6.2.1 of the trial protocol -Have ECOG performance status of 0 or 1 -Life expectancy of at least 6 months -Demonstrate adequate organ function -Female patients of childbearing potential must have a negative urine or serum pregnancy test -Willing to comply with the contraception requirements -Written informed consent

Exclusion Criteria:

-Received chemotherapy or targeted small molecule therapy within 4 weeks prior to study entry or has not recovered from adverse events due to agents administered > 4 weeks earlier (except patients with < = grade 2 neuropathy) -Is currently or has participated in an IMP or device study within 4 weeks prior to the first dose of pembrolizumab -Received any other monoclonal antibody within 4 weeks prior to the first dose of pembrolizumab or has not recovered (< = grade 1 or to baseline level) from adverse events due to agents administered > 4 weeks earlier -Additional malignancy that is progressing or requires active treatment -Patients with known central nervous system (CNS) involvement with lymphoma -Hypersensitivity to pembrolizumab or its excipients -Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. -Has a diagnosis of immunodeficiency or is receiving systemic corticosteroid / immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab -Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 therapy -Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia -Has known history of, or any evidence of active, non-infectious pneumonitis -History of other pulmonary disease such as interstitial lung disease, emphysema or chronic obstructive pulmonary disease -Is pregnant or breastfeeding -Has a known history of active TB -Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with the subject’s participation for the full duration of the trial or to participate in the trial is not in the patient’s best interest, in the opinion of the treating investigator -Has known psychiatric or substance abuse disorders that would interfere with the requirements of the trial -Has a known history of HIV -Has known active Hepatitis B or Hepatitis C -Has received a live vaccine within 30 days prior to the planned start of study medication (see section 6.2.2 of the trial protocol) -Patients who have previously received a solid organ transplant

Sub Specialty:

Lymphoma

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An international prospective study on clinically standard¬risk medulloblastoma in children older than 3 years with lowrisk biological profile (PNET 5 MB¬LR) or average¬risk biological profile (PNET 5 MB¬SR) ¬ SIOP PNET 5 Medulloblastoma

Research Summary

The PNET 5 study has been designed for children and young people aged from 3 yrs to 22 yrs with standard risk medulloblastoma who have undergone surgery to remove the primary tumour. The presence of biological markers of the WNT medulloblastoma disease subgroup (mutation of the beta¬catenin gene, or presence of the beta¬catenin protein and loss of chromosome 6) and aged < 16 defines the patient as Low Risk biological profile. The presence of the WNT markers and aged 16 and over, or the absence of the WNT markers defines the patient as Standard Risk biological profile. Low risk group patients will receive reduced doses of radiotherapy (compared to previous study PNET 4) to the brain and spine every day for 10 days, together with boost doses to the primary tumour for a further 20 days. Maintenance chemotherapy will consist of 6 cycles of Regimen A alternating with 6 cycles of Regimen B for a total duration of 27 weeks. Standard risk group patients will be randomised into two arms. One arm will receive doses of radiotherapy to the brain and spine every day for 13 days, together with boost doses to the primary tumour for a further 17 days, and the other arm will receive the radiotherapy together with the drug Carboplatin. Maintenance chemotherapy will consist of 8 cycles of Regimen A alternating with 8 cycles of Regimen B for a total duration of 36 weeks. The primary objectives of the study are :¬ * to confirm the 3 year Event Free Survival rate in low risk biological profile patients remains in excess of 80% when patients receive reduced intensity radiotherapy and chemotherapy, * to test whether the Event Free Survival rate in standard risk biological profile patients is different for patients treated with or without carboplatin concomitantly with radiotherapy, followed by a modified maintenance chemotherapy.

Inclusion Criteria:

Inclusion Criteria Note: with the exception of criterion f), the Inclusion Criteria are the same for PNET 5 MB ¬ LR and PNET 5 MB ¬ SR. To be eligible for inclusion in either study, patients must meet all of the following criteria: a) Age at diagnosis, at least 3 ¬ 5 years (depending on the country) and less than 16.0 years (LR¬arm) or 22.0 years (SR¬arm). The date of diagnosis is the date on which first surgery/biopsy is undertaken. b) Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007): Classic medulloblastoma Desmoplastic/nodular medulloblastoma Pre-treatment central pathology review is considered mandatory. c) Standard risk medulloblastoma, defined as: • total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumour on early postoperative MRI, without and with contrast, on central review; • no CNS metastasis on MRI (cranial and spinal) on central review; • no tumour cells on the cytospin samples of lumbar CSF (see chapter 8.1.2. Post¬operative Period, page 58), according to national regulations a CSF review might me required. • no clinical evidence of extra¬CNS metastasis. In patients with significant residual tumour (> 1.5 cm2) after first surgery, secondary surgery should be considered. Patients with a reduction of postoperative residual tumour through second surgery to less than or equal to 1.5 cm2 are eligible, if timeline for start of radiotherapy can be kept. d) Submission of high quality biological material including fresh frozen tumour samples for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centers. Submission of blood is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended. e) No amplification of MYC or MYCN (determined by FISH). f) For PNET 5 MB ¬ LR, low¬risk biological profile, defined as WNT subgroup positivity, in patients aged < 16.0 years at diagnosis. The WNT subgroup is defined by the presence of (i) ߬catenin mutation (mandatory testing), or (ii) ߬catenin nuclear immuno¬positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ߬catenin nuclear immunopositivity by IHC and monosomy 6 (optional testing). For PNET 5 MB ¬ SR, average¬risk biological profile, defined as WNT subgroup negativity. WNT¬negative tumours are defined by (i) ߬catenin nuclear immuno¬negativity by IHC (mandatory testing), and the absence of ߬catenin mutation (mandatory testing) and monosomy 6 (optional testing), or (ii) ߬catenin nuclear immuno¬positivity by IHC (mandatory testing) in the absence of ß-catenin mutation and monosomy 6, or (iii) monosomy 6 in the absence of ߬catenin nuclear immuno¬positivity by IHC or ߬catenin mutation. OR WNT subgroup positive tumours arising in patients age ≥16.0 years at diagnosis. The WNT subgroup is defined by the presence of (i) ߬catenin mutation (mandatory testing), or (ii) ߬catenin nuclear immuno¬positivity by IHC (mandatory testing) and ߬catenin mutation, or (iii) ߬catenin nuclear immuno¬positivity by IHC and monosomy 6 (optional testing). g) No prior therapy for medulloblastoma other than surgery. h) Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study. i) Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy. j) CTC grades < 2 for liver, renal, and haematological function. k) no significant sensineural hearing deficit as defined by pure tone audiomentry with bone conduction or air conduction and normal tympanogram shows no impairement ≥ 20 dB at 1¬3 kHz. If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history of hearing deficit. l) No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Njimwegen breakage syndrome) Gorlin Syndrome or other reasons as defined by patient’s clinician; m) No identified Turcot and Li Fraumeni syndrome. n) Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation. o) National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).

Exclusion Criteria:

Exclusion Criteria Note: the Exclusion Criteria are the same for PNET 5 MB ¬ LR and PNET 5 MB ¬ SR. To be eligible for inclusion in either study, patients must meet none of the following criteria: a) One of the inclusion criteria is lacking. b) Brainstem or supratentorial primitive neuro¬ectodermal tumour. C) Atypical teratoid rhabdoid tumour. d) Medulloepithelioma Ependymoblastoma. e) Large¬cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), centrally confirmed. f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or not determinable MYC or MYCN or WNT subgroup status. g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF). h) Patient previously treated for a brain tumour or any type of malignant disease. i) DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin, Turcot, or Li Fraumeni syndrome. j) Patients who are pregnant. k) Female patients who are sexually active and not taking reliable contraception. l) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons. m) Patients in whom non¬compliance with toxicity management guidelines can be expected.

Sub Specialty:

Brain Cancer Children's Cancer and Leukaemia

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Avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III dMMR or POLE exonuclease domain mutant colon cancer: A phase III randomised study.

Research Summary

In locally advanced colon cancer the standard of care is surgical resection and chemotherapy. Most patients are cured however not all of them are. To improve the cure rate we need to target sub groups of patients who are likely to respond to new drugs. We aim to look at 2 sub groups of patients - Mismatch repair deficient and POLE exonuclease mutant. We think that because of these tumours having a high mutational load, they are likely to respond to a new group of treatments called checkpoint inhibitors. This study will compare the standard of care - surgery and chemotherapy with this plus Avelumab - an immune checkpoint inhibitor. It will be a randomised study.

Inclusion Criteria:

1. Male or female subjects aged > = 18 years 2. ECOG PS 0/1 3. Histologically proven, stage III (i.e., any T, N1 or N2, M0) adenocarcinoma of the colon (as defined by the presence of the inferior pole of the tumour above the peritoneal reflection - that is, at least 15 cm from the anal margin). 4. Fully surgically resected tumour with clear resection margins (i.e., > 1 mm) 5. Locally confirmed defective mismatch repair (dMMR) tumour (as defined by the lack of staining on either the pre-operative biopsy samples or resection specimens of at least one of the following proteins: MLH1, MSH2, MSH6, PMS2) or centrally confirmed POLE exonuclease domain mutated tumour (in subjects < 50 years old with pMMR tumours) 6. Absence of metastases as shown by post-operative CT scan 7. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would contraindicate adjuvant chemotherapy 8. Adequate hematological function defined by absolute neutrophil count (ANC) > = 1.5 × 109/L, platelet count > = 100 × 109/L, and hemoglobin > = 9 g/dL (blood transfusion before recruitment is allowed) 9. Adequate hepatic function defined by a total bilirubin level < = 1.5 × the upper limit of normal (ULN) range and AST and ALT levels < = 2.5 × ULN 10. Adequate renal function defined by an estimated creatinine clearance > = 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) 11. Negative serum or urine pregnancy test at screening for women of childbearing potential 12. Fertile men and women must agree to take highly effective contraceptive precautions during, and for 6 months after the last dose of chemotherapy or for 1 month after the last dose of Avelumab

Exclusion Criteria:

1. Rectal tumours (as defined by the presence of the inferior pole of the tumour below the peritoneal reflection - that is, < 15 cm from the anal margin). 2. Inability to start adjuvant chemotherapy within 12 weeks after surgery 3. Administration of neoadjuvant systemic chemotherapy or radiotherapy before surgical resection of colon cancer 4. Prior organ transplantation, including allogeneic stem cell transplantation 5. Significant acute or chronic infections including, among others: - known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - positive test for HBV surface antigen or anti-HCV antibody and confirmatory HCV RNA test 6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: - Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible - Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses < = 10 mg/day of prednisone or equivalent - Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade > = 3 NCI CTCAE v4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) 8. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.0; however, alopecia and sensory neuropathy Grade < = 2 is acceptable unless oxaliplatin administration is planned as part of the adjuvant treatment 9. Pregnancy or lactation 10. Known alcohol or drug abuse 11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (> = New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication 12. Known history of colitis, pneumonitis and pulmonary fibrosis (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment. 13. Any psychiatric condition that would prohibit the understanding or rendering of informed consent 14. Vaccination within 4 weeks of the first dose of Avelumab and while on trial is prohibited except for administration of inactivated vaccines 15. Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured. Cancer subjects with incidental histological findings of prostate cancer (tumour/node/metastasis stage of T1a or T1b or prostate-specific antigen ˂10) who have not received hormonal treatment may be included, pending a discussion with the study physician.

Sub Specialty:

Colorectal Cancer

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Planning treatment for oesophago-gastric cancer: a randomised maintenance therapy trial (PLATFORM Trial)

Research Summary

Advanced cancers of the stomach or oesophagus are normally treated with 2drug or 3drug combination chemotherapy regimens. In patients with tumours that are negative for a protein called HER2, the normal management after completion of the chemotherapy is to proceed with regular follow up ‘surveillance’ to monitor for any signs of the cancer starting to regrow. In patients with tumours that are positive for HER2, the normal treatment after completion of the chemotherapy is to proceed with an antibody drug called trastuzumab on its own and continue to monitor for evidence of the cancer starting to regrow. In both cases, the break from chemotherapy will usually allow patients to recover from any treatment side effects. Further chemotherapy may be given at the time of the cancer starting to regrow. However, there is interest in developing drugs which may be more tolerable than traditional chemotherapy, and which could be administered during this surveillance period to try and prolong the length of time until the tumour starts to regrow. Within the PLATFORM study, researchers are evaluating a number of different drugs which could be added in this ‘maintenance’ setting to see whether any of them may improve disease control and the length of time that somebody lives with advanced cancer of the stomach or oesophagus.

Inclusion Criteria:

• Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach. • Completion of at least 6 cycles of firstline chemotherapy for locally advanced / metastatic disease (this must have included a platinum and fluoropyrimidine in all cases; HER2 positive patients must have received trastuzumab alongside chemotherapy) with > stable disease on the end of treatment CT scan. • Disease which, following firstline chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy. • Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy. • Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis. • Unidimensionally measurable disease (CT or MRI as per RECIST). • Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease. • No prior radiotherapy in the advanced disease setting. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator. • Male/female patients aged ≥18 years. • WHO Performance status 0, 1 or 2. • Patients should have a projected life expectancy of at least 3 months. • Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be posttransfusion). • Adequate renal function: calculated creatinine clearance ≥50ml/minute. • Adequate liver function: serum bilirubin ≤1.5x ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present). • Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 60 days following the last dose of assigned study drug(s). • Written informed consent must be obtained from the patient before any study-specific procedures are performed.

Exclusion Criteria:

• Concurrent enrolment in another clinical trial unless it is an observational (noninterventional) clinical study. • Tumours of squamous histology. • Documented brain metastases, central nervous system metastases or leptomeningeal disease. • Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other antineoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be < grade 2 according to NCI CTCAE version 4.0. • Any major surgery within 4 weeks prior to the start of study treatment. • Uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 100 mm Hg). • Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior history of clinically significant cardiac failure are excluded from study entry. • History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan. • Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication. • Patients who are pregnant or lactating. • Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection. • Other clinically significant disease or comorbidity which may adversely affect the safe delivery of treatment within this trial. • Any other malignancies within the last 3 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). • Treatment with another investigational agent within 30 days of commencing study treatment.

Sub Specialty:

Upper GI

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PLATO - PersonaLising Anal cancer radioTherapy dOse - Incorporating Anal Cancer Trials (ACT) ACT3, ACT4 and ACT5

Research Summary

Anal cancer is rare, but its incidence is rising rapidly. Approximately 1000 cases are diagnosed each year in the UK. Standard treatment usually involves a combination of chemotherapy and radiotherapy (chemoradiotherapy (CRT)). Often the same radiotherapy dose is given regardless of disease stage. Recent improvements in radiotherapy means altered doses can now be given to the tumour whilst sparing normal tissues. PLATO is an integrated protocol, comprising 3 separate trials (ACT3, ACT4 and ACT5) which aims to optimise radiotherapy dose for low-, intermediate- and high-risk disease. ACT3: a prospective non-randomised phase II trial which will evaluate a treatment plan in patients with early, small tumours who have undergone surgery (local excision). Patients with no tumour cells close to the cut edge of the removed tissue (margins > 1mm) have no further treatment, and those with tumour cells close to the cut edge (margins ≤1mm) receive additional lower-dose CRT (41.4Gy in 23 fractions). We aim to determine whether this treatment strategy results in acceptably low rates of the cancer coming back ACT4: a randomised phase II trial. Compares standard-dose CRT (50.4Gy in 28 fractions) with reduced-dose CRT (41.4Gy in 23 fractions) in patients with intermediate-risk disease, to see if less radiotherapy is able to maintain the excellent success rates in treating the cancer, while reducing the side effects of treatment. ACT5: a seamless randomised pilot, phase II and phase III trial that compares standard-dose CRT (53.2Gy in 28 fractions) with two higher doses of CRT (58.8Gy and 61.6Gy, both in 28 fractions), in patients with locally advanced anal cancer, to see if giving a higher dose of radiotherapy reduces the chance of the cancer coming back, whilst not causing too many extra side effects. One of the two higher-dose experimental arms will be selected for the phase III component of the study.

Inclusion Criteria:

Key inclusion criteria for all three trials include: - written informed consent; - histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anus; - adequate bone marrow, hepatic and renal function; - HIV negative or HIV positive and receiving effective antiretroviral therapy and CD4 count > 200; - - aged 16 years or over; - fit for all protocol defined treatments; - prepared to practice methods of contraception during treatment and until 6 months post end of treatment - able to undergo all mandated staging and follow-up investigations, including MRI Trial-specific inclusion criteria: ACT3 – T1 N0 or Nx anal margin tumour treated by local excision; ECOG performance status 0-2 ACT4 – T1-2 up to 4cm N0 or Nx anal canal or anal margin tumour; ECOG performance status 0-1 ACT5 – T2 N1-3 or T3-4 Nany anal canal or anal margin tumour; ECOG performance status 0-1

Exclusion Criteria:

Key exclusion criteria for all three trials include: - definite evidence of metastatic disease; - prior invasive malignancy unless disease-free for a minimum of 3 years (exluding basal cell carcinoma of the skin or other in situ carcinomas); - prior systemic chemotherapy for anal cancer; - prior radiotherapy to the pelvis; - uncontrolled cardiorespiratory comorbidity; - pregnant or lactating; - immunocompromised (organ transplant) Trial-specific exclusion criteria: - ACT3 - where a piecemeal local excision precludes assessment of tumour size and margin status

Sub Specialty:

Colorectal Cancer

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UK Genetic Prostate Cancer Study (formerly the Familial Prostate Cancer Study)

Research Summary

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Inclusion Criteria:

All patients attending the Royal Marsden Hospital prostate clinics with a diagnosis of prostate cancer. Additionally, outside referrals of single cases of prostate cancer diagnosed at age 60 or under, first degree related pairs with at least one diagnosed at age 65 or under and any family with three or more cases of prostate cancer, at any age.

Exclusion Criteria:

Men who do not have prostate cancer or who do not fall within the inclusion criteria.

Sub Specialty:

Genetics Prostate Cancer Surgical Urology

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A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost

Research Summary

Prostate cancer accounts for 25% of new cancer diagnoses in the UK, and is the most common cancer diagnosis in men. Patients with intermediate and high risk localised prostate cancer are recommended to have either radical prostatectomy or radical radiotherapy combined with hormone therapy. 20-30% of those in higher risk groups are likely to recur following radiotherapy. Intensity modulated radiotherapy(IMRT) and image guidance techniques provide scope for intensifying prostate radiotherapy treatment whilst minimising any associated increase in radiotherapy related side effects. It is, however, currently uncertain whether promising results from planning and cohort studies of these approaches would translate into improved outcomes, without substantial increase in toxicity, in the context of a randomised controlled trial. PIVOTALboost aims to determine whether the addition of pelvic node IMRT and/or prostate boost to standard prostate IMRT improves failure-free survival (FFS) compared to standard prostate IMRT alone in patients with high or intermediate risk localised prostate cancer. PIVOTALboost is a randomised controlled parallel 4-arm phase III multicentre trial in men with localised high and intermediate risk prostate cancer. Consenting patients will be randomised to receive either: A) Prostate IMRT (control) B) Prostate and pelvic IMRT C) Prostate IMRT and prostate boost D) Prostate and pelvic IMRT and prostate boost All radiotherapy will be delivered using image guidance. Prostate boost will be delivered to the whole gland using High-Dose Rate Brachytherapy (HDRB), or to focal disease using focal HDRB or focal Intensity Modulated Radiotherapy (IMRT). Patients will be followed up for disease outcome, acute and late toxicity and quality of life; health economic details will also be captured. The study will recruit 1952 patients.

Inclusion Criteria:

1. Histologically confirmed, adenocarcinoma of the prostate using the Gleason scoring system (histological confirmation can be based on tissue taken at any time, but a re-biopsy should be considered if the biopsy is more than 12 months old). 2. PSA < 50ng/ml prior to starting ADT. 3.1. NCCN localised high risk or locally advanced disease • T3a, T3b or T4 N0M0 (clinical and/or MRI) and/or • dominant Gleason 4 or 5 and/or • PSA > 20; or 3.2. NCCN intermediate risk disease • T2b-c N0M0, and/or Gleason 3+4 and /or PSA 10-20 ng/ml and • Adverse feature, for example: Maximum tumour length (MTL) > 6mm and/or 50% biopsy cores positive and / or PI-RADS score 3, 4 or 5, lesion > 10mm on staging MRI. 4. Age > = 18 years. 5. Signed, written informed consent. 6. WHO performance status 0-2.

Exclusion Criteria:

1. Prior radiotherapy to the prostate or pelvis. 2. Prior radical prostatectomy. 3. Prior ADT for > 6 months at consent (as patients will need to commence radiotherapy at months 3-5 (maximum 7) following start of ADT). 4. Adjuvant docetaxel chemotherapy. 5. Radiologically suspicious or pathologically confirmed lymph node involvement. 6. Evidence of metastatic disease. 7. Life expectancy < 5 years. 8. Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artifacts and would make pelvic node planning more difficult. 9. For patients having fiducials inserted: Anticoagulation with warfarin/ bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician. 10. For patients being considered for randomisation options C2 and D2 only and are undergoing a planning MRI scan: Contraindication to undergo a MRI scan. 11. For undergoing HDR brachytherapy: long-term anticoagulation therapy which cannot be temporarily stopped, prostate surgery (TURP) with a significant tissue cavity, a history of recent deep vein thrombosis or pulmonary embolus, significant cardiovascular comorbidity, unfit for prolonged general anaesthetic. 12. Medical conditions likely to make radiotherapy inadvisable e.g. inflammatory bowel disease, significant urinary symptoms. 13. Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival. 14. Any other contraindication to external beam radiotherapy to the pelvis.

Sub Specialty:

Prostate Cancer

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A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination with Olaparib versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-related Genes (including BRCA1/2)

Research Summary

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Inclusion Criteria:

1. * Provision of informed consent prior to any study specific procedures. 2. * Patients must be male or female ≥ 18 years of age. 3. * Progressive cancer at the time of study entry. 4. * Histologically or cytologically confirmed TNBC with evidence of metastatic disease (defined as ER and PgR negative [IHC nuclear staining < 1% positive] and HER2 negative [IHC 0, 1+ or 2+ and/or IHC non amplified with ratio less than 2.0]). 5. * Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) unless contraindicated and/or a taxane (eg, paclitaxel, docetaxel). * Patients who have received platinum (cisplatin or carboplatin, either as monotherapy or in combination) for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy. * Patients who have received prior platinum based chemotherapy are eligible if platinum was given either as potentially curative treatment for a prior non breast cancer (eg, ovarian cancer) with no evidence of disease for ≥ 5 years prior to study entry or as adjuvant/neoadjuvant treatment for breast cancer provided at least 12 months have elapsed between the last dose of platinum-based treatment and randomisation. 6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.  FFPE tumour tissue blocks are required for each patient, but if not available, tissue sections are accepted. At least twenty (20) (thirty [30] preferable) unstained sections without cover slips must be submitted to ensure sufficient material for the prospective Lynparza HRR testing to determine study eligibility and research that will aid understanding of the patient population relative to treatment with DDR and other cancer agents.  If a patient has a previously known qualifying BRCA1/2 mutation (in blood or tumour tissue), then the patient can be invited to consent to the full study. The patient will need to consent to provide an archival tumour block or tissue sections for central assessment of the HRR mutation status.  If patients have a mutation in one of the 13 other non BRCA HRR genes based on prior breast cancer tissue specimen testing by the commercially available FoundationOne® assay, they must have the mutation confirmed as a qualifying mutation by FMI. Similarly, if patients have no detected mutation in any of the 15 HRR genes based on prior breast cancer tissue specimen testing by the FoundationOne® assay, they must have the lack of HRR mutation confirmed by FMI. The patient will need to consent to provide an archival tumour sample (tissue block or sections) and a blood sample computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. 8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomisation as defined below: (a) Haemoglobin (Hb) ≥ 10.0 g/dL with no blood transfusions (packed red blood cells) in the past 28 days (b) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (c) Platelet count ≥ 100 x 109/L with no platelet transfusions in the past 28 days (d) Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) unless the patient has documented Gilbert’s Syndrome (e) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN unless liver metastases are present in which case they must be ≤ 5 x ULN (f) Serum or plasma creatinine 1.5 x institutional ULN (g) Patients must have creatinine clearance (CrCl) estimated using the Cockcroft-Gault equation of ≥ 51 mL/min: Estimated CrCl = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 a where F= 0.85 for females and F= 1 for males 9. * ECOG PS 0-1 within 28 days of randomisation.

Exclusion Criteria:

1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment. 2. * More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.  Prior treatments with hormonal therapy and non hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy.  For the purposes of this protocol, the combination of an aromatase Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment. 3. * More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.  Prior treatments with hormonal therapy and non hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy.  For the purposes of this protocol, the combination of an aromatase inhibitor and everolimus is not considered cytotoxic chemotherapy.inhibitor and everolimus is not considered cytotoxic chemotherapy.  Treatment with biologics will not be considered as prior line of therapy. 4. * Previous randomisation in the present study. 5. * Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless treatment was for less than 3 weeks duration and at least 12 months have elapsed between the last dose and randomisation. Patients that did not tolerate prior treatment are excluded). 6. * Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation. The minimum washout period for immunotherapy shall be 42 days. 7. * Patients with MDS/AML or with features suggestive of MDS/AML. 8. * Patients with second primary cancer, EXCEPTIONS: adequately treated non melanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years prior to study entry (including lymphomas [without bone marrow involvement]).

Sub Specialty:

Breast Cancer

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The UK plasma based Molecular profiling of Advanced breast cancer to inform Therapeutic Choices (plasmaMATCH) Trial: A multiple parallel cohort, open-label, multi-centre phase IIa clinical trial aiming to provide proof of principle efficacy for designated targeted therapies in patients with advanced breast cancer where the targetable mutation is identified through ctDNA screening

Research Summary

There are many different types of breast cancer defined by the genetic code present within cancer cells. The genetic code is stored in the form of DNA, and changes within DNA are called mutations. Mutations are usually identified by analysis of tumour samples obtained through surgery or biopsy. Treatments that target specific mutations (known as targeted therapies) have led to improvements in the treatment of breast cancer. DNA from cancer cells is found in the blood of over 90% of patients with advanced breast cancer (breast cancer that has either reappeared following treatment, known as recurrent or locally advanced breast cancer, or breast cancer that has spread to another part of the body, known as metastatic breast cancer). DNA from cancer cells found in the blood is called circulating tumour DNA (ctDNA). Patients with advanced breast cancer will be asked to provide a blood sample which will be analysed for several specific mutations in the ctDNA. Depending on the ctDNA screening results, the patient may be invited to enter a treatment cohort and receive a treatment targeted to their type of disease. Patients will receive treatment until their cancer gets worse (progresses). The main aims of plasmaMATCH are to assess whether ctDNA screening can be used to detect patient subgroups who will be sensitive to targeted therapies and then to assess the safety and activity of the targeted treatments. Treatment cohorts: Cohort A: Patients with an ESR1 mutation will receive extended-dose fulvestrant. Cohort B: Patients with a HER2 mutation will receive neratinib. Patients with estrogen receptor (ER) positive breast cancer in this cohort will also receive fulvestrant. Cohort C: Patients with ER positive breast cancer and an AKT1 mutation will receive AZD5363 and fulvestrant. Cohort D: Patients with one of several mutations that activate a process called the ‘AKT pathway’ will receive AZD5363. Cohort E: Patients with triple negative breast cancer on their most recent tumour biopsy who do not have a targetable mutation identified by ctDNA screening or tumour sequencing that would allow entry into Cohorts A to D, or who have an actionable mutation identified but are not otherwise eligible for Cohorts A to D, will be invited to enter Cohort E and receive AZD6738 and olaparib.

Inclusion Criteria:

1. Female. 2. Aged ≥ 18 years old. 3. Histologically confirmed invasive breast carcinoma. 4. Metastatic or recurrent locally advanced breast cancer that is not suitable for treatment with radical or curative intent. 5. Demonstrated progression of disease by radiological assessment or by clinical assessment within the last 6 weeks. 6. Measurable disease by RECIST v1.1. 7. Patients must have completed at least one prior line of treatment for advanced breast cancer and/or relapse within 12 months of completing (neo)adjuvant chemotherapy. Patients with HER2 positive breast cancer must have been treated with at least two courses of HER2 targeted therapy in the advanced setting (or one course if no further courses of HER2 targeted therapy are available locally). 8. Patient must either be suitable for a baseline biopsy of recurrent disease or have an archival biopsy of recurrent disease available. Patients are requested to consent to a baseline biopsy but if deemed unsafe by the Investigator, an archival biopsy of recurrent disease can be used instead. If it is deemed unsafe to proceed with baseline biopsy, and no archival recurrent disease biopsy is available, the patient will not be eligible for entry into the treatment cohort. 9. ECOG performance status ≤ 2. 10. Life expectancy > 3 months. 11. Patients must be surgically sterile, be postmenopausal or must agree to use effective contraception during the period of trial treatment and be willing to do so for 6 months following the end of trial treatment. Effective contraception is defined as double barrier contraception (e.g. condom plus spermicide in combination with a diaphragm, cervical cap or intrauterine device). Ovarian suppression with an LHRH agonist is not a method of contraception. 12. Patients of childbearing potential should have a negative serum pregnancy test within 14 days prior to initiation of trial treatment. 13. At least 4 weeks washout period after the end of trial treatment on a different cohort within plasmaMATCH. 14. Adequate haematological, renal and hepatic function as defined by: • Haematology: - Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 x 109/L) - Platelet count ≥100,000/mm3 (≥100 x 109/L) - Haemoglobin ≥9g/dL (≥90g/L) • Renal function: - Serum creatinine ≤1.5 x upper limit of normal (ULN) and calculated creatinine clearance more than 30ml/min • Liver function tests: - Total bilirubin ≤1.5 ULN - Alanine aminotransferase (ALT) ≤3 ULN. In the presence of liver metastases ALT ≤5 ULN. For patients in Cohort B, C and D: aspartate aminotransferase (AST) ≤3 ULN. In the presence of liver metastases AST ≤5 ULN. 15. For patients with ER positive breast cancer in Cohorts A, B and C: EITHER postmenopausal, as defined by at least one of the following criteria: • Age > 60 years; • Age < 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females; • Documented bilateral oophorectomy; medically confirmed ovarian failure. OR Pre-/peri-menopausal (i.e. not meeting the criteria for being postmenopausal) if being treated with an LHRH agonist that was commenced at least 4 weeks prior to Cycle 1 Day 1, and continues on the LHRH agonist throughout the trial period. NB. Additional eligibility criteria apply for entry into each treatment cohort.

Exclusion Criteria:

1. Prior treatment with radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy or IMPs during the previous 4 weeks (6 weeks for nitrosoureas, Mitomycin-C) before trial treatment, except for hormonal therapy with LHRH analogues, which are permitted, and bisphosphonates or RANK ligand antibodies that are permitted for the management of bone metastases. 2. Uncontrolled CNS disease (brain metastases or leptomeningeal disease). Patients with prior diagnosis of CNS metastases must be stable by clinical assessment having ceased steroids after prior treatment. 3. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction within the last 6 months or ventricular arrhythmia. Patients with a history of any of the above listed cardiac conditions judged not to be clinically significant by the local investigator must be notified to the trial team at the ICR-CTSU for approval by the CI and/or Cohort Lead. 4. Ongoing toxic manifestations of previous treatments Grade ≥1. Exceptions to this are alopecia or toxicities which in the opinion of the Investigator should not exclude the patient. Such cases should be clearly documented in the patient’s notes by the Investigator. 5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of trial treatment. 6. Pregnant or breastfeeding. 7. Any condition that according to the treating physician may compromise the patient’s safety or the conduct of the trial. 8. Current malignancies of other types, with the exception of adequately treated in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy and have no evidence of the disease for 3 years or more are eligible for the trial. NB. Additional eligibility criteria apply for entry into each treatment cohort.

Sub Specialty:

Breast Cancer

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A phase Ib study to assess the safety and tolerability of oral Ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN.

Research Summary

To establish the maximum tolerated dose (MTD) and safety of ruxolitinib in combination with 5-azacitidine

Inclusion Criteria:

For the Interventional component: •Age ≥16 years old •A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP) •In need of treatment in the opinion of the investigator •Eastern Cooperative Oncology Group (ECOG) performance status 0-3 •Adequate liver and renal function, defined as: - Liver transaminases ≤3 × ULN (AST/SGOT and ALT/SGPT) - Bilirubin < 4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible) - GFR ≥40 ml/min •Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments •Able to give valid informed consent For the Observational Component •Age ≥16 years old •A prior diagnosis of ET, PV or MF with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP) - Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients previously treated post transformation into MPN-AP/MPN-BP, or entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only. - Able to give valid informed consent

Exclusion Criteria:

For the Interventional Component: •Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial •New York Heart Association Class II, III, or IV congestive heart failure •On-going cardiac dysrhythmias of grade 3, QTc prolongation > 480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium < 3.0 mEq/L, family history of long QT interval syndrome) •Erythropoietic agent within 28 days prior to registration •Thrombopoietic agent within 14 days prior to registration •CYP3A4 inhibitor within 7 days prior to registration •Experimental treatment within 14 days prior to registration •Previous treatment for MPN-AP or MPN-BP, including stem cell transplant and low intensity AML chemotherapy •Previously received 5-azacitidine. Ruxolitinib can be taken up until study entry at the pre-study dose. Hydroxycarbamide prescribed prior to study entry must be stopped before the first scheduled day of trial treatment •Known contraindications to receiving azacitidine or ruxolitinib •Known HIV seropositivity •Known to have active hepatitis A, B, or C •Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry •Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose. For the Observational Component: No Exclusions planned.

Sub Specialty:

Haematological Oncology

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Paediatric Hepatic International Tumour Trial

Research Summary

PHITT is an international, phase III, open-label trial with 4 randomised comparisons for paediatric, adolescent and adult patients with newly diagnosed hepatoblastoma (HB) and hepatocellular carcinoma (HCC), which are types of liver cancer. The 5 year overall survival (OS) for children with HB ranges from 53-100% depending on the extent of the disease and risk factors. Among those ‘cured’, current treatment regimens have significant side effects including cisplatin induced hearing loss and kidney problems, doxorubicin induced heart problems and secondary cancers. This study aims to reduce treatment for the very low and low risk group patients, while maintaining the excellent event-free survival (EFS) in these groups to reduce side effects of treatment. Intensification of therapy in the high risk group aims to improve the surgery options available and the EFS, while testing the use of new drugs in a clinical trial setting. The study also seeks to compare different regimens to improve surgical options in intermediate risk HB. Evaluation of the biology and genetics of HB and HCC as part of this study will identify prognostic and toxicity biomarkers.

Inclusion Criteria:

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Exclusion Criteria:

• Any previous chemotherapy or currently receiving anti-cancer agents • Recurrent disease • Previously received a solid organ transplant • Uncontrolled infection • Unable to follow the protocol for any reason • Second malignancy • Pregnant or breastfeeding women

Sub Specialty:

Children's Cancer and Leukaemia Teenage and Young Adult's Cancer Upper GI

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PETReA: Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma

Research Summary

Follicular lymphoma (FL) is a slowly growing cancer of the lymph glands. It often responds well to treatment but has a tendency to come back again (relapse) and therefore needs to be treated more than once. Initial treatment is usually with a 6-month course chemotherapy combined with an antibody drug called rituximab (R+chemo). Most patients who respond to R+chemo are offered further (maintenance) therapy with rituximab alone over a period of 2 years with the aim of delaying relapse. However, there is growing controversy about the routine use of rituximab maintenance after initial R+chemo for the following reasons: (1) It does not prolong survival; (2) It is associated with an increased risk of infection (responsible for 7-8% of all deaths in FL); (3) It prolongs remissions only in the minority of patients whose disease was destined to relapse within 2-3 years. A one-size-fits-all approach to rituximab maintenance is therefore not ideal as many patients will experience complications without deriving any benefit. The PETReA trial will use a new scanning technique called Positron Emission Tomography (PET) to identify which patients are more or less likely to benefit from rituximab maintenance after initial R+chemo treatment. We know that patients whose PET scans return to normal have a low-risk of early relapse, and the trial will therefore investigate if rituximab maintenance can be omitted in this group. In contrast, patients whose PET scans remain abnormal have a high risk of early relapse. The trial will investigate whether this group will benefit from the addition of a drug called lenalidomide to rituximab maintenance. PETReA, which is funded by Cancer Research UK, aims to recruit more than 800 patients from across the UK over a period of 4.5 years and is potentially available for any patient with FL who requires initial R+chemo treatment.

Inclusion Criteria:

1. Must be > = 18 years of age at the time of signing the informed consent form. 2. Must be able to adhere to the study visit schedule and other protocol requirements. 3. Must have a documented diagnosis of follicular lymphoma (grade 1, 2 or 3a). 4. Must be at non-contiguous stage II, stage III or stage IV. 5. Must fulfil at least one of the Groupe d'Etude des Lymphomas Folliculaires (GELF) GELF criteria for high tumour burden: a. Systemic symptoms (> 10% weight loss, temperature > = 38°C for more than 5 days, abundant night sweats) b. Performance status (PS) greater than 1 according to the Eastern Cooperative Oncology Group (ECOG) scale c. Elevated lactate dehydrogenase (LDH) level d. β2-microglobulin level greater than 25.5 nM/L (3 μg/mL) e. A single lymph node larger than 7 cm f. Involvement of at least 3 nodal sites, each with diameter greater than 3 cm g. Marked splenomegaly h. Organ failure i. Pleural effusion or ascites j. Orbital or epidural involvement k. Blood infiltration l. Cytopenia 6. Must not have received prior systemic therapy (local radiotherapy is permitted). 7. Must have a WHO performance status score of less than or equal to 2. 8. Must agree to adhere to the Celgene guidance on pregnancy prevention.

Exclusion Criteria:

1. Any serious medical condition that would prevent the subject from participating in the study. 2. Known active infection with HIV, HBV or HCV. 3. Pregnant or lactating females. 4. Central nervous system involvement as documented by spinal fluid cytology or imaging. 5. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer (TNM stage of T1a or T1b) 6. Any of the following laboratory abnormalities: a. Absolute neutrophil count (ANC) < 1,000/μL (1.0 X 109/L) b. Platelet count < 50,000/μL (50 X 109/L) c. Serum alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN) d. Serum total bilirubin > 1.5 x ULN unless due to Gilbert's Syndrome or biliary obstruction by lymphoma

Sub Specialty:

Lymphoma

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Pilot study to investigate the early prediction of toxicity following induction chemotherapy in Ewing’s sarcoma by blood-borne biomarkers and correlation with age-dependent pharmacokinetic variation

Research Summary

Ewing’s sarcoma is a bone cancer most commonly diagnosed in teenagers. Current treatment strategies result in approximately 60% of patients being cured but with serious sideeffects often associated with treatment. Routine tests do not accurately predict who will be cured or will experience increased side effects. By learning about what happens to the key drugs administered to Ewing’s sarcoma patients following administration, how they are broken down and what factors are important in determining response and toxicity, we will look to improve treatment strategies. This may be particularly important for teenagers and young adults, who may handle drugs differently than younger children. Modifying drug doses for different patient groups will allow the achievement of drug exposures which are most likely to be beneficial, whilst minimising commonly observed and often severe sideeffects. As part of the same clinical trial we shall also perform a series of blood tests that predict sideeffects of chemotherapy in some adult patients, to see if they are helpful in children to allow us to target those children for extra support and treatment. Improved management of cancer patients is anticipated by adjusting treatment of future patients based on differences in drug exposure and expression of biomarkers predictive of response to treatment and toxicity. Although the study focuses on children with Ewing’s sarcoma, the drugs involved in the treatment of this disease and the findings of the study will be applicable across many different types of sarcoma.

Inclusion Criteria:

a) Diagnosis of histologically confirmed Ewing sarcoma. b) Receiving VIDE or VDC/IE as part of standard clinical treatment. c) Single or double lumen central venous catheter in place. d) Written informed consent. e) Protocol approval by national and local ethics committee, regulatory authority and Trust R&D Departments.

Exclusion Criteria:

a) Receiving nonstandard dose chemotherapy. b) Glomerular filtration rate < 60 ml/min/1.73m2.

Sub Specialty:

Children's Cancer and Leukaemia

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A Phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV)-positive oropharyngeal cancer

Research Summary

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Inclusion Criteria:

• Histologically confirmed diagnosis of squamous cell carcinoma of the oropharynx. • HPV positive on central testing. • UICC TNM (7th edition) stage T1T3, N0N2b tumours of the oropharynx. Staging should be based on cross sectional imaging investigations carried out within 6 weeks of study entry*. • Local MDT decision to treat with primary transoral resection and neck dissection. • Patients considered fit for surgery and adjuvant treatment by the local MDT. • Aged 18 or over. • Written informed consent provided. * Please Note: Current smokers with N2b disease (including smokers up to 2 years before diagnosis) are not eligible to be included.

Exclusion Criteria:

• HPV negative squamous cell carcinomas of the head and neck. • Patients with T4 primary oropharyngeal tumours and/or T1T3 tumours where transoral surgery is considered not feasible. • N2cN3 nodal disease. • Unresectable retropharyngeal node involvement. • Current smokers with N2b disease (including smokers up to 2 years before diagnosis). • Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction. • Patients with distant metastatic disease (UICC TNM stage IVC disease) as determined by routine preoperative staging radiological investigations e.g., CT thorax and upper abdomen or PETCT. • Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix. • Pregnant or lactating women and fertile women who will not be using contraception during the trial.

Sub Specialty:

Head and Neck Cancer

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The PEACE (Posthumous Evaluation of Advanced Cancer Environment) Study

Research Summary

PEACE is a multi-centre prospective observational study intended to facilitate tissue donation from multiple tumour sites in the post-mortem setting. Potential study sites will be assessed to ensure that they have the infrastructure and ability to consent an adequate number of patients for the study so that at least 10-15 tumour harvests are performed per year. This has taken into account a likely attrition rate as a result of missed cases from consent to death. The PEACE protocol has been written in collaboration with oncologists, palliative care teams, molecular and histopathologists, ethicists, medical lawyers, and the patient advocate group ‘Independent Cancer Patients’ Voice’ (ICPV). The study consent and tumour harvesting procedure have been developed in accordance with the Human Tissue Act 2004, and the consent allows for the use of collected samples in future ethically approved studies.

Inclusion Criteria:

1. Age 18 years or older 2. Confirmed diagnosis of a solid malignancy with metastatic disease 3. Oral and written informed consent from patient to enter the study and to undergo post-mortem tissue sampling

Exclusion Criteria:

1. Medical or psychiatric condition that would preclude informed consent 2. History of high-risk infections (e.g. HIV-positive, hepatitis C, tuberculosis and Creutzfeldt-Jacob disease)

Sub Specialty:

Lung Cancer

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A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.

Research Summary

This trial is for men with prostate cancer that has spread to the bones (advanced cancer). It is for men with two or more areas of cancer in the bones. Prostate cancer can be treated with hormone therapy. But after some time, it can spread to the bones. This is castration resistant prostate cancer. If this happens, you can have more hormone therapy. Often with a drug called enzalutamide (also called Xtandi). Researchers are looking at new ways of helping men in this situation. In this study, they are looking at radium 223 (Ra223 also called Xofigo). Ra223 is already used to treat cancers that have spread to the bones. But doctors want to find out if having it with enzalutamide is better. Ra223 is a type of internal radiotherapy. Bone cells take up the radium 223 and once it’s in the bones, it releases radiation. In this study, people have one of the following: • enzalutamide or • enzalutamide with Ra223 The main aims of this study are to: • find out how well enzalutamide with Ra223 work as a treatment • learn about the side effects of enzalutamide with Ra223 • learn how well people cope with the treatment and side effects

Inclusion Criteria:

♦Histologically confirmed diagnosis of prostate adenocarcinoma ♦ Asymptomatic or mildly symptomatic (defined as no opioids and Brief Pain Inventory score, i.e. short form question #3 worst pain must be < 4) ♦ Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTC Bone Scan (BS) confirmed by standard XRay, CT, or MRI) with or without additional lymph node metastases. Patients with visceral metastases are not allowed ♦ Progressive CRPC according to Prostate Cancer Working Group 2 (PCWG2) i.e. either - For patients who manifest disease progression solely as a rising PSA level, PCWG2 criteria require documentation of a sequence of rising PSA values at a minimum of 1week intervals with the last value ≥ 2 ng/ml. - For patients with disease progression manifest in the bone, irrespective of progression by rising PSA, PCWG2 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan and XRay (e.g.: CTscan or MRI). - For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG2 requires progression according to RECIST 1.1. Ongoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy. ♦ Patients must be at least 18 years old ♦ WHO Performance status 01 ♦ Charlson score ≤ 3 ♦ Castrate serum levels of testosterone < 50 ng/dL ♦ Biochemistry and hematology - Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 109/L; platelets ≥100 109/L, and haemoglobin ≥ 10.0 g/dl.). - Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patient with Gilbert’s disease ≤ 5.0 × ULN. - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN. - Creatinine ≤ 1.5 x ULN - Albumin > 25 g/L ♦ Normal cardiac function according to local standard by 12lead ECG (complete, standardized 12lead recording). ♦ Able to swallow the study drug and comply with study requirements ♦ Prior or concomitant therapy. - Prior docetaxel is permitted under the following conditions: started within 2 months of ADT initiation, given for a maximum of 6 cycles and progression after 6 months of the last dose of docetaxel. - Previous treatment with bicalutamide, flutamide, prednisone, or dexamethasone is allowed if it was stopped at least 4 weeks prior to randomization. ♦ Patients taking bisphosphonates or denosumab are eligible if they have received a stable dose for 4 weeks or more prior to randomization. (These treatments may then be continued on study). ♦ Drugs known to lower the seizure threshold or prolong QT interval are not permitted. ♦ Participants who have partners of childbearing potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after last dose of enzalutamide and 6 months after the last dose of Ra223. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. ♦ Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. ♦ For participation in translational research, specific consent must be given.

Exclusion Criteria:

♦ Known central nervous system metastases or leptomeningeal tumor spread. ♦ Significant cardiovascular disease including: - Myocardial infarction within 6 months prior to screening. - Uncontrolled angina within 3 months prior to screening. - Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multigated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45% - History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes). - History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. - Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 millimeters of mercury (mm Hg) or diastolic blood pressure > 105 mm Hg at screening. - Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening ECG and on physical examination. ♦ Prior treatment with enzalutamide or Ra223. ♦ Prior or concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole. ♦ Prior hemibody external radiotherapy. Patients who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count and platelets. ♦ Prior therapy with other radionuclides (e.g., strontium89, samarium153, rhenium186, or rhenium188). ♦ Involvement in another therapeutic trial involving an experimental drug. ♦ Anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization. ♦ Known hypersensitivity to compounds related to enzalutamide or Ra223. ♦ Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, insitu carcinoma or lowgrade superficial bladder cancer), or the patient has been free of malignancy for a period of 3 years prior to randomization date. ♦ History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of randomization, OR any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). ♦ Major surgery within 4 weeks prior to treatment. ♦ Drug or alcohol abuse. ♦ Other serious illness or medical condition, such as but not limited to: - Any infection ≥ Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 4. - No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease). - Crohn’s disease or ulcerative colitis. - Bone marrow dysplasia. - Fecal incontinence. - Lifethreatening illness unrelated to cancer. ♦ Condition which, in the investigator’s opinion, makes the patient unsuitable for trial participation.

Sub Specialty:

Prostate Cancer

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The ORANGE II PLUS Trial: An international multicentre randomised controlled trial of open versus laparoscopic hemihepatectomy

Research Summary

Surgical removal of part of the liver is primarily indicated as a treatment for cancer, either a cancer which has arisen in the liver or has spread from elsewhere, commonly the bowel. The number of such operations performed is increasing year on year due to improvements in non-surgical treatments for cancer and in surgical expertise which yields more patients suitable for surgery. The standard method by which this surgery is performed is through a large abdominal incision. Increasingly the keyhole approach is advocated as resulting in less pain after surgery, better cosmesis and a quicker recovery. However to date there is a lack of good quality evidence to support the use of keyhole surgery over the traditional open approach. The proposed research trial should address this knowledge gap. The research will be carried out in centres in the UK capable of performing such specialist surgery, Southampton and Cardiff. A random process will be used to allocate patients to either the open or keyhole approach. The main determinant of which operation is superior will be the time it takes for patients to recover from the surgery. Other criteria that will be assessed include duration of hospital stay, complications, quality of life, cost of treatment and overall survival.

Inclusion Criteria:

•Patients requiring left or right hemihepatectomy with or without the need for one additional hepatic wedge resection or metastasectomy •Able to understand the nature of the study and what will be required of them •Men and nonpregnant, nonlactating women aged over 18 •BMI between 18-35 •Patients in ASA IIIIII

Exclusion Criteria:

•Inability to give written informed consent •Patients undergoing liver resection other than left or right hemihepatectomy with or without the need for one additional hepatic wedge resection or metastasectomy •Patients with hepatic lesion(s), located with insufficient margin from vascular or biliary structures to be operated laparoscopically. •Patients in ASA IVV •Repeat hepatectomy

Sub Specialty:

Hepatobiliary Surgery Upper GI

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Randomised, phase II/III, 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA

Research Summary

This is a clinical trial for patients diagnosed with early stage breast cancer i.e. that has not spread to other organs such as the lungs, liver or bones, who have been advised to receive chemotherapy before surgery (neoadjuvant) chemotherapy. The trial investigates the safety and effectiveness of olaparib, a drug which targets part of the pathway that repairs damaged DNA, in addition to platinum-based neoadjuvant chemotherapy. The trial is open to patients who have breast cancer caused by an inherited mutation (change from the normal DNA sequence) in the BRCA 1 or BRCA 2 genes. In addition, it is open to patients who do not have hormone-responsive (oestrogen) breast cancer that also does not over-express a protein called HER2. These breast cancers are called triple negative breast cancers (TNBC). BRCA–mutated (gBRCA) and TNBC are considered to have a higher risk of disease recurrence after surgery and are usually treated with chemotherapy. The chemotherapy to be given are drugs called paclitaxel (given weekly) and carboplatin (given once every 3 weeks) followed by drugs called anthracyclines. Both of these drugs have been used in breast cancers of these types and stage previously but not in combination with olaparib. However, they have been used in combination with olaparib in women with more advanced breast cancers with good results. So this trial investigates whether introducing olaparib at an earlier stage of breast cancer might produce more shrinkage of the breast cancer before surgery, which may allow a better chance of avoiding mastectomy and may lead to a better chance of avoiding recurrence of the breast cancer.

Inclusion Criteria:

• Written informed consent. • Aged between 16 and 70 • Histologically confirmed invasive breast cancer. • Clinical stage T1-4 N0-2 (tumour or metastatic node diameter > 10mm) • Confirmed ER-negative and HER2-negative. or • Germline BRCA mutation positive, irrespective of hormone status but HER2 negative. • Performance Status 0-1

Exclusion Criteria:

T0 tumour in absence of axillary node > 10mm • TNBC with a non-basal phenotype and over-expressing Androgen Receptor • Not suitable for neoadjuvant chemotherapy • Distant metastases apparent prior to randomisation • Prior history of invasive breast cancer within the last 5 years • Previous PARP inhibitor use or any previous chemotherapy or targeted agent. • Any previous chemotherapy or agent used for the treatment of cancer within the last 5 years

Sub Specialty:

Breast Cancer

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A study of Thalidomide, Bendamustine, and Dexamethasone (BTD) vs Bortezomib, Bendamustine, and Dexamethasone (BBD) in patients with renal failure defined as a GFR below 30 mls/min

Research Summary

Renal impairment is a life threatening complication of myeloma. Up to 20-25% of patients will present at myeloma diagnosis with renal dysfunction. In this Phase II study, 120 newly diagnosed myeloma patients with eGFR less than 30ml/min from approximately 20 centres will be randomised to receive either Thalidomide or Bortezomib; all patients will receive bendamustine and dexamethasone in three weekly cycles. All patients will receive a minimum of 4 cycles. Aims 1) Establish whether proteasomal inhibition (bortezomib) or IMiD (thalidomide) based therapy achieves threshold reduction of sFLC in a significant majority of patients 2) Establish whether sFLC response to the first two cycles (early responder) predict haematological and renal response to next two cycles of therapy 3) Establish an early time point for assessment of sFLC reduction as a biomarker for response

Inclusion Criteria:

1. Patients attending NHS Haemato-oncology centres 2. Patients with newly diagnosed symptomatic myeloma and renal al failure 3. Patients willing and able to give written informed consent 4. Chronic kidney disease stage 4 or 5 5. GFR < 30mls/min 6. A number of patients with newly diagnosed myeloma and renal failure will have a pre-existing medical condition (hypertension, diabetes etc) causing renal damage. Where there is a medical condition (eg. hypertension, diabetes) which may cause renal damage, there must have been a further decline (≥15mls/min) between previous steady state and the study screening 7.Female WCBP and male participants whose partner is a WCBP must be prepared to use contraception in accordance with (and consent ) to the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention Programme 8. Women of childbearing potential (WCBP) must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene-approved process for thalidomide and lenalidomide Risk management and Pregnancy Prevention. 9. Free of prior malignancies for ≥ 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, localised prostate cancer or carcinoma "insitu" of the cervix or breast 10. In the Investigator's opinion, is able and willing to comply with all trial requirements 11. Willing to allow his or her GP and consultant, if appropriate, to be notified of participation in the trial

Exclusion Criteria:

1. Female patient who is pregnant, lactating or planning pregnancy during the course of the trial or the female partner of a male participant planning a pregnancy during the course of the trial 2. Age < 18 years 3. Known allergy to investigational drugs 4. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial 5. Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) < 1.0 x 10(9)/L Platelet count < 75 x 10(9)/L Serum SGOT/AST or SGPT/ALT > 3 x upper limit of normal 5. Use of any standard/experimental anti myeloma drug therapy 14 days prior to trial entry 6. CKD < 4 7. Intention to use a physical method of serum free light chain removal such as plasma exchange or high cut off dialysis 8. Grade 2 neuropathy (NCICTCAE v 4.0) or more will preclude use of thalidomide and bortezomib 9. Participants who have participated in another research trial involving an investigational product in the past 12 weeks.

Sub Specialty:

Haematological Oncology

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The Impact of the Oncotype DX® Breast Cancer Assay on Treatment Decisions in a UK Population of Patients with Estrogen Receptor-Positive Early Breast Cancer with 1-3 Positive Lymph Nodes, who are Potential Candidates for Chemotherapy, but for whom the Benefits of Chemotherapy are Uncertain

Research Summary

The main goal of this study is to show how the results of the Oncotype DX® test changes the decisions of physicians in the UK for women with ER-positive (ER+), early breast cancer (EBC) with 1-3 positive lymph nodes who are potential candidates for chemotherapy, but for whom the benefits of chemotherapy may be uncertain. This study will also assess how the results of the Oncotype DX assay affect the treatment preferences of the patient.

Inclusion Criteria:

1. Patients must have undergone surgical treatment for breast cancer with adequate evaluation of lymph node status with a sentinel lymph node procedure or full axillary dissection, with positive involvement of 1-3 axillary lymph nodes as confirmed by histologic examination. 2. Patient must have adequate performance status (PS ECOG 0, 1) 3. Patient must be a candidate for treatment of their cancer with systemic chemotherapy in addition to hormonal therapy. 4. Patients should, in the treating physician’s judgment, represent the population for which the benefit of adding systemic chemotherapy to hormonal therapy is either unclear or may not be large enough to warrant the risk of undergoing chemotherapy. 5. Eligible Staging Criteria: - T1-3 N1, M0 (inclusive of N1mic) 6. Patient’s tumour must undergo central pathology review at Genomic Health Inc. (GHI) and must be found adequate for the Oncotype DX assay. 7. Patient’s tumour must be oestrogen-receptor positive (ER+, Allred score > 2) as per institutional guidelines and not have HER2 positive tumours by immunohistochemistry (IHC) or in situ hybridisation (ISH). 8. Patient must be over 18 years of age.

Exclusion Criteria:

1. Patients have ER negative tumours (ER-, Allred score ≥ 2) 2. Patients have HER2 positive tumours (HER2+) as defined by IHC 3+ or HER2 gene amplified if tested by ISH 3. Patients have not had evaluation of lymph node involvement, have been deemed not to have lymph node involvement, or have only immunohistochemical confirmation (N0(i+)) of node involvement 4. Patients have a prior history of breast cancer in the same breast 5. Patients have been newly diagnosed with more than one operable primary breast tumour 6. Patients have multi-centric tumours (note: patients with multi-focal tumours may be included) 7. Patients have known metastatic breast cancer 8. Patients have < 2mm invasive tumour as assessed by local pathologist 9. Patients have received any kind of neo-adjuvant treatment 10. Patients have poor performance status (ECOG 2, 3, 4) and/or other clinical factors that would render the patient a non-viable candidate for adjuvant chemotherapy 11. Patients with a current medical condition such as psychiatric illness that would interfere with their ability to consent and participate in this study 12. Male patients with breast cancer

Sub Specialty:

Breast Cancer

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Optimal Personalised Treatment of early breast cancer using Multiparameter Analysis

Research Summary

It is normal clinical practice to offer several months of adjuvant chemotherapy to patients with early breast cancer who have involved axillary lymph nodes. A recommendation for chemotherapy is incorporated into a number of guidelines. Recently however it has been argued that chemotherapy may have little effect on the subtype of breast cancer that is broadly identified as being hormonally responsive without HER2 gene amplification/HER2 protein overexpression and with a low or intermediate grade. These patients already benefit substantially from hormonal therapies and for many, the addition of chemotherapy is thought to confer no significant additional survival advantage. Conventional clinico-pathological assessment however does not reliably identify those individuals with this breast cancer subtype who can safely avoid chemotherapy. Preliminary evidence however strongly suggests that multi-parameter genomic tests are superior to conventional assessment at identifying patients who will not significantly benefit from chemotherapy despite being at risk of relapse as a result of tumour size or lymph node involvement. The OPTIMA trial seeks to advance the development of personalised treatment of early breast cancer by the prospective evaluation of multi-parameter analysis as a means of identifying those patients who are likely to benefit from chemotherapy whilst sparing those who are unlikely to do so from an unnecessary and unpleasant treatment, and to establish the cost-effectiveness of this approach. The OPTIMA study population would ordinarily be treated with a combination of chemotherapy and endocrine therapy. The trial compares the management of patients using test-directed assignment to chemotherapy with standard management (chemotherapy) in a non-inferiority design. A preliminary phase of the study, OPTIMA prelim, was successfully completed. OPTIMA prelim demonstrated the feasibility of a large scale trial and selected the test technology to be used in the main trial.

Inclusion Criteria:

• Female or male, age ≥ 40 • Excised invasive breast cancer with local treatment either completed or planned according to trial guidelines. • ER positive (Allred score ≥3 or H-score ≥10 or > 1% of tumour cells stained positive) as determined by the referring site (in a laboratory meeting NEQAS standards). • HER2 negative (IHC 0-1+, or ISH negative/non-amplified [ratio of HER2/chromosome 17 < 2.00 and copy number < 6]) as determined by the referring site (in a laboratory meeting NEQAS standards). • Axillary lymph node status: i. 1-9 lymph nodes involved and if 1-3 nodes, at least 1 node containing a macrometastasis (i.e. deposit > 2mm diameter) ii. 1-3 lymph nodes involved with micrometastases only (i.e. deposit > 0.2-2mm diameter) AND tumour size ≥ 20mm iii. node negative AND tumour size ≥ 30mm. • Considered appropriate for adjuvant chemotherapy by treating physician. • Patient must be fit to receive chemotherapy and other trial-specified treatments with no concomitant medical, psychiatric or social problems that might interfere with informed consent, treatment compliance or follow up. • Bilateral cancers are permitted provided at least one tumour fulfils the entry criteria and none meet any of the exclusion criteria. • Multiple ipsilateral cancers are permitted provided at least one tumour fulfils the entry criteria and none meet any of the exclusion criteria. • Written informed consent for the study.

Exclusion Criteria:

• ≥10 involved axillary nodes (with either macrometastases and/ or micrometastases) or evidence for internal mammary node involvement. • ER negative OR HER2 positive/amplified (as determined by the referring site). • Metastatic disease. • Previous diagnosis of malignancy unless: i. managed by surgical treatment only and disease-free for 10 years ii. basal cell carcinoma of skin or cervical intraepithelial neoplasia iii. ductal carcinoma in situ (DCIS) of the breast treated with surgery only iv. lobular carcinoma in situ (LCIS) or lobular neoplasia of the breast. • The use of oestrogen replacement therapy (HRT) at the time of surgery. Patients who are taking HRT at the time of diagnosis are eligible provided the HRT is stopped before surgery. • Pre-surgical chemotherapy, endocrine therapy or radiotherapy for breast cancer. Treatment with endocrine agents known to be active in breast cancer treatment including ovarian suppression is permitted provided this was completed > 1 year prior to study entry. • Commencement of adjuvant treatment prior to trial entry. Short-term endocrine therapy initiated because of, for instance, prolonged recovery from surgery is permitted but must be discontinued at trial entry. • Trial entry more than 8 weeks after completion of breast cancer surgery. • Planned further surgery for breast cancer, including axillary surgery, to take place after randomisation, except either re-excision or completion mastectomy for close or positive/involved margins which may be undertaken following completion of chemotherapy.

Sub Specialty:

Breast Cancer

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Oesophageal Cancer Clinical and Molecular Stratification Study (OCCAMS) - A Multicentre Study to Determine Predictive and Prognostic Biomarkers and Therapeutic Targets for Oesophageal and Junctional Adenocarcinoma including Whole Genome Sequencing.

Research Summary

Cancers that occur at the junction between the oesophagus (gullet) and the stomach are called gastro oesophageal junction (GOJ) adenocarcinomas. They are 6 times more common than they were 30 years ago and have a very poor outcome (only 1 in 5 patients will survive five years). We have previously developed a new way of determining how advanced a patient’s GOJ adenocarcinoma is (what we call staging) using both the physical features determined by the radiology tests and the molecular features of the cancer. This system works significantly better than the existing way we stage these cancers. However this new system was developed using patients who had already had their surgery. We now want to test it on patients at the beginning of their treatment- or what we term prospectively. The patient’s management will not differ from current practice but as well as looking at the features used for staging at the moment we will also record our new system in parallel. We will also test samples of the cancer, which are already routinely taken, for the molecular changes we think will predict survival. After this patients will undergo the standard treatment at each of the centres involved. It will then be possible to determine both how practical our new system is and how good it is at predicting survival. We will be running this prospective trial in multiple hospitals across the country to ensure that our system is broadly applicable. If we can prove that our revised staging system, using both the physical features of the tumour and the molecular changes, can accurately predict outcome this will allow us to give far better information to our patients about their chance of a cure but also it will also allow treatments to be targeted at those who will benefit the most.

Inclusion Criteria:

The inclusion criteria is any patient with tissue proven diagnosis of adenocarcinoma of the oesophagus, stomach and gastro-oesophageal junction including those undergoing endoscopic therapy (endoscopic mucosal resection +/- radiofrequency ablation or stent insertion in palliative patients ) or surgery (oesophagectomy or extended total gastrectomy). This includes patients with intramucosal cancer and advanced disease.

Exclusion Criteria:

Patients for palliative treatment

Sub Specialty:

Gastroenterology Upper GI Upper GI Surgery

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OCTOPUS: Ovarian Cancer Trials of Weekly Paclitaxel ­ Umbrella Study A Randomised, Phase II Umbrella Trial of a Weekly Paclitxel +/­ Novel Agents in Platinum­Resistant Ovarian Cancer

Research Summary

More than 4,200 women with ovarian cancer die from the disease every year in the UK. Most patients with relapsed ovarian cancer initially respond to chemotherapy but then the disease becomes resistant to treatment. Eventually, all patients develop relapse within 6 months from the end of last platinum containing chemotherapy - a term called platinum-resistance.The response rate to chemotherapy for women with platinum-resistant ovarian cancer is low (10-55%). The average time before the cancer worsens (‘median progression-free survival’) is approximately 4 months and overall survival is only 12 months. There is an urgent need to improve patient outcomes. Chemotherapy using paclitaxel delivered weekly is a useful strategy. OCTOPUS is a phase II clinical trial framework for testing whether novel targeted agents (either as single agents or in combination with weekly paclitaxel-‘experimental’ arm) provide any promising activity signals in platinum-resistant ovarian cancer compared to weekly paclitaxel alone (standard care). This trial design allows for new targeted agents to be screened in the context of a rolling, randomised, placebo-controlled phase II setting. New agents will be introduced/removed from OCTOPUS by amendment thus reducing the study time and costs. In each randomised placebo controlled study, a total of 140 patients will be recruited and randomised in a 1:1 ratio to receive paclitaxel plus novel agent or paclitaxel plus placebo. The aim of the trial is to investigate whether the experimental arm is superior to standard chemotherapy (paclitaxel), to determine the safety, quality of life and to explore whether markers predicting which patients are likely to benefit most can be found. The first drug to be tested in combination with weekly paclitaxel is AZD2014. This oral drug blocks molecules called mTORC1 and 2 which are known to be involved in cancer growth. Early clinical trials have shown very promising results in ovarian cancer.

Inclusion Criteria:

1. Age ≥ 18 years 2. Histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer (please note that patients who have an original diagnosis based on cytology only will not be eligible for entry into the study unless a biopsy confirming high grade serous histology is performed). Please note that Grade 3 serous on pathology reports are accepted as high grade serous. Any patient originally diagnosed with a ‘grade 2 serous’ pathology must undergo pathology review to confirm high grade pathology. 3. Platinum-resistant disease defined as progression within 6 months of completing prior platinum therapy. This includes platinum-refractory disease. Progression is defined by RECIST criteria v1.1 (radiologically with measurable disease), but patients with CA125 progression (GCIG CA125 Criteria) plus symptoms indicative of progression will also be allowed to enter. 4. Measurable or evaluable disease (if not measurable by RECIST criteria v1.1, must be evaluable by GCIG CA125 criteria). Patients with CA125 progression in the absence of symptoms will NOT be eligible. 5. Histological tissue specimen available (tissue block or 810 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, a biopsy must be carried out to obtain sufficient tissue for histological assessment. 6. Willingness to undergo mandatory biopsy pre cycle 1 day 1. Target lesions (RECIST criteria v1.1) should be avoided if possible. 7. Prior taxane use: Patients whom have received prior 3 weekly paclitaxel (or other 3 weekly taxane) are permitted. Patients whom received weekly paclitaxel as part of first line treatment in combination with platinum are eligible if the interval since the last dose of weekly paclitaxel is > 6months at the time of randomisation. Patients whom received prior weekly paclitaxel (alone or in combination) for platinum-resistant disease are excluded. If patients have received prior taxane, the interval since the last taxane treatment must be known. The treatment immediately prior to study entry need not be platinum-based. Entry into the trial is not limited to first line treatment for platinum-resistant ovarian cancer i.e. patients can have prior lines of therapy for platinum-resistant disease. 8. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed 9. Adequate haematological and biochemical function as indicated below. These measurements must be performed within 7 days prior to randomisation: • Absolute neutrophil count ≥1.5 x 109/L • Platelet count ≥100 x 109/L • Haemoglobin ≥90 g/L • Serum creatinine < 1.5 times ULN or creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation/Wright formula); confirmation of creatinine clearance is only required when serum creatinine is ≥1.5 times the ULN • Total bilirubin < 1.5 times ULN. In cases of Gilbert’s syndrome, bilirubin < 2 x ULN is allowed • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or < 5 times ULN in the presence of liver metastases • Alkaline phosphatase < 5 x ULN 10. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other study procedures 11. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of trial treatment a. Postmenopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeaic for at least 12 months following cessation of all exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution OR b. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 12. Patients with synchronous tumours e.g. ovarian and endometrial or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable on CT and/or MRI is ovarian in origin. 13. Life expectancy of at least 12 weeks 14. ECOG Performance Status of 0,1

Exclusion Criteria:

1. Non high grade serous histologies including carcinosarcoma. 2. Prior chemotherapy, biological therapy, radiation therapy, hormonal anti-cancer therapy, immunotherapy, other anti-cancer agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites). Treatment with any investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer. 3. Pregnant or lactating women 4. Women of childbearing age and potential who are not willing to use two highly effective forms of contraception as detailed Pregnancy section. In addition, patients will be excluded if they are not willing to use contraception for the duration as documented in Pregnancy Sections. 5. With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.03) Grade 1 at the time of starting study treatment. 6. Major surgery within 4 weeks prior to entry to the study or minor surgery within 2 weeks of entry into the study (excluding placement of vascular access) 7. Spinal cord compression, known leptomeningeal involvement or brain metastases, unless treated and stable off steroids for at least 4 weeks prior to randomisation 8. Oral anticoagulants such as warfarin are not permitted, with the exception of 1mg daily warfarin dose for the prevention of hickman line clotting. Anticoagulation with low molecular weight heparin is allowed. 9. Any haemopoietic growth factors (e.g., GCSF, GMCSF) and blood transfusions within 2 weeks prior to randomisation 10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, uncontrolled hypertension, active bleeding diatheses or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required. 11. Torsades de Pointes within 12 months of study entry 12. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements 13. Patients with a history of grade 3 or 4 allergic reaction (CTCAEv4.03) to paclitaxel are not permitted. Patients who have had prior grade 1 or 2 hypersensitivity reactions are permitted providing the weekly paclitaxel is administered using the desensitisation schedule (section 5.7.2). 14. Patients who have a new diagnosis of deep vein thrombosis or pulmonary embolism within 2 weeks of randomisation are permitted if clinically stable on a therapeutic dose of LMWH.

Sub Specialty:

Gynaecological Cancers

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A prospective UK population-based study of incidence, biology, treatment and outcomes of non-­Hodgkin's Lymphoma in young adults

Research Summary

Non-Hodgkin’s Lymphoma (NHL) is the fifth commonest malignant disease in adolescents and young adults. It is a spectrum of malignant tumours of lymphocytes and lymph glands. Each different type of NHL requires a different treatment to achieve cure. NHL occurs in both children and adults, though the relative incidence of the different types changes with age. Cancer registry data show consistently lower survival for NHL patients aged 15 to 24 years compared to younger children. It is unknown whether this is a consequence of the different chemotherapy regimens used by paediatric and adult oncologists, or a change in disease biology during adolescence. There is no information available to address these questions. There is no record of how many young adults are treated on individual chemotherapy regimens and few enter clinical trials. Even the exact incidence of each NHL type is uncertain as new knowledge of tumour biology has changed the way NHL has been classified over the past decade. In cancer registries, which use older classifications, more than 40% are recorded as NHL without stating which type. This epidemiological study will collect diagnosis, treatment and outcome data on every 15 to 29 year old with NHL, diagnosed during a 3 year period in England, Scotland and Wales. The aim is to establish the incidence of each NHL type, document the treatments being used and record remission and cure rates. We will also make an inventory of whether there is spare lymphoma tissue, taken originally for diagnosis, which can be made available for future biological study of young adult NHL. The development of young adult cancer services in the UK puts us in a unique position to understand NHL in this age group. The new information from this study will provide a more rational basis for treatment recommendations, for future clinical trial design, and ultimately lead to improvements in patient cure and survival.

Inclusion Criteria:

All patients within the target age (15-29) with a new diagnosis of Non-Hodgkin's Lymphoma, diagnosed in England, Wales and Scotland.

Exclusion Criteria:

None.

Sub Specialty:

Lymphoma

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National Study of Colorectal Cancer Genetics

Research Summary

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Inclusion Criteria:

Patients aged 18-59 at date of diagnosis, who have had a diagnosis of adenocarcinoma of the colon or rectum within the last five years. Patient must have a family history of bowel cancer (parent/sibling/child also diagnosed).

Exclusion Criteria:

Patients will be excluded if they do not meet the inclusion criteria.

Sub Specialty:

Colorectal Cancer Genetics

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A multi-centre, randomised, parallel group, open-label, phase II, single-stage selection trial of nanoliposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (NEC)

Research Summary

There is currently no standard treatment beyond first-line etoposide/platinum-based chemotherapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma. Therefore the treatment of patients whose disease progresses on or after this first-line treatment is an area of unmet need. Combination regimens such as irinotecan/5-flourouracil/folinic acid are a second-line treatment option currently used in Europe and world-wide for this subset of patients. However, there is currently no trial evidence supporting this treatment regimen in these patients. Results of the NAPOLI-1 phase III trial of liposomal irinotecan in the treatment of patients with metastatic pancreatic adenocarcinoma after gemcitabine-based therapy reported improved survival for those patients who received a combination of liposomal irinotecan with 5-FU/folinic acid compared to those patients who received 5-FU/folinic acid alone. Liposomal irinotecan has been found to show an improved distribution into tumour tissue in comparison to irinotecan, and this may have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma. Docetaxel is standardly used as a second-line treatment option in patients with small cell lung cancer who have progressed on primary etoposide-platinum combination therapy. Therefore this drug could also have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma as the biology of the disease is similar to small cell lung cancer. The overall aim of the NET-02 trial is to select a treatment for continuation to a Phase III trial. The intention of the trial is to determine whether liposomal irinotecan/5-fluorouracil/folinic acid and docetaxel are sufficiently active in this population of patients. If both treatments are found to be efficacious, selection criteria will be applied to select a treatment to take forward. 102 eligible participants will be randomised to receive either liposomal irinotecan/5-fluorouracil/folinic acid given every 14 days, or docetaxel given every 21 days. Participants will be treated for a minimum of 6 months or until discontinuation of treatment as per protocol.

Inclusion Criteria:

1. Age > = 18 years and life expectancy > 3 months. 2. Diagnosed with poorly differentiated (as defined by the World Health Organisation in 2010, Ki 67 > 20%) extra-pulmonary neuroendocrine carcinoma (NEC grade 3). (Carcinoma of unknown primary is allowed if lung primary has been excluded). 3. Prior treatment with first-line platinum-based chemotherapy for NEC in the advanced setting and > = 28 days from Day 1 of the previous treatment cycle. 4. Documented radiological evidence of disease progression OR discontinuation of first-line platinum-based chemotherapy due to intolerance. 5. Measurable disease according to RECIST 1.1 (Appendix 1). 6. Eastern Co-operative Oncology Group (ECOG) performance status < = 2 (see Appendix 2). 7. Adequate renal function with serum creatinine < = 1.5 times upper limit of normal (ULN) and creatinine clearance > = 50ml/min according to Cockroft-Gault or Wright formula (see Appendix 3). 8. Adequate haematological function: Hb > = 90g/L, WBC > = 3.0 x 109/L, ANC > = 1.5 x 109/L, platelet count > = 100 x 109/L. 9. Adequate liver function: serum total bilirubin 1.5 x ULN (biliary drainage is allowed for biliary obstruction) and ALT and/or AST 2.5 x ULN in the absence of liver metastases, or 5 x ULN in the presence of liver metastases. 10. A negative pregnancy test is required at registration in women of childbearing potential . 11. Men* and women** of reproductive potential must agree to use a highly effective form of contraception*** during the study and for 6 months following the last dose of trial treatment. In addition, male participants should use a condom during study participation and for 6 months following the last dose of trial treatment. 12. Patients must be able to provide written informed consent. 13. Patients must be able and willing to comply with the terms of the protocol. * Women of reproductive potential are defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. ** Men of reproductive potential are defined as post-pubescent and not permanently sterile by vasectomy or bilateral orchidectomy. *** Highly effective contraception is defined as one of the following: combined (oestrogen and progesterone-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence (when this is in line with the preferred and usual lifestyle of the subject).

Exclusion Criteria:

1. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients. 2. Use (including self-medication) within one week of randomisation and for the duration of the study of any of the following: St. John’s wort, grapefruit, Seville oranges, medicines known to inhibit UGT1A1 and medicines known to inhibit or induce either CYP3A4 or CYP3A5 (see Appendix 8 of protocol for list*). 3. Previous treatment (for neuroendocrine carcinoma) with any of the components of combination chemotherapy regimens detailed in this study (nal-IRI or 5-FU or irinotecan or topoisomerase inhibitors or taxane-based therapy). 4. Incomplete recovery from previous therapy in the opinion of the investigator (surgery/adjuvant therapy/radiotherapy/chemotherapy in advanced setting), including ongoing peripheral neuropathy of > CTCAE grade 2 from previous platinum-based therapy. 5. First line treatment administered within 4 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to treatment start in this study. 6. Concurrent palliative radiotherapy involving target lesions used for this study (< 28 days from discontinuation of radiotherapy). Radiotherapy for non-target lesions is allowed if other target lesions are available outside the involved field. 7. Patients must not have a history of other malignant diseases (within the previous 3 years, and there must be no evidence of recurrence), other than: • Extra-pulmonary neuroendocrine carcinoma. • Non-melanoma skin cancer where treatment consisted of resection only or radiotherapy. • Ductal carcinoma in situ (DCIS) where treatment consisted of resection only. • Cervical carcinoma in situ where treatment consisted of resection only. • Superficial bladder carcinoma where treatment consisted of resection only. 8. Documented brain metastases, unless adequately treated (surgery or radiotherapy only), with no evidence of progression and neurologically stable off anticonvulsants and steroids. 9. Clinically significant gastrointestinal disorder (in the opinion of the treating clinician) including hepatic disorders, bleeding, inflammation, obstruction, or diarrhoea > CTCAE grade 1 (at time of study entry). 10. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion. 11. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure**. 12. Severe bone marrow failure or bone marrow depression after radiotherapy or treatment with other antineoplastic agents (defined as haematological values of haemoglobin or white blood cells or neutrophils or platelets not meeting inclusion criteria). 13. Known active hepatitis B virus, hepatitis C virus or HIV infection. 14. Active chronic inflammatory bowel disease. 15. Breastfeeding women. 16. Evidence of severe or uncontrolled systemic diseases which, in the view of the treating clinician, makes it undesirable for the patient to participate in the trial. 17. Evidence of significant clinical disorder or laboratory finding which, in the opinion of the treating clinician, makes it undesirable for the patient to participate in the trial. 18. Medical or psychiatric conditions that impair the ability to give informed consent. 19. Any other serious uncontrolled medical conditions (in the opinion of the treating clinician). * For patients receiving any of these medications, use of an alternative agent is recommended. ** It is recommended that subjects should have a systolic blood pressure of either less than 150 mmHG, and/or a diastolic blood pressure of less than 100 mmHg at rest (average of 3 consecutive readings 3-5 minutes apart). Anti-hypertensive drugs may be used to achieve these values.

Sub Specialty:

Upper GI

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NICE Guidelines + the place of the Faecal Immunochemical Test as a triage tool for predicting Bowel Cancer

Research Summary

At present, there are no means of predicting if patients' symptoms are due to bowel cancer. When patients present to their GP with bowel symptoms that need investigating, they will be referred for a colonoscopy. We are conducting a study that aims to determine whether the Faecal Immunochemical Test (FIT) can be used in the future as an effective tool to identify patients at risk of bowel cancer. In 2005, NICE introduced guidelines where patients with certain symptoms that are associated with a high probability of bowel cancer are referred under the two week rule to secondary care for investigations. These patients must be seen within two weeks of referral and if a cancer is diagnosed, patients must be treated within 62 days of referral. The vast majority of patients referred undergo an endoscopic examination either a colonoscopy (to view the whole colon) or a flexible sigmoidoscopy (to view the left side of the colon) to confirm whether a patient has an underlying cancer or not. However, only 10-15% of these referrals have underlying bowel cancer or significant pathology such as precancerous polyps. The remaining patients do not have significant pathology. In 2015, NICE expanded the criteria significantly in order to increase the pick up rates of bowel cancer from these two week referrals. This means that a large number of patients unnecessarily undergo endoscopic examination with the associated risk of bowel perforation, sedation and the procedure itself. This also strains the cash-strapped resources of the NHS. The FIT test is a simple one-off stool test that patients can do at home and has shown promise in predicting bowel cancer in both the screening (Moss et al 2016) and symptomatic (MacDonald et al 2015, Auge et al 2015, Mowat et al 2015, Cubiella et al 2015) patient settings.

Inclusion Criteria:

Referred for colonoscopy under 2 week rule for suspected colorectal cancer Informed consent

Exclusion Criteria:

Unable to give informed consent Stool sample taken during bowel preparation Unable to take adequate stool sample Unable to complete bowel preparation Unable to tolerate complete colonoscopic examination

Sub Specialty:

Colorectal Cancer Colorectal Surgery

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Randomised Clinical Trial of neoadjuvant and adjuvant chemotherapy (MAGIC regimen) vs. neoadjuvant chemoradiation (CROSS protocol) in adenocarcinoma of the oesophagus and oesophago-gastric junction.

Research Summary

The Primary objective is to compare two Level-1 evidence based approaches to adenocarcinoma of the oesophagus and oesophago-gastric junction. The MAGIC study included a minority of patients with oesophageal and junctional tumours and staging and QA modalities did not encompass current standards. The CROSS trial was not specific to adenocarcinoma, and compared a multimodal regimen to surgery alone.

Inclusion Criteria:

1. Histologically-verified adenocarcinoma of the oesophagus or oesophagogastric junction based on OGD. 2. CT- 18FDG-PET in all patients and EUS, if feasible 3. Staging laparoscopy will be performed for tumours of the abdominal oesophagus, junction and proximal stomach i.e. AEG II and AEG III (at the investigator's discretion) 4. Pre-treatment stage cT2-3, N0-3, M0 5. No prior abdominal or thoracic radiotherapy 6. Male/female patients aged > 18 years 7. ECOG Performance Status 0, 1 or 2 8. ASA Grading I-II 9. Adequate cardiac function. For all patients an ejection fraction > 50% is required. If patients have a known history of significant cardiac disease (e.g. known ischaemic heart disease, cardiomyopathy) an ejection fraction > 50% and cardiac clearance by a consultant cardiologist for major surgery and cancer therapies is required. Where necessary, the Chief Investigator should be consulted to discuss the patient's eligibility. 10. Adequate respiratory function. Patients should have pulmonary function tests completed with FEV1 > 1.5L 11. Adequate bone marrow function: absolute neutrophil count (ANC) > 1.5x109/l; white blood cell count > 3x109/l; platelets > 100x109/l; haemoglobin (Hb) > 9g/dl (can be post-transfusion). 12. Adequate renal function: glomerular filtration rate > 60ml/minute calculated using the Cockcroft-Gault Formula 13. Adequate liver function: serum bilirubin < 1.5x ULN; AST < 2.5x ULN and ALP < 3x ULN (ULN as per institutional standard) 14. Written informed consent must be obtained from the patient before any study-specific procedures are performed. 15. Women of child-bearing potential and male subjects must agree to use an effective barrier method of contraception for up to 6 months following discontinuation of therapy. Effective barrier method of contraception is defined as any medically recommended (or combination of methods) as per standard of care. 16. Women of child-bearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to treatment.

Exclusion Criteria:

1. Tumours of squamous histology. 2. Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma. 3. Any prior chemotherapy for gastrointestinal cancer. 4. Prior abdominal or thoracic radiation. 5. Patients who are unfit for surgery or cancer treatments based on cardiac disease. 6. Patients with acute systemic infections. 7. Patients who are receiving treatment with sirivudine or its chemical related analogues such as brivudine, which is contraindicated with capecitabine administration. 8. Clinical COPD with significant obstructive airways disease classified by FEV1 < 1.5 L or PaO2 less than 9kPa on room air. 9. Known peripheral neuropathy >Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible). 10. Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection. 11. Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). 12. Women who are pregnant or breastfeeding.

Sub Specialty:

Upper GI

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Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature

Research Summary

Prostate cancer is the most common cause of cancer in men. Prostate cancer that has spread to other parts of the body (metastatic) is incurable and is often fatal. New drugs called immune checkpoint inhibitors work with the patient’s own immune system to fight the cancer. These drugs look promising in other cancers but have not been as successful in prostate cancer. However, we and others have done research which showed that it may be possible to pick out people more likely to respond to these types of drugs by looking at certain features of the cancer tissue. If the cancer tissue contains a lot of DNA mutations, show deficiencies in its ability to repair DNA, or if we see a lot of cells from the immune system in the tissue, we say it has a positive immunogenic signature (ImS +ve) and we think it is more likely to respond to treatment with immune checkpoint inhibitor drugs. We plan to enrol patients with metastatic prostate cancer. Patients with ImS +ve cancer could go on to have treatment with a combination of two immune checkpoint inhibitors, nivolumab (Nivo) and ipilimumab (Ipi). About 1 in 4 prostate cancer patients will have ImS +ve disease. We plan to test around 175 men for the ImS to identify 35 with ImS +ve cancer who will go on to have the study treatment. The main aim is to see if these men do better on treatment with Nivo and Ipi than we would expect if they were having routine treatment. Both drugs are given intravenously in the hospital every 3-4 weeks. Treatment lasts for up to a year and patients will be followed up for up to 5 years after registration in the main study. The study will recruit patients from around 15 sites in the UK. We expect recruitment to start in the fourth quarter of 2017 and it will take about 18 months to recruitment.

Inclusion Criteria:

Inclusion criteria for Pre-Screening (Assessment of ImS): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Patient has archival prostate cancer tissue available or has disease amenable to biopsy and is willing to undergo a new biopsy for assessment of ImS. Disease amenable to biopsy is: o Soft tissue lesion meeting RECIST criteria that in the opinion of clinician and interventional radiologist is safe to biopsy, or o Bone lesion that is deemed suitable to biopsy by a suitably trained clinician. • Men > = 18 years. • Adequate venous access for administration of treatment and collection blood samples for exploratory biological samples. • Life expectancy of > 6 months. • Has had or is having > = 1 line of systemic treatment for CRPC, or is currently having first line systemic treatment for mCRPC. • Reasonable expectation that the patient does currently, or will within the next year, fulfil all eligibility criteria for trial treatment Inclusion Criteria for Main Study (Treatment): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Immunogenic signature positive disease within 1 year of registration to Pre-screening part of trial • Patients with disease amenable to biopsy must be willing to have a new biopsy (if new biopsy was not required for assessment of ImS). • WHO performance status of 0-1. • Adequate haematological status. • Adequate liver and renal function. • Has had 1 line of systemic treatment for CRPC. • Documented prostate cancer progression within 6 months prior to screening for the Main Study • Ongoing androgen deprivation with serum testosterone < 1.73 nmol/L.

Exclusion Criteria:

Exclusion criteria for Assessment of ImS: • Any history of autoimmune disease, with the exception of patients with a history of autoimmune-related hyperthyroidism or hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone • Patients with prior allogeneic stem cell or solid organ transplantation • Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field is permitted). • Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity • Patients with the following risk factors for bowel perforation: o History of acute diverticulitis or intra-abdominal abcess in the last 3 years o History of GI obstruction or abdominal carcinomatosis • History of grade > = 2 peripheral neuropathy. • Prior treatment with Sipuleucel-T, immune checkpoint targeting agents or other novel immune-oncology agents • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina. • Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stable insulin regimen are eligible. • Patients with uncontrolled adrenal insufficiency. • Known active hepatitis B or C infection. • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Exclusion criteria for treatment: All exclusion criteria to exclude patients from Assessment of ImS apply • Patients with risk factors for bowel perforation. • Patients must not have had systemic corticosteroid therapy (> 10mg daily prednisone equivalent) for 14 days prior to study entry, or concomitant use of other immunosuppressive medications. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. • Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.

Sub Specialty:

Prostate Cancer

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National cohort study of late effects of Hodgkin lymphoma treatment

Research Summary

This study proposes to investigate a range of clinically significant co-morbidities which develop in female Hodgkin Lymphoma survivors treated in childhood and young adulthood. Hodgkin Lymphoma is one of the most common malignancies in young adults and has seen significant improvement in survival over recent decades resulting in an increasing number of long term Hodgkin Lymphoma survivors. However, the high dose chemotherapy and radiotherapy treatments used are known to be toxic to patients and can greatly increase long-term risks of side effects such as second primary cancers, cardiovascular disease, and other adverse events. Relatively little has been published about the full range of long­term treatment­related effects that impact on life quality and health status in Hodgkin Lymphoma patients. There is also a lack of information on the effects of more modern treatments, intended to reduce long-term toxicity, and a lack of consensus about how to tailor long-term follow-up to best diagnose and manage late-effects. This study will collect and analyse treatment and co-morbidity information on women treated for Hodgkin Lymphoma across England and Wales at ages ≤35 years during 1956-2010. We will expand an existing national cohort study of 5,000 women treated for Hodgkin Lymphoma, the largest of its kind in the world, which has undertaken research to inform the risks of developing breast cancer after Hodgkin Lymphoma treatments. The cohort would be doubled in size to include young female Hodgkin Lymphoma patients who have been treated with a much wider range of treatments and more recently diagnosed patients. We aim to improve understanding of late-effects of different types of treatment, of longer follow-up periods and to greatly expand the range of long-term effects which have been reported on. By doing so we aim to contribute to the development of risk profiles to help inform treatment choices and personalised follow-up and screening schedules for Hodgkin Lymphoma patients.

Inclusion Criteria:

Women diagnosed with Hodgkin Lymphoma and treated before the age of 36 years. Treated for Hodgkin Lymphoma before 2010. Treated in England and Wales.

Exclusion Criteria:

Male. Treated outside UK. Resident outside UK. Treated for Hodgkin Lymphoma (for the first time) over the age of 35 years.

Sub Specialty:

Lymphoma

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National Lung Matrix Trial: Multi-­drug, genetic marker-directed, non­-comparative, multi-­centre, multi­-arm phase II trial in non-small cell lung cancer

Research Summary

The trial consists of a series of parallel multi-centre single arm Phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers. The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive design is adopted to achieve this objective. The trial is primarily an enrichment putative biomarker design, including patients who are positive for at least on of the actionable targets included in the trial. Patients who are positive for just one putative biomarker will receive the experimental targeted drug specific for that putative biomarker. Putative biomarkers within each drug cohort have been chosen such that in the majority of cases it is not expected that patients will be positive for two or more putative biomarkers within the same drug. In the rare situation that patients are positive for two or more putative biomarkers relevant across different drugs, treatment will be allocated in accordance with the following strategy: - All amplifications and rearrangements will be treated with targeted agent appropriate to them irrespective of concomitant mutations. This will yield crucial predictive biomarker information. - For concomitant mutations decisions will be made by the Chief Investigator on a case-by-case basis and based on close consideration of pathway preference and likely dominance of one signal pathway over another together with any pre-clinical efficacy studies that address the activity of the drugs in the presence of concomitant mutations.

Inclusion Criteria:

• Patients must have completed all standard of care therapy that the treating oncologist thinks is appropriate. As a minimum patients must have failed one or more lines of treatment (either radiological documentation of disease progression or due to toxicity). • Patients who have progressed after surgical resection and adjuvant therapy will be eligible for entry without the need for the administration of first line metastatic therapy, if they have progressed within 6 months of completing their adjuvant treatment. • Patients will also be eligible without the necessity for first line regimen if they have relapsed within 6 months of completion of definitive chemoradiation. • Consented and provided an adequate specimen to adequately characterise the molecular genotype of the tumour in the molecular pre-screening according to the molecular exclusion rules (see section 6.4 for definition of an adequate sample). • Histological or cytologically confirmed NSCLC stage III (not suitable for radical radiotherapy or surgery) or stage IV. This includes patients who may have abnormal histology, but IHC strongly support either squamous cell carcinoma (p63 positivity) or adenocarcinoma (Thyroid transcription factor 1 [TTF1] positivity). If a physician and pathologist are convinced after multi-disciplinary review that the patient has stage III or IV NSCLC but where all the IHC is negative and the morphology does not distinguish a specific sub-type, these patients will be eligible for non-histology specific cohorts. • CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1 (see Appendix 1). • Adequate haematological function within 7 days of treatment. o Haemoglobin ≥ 90 g/L. o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. o Platelets ≥ 100 x 109/L. • Adequate hepatic function within 7 days of treatment in patients with no liver metastasis (see arm specific entry criteria for adequate hepatic function in patients with liver metastases). o Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN). o Alanine transferase (ALT) ≤ 2.5 x ULN. o Aspartate transferase (AST) ≤ 2.5 x ULN. • Adequate renal function within 7 days of treatment. o Creatinine clearance (CLcr) > 50 ml/min (measured or calculated by Cockcroft and Gault equation – see Appendix 4). • Age ≥ 18 years. • Females must agree to use adequate contraceptive measures (as defined in Section 6.3), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. o Women aged under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution. • Provision of signed and dated, written informed consent prior to any study specific

Exclusion Criteria:

• Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment. • Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption. • Any psychological, familial, sociological or geographical condition hampering protocol compliance. • Concurrent malignancies or invasive cancers diagnosed within past 3 years except for adequately treated basal cell carcinoma of the skin and in situ carcinoma of the uterine cervix. • Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. • Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration (see CTCAE - Appendix 3). • Patients who have previous symptomatic brain metastases or spinal cord compression are excluded unless they have had adequate treatment, no evidence of progression or symptoms, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • Patients with asymptomatic brain metastases picked up at screening CT scan are not excluded providing that in the view of the investigator they do not require immediate radiotherapy or surgical intervention, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. • Pregnant or breast-feeding women.

Sub Specialty:

Lung Cancer

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International Randomised Phase III Clinical Trial in Children with Acute Myeloid Leukaemia - Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination with Induction Chemotherapy

Research Summary

The main purpose of this study is : To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.

Inclusion Criteria:

Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation): • A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary) • Age < 18 years • No prior chemotherapy or biological therapy for AML other than that permitted in the protocol • Normal cardiac function (fractional shortening ≥28% or ejection fraction ≥55%) • Fit for protocol chemotherapy • Documented negative pregnancy test for female patients of childbearing potential • Patient agrees to use effective contraception (patients of childbearing potential) • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study: • Patients meets the inclusion criteria for trial entry • Age ≥12 months for the major dose finding study • Age ≥ 12 weeks and < 12 months for the minor dose finding study • Karnofsky or Lansky performance score of ≥50 • Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2 • Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert’s syndrome or similar disorder • ALT or AST ≤10 x ULN for age • Written informed consent from the patient or parent/legal guardian Inclusion criteria for participation in R3: • Patient meets the inclusion criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial • Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories, see national MyeChild 01 Laboratory Manual): 1) Patients with good risk cytogenetics/molecular genetics and a MRD level < 0.1% by flow after course 2, or a decrease in transcript levels of > 3 logs after course 2 for those with an informative molecular marker but without an informative marker of sufficient sensitivity for flow MRD monitoring Or 2)Patients with intermediate risk cytogenetics/molecular genetics with a MRD level < 0.1% by flow after course 1 and course 2, or a decrease in transcript levels of > 3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in R4: • Patient meets the eligibility criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial • Patient is in CR or CRi defined as < 5% blasts confirmed by flow cytometry//molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4. • Patient meets one of the following criteria and is a candidate for haemopoeitic stem cell transplant (HSCT) as per the protocol: 1) High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi) 2) Intermediate risk cytogenetics with MRD > 0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of > 0.1% may be used 3) Good risk cytogenetics with flow MRD > 0.1% confirmed by a decrease in molecular MRD of < 3 logs or rising transcript levels after course 3 despite treatment intensification (FLAIda) and after discussion with the Clinical Coordinators Availability of a 910/10 human leukocyte antigen (HLA) matched family or unrelated donor or 58/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1 • Written informed consent from the patient or parent/legal guardian

Exclusion Criteria:

Exclusion criteria for all randomisations • Acute promyelocytic leukaemia (APL) • Myeloid leukaemia of Down Syndrome (ML DS) • Blast crisis of chronic myeloid leukaemia • Relapsed or refractory AML • Bone marrow failure syndromes • Prior anthracycline exposure which would inhibit the delivery of study anthracyclines • Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML • Pregnant or lactating females

Sub Specialty:

Haematological Oncology

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A phase III study to determine the role of ixazomib as an Augmented Conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT Consolidation and maintenance strategy in patients with Relapsed multiple myeloma.

Research Summary

Background: Multiple myeloma (MM) is a blood cancer with approximately 4500 new cases in the UK each year. Treatment for MM has changed in the last decade with the arrival of new drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). These new drugs have been shown to improve response rate and duration of response in second-line treatment (second treatment for patients whose MM has deteriorated since their first treatment). The Myeloma X study showed that an autologous stem cell transplant (ASCT) (using the patient’s own stem cells) as part of second-line treatment prolongs progression free survival (PFS) following chemotherapy containing a proteasome inhibitor (known as re-induction therapy). Consequently, the number of second ASCTs performed in the UK has risen and is now recommended (for suitable patients) by the International Myeloma Working Group. However, the Myeloma X study showed that depth and duration of response in second-line ASCT, was less than that of first-line ASCT. Hence, this study will investigate whether depth and duration of response can be improved by the addition of a proteasome inhibitor called ixazomib to melphalan conditioning, consolidation and maintenance treatment. Aims: This trial aims to determine and compare: a) The depth of response between standard melphalan conditioning and augmented (adding ixazomib) melphalan conditioning at second ASCT. b) The impact of adding consolidation and maintenance treatment versus no further treatment, on progression free survival. Methods: This is a phase III, randomised, controlled, multi-centre, open-label trial with a single intervention registration stage and two randomisations. The first randomisation will be between augmented ASCT and standard ASCT. The primary end-point is to assess improvement in depth of response. The second randomisation will be between consolidation and maintenance treatment versus no further treatment. The primary end-point being to assess the duration of response as determined by PFS.

Inclusion Criteria:

1.Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) previously treated with ASCT). 2.First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy. 3.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3). 4.Aged at least 18 years. 5.Participants must have the following blood results within 14 days before registration: a.Absolute neutrophil count (ANC) ≥1x109/L b.Platelet count ≥75x109/L. If the participant has ≥50% bone marrow infiltration a platelet count of ≥50x109/L is allowed. Platelet transfusions are not allowed within 3 days before registration in order to meet these values. 6.Adequate renal function within 14 days before registration: a.Creatinine clearance ≥30ml/min (calculated according to Cockcroft-Gault equation or other locally approved formula) 7.Adequate hepatobiliary function within 14 days before registration: a.Total bilirubin < 2 x upper limit of normal (ULN) b .ALT < 2 x ULN 8.Adequate pulmonary function within 14 days before registration: a.Adequate respiratory functional reserve (delineated by KCO/DLCO (carbon monoxide diffusion in the lung) of ≥50%). No evidence of a history of pulmonary disease. If a significant history, then a review by a respiratory medicine physician is required. 9.Adequate cardiac function within 12 weeks before registration: a.Left ventricular ejection fraction (LVEF) ≥40%. Note: repeat confirmation of cardiac function is needed if treatment is given between this assessment and registration. 10.Female participants who: a.Are not of childbearing potential (Appendix 8), OR b.If they are of childbearing potential (Appendix 8), agree to practice 2 effective methods of contraception (Appendix 8), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a.Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Contraception for female and male participants must be in accordance with (and consent to) the Celgene-approved Thalidomide Pregnancy Prevention Programme. 11.If female and of childbearing potential (see Appendix 8), must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Thalidomide Pregnancy Prevention Programme. 12.Patients agree not to receive other clinical trials treatment, including investigational medicinal products (IMPs) not included in this trial, within 30 days of trial registration and throughout the duration of the trial, until disease progression. 13.Able to provide written informed consent.

Exclusion Criteria:

1.Received prior second line therapy for their relapsed disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone (up to a maximum of 200mg is allowed but not within 30 days prior to registration). Radiotherapy sufficient to alleviate or control pain of local invasion is permitted, but must not be within 14 days before registration. Patients who have received hemi-body radiation or similar since relapse will not be eligible. 2.≥Grade 2 peripheral neuropathy within 14 days before registration. 3.Known HIV or Hepatitis B/C seropositivity. 4.Known resistance, intolerance or sensitivity to any component of the planned therapies. 5.Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 6.Previous or concurrent malignancies at other sites (excluding completely resected non-melanoma skin cancer or carcinoma in situ of any type, such as cervical cancer). 7.Pregnant, lactating or breast feeding female participants. 8.Failure to have fully recovered (i.e. less than or equal to Grade 1 toxicity) from the reversible effects of prior chemotherapy. 9.Major surgery within 14 days before registration. 10.Central nervous system involvement with myeloma. 11.Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration. 12.Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 13.Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 14.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing. 15.Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.

Sub Specialty:

Haematological Oncology Haematology

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MUK nine b: OPTIMUM. A phase II study evaluating multiple novel agentsoptimised combination of biological therapy in newly diagnosed high risk multiple myeloma and plasma cell leukaemia.

Research Summary

Multiple myeloma is a disorder of plasma cells which accumulate in the bone marrow. It is the second most common haematologic cancer in the EU, causing about 21,000 deaths in the EU in 2008. Approximately 20% of patients with myeloma have an extremely poor survival of less than 3 years and these patients are characterised as having high risk (HR) disease. There have been no improvements in outcome over the last decade for patients with HR disease. However recent data has shown that combination of multiple novel agents is potentially better and therefore in this phase II trial we wish to evaluate whether we can improve the outcomes for high risk patients by using multiple biological agents during treatment over a number of stages. The primary objective of this trial is to look at whether a combination of four novel agents bortezomib (Velcade), lenalidomide (Revlamid) dexamethasone & Daratumumab(darzalex) with cyclophosphamide is active in a high risk patients, to take forward into a phase III trial compared to standard treatment. Approximately 560 participants with myeloma will need to be registered for screening at diagnosis in order to include 95 high risk participants in the MUK nine b:Optimum Protocol.

Inclusion Criteria:

Target participants: • Confirmation of High Risk status from ICR following bone marrow and blood sample processed through the screening protocol. • Previously untreated participants, although participants may have received up to 2 cycles of CTD (Cyclophosphamide, thalidomide, dexamethasone), CVD (Cyclophosphamide, velcade, dexamethasone), CRD (cyclophosphamide, revlamid, dexamethasone) or VTD (velcade, thalidomide, dexamethasone) pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUK nine a Protocol.(In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted). • Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment: - Paraprotein > = 5g/L or > = 0.5 g/L for IgD subtypes. - Serum free kappa or lambda light chains > = 100 mg/L with abnormal ratio (for light chain only myeloma). - Urinary Bence Jones protein > = 200 mg/L. • Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance. • Aged 18 years or over. • Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion). • ECOG Performance Status (Eastern Cooperative Oncology Group) < = 2. • The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this: • Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe. • Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy • Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for 4 months after discontinuation from this trial • All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial. - Calculated creatinine clearance > = 30mL/min (using Cockcroft-Gault formula). - ALT and/or AST < = 2.5 times upper limit of normal (ULN). - Bilirubin < = 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin < = 2.0 times ULN - Platelet count > = 75 x 109/L. (> = 50 x 109/L if myeloma involvement in the bone marrow is > 50%). Platelet support is permitted. - Absolute neutrophil count (ANC) > = 1.0 x 109/L. Growth factor support is permitted. - Haemoglobin > = 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines. - Corrected serum calcium < = 3.5 mmol/L. Eligibility criteria for ASCT • Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight. • Received a minimum of 4, unless CR has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd - cyclophosphamide, bortezomib, lenalidomide, daratumumab, dexamethasone) cycles. • Achieved a response of SD or better. Eligibility Criteria for Consolidation Part 1 (VRDd - bortezomib, lenalidomide, daratumumab, dexamethasone) • Undergone autologous transplant with HDM-V (high dose melphalan-bortezomib) conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted. Eligibility Criteria for Consolidation Part 2 (VRD - bortezomib, lenalidomide, daratumumab) • Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted. Eligibility Criteria for Maintenance (RD - lenalidomide, daratumumab) • Received 12 cycles of Consolidation Part 2 (VRD). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted.

Exclusion Criteria:

Exclusion Criteria • Participants that have progressive disease • Solitary bone/solitary extramedullary plasmacytoma. • Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom’s Disease. Medical history and Concurrent disease: • Prior or concurrent invasive malignancies except the following: o Adequately treated basal cell or squamous cell skin cancer. o Incidental finding of low grade (Gleason 3+3 or less) prostate cancer. o Any cancer from which the subject has been disease free for at least 3 years. • Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous (e.g uncontrolled diabetes or uncontrolled coronary artery disease). o Any clinically significant cardiac disease, including: o myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV. o uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade > = 2) or clinically significant ECG (Electrocardiogram) abnormalities. o screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec. • Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second < 60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening. • Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C. • Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products. • Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone. • Previous treatment with daratumumab or any other anti-CD38 therapies. • Participants with contraindication to thromboprophylaxis. • Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0). • Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). • Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study. • Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. • Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial, 4 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial, within 4 months after the last dose of trial treatment. • Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery. • Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study.

Sub Specialty:

Haematological Oncology

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A randomised phase II trial of Selinexor, cyclophosphamide and prednisolone vs cyclophosphamide and prednisolone in relapsed or refractory multiple myeloma (RRMM)patients

Research Summary

The new treatment being tested in this study is called Selinexor - this is a type of Selective Inhibitor of Nuclear Export (SINE) drug, which is taken orally. This will be given with cyclophosphamide and prednisolone to see if this combination is effective at treating patients with relapsed and refractory multiple myeloma (RRMM). This study is part of the Myeloma UK Clinical Trial Network portfolio of prioritised multiple myeloma clinical studies. There will be up to 60 participants who will take part in this trial from hospitals throughout the UK. The aim of this trial is to compare two different combinations of drugs used to treat multiple myeloma that has relapsed after two or more treatment lines of anti-myeloma therapy. Cyclophosphamide and prednisolone are both very commonly used in the treatment of multiple myeloma, and will often be given with a third drug (e.g. thalidomide, lenalidomide or bortezomib). However, there are currently few treatments available to patients who have not responded well (are refractory) to their previous treatment or who need further treatment because their myeloma has come back. This study is designed to compare a new combination of Selinexor, cyclophosphamide and prednisolone, with cyclophosphamide and prednisolone alone followed by SCP at disease progression.

Inclusion Criteria:

1. Able to give informed consent and willing to follow study protocol assessments 2. Aged 18 years or over 3. Participants with confirmed myeloma based on International Myeloma Working Group (IMWG) criteria Rajkumar et al. (2014) 4. Measurable disease with at least one of the following: - Paraprotein > = 5g/L - Serum free light chains > = 100mg/L with abnormal ratio for light chain only myeloma - Bence Jones protein > = 200mg/L 5. Participants with relapsed or relapsed refractory myeloma who have received > = 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide, and now require further treatment 6. Patients for which cyclophosphamide and prednisone alone would be a suitable treatment 7. Eastern Cooperative Oncology Group (ECOG) performance status of < = 2 8. Female participants of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative urine pregnancy test at screening. Male participants must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment 9. Required laboratory values within 14 days prior to randomisation: - Platelet count > = 50x109/L. Platelet count of 30-50 is acceptable if bone marrow aspirate or trephine shows tumour replacement of > 50%. Platelet support is permitted within 14 days prior to randomisation, although platelet transfusions to help participants meet eligibility criteria are not allowed within 72 hours prior to the blood sample to confirm protocol eligibility - Absolute neutrophil count > = 1.0 x 109/L. Growth factor support is not permitted within 14 days prior to randomisation - Haemoglobin > = 90 g/L. Blood support is permitted - Alanine transaminase (ALT) and / or aspartate transaminase (AST) < = 3 x upper limit of normal - Creatinine clearance > = 30 ml/min (using Cockcroft Gault formula) - Bilirubin < = 1.5 x upper limit of normal

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not eligible to take part in this trial: 1. The following participants will be excluded: - those with non-measurable disease - those with a solitary bone or solitary extramedullary plasmacytoma - plasma cell leukaemia 2. Participants with a history of malignancy (other than myeloma) within 5 years before the date of randomisation (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator, with concurrence with the Chief Investigator, is considered cured with minimal risk of recurrence within 5 years) 3. Participants with a known or underlying uncontrolled concurrent illness that, in the investigator’s opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study, including, but not limited to the following: - acute or chronic graft versus host disease, - uncontrolled hypertension, - symptomatic congestive heart failure, - unstable angina pectoris, - myocardial infarction within past 6 months, - uncontrolled cardiac arrhythmia, - active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis - psychiatric or social conditions that may interfere with participant compliance, - uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral - or any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study 4. Participants who have previously received Selinexor. 5. Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment. (NB: Prednisone up to a dose of 175 mg per week may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease are also permitted). 6. Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures or conditions that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s) 7. Female participants who are lactating or have a positive pregnancy test at screening 8. Known allergy or intolerance to any of the study medications, their analogues, or excipients in the various formulations of any agent 9. Major surgery within 14 days prior to randomisation 10. Radiotherapy within 7 days prior to randomisation for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation 11. Chemotherapy or immunotherapy or any other anticancer therapy within 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1 (except steroids in the doses outlined above) 12. Myeloma involving the Central Nervous System

Sub Specialty:

Haematological Oncology

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Molecular pathology of Colorectal Cancer: Investigating the the role of microRNA's and their molecular targets in Colorectal Cancer progression

Research Summary

-

Inclusion Criteria:

18 and over

Exclusion Criteria:

other cancer

Sub Specialty:

Colorectal Cancer

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MUKnine a: An observational and screening study to identify high risk myeloma patients suitable for novel treatment approaches and determine treatment outcomes for non-high risk myeloma patients

Research Summary

Multiple myeloma is a disorder of plasma cells in the bone marrow. It is the second most common haematologic cancer in the EU, causing about 21,000 deaths in the EU in 2008. Approximately 20% of patients with myeloma have an extremely poor prognosis with a survival of less than 3 years and these patients are characterised as having high risk (HR) disease. There have been no significant improvements in outcome over the last decade for patients with HR disease. However recent data has demonstrated the efficacy of the combination of multiple novel agents in high risk disease. The aim of this phase II study is to assess whether future trials in this setting are feasible, and to determine risk status for participants with myeloma, in order to recruit high risk participants into MUK nine B. Participants who are found to be high risk and who are eligible will be provided with information on MUK nine B. Participants who are found not to be high risk will be treated according to NICE standard treatment (which may include other clinical trials). Patients will be followed up and data and biological samples will be centrally collected according to the schedule of MUK nine A to generate a knowledge resource about real-world treatment outcomes in newly diagnosed myeloma in the UK. The study includes approx 560 adult participants undergoing bone marrow investigation due to suspected symptomatic multiple myeloma or participants with biopsy confirmed symptomatic multiple myeloma, willing to undergo a further study bone marrow aspirate for molecular profiling. Participants will be recruited from approximately 30 approved NHS Hospitals throughout the UK.

Inclusion Criteria:

• Undergoing bone marrow investigation due to suspected symptomatic multiple myeloma or Participants with biopsy-confirmed symptomatic multiple myeloma, willing to undergo a further study bone marrow biopsy for molecular profiling. • Aged 18 years or over • Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion) • ECOG (Eastern Cooperative Oncology Group) < = 2

Exclusion Criteria:

Solitary bone/solitary extramedullary plasmacytoma Primary diagonosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstroms Disease Received therapy for myeloma other than local radiotherapy, therapeutic plasma exchange or dexamethasone up to a maximum of 160mg. (Radiotherapy sufficient to alleviate or control pain or local invasion is permitted). • Unfit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion) • Prior or concurrent invasive malignancies except the following: o Adequately treated basal cell or squamous cell skin cancer o Incidental finding of low grade (Gleason 3+3 or less) prostate cancer o Any cancer from which the subject has been disease free for at least 3 years. • Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including: o NYHA functional classification III or IV congestive heart failure o Uncontrolled angina, hypertension or arrhythmia o Myocardial infarction in the past 6 months • Grade 2 or greater peripheral neuropathy • Participants with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy • Unwilling to participate in a clinical trial, in principle.

Sub Specialty:

Haematological Oncology

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A Phase I study of 131-1 mIBG followed by Nivolumab and Dinutuximab beta in children with relapsed/refractory neuroblastoma

Research Summary

Neuroblastoma is one of the commonest childhood malignancies and accounts for 15% of paediatric cancer deaths. Prognosis for children with metastatic disease remains poor. In recent years antibody based immunotherapies have shown considerable promise in this area. This is a phase 1 study to test the toxicity and tolerability of combining i) radiotherapy targeting neuroblastoma cells (131-I mIBG therapy) ii) antibody targeting the ganglioside molecule GD2 on neuroblastoma cells (Dinutuximab beta Apeiron) iii) Nivolumab, an antibody that binds to the immune molecule PD-1. This novel combination is based on pre-clinical work demonstrating that these agents may work together to kill neuroblastoma cells and generate long term immunity against the tumour. Both 131-I mIBG therapy and Dinutuximab beta have been widely used in neuroblastoma, with therapeutic activity as single agents. Nivolumab has undergone paediatric phase I testing, but has not been widely used in neuroblastoma. This study will be performed in patients with relapsed or refractory neuroblastoma, for whom there are no other curative options. The first cohort of patients will receive 131-I mIBG therapy followed by treatment with Nivolumab. If there is no unexpected toxicity, the next cohort of patients with received 131-I mIBG, Nivolumab and a reduced (50%) dose of Dinutuximab beta. If this is tolerated then a larger cohort of patients will receive all 3 agents at the full dose. Imaging of the tumour, as well as detailed monitoring of the immune response will be performed (by serial blood tests) to seek evidence of anti-tumour effects.

Inclusion Criteria:

• At study entry patients must be > 1 year • Relapsed or refractory high risk neuroblastoma (as defined by INRG criteria) • MIBG avid disease on imaging within 4 weeks to study entry. • > = 3 months since any myeloablative chemotherapy / stem cell rescue • > = 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half-lives since last dose of any monoclonal antibody therapy. • Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky, see Appendix 1: Performance Scales) • Estimated life expectancy > = 12 weeks • Adequate bone marrow function: ANC > 1.0 x 109/L, platelets > = 50 x 109/L and haemoglobin > 8.0 g/dL • Adequate renal function: serum creatinine < 1.5 mg/dL or a estimated creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73m2 • Adequate cardiac function: shortening fraction of > = 28 % by echocardiogram • Adequate hepatic function: ALT or AST < 5 x ULN and a total bilirubin < 1.5 x ULN • Adequate lung function: FEV1 and FVC > 60% of predicted by pulmonary function tests. Children unable to do PFTs should have no dyspnea at rest and a pulse oximetry > 94% on room air • Adequate pancreatic function: serum lipase < 1.5 x upper limit normal • Patients may have had prior CNS metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema • Patients must consent to the placement of a central venous line, if one has not already been placed. • Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery. • Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method to avoid pregnancy for 5 months after last dose of trial medication. Female patients who are lactating must agree to stop breast-feeding. Male patients who are sexually active must be instructed to use contraception throughout treatment and for a period of 7 months after last dose of trial medication. • Patients with seizure disorders may be enrolled if seizures are well controlled. • All patients and/or their parents or legal guardians must sign a written informed consent • All institutional and national requirements for clinical trials must be met. • Expression of PD-L1 by tumour is not a pre-requisite • Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration • Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy • Patients who have previously received Dinutuximab beta (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously. • Patients who have had previous 131-I mIBG therapy will not be excluded • At least 1 x 106 /Kg autologous stem cells stored and available if needed • Patients and/or their parents or legal guardians must agree that no standard or experimental anti-tumour treatment, except when specified in the protocol, is allowed any time during the study treatment.

Exclusion Criteria:

• Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study • Previous allogeneic stem cell transplant or solid organ transplant • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger • Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry. Local steroid treatments (e.g. dermal, mucosal, inhaled) are allowed. • Unable to maintain platelets > = 50 x 109/L without transfusion • HIV or Hepatitis B or C infection • Patients who have had major surgery (e.g laparotomy or thoracotomy) within the past 2 weeks. • Patients with significant intercurrent illnesses and/or any of the following: o Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance. o Patients with significant psychiatric disabilities or uncontrolled seizure disorders. o Patients with active infections, or active peptic ulcers, unless these conditions are corrected or controlled. o Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade > 2) are ineligible. o Patients with clinically significant, symptomatic, pleural effusions. Patients with uncontrolled hypertension

Sub Specialty:

Children's Cancer and Leukaemia

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Identification of critical molecular and biological events in the genesis of non-melanoma skin cancers and their modification by environment, immune status and viral infection

Research Summary

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Inclusion Criteria:

18 years or over and undergoing surgery for removal of pre-malignant or malignant skin lesion

Exclusion Criteria:

Pregnant women, language difficulties or mental illness/impairment

Sub Specialty:

Skin Cancer

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The use of Microwave Ablation in the treatment of advanced melanoma with cutaneous metastases. An observational study using Emblation's microwave based treatment system SwiftTM

Research Summary

Malignant melanoma is the fifth most common cancer in the UK, 14,500 new cases were diagnosed in 2013. In metastatic melanoma, cancerous cells spread around the body to sites distant from the original skin tumour. Up to 45% of individuals suffering with metastatic melanoma will develop skin deposits (metastases). If left untreated they can grow in size, ulcerate or cause distress through their appearance. Current treatment options include surgery and radiotherapy which can involve separate hospital visits as well as follow up appointments for aftercare. Unfortunately, despite these treatments, the response by metastases is very variable and although some patients improve, others do not show a good response. Microwave ablation (MWA) is the thermal destruction of cells through the generation of heat from oscillating water molecules. It is already used in the management of internal malignancies. Melanoma skin metastases represent an ideal target for MWA treatment due to their accessible nature. Recent advances in systemic immunotherapy for melanoma have shown the effectiveness of treatments aimed at enhancing the immune response to melanoma. We have previously shown in a study of Human Papilloma Virus (HPV) skin infection that microwave therapy is well tolerated and induces an anti-HPV immune response. It is possible that MWA may be able to stimulate and augment a systemic anti-melanoma response as well providing local destruction of melanoma metastases. We propose a pilot study to establish if MWA can successfully treat metastatic melanoma deposits using the Swift device manufactured by Emblation. We hypothesise that precise delivery of microwave energy onto a melanoma deposit will lead to its destruction. In this biomarker driven study we will analyse the treated melanoma tumours for histological, morphological and gene expression changes before and after treatment. We will assess circulating T-cells for antimelanoma activity before and after treatment.

Inclusion Criteria:

1. Stage 4 or inoperable stage 3 metastatic melanoma 2. Age > 18yrs 3. Targeted treatment of cutaneous metastases deemed inappropriate or unwanted

Exclusion Criteria:

1. Aged under 18 2. Inability to provide informed consent 3. Unable to fulfil study requirements

Sub Specialty:

Skin Cancer

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MINITUB REGISTRATION STUDY Prospective Registration Study on Sentinel Node (SN) Positive Melanoma Patients with Minimal SN Tumor Burden Managed without Complete Lymph Node Dissection (CLND) A Prospective Multicentre Single-Arm Registration Trial within the EORTC Melanoma Group Network

Research Summary

The aim of this prospective non-interventional registry is to establish an accepted standard of care for melanoma patients with minimal sentinel node (SN) tumour burden. Currently, if a melanoma patient has a positive (or metastatic) SN, this patient will be offered a Completion Lymph Node Dissection (CLND). This is a surgery which aims to remove all lymph nodes from the same area as the SN. However, if the positive SN is only minimally involved, some centres do not normally offer a CLND. In fact, the CLND does not increase survival for patients with a minimal SN tumour burden, but it can give doctors some information that may help them to make treatment decisions. This surgical operation may have significant side effects for the patient. In addition, only approximately 20% of patients with a positive SN have further lymph node metastases in the same area. This means that about 4 patients out of 5 will not benefit from a CLND. As a result, there is an urgent need to identify which SN positive patients could be safely spared from a CLND. Evidence shows that breast cancer patients with minimal SN tumour burden can be safely managed with observation only, and without a CLND. There is some evidence that the same situation exists in melanoma as well. The purpose of this registry is to confirm this. The results of this registry will support the aim of discovering whether melanoma patients with minimal SN tumour burden should undergo a complete lymph node dissection (CLND) or not. In addition, translational research on the tumour tissue will be carried out if participants consent to use of their tissue for such purposes. This is optional; participants will be able to refuse permission to use their tumour tissue and still participate in the main study.

Inclusion Criteria:

♦ Histological evidence of primary cutaneous melanoma ♦ Metastases solely confined within the SN: - in the sub-capsular space (with no parenchymal infiltration) and with a maximum diameter of the largest metastasis not greater than 0.4 mm or - regardless of the site, any sub-micrometastasis with a maximum diameter not greater than 0.1 mm If there is more than 1 metastatic SN, the patient will be still eligible provided that all involved SN have minimal tumor burden, regardless of the amount of positive SNs and the basin of interest ♦ Absence of clinically apparent metastatic disease at the time of or before undergoing a SN procedure ♦ No previous SN procedure for locally recurrent melanoma or uncertain malignant disease, such as atypical Spitz tumor/naevi ♦ Age ≥18 years ♦ No history of a previous melanoma (preceding the melanoma which prompted the SN biopsy) ♦ No history of any other malignancy within the past 5 years, except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and in situ cervical cancer ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial ♦ Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria:

See Main Inclusion Criteria

Sub Specialty:

Skin Cancer

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Mesothelioma Stratified Therapy (MiST): A stratified multi-arm phase IIa clinical trial to enable accelerated evaluation of targeted therapies for relapsed malignant mesothelioma. MiST 1 Rucaparib

Research Summary

Malignant mesothelioma (MM) is an aggressive, frequently drug resistant, and incurable disease that is increasing in incidence in the UK and worldwide. All patients with MM, subsequently relapse and die following first-line therapy, and at present, there is no standard treatment available in the second-line setting or beyond. It has been recognised that MMs are genetically different, therefore patients with this condition will respond differently to various drugs dependent on their particular MM genetic makeup. The purpose of this study is to advance personalised therapy for relapsed MM. Targeted drugs to be received will be selected based on the specific genetic changes identified in the patient’s tumour DNA. We will assess how well this treatment works, monitor tumour shrinkage, and learn more about the disease and how it changes over time. Patients that enrol will have received standard first-line chemotherapy (a drug treatment aimed at killing cancer cells). At the end of first-line therapy, patients whose tumours have started to grow again, and for whom there is no standard therapy will be eligible. If the tumour has not shrunk or has grown, patients may be eligible to enter the trial to receive treatment based on their particular genetic subtype. Throughout the trial we will use Computed Tomography (CT) scans to track the size of the tumours and use results from the tumour biopsy taken at the beginning and end (optional) of the treatment to decipher the genetic evolution of those tumours that acquire drug resistance. This will help us to refine predictive biomarkers to support future personalised drug development. Treatment will continue for the duration of the study protocol or until there is evidence that the MM has grown, the patient or doctor decides to stop it due to side effects or the patient dies.

Inclusion Criteria:

Stage 1: Registration Inclusion Criteria: •Histologically confirmed MM an available biopsy for research •Male or female patients aged > = 18 years. •Expected survival of > = 12 weeks or greater •ECOG PS 0-1 •CT scan chest, abdomen (and pelvis if applicable) confirming disease progression Patients must have received at least one prior line of therapy to include a platinum doublet first-line chemotherapy (within or outside of another clinical trial) • Willing to consent for molecular screening of archived tumour block (PIS1 & CF1) Stage 2: Treatment Based on the result of Stage 1 (registration), patients will be enrolled according to the MiST arm eligibility criteria which will be protocol specific.

Exclusion Criteria:

Stage 1: Registration Exclusion Criteria: •Patients with a diagnosis of a second malignancy except prostate or cervical cancer in remission, patients with a diagnosis of basal cell carcinoma of the skin or superficial bladder cancer. •Uncontrolled CNS disease. Asymptomatic brain metastases are allowed if previously treated with radiotherapy > 28 days prior to starting the investigational agent. •New York Heart Association Class II or greater congestive heart failure. •Patients with severe hepatic insufficiency or severe renal impairment. •Patients requiring long term oxygen therapy. •Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study. Stage 2: Treatment Please refer to the exclusion criteria of the specific treatment protocol.

Sub Specialty:

Lung Cancer

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Can patients with multiple breast cancers in the same breast avoid mastectomy by having multiple lumpectomies to achieve equivalent rates of local breast cancer recurrence? A randomised controlled feasibility study.

Research Summary

Sometimes women have more than one breast cancer in the same breast at the same time. These women are usually offered a mastectomy (removal of that breast) and breast reconstruction. It may be possible to treat these patients by removing each cancer using breast-saving surgery (lumpectomies), used for women with only one breast cancer. Databases show that women who had lumpectomies did well, but they may have been healthier before the surgery than those who had a mastectomy. We need to be sure that lumpectomy is effective, safe, and acceptable for this patient group before making it universally available. We will run a small study to evaluate whether a sufficient number of eligible patients can be identified and are willing to accept randomisation of the interventions in question. Recruitment and compliance rates of which will inform the feasibility and design of a larger trial. This will comprise a multi-centre randomised controlled trial in women with Multiple Ipsilateral Breast cancer (MIBC) requiring surgery. Participants will receive either Therapeutic Mammoplasty (TM) following excision of each cancer focus or mastectomy (+/- reconstruction). Patients will be randomised (1:1) into either intervention or control group. Therapeutic mammoplasty is an operation to remove breast cancer(s) whilst also significantly reducing the size of the breast. Therapeutic mammoplasty can be used to remove more than one cancer in the breast using separate lumpectomies. Both skin and breast tissue are removed, leaving scars similar to those seen after a standard breast reduction. Each patient is followed up for 12 months post treatment with a total of 50 patients recruited. Timings of the follow-up visits are aligned with standard of care practice for this patient population with quality of life questionnaires and clinical photographs completed before and after surgery. Twenty women will also be invited to an optional semi-structured interview at twelve months.

Inclusion Criteria:

1. > 40 years with MIBC, with the largest clinical cancer measuring 30mm as part of multifocal or multicentric “disease sites”. 30mm may include the size of a single cancer and its surrounding small satellite cancers. Clinically diagnosed (ultrasound and biopsy) either axillary lymph node negative or positive where axillary treatment depends on local policy.
 2. Minimum of two invasive foci of breast cancer as defined within a “disease site”. 3. Suitable for TM (best practice) using one large lumpectomy (multifocal) or any number of “distant” lumpectomies (multicentric) to excise “disease sites”. 4. Fit for adjuvant therapy as per pre-operative evaluations (ECG, Chest X-ray, blood biochemistry). 5. Willing and able to provide written informed consent

Exclusion Criteria:

1. Neo-adjuvant therapy 
 2. Women considered high risk by local centre or known to have BRCA1/2 gene mutation 
 3. Ductal Carcinoma in situ (DCIS) only, and extensive DCIS 
 4. Bilateral breast cancers 
 5. Previous breast cancer (invasive or DCIS in either breast) 
 6. Pregnancy as confirmed on blood tests or ultrasound examination. 7. Metastatic disease. 8. Any previous type of breast radiotherapy 
 9. Significant other clinical risk factors and co-morbidities at the discretion of the treating clinicians. 10. Previous or concomitant malignancy except adequately treated: non-melanomatous skin cancer; in situ carcinoma of the cervix and in situ melanoma

Sub Specialty:

Breast Cancer

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Establishing a Biobank and Database as a National Resource for Characterising Indolent and Aggressive forms of Mantle Cell Lymphoma, an Observational Study.

Research Summary

Mantle Cell Lymphoma (MCL) is a type of non-Hodgkin's lymphoma; a cancer of the lymphocytes (white blood cells) that occurs when the growth of these cells is out of control. MCL is a relatively rare, usually aggressive cancer for which there is currently no known cure. Many patients are treated as soon as they are diagnosed because they generally have a poor prognosis. However, our experience tells us that there is a sub-set of patients that have a less aggressive form of the disease. They can remain asymptomatic, sometimes for years. These patients need not be treated with systemic chemotherapy straight away and ‘watching and waiting’ does not affect the outcome at all. There are currently no tests that can tell us which patients have indolent behaving disease at diagnosis. Knowing this will be really helpful in finding the best way to treat people with this disease in the future. The only way that we can really be sure which type of MCL a patient has, is to observe what happens to them over the next few years. We will collect baseline blood and saliva samples, diagnostic biopsy material and clinical information from patients who are newly diagnosed with MCL. These samples will be stored in a Biobank. After this, patients will not directly be involved as the information we need to collect can be found in the medical notes. We aim to recruit 300 participants over 3 years. Once the study is completed, we will know which patients have indolent MCL and which patients have aggressive MCL. We will then study the stored samples to try to identify and understand the differences between indolent and aggressive forms of MCL.

Inclusion Criteria:

aged 16 and over newly diagnosed mantle cell lymphoma able to give consent

Exclusion Criteria:

Received systemic treatment for mantle cell lymphoma (localised radiotherapy is acceptable)

Sub Specialty:

Lymphoma

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Molecular and functional characterisation of bone marrow function in normal subjects, myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML) and secondary disorders of haematopoiesis

Research Summary

The aims of the study are: 1.) To provide diagnostic and follow-up bone marrow samples and complete follow-up clinical data from patients suspected to have a myeloid disorder to clinician scientists 2.) To create a population register to inform the results of laboratory studies

Inclusion Criteria:

Patients: i) Patients with an abnormal blood count requiring investigation by blood and bone marrow sample. OR ii) Patients known to have a blood disorder who are having a bone marrow sample taken as part of the assessment of that disorder. OR iii) Patients under follow-up with an established diagnosis of MDS/CMML who do NOT require a bone marrow biopsy but can be followed clinically for registry purposes. Control subjects (Nuffield Orthopaedic Centre, Oxford only centre doing this at present. This is not expected of other collaborating centres): Patients having elective orthopaedic surgery who have a normal blood count .

Exclusion Criteria:

Patients i) Age < 18. Controls i) Age < 18. ii) On treatment likely to impair bone marrow function iii)History of having had treatment likely to have impaired bone marrow function

Sub Specialty:

Haematological Oncology

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Methylphenidate versus placebo for fatigue in advanced cancer (MePFAC)

Research Summary

Patients with cancer often experience fatigue which can affect their ability to look after themselves and reduce their quality of life. Previous studies have suggested that the drug methylphenidate [MPH] may have some benefits, but the evidence is not clear. Patients with secondary cancer and fatigue will be invited to participate. If they agree they will receive nine weeks’ treatment with MPH or placebo (an inactive “dummy” pill). Which treatment people receive will be determined randomly by computer to ensure that our study is a “fair test”. The tablets will be made to appear identical so that neither the patient nor the staff knows which treatment is being used. Patients will be telephoned by a research nurse every week to advise them about which dose of study medication to take. At the start of the study, after three, six and nine weeks, patients will be seen face-to-face at an outpatient appointment, reassessed and asked to complete some questionnaires about their fatigue, their quality of life, a blood pressure check and to be re-supplied with medication. Everyone will start on the lowest dose of the study medication. The dose will be adjusted over the telephone or at outpatient appointments, depending on response and side effects. All participants will be seen at the end of the study to ask how fatigued they feel, about their quality of life and about any side-effects. This will allow us to quantify the longer term benefits and side-effects of treatment. After nine weeks the study will be finished. At that point usual clinical care will be resumed. Medical staff will be at liberty to use methylphenidate or any other treatment to help with fatigue dependent upon clinical circumstances.

Inclusion Criteria:

1. Aged 18 years or over 2. Participant is willing and able to give informed consent for participation 3. Advanced incurable cancer of all tumour types 4. Moderate or severe fatigue (> 3/10 on a numerical rating scale) 5. Prognosis 2-12 months (as estimated by clinician) 6. Able and willing to comply with all study requirements, including ability to participate in study for nine weeks 7. Under the care of a specialist palliative care team 8. Willing to allow his or her General Practitioner to be notified of participation in the study

Exclusion Criteria:

1. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; true abstinence) from the time consent is signed until 6 weeks after treatment discontinuation and inform the trial if pregnancy occurs. For the purpose of clarity, true abstinence is when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence, withdrawal, spermicides only or lactational amenorrhoea method for the duration of a trial, are not acceptable methods of contraception) 2. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment. 3. Females must not be breastfeeding. 4. Known sensitivity to methylphenidate or to any of the excipients. 5. History of glaucoma 6. Known phaechromocytoma 7. Planned general anaesthesia in the next nine weeks 8. During treatment with non-selective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 14 days of discontinuing those drugs 9. Hyperthyroidism or thyrotoxicosis 10. Known diagnosis or history of severe depression, anorexia nervosa/anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic/borderline personality disorder 11. Known diagnosis or history of severe and episodic (Type 1) Bipolar (affective) disorder (that is not well controlled) 12. Known pre-existing cardiovascular disorders including severe hypertension (BP > 160/100mmHg), heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies 13. Pre-existing cerebrovascular disorders, cerebral aneurysm, vascular abnormalities including vasculitis or stroke or known risk factors for cerebrovascular disorders 14. Current or previous psycho-stimulant use in last month 15. Severe anaemia (Haemoglobin < 80g/L) 16. Platelets < 50 × 103/μL 17. White blood count > 30 × 109/L 18. Estimated glomerular filtration rate [eGFR] < 60 ml/minute per 1·73 m² 19. Liver function tests elevated > 3 x upper limit of normal (either ALT > 165 U/L; or AST > 144 U/L; or ALP > 345 U/L; or GGT > 144 U/L; or Bilirubin > 3.6mg/dL) 20. Currently an inpatient in a hospital or a hospice 21. Currently participating in another research study involving an investigational product 22. English not first language or unable to read English 23. Current treatment with clonidine, warfarin, monoamine oxidase inhibitors or modafinil 24. History of previous or current substance or alcohol abuse 25. Unable to swallow tablets/capsules 26. History of poorly controlled epilepsy, or seizures related to underlying brain tumour 27. Any other significant disease or disorder which, in the opinion of the Investigator, may put the participant at risk or affect the participant’s ability to take part in the study We will not exclude patients who are still receiving tumour-directed therapies (e.g. chemotherapy or radiotherapy) provided that the treatment is with palliative intent and that the expected prognosis is 2 – 12 months. We believe that to exclude such patients would make recruitment very difficult and would also mean that the study population was not representative of the broader palliative care population (in whom disease modifying treatments are frequently used up until a few weeks or months before death). Nonetheless we will stratify patients by whether or not they are in receipt of disease-modifying treatment as this may be expected to affect their fatigue levels one way or another.

Sub Specialty:

Psychosocial Oncology and Survivorship

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Molecular profiling for lymphoma

Research Summary

This study is being set up in order to permit prospective molecular typing of samples of non Hodgkin lymphoma from surplus material obtained at routine biopsies. It is intended to facilitate identification of patients for whom molecular targeted therapies may be available. The results of molecular typing will be returned to the clinical team caring for the patient, in order to make them aware of specific abnormalities which would make specific targeted therapy an option within a clinical trial.

Inclusion Criteria:

A diagnosis of diffuse large B-cell lymphoma or follicular lymphoma in an adult patient.

Exclusion Criteria:

None

Sub Specialty:

Lymphoma

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A longitudinal observational study with phenotypic, functional and molecular characterization of the tumor lymphoid cells in patients with mature lymphoid malignancies in the South Coast

Research Summary

The purposeThe purposes of this study are i) to characterize those phenotypic, functional and molecular factors that can predict clinical prognosis and outcome of patients with lymphomas and leukaemias whose material is collected and stored in the South Coast Tissue Bank (SCTB) at the Cancer Sciences Unit in Southampton, ii) to provide research material to clinicians and scientists within the remit of the SCTB through a centralised scientific and ethical review process, suitable biological tissues from the SCTB for projects approved by the access committee following clinical and scientific peer review, iii) to perform a panel of established biomarkers on those patients with chronic lymphocytic leukaemia and lymphoproliferative disorders. This will enable researchers to request those samples most suitable for their research. This study will provide a unique, population-based tissue repository of patients with long longitudinal follow up exhibiting indolent and aggressive clinical characteristics. This allows the potential of discovering factors in the retrospective cohort and validating them in the prospective cohort that distinguish the indolent sub-type with thepossibility of the development of a diagnostic test.

Inclusion Criteria:

• Patients with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis, or other mature B-cell neoplasm according to the WHO classification (2008) • Measurable disease • Patients over 18 years old • Able to give written, informed consent.

Exclusion Criteria:

• Individuals who lack capacity to give informed consent • No informed consent • Consent withdrawn • Prior treatment at time of first consent and material collection • No medical history available

Sub Specialty:

Lymphoma

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Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal Cancer

Research Summary

Drugs that stimulate the immune system to attack tumours are revolutionising treatment for some cancers. Results in oesophageal cancer have not been as exciting as in lung or skin cancer, so the drugs have not replaced existing treatments like chemotherapy and radiotherapy. We don't yet know if giving them with the usual treatments will help. The trial will give a first look at the potential to add durvalumab, a new drug that activates the immune system, to current standard treatments for oesophageal cancer. First we will check that durvalumab can be given safely with chemotherapy in patients with oesophageal cancer that has spread. If this is safe we will then test durvalumab with chemotherapy or chemoradiotherapy given before surgery to patients with potentially curable disease. Depending on how the first part of the trial goes we may also check if we can add a second immunotherapy drug, called tremelimumab, to chemotherapy for inoperable oesophageal cancer. As well as looking at how safe and effective this is we will study the effect of treatment on patients' tumours. The study will run in 2 academic centres in the UK, and is sponsored by the Ludwig Institute for Cancer Research, supported by the University of Oxford. Astrazeneca is providing the durvalumab and tremelimumab for the trial. Patients being treated in the trial will have the usual treatment, lasting 2 to 6 months, but with the new drug(s) added. Durvalumab may also be given after the usual treatment has finished, for up to 6 months.

Inclusion Criteria:

1. Histological diagnosis of oesophageal or gastrooesophageal cancer - Cohorts A and B - metastatic/locally advanced cancer - Cohorts C and D - deemed suitable for surgery with curative intent 2. Recovered from prior therapy (Grade 1 persistent AEs acceptable) 3. Anticipated lifespan greater than 4 months 4. ECOG performance status of 0 or 1 5. At the time of day 1 of the study, subjects with brain metastases must be asymptomatic and show evidence that their CNS disease is not progressing 6. Adequate normal organ and marrow function as defined in detail in the protocol 7. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 8. Age ≥18 years 9. Have been informed of other treatment options 10. Willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits, examinations, biopsies and follow up

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study. 2. Participation in another clinical study with an investigational product during the last 6 weeks 3. Prior or concurrent systemic anti-cancer therapy 4. Mean QT interval corrected for heart rate (QTc) ≥470 ms 5. Current or prior use of immunosuppressive medication within 28 days 6. Active or prior documented autoimmune disease within the past 2 years 7. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 8. History of allogeneic organ transplant 9. Uncontrolled intercurrent illness 10. Known history of previous clinical diagnosis of tuberculosis 11. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab 12. Prior exposure to tremelimumab / durvalumab or checkpoint inhibitors 13. History of severe allergic reactions to any unknown allergens or any components of the study drugs. 14. Known dihydropyrimidine dehydrogenase (DPD) deficiency 15. Treatment with sorivudine or its chemically related analogues, such as brivudine 16. Peripheral sensitive neuropathy with functional impairment prior to first course 17. History of sarcoidosis syndrome. 18. Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may be available. 19. Known immunodeficiency or active HIV. 20. History of pneumonitis or interstitial lung disease. 21. Major surgical procedure (as defined by the investigator) within 30 days prior to Day 1 or still recovering from prior surgery. 22. Women who are breast feeding or pregnant 23. Any condition that, in the clinical judgment of the treating physician, is likely to interfere with evaluation of study treatment, interpretation of subject safety or study results, prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk. 24. Subjects should not donate blood while participating in this study

Sub Specialty:

Upper GI

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Identification and characterisation of prognostic factors in chronic B-cell lymphoproliferative disorders

Research Summary

-

Inclusion Criteria:

Patients with either Monoclonal B cell lymphocytosis, Chronic Lymphocytic Leukaemia or Splenic marginal Zone lymphoma. Samples should be taken at defined time points eg diagnosis, pre-therapy or refractory disease Clinical and outcome data should be available

Exclusion Criteria:

tbc

Sub Specialty:

Lymphoma

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A Phase III Trial of Surgery versus Active Monitoring for Low Risk Ductal Carcinoma in Situ (DCIS)

Research Summary

The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year feasibility phase, in women confirmed by Central Histopathology Review to have low risk DCIS. Comprehensive site training will be complimented by a patient friendly DVD designed to ensure consistent and appropriate use of terminology. Patients will be randomised between standard surgery and active monitoring with annual mammography. Follow-up will be for a minimum of 10 years.

Inclusion Criteria:

1) Female, aged ≥ 46 years 2) Screendetected or incidental microcalcification (unilateral or bilateral) 3) Histologically confirmed diagnosis of non-high grade DCIS confirmed by local pathologist on either small volume core biopsy and/or Vacuum Assisted Core Biopsy (VACB) or on open diagnostic surgical biopsy (without clear margins) 4) DCIS diagnosed ≤90 days before registration 5) Able to give informed consent and comply with the trial schedule and completion of Patient Reported Outcome questionnaires 6) Patient fit to undergo surgery 7) Written informed consent obtained

Exclusion Criteria:

1) Previous or current diagnosis of invasive cancer or ipsilateral DCIS (previous surgically treated contralateral DCIS is permitted) 2) A mass lesion clinically on mammogram or on ultrasound scan (if performed) at the site of the microcalcification before biopsy 3) Any serious and/or unstable preexisting medical, psychiatric, or other condition that would prevent compliance with the trial or consent process 4) Recent onset ipsilateral bloodstained nipple discharge, unless cytology and/or Ultrasound Scan (USS) confirmed concomitant duct ectasia 5) High risk group for developing breast cancer (as defined in current NICE guidelines for familial breast cancer, or due to prior exposure to mantle field radiotherapy)

Sub Specialty:

Breast Cancer Breast Surgery

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LuCID: Lung Cancer Indicator Detection

Research Summary

Rationale Early detection of lung cancer is of paramount importance to improve patient outcome. Unfortunately most early stage tumors are asymptomatic. At this stage cancer cells do already have considerable changes in their metabolism. Part of these metabolites are exhaled through the breath and their detection is a potential tool for early diagnosis of lung cancer. The Lung Cancer Indicator Detection (LuCID) study aims to validate the use of a high-­throughput breath analysis technique in a population of patients whom are clinically suspected of having lung cancer. Methods LuCID is a multi­national, multi­center cross­-sectional case-­control study. Patients referred by their GP or treating specialist for a diagnostic lung cancer work­-up will be invited to participate in the study. Depending on interim sample size analysis two­ to six­hundred patients whom consent to partake in this study will be asked to provide a breath sample. This is a non-­invasive procedure during which subjects breath normally into a face-mask to collect 2.5l of breath (±10 minutes). The resulting samples will be analyzed for VOCs by Gas Chromatography coupled to Mass Spectrometry (GC­MS) and Gas Chromotography coupled to Field Assymetrical Ion Mobility Spectrometry (GC­FAIMS). The resulting VOC profiles will be used to generate a diagnostic algorithm differentiating between patients with and without lung cancer in the intention to diagnose population. This study will in no way intervene with the standard care offered at the clinical sites. Expected outcome The results of this study will provide detailed insights into the accuracy of breath analysis for the detection of lung cancer in the intention to diagnose population. If sufficiently accurate for early stage disease, analysis of breath VOCs could help implement large­-scale screening for lung cancer, significantly decreasing the morbidity and mortality of the disease.

Inclusion Criteria:

o 18 years or older at time of consent o Referred for investigation due to suspicion of lung cancer o Capable of understanding written and/or spoken English o Able to provide informed consent

Exclusion Criteria:

o (Anticipated) inability to complete breath sampling procedure due to e.g. hyperor hypoventilation, respiratory failure or claustrophobia when wearing the sampling mask o Participating in an interventional drug trial o CTscan with contrast in the past 48 hours o Received diagnostic bronchoscopy in past 48 hours o Current active malignancy or nonlung cancer tumor in the past 3 years

Sub Specialty:

Lung Cancer Respiratory Disorders

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Leukaemia Lymphoma Research and NCRI Working Group Pick a Winner Programme (LI1) Trial

Research Summary

LI (less intensive)-1 will evaluate several relevent therapeutic questions in Acute Myeloid Leukemia (AML) as defined by the WHO and High-Risk Myelodysplastic Syndrome. The trial is primarily designed for patients ver 60 years for whom conventional chemotherapy is not considered suitable. The trial is part of a continuous program of developement aimed at improving the outcomes of treatment in this patient population.

Inclusion Criteria:

1. One of the forms of AML (except APL) 2. Over 60 years of age (usually) 3. Informed consent taken. 4. AC220 intervention only, additional cardiac criteria must be met and electrolyte levels corrected pre-treatment.

Exclusion Criteria:

1. Less than 60 years of age (usually). 2. Previously received cytotoxic chemo for AML treatment. 3. In blast transformation of CML. 4. Concurrent active malignncy under treatment. 5. Pregnant or lactating. 6. APL. 7. Known HIV positive. 8. Bilirubin ≥ 1.5xULN, unless with Gilbert's syndrome. 9. AST ≥ 2.5 x ULN 10. Alk phos ≥ 2.5 x ULN 11. Serum creatinine ≥ 2.0mg/dL 12. History of MI, unstable angina CVA/ITA within 6 months 13. AC220-only cardiac exclusions.

Sub Specialty:

Haematological Oncology

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A Randomised Controlled Trial of the Clinical and Cost Effectiveness of Low Level Laser in the Management of Oral Mucositis in Head and Neck Cancer Irradiation.

Research Summary

There are around 4000 people every year in England and Wales who are given chemotherapy or radiotherapy for their head and neck cancer. Most of these people will get a condition called oral mucositis as a side effect of their therapy. Patients with oral mucositis are likely to find that their ability to talk, eat and drink is affected and find it difficult to swallow. They can get painful swelling and ulcers in their mouth and on their tongue and lips. The treatment for oral mucositis is not the same at every hospital but usually includes helping the patient keep their mouth and teeth clean, having a healthy balanced diet and drinking enough fluid. Patients can be given drugs to help with pain as well as special mouthwashes and coating gels. We call this the ‘standard treatment’. There is a new treatment called Low Level Laser Therapy. This involves shining a weak laser light on the lining of the mouth. Early studies have shown that it may take down swelling, reduce pain and help healing. LiTEFORM will tell us how good the laser light is at cutting down pain and swelling during head and neck cancer treatment. It will also measure any impact on the quality of life for patients. All patients will have the standard treatment at their hospital, and half the patients taking part in LiTEFORM will also be given laser therapy. Patients in group 1 will get the active laser therapy. Patients in group 2 will get the inactive therapy or ‘sham’ therapy, where the machine will not actually shine any light into the mouth. Patients will be randomly allocated to Group 1 or Group 2, with an equal chance of being in either group. The patient, machine operator and LiTEFORM team will not know which group the patient is in. • Patients will be asked to complete some questionnaires once a week for six weeks, and again at their 4 months and 14 months head and neck follow up appointment. • They will be asked to drink 100 millilitres of water as quickly as possible, on four occasions (before radiotherapy, on finishing radiotherapy, three and twelve months afterwards). • They will be given up to three laser therapy sessions every week for six weeks. This will be done before their planned radiotherapy treatment. A sample of patients who have consented or declined the main trial will be invited to take part in a telephone interview. This is to find out about patient views and experiences of LiTEFORM and laser therapy if applicable. The initial consent discussion will be audio-recorded and then transcribed (written out). Staff involved in delivering LiTEFORM will be invited to interview (telephone/face to face) and some may also be observed during training sessions. Up to 10 centres across England, Scotland and Wales will take part and use the laser therapy machine for this trial.

Inclusion Criteria:

• Adults aged > = 18 years diagnosed with HNC • Capacity to provide informed written consent • Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, larynx, hypopharynx or unknown squamous cell primary of head and neck origin histologically confirmed • (C)RT patients discussed in a Head and Neck MDT meeting and deemed medically fit for an agreed treatment plan for primary or adjuvant radiotherapy ± concurrent or induction chemotherapy (cisplatin or cetuximab) • Patients planned to receive a minimum of 60Gy to a defined clinical target volume in the oral cavity or oropharynx, or neck levels Ia/b as defined by the current RTOG criteria

Exclusion Criteria:

• Known to be pregnant or planning to become pregnant within the trial treatment period • Parotid tumours • Previous radiotherapy for HNC • Current/ongoing OM and trismus limiting laser access for treatment • Patients who are experiencing active heavy tumour bleeding from the mouth (haemorrhage) • Patients for whom the MDT recommend short course palliative radiotherapy • Patients on immune suppressant drugs (except low dose steroids) • Participation in other trials assessing different treatments for OM • Unable to provide written informed consent

Sub Specialty:

Head and Neck Cancer Other

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LCH-­IV ­International Collaborative Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis

Research Summary

Langerhans Cell Histiocytosis (LCH) is a rare disorder with highly variable clinical presentation and biological behaviours. It can affect a single system/organ (SS­LCH) or multiple systems/organs (MS­LCH). Patients with SS­LCH of the skeleton, skin or the lymph nodes have an excellent prognosis and may need no, or minimal treatment. MS­LCH is unpredictable upon diagnosis, ranging from spontaneous resolution to rapid progression and fatal outcome. Previous research has shown that combination therapy with vinblastine and prednisolone is effective for MS­LCH however more than a third of patients suffer disease reactivation. LCH patients may also suffer permanent consequences including hormone deficiencies, a neurodegenerative syndrome and lung fibrosis. This study aims to improve overall survival, reduce reactivation rates and reduce the permanent consequences. The trial is split into seven strata, designed to tailor treatment based on disease features at diagnosis and on response to treatment. Stratum I is investigating a prolongation (12 vs. 24 months) and intensification (addition of mercaptopurine) of first line therapy (vinblastine and prednisolone) via a randomisation. In stratum II, the response to a uniform initial second line therapy (prednisolone, cytarabine and vincristine) for those patients without risk organ involvement is studied following a randomised comparison of maintenance therapy with either indomethacin or mercaptopurine and methotrexate. Stratum III (cladribine/cytarabine based salvage treatment) and stratum IV (reduced intensity haemapoietic stem cell transplant) are single arm studies of second line therapy for those patients withrisk organ involvement. Stratum V explores the course and treatment of Central Nervous System­LCH (CNS­LCH). Stratum VI is an observational stratum for SS­LCH which does not require systemic treatment at diagnosis.

Inclusion Criteria:

Exclusion Criteria:

Each stratum has its own exclusion criteria. Stratum I: ­ Pregnancy (patients of child­bearing age must be appropriately tested before chemotherapy) ­ LCH­related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis etc.) in the absence of active disease ­ Prior systemic therapy Stratum II: ­ Patients with progressive disease in risk organs ­ Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis etc.) without evidence of active LCH in the same organ or in any other locations Stratum III: ­ Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of organ involvement ­ Inadequate renal function as defined by serum creatinine > 3 x normal for age. Stratum IV: ­ Pulmonary failure (requiring mechanical ventilation) not due to active LCH ­ Isolated liver sclerosis or pulmonary fibrosis, without active LCH Uncontrolled active life­threatening infection ­Decreased renal function with a GFR of < 50ml/1.73m2/min. ­Pregnancy or active breast feeding Stratum VI: ­Patients with SS­LCH who have an isolated tumorous CNS lesion (eligible for stratum V) ­Patients with isolated "CNS­risk" or multifocal bone lesions (eligible for stratum I, group 2).

Sub Specialty:

Haematological Oncology Haematology

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Investigation of the molecular and genetic mechanisms promoting pancreatic cancer development and progression

Research Summary

Pancreatic Cancer (PC) is the 11th most common cancer in the UK with approximately 7,600 new cases annually. Due to it's aggressive nature PC has one of the worse prognoses of any cancer with a 5-year survival rate of only 3%, and a median survival of less than 6 months. PC is characterised by aggressive local tumour growth, early metastasis, a limited response to chemo- and radiotherapy, and an intense fibrotic reaction resulting in a very poor prognosis. Despite advances in the understanding of underlying mechanisms in PC little progress has been made in the prevention, early diagnosis and clinical treatment of patients with PC. To significantly improve the outcome from this devastating disease it is imperative that we gain a better understanding of the molecular and cellular mechanisms involved in order to propel the way for more effective treatments. The aim of this study is to increase the understanding of the mechanisms promoting the development and progression of pancreatic cancer. The areas where the research will be principally concentrated are: 1. Investigating the mechanism(s) regulating tumour cell invasion 2. Investigating the interplay between tumour cells and supporting, non malignant cells of the tumour stroma (fibroblasts, endothelial cells and inflammatory cells) 3. Identification of biological mechanisms and markers that are predictive of malignant transformation and aggressive malignant disease, which may represent novel therapeutic targets.

Inclusion Criteria:

1. All patients undergoing surgical resection of the pancreas 2. A pre-treatment EUS biopsy may also be collected if patients undergo this procedure

Exclusion Criteria:

Children (age less than 16). The reason to exclude children is that pancreatic cancer is extremely rare in this age group

Sub Specialty:

Upper GI

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IoN Is ablative radio-iodine necessary for low risk differentiated thyroid cancer patients

Research Summary

Total thryroidectomy(surgery to remove the thyroid gland) followed by Radioactive Iodine Ablation is the standard treatment for patients presenting with intermediate or high risk well differentiated thyroid cancer. Radioiodine (RAI) is mainly used to eliminate any residual normal thyroid tissue. In a subgroup of patients characterised as having low risk of recurrence there is debate as to whether ablation represents overtreatment. RAI causes many side effects including increased risk of a second primary cancer. IoN will answer the question of whether RAI is necessary for low risk differentiated thyroid cancer patients who already have been offered the other two important modalities of treatment i.e. Total Thyroidectomy and optimal TSH (Thyroid Stimulating Hormone) suppression. Patients who have undergone a total thyroidectomy will be randomised (allocated randomly) into one of two groups by a computer program. One group will receive ablation at an activity of 1.1 GBq (Giga Becquerels), the other will not receive ablation. There will be an equal number of patients in both groups. The study is being funded by Cancer Research UK and has a phase II component to assess whether recruitment is feasible before moving to a phase III study. 570 patients will be recruited for the study.

Inclusion Criteria:

• R0 total thyroidectomy (Rx at the discretion of the MDT) completed within 6 months prior to randomisation (for 2 stage TTs, only the second stage must have been carried out within the 6 month time frame) • Negative pregnancy test in women of child bearing potential • Aged 16 or over • WHO performance status 0 – 2, self-caring • Histological confirmation of differentiated thyroid carcinoma (MDT decision for inclusion based on overall clinic-pathological assessment): • Papillary thyroid cancer o Non aggressive histological features (small foci of aggressive histology allowed at the discretion of the MDT) o pT1a(m): all individual foci ≤1cm o pT1b and pT1b(m): > 1-2cm o pT2 and pT2(m): > 2-4cm o pT3 and pT3(m): > 4cm o pT3 R0: any size with minimal extrathyroidal extension recommended by the MDT o pN0 o pN1a o pNX • Follicular thyroid cancer/Hürthle cell cancer, minimally invasive with capsular invasion only (or up to four foci of possible invasion of intra-capsular vessels at the discretion of the MDT) o pT1b: > 1-4cm intrathyroidal o pT3 R0: up to 4cm only with minimal extrathyroidal extension recommended by the MDT • Histological material available for Central Review (see section 8.6) • Willing to use contraception for the duration of the trial until 6 months post radioiodine treatment (for females) or 4 months post treatment (for males) (see section 5.5.3), if allocated to the ablation group. NB: Multifocal tumours (≥2 foci) of all histological types should be designated with “(m)”, and the size of the largest focus determines the classification (as described in the TNM 7th edition). For example, if there are two foci, one 0.8cm and the other 3cm, the classification is based on the 3cm focus; i.e. pT2(m).

Exclusion Criteria:

• pT1a - Papillary and Follicular carcinoma which is unifocal and ≤1cm in size • < 4cm Encapsulated Follicular Variant of Papillary Thyroid Cancer (EFVPTC) with no capsular invasion • Anaplastic or medullary carcinoma • R1 or R2 thyroidectomy • Patients with: o pN1b o M1 • Aggressive Papillary thyroid cancer with any of the following features: o Widely invasive o Poorly differentiated o Anaplastic o Tall cell o Columnar cell o Diffuse sclerosing variants • Follicular thyroid cancer/Hürthle cell cancer with any of the following features: o Anaplastic o Widely invasive o Poorly differentiated o Tumours greater than 4cm • Incomplete resection or lobectomy • pT4 or macroscopic and microscopic tumour invasion of loco-regional tissues or structures • Pregnant women or women who are breast feeding • Patients who have had CT performed with iv contrast less than 2 months before ablation • Previous treatment for thyroid cancer (except surgery) • Previous malignancies with limited life expectancy or likely to interfere with the patient’s ability to be able to comply with treatment and/or follow-up for at least 5 years • The following GI conditions: dysphagia, oesophageal stricture, active gastritis, gastric erosions, peptic ulcer, suspected reduced gastrointestinal motility • MDT decision against ablation or suitability for trial in light of severe co-morbid condition/s including: o Unstable angina o Recent myocardial infarction or cerebrovascular accident (CVA) o Severe labile hypertension o Any patient who cannot comply with radiation protection including:  patients with learning difficulties  patients with dementia  patients with a tracheostomy that require nursing care  patients requiring frequent nursing/ medical supervision

Sub Specialty:

Head and Neck Cancer

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A phase III multicentre trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer

Research Summary

To investigate in a randomised trial whether additional short-course chemotherapy given on a weekly schedule immediately before standard chemoradiation leads to an improvement in overall survival in patients with locally advanced cervical cancer.

Inclusion Criteria:

A patient with all the following characteristics may be included in the study: • Histologically confirmed FIGO stage Ib2-IVa squamous, adeno or adenosquamous carcinoma of the cervix (except FIGO IIIA). Patients with histologically confirmed FIGO stage IB1 and positive lymph nodes are also eligible. • Deemed suitable and fit for radical chemoradiation • Medically fit to receive carboplatin and paclitaxel • ECOG performance status 0 – 1 see Appendix II • No evidence of active TB • Aged 18 and over • Adequate renal function, defined as a GFR ≥ 60 ml/min calculated using the Wright equation (or ≥ 50 ml/min for radioisotope GFR assessment) • Adequate liver function, as defined by ALT or AST < 2.5 ULN and bilirubin < 1.25 ULN • Adequate bone marrow function as defined by ANC ≥1.5 x 109/L, platelets ≥ 100 x 109/L • Using adequate contraception precautions if relevant • A documented negative HIV test (patients recruited from high risk countries or who have moved within the past 10 years from high risk countries) • A documented negative pregnancy test (if applicable) • Capable of providing written or witnessed informed consent Patients with positive nodes (either histologically/PET positive ≥15 mm on CT/MRI) at or below the level of the aortic bifurcation may be included in the study provided none of the exclusion criteria apply.

Exclusion Criteria:

A patient with any of the following characteristics is excluded from the study: • Previous pelvic malignancy (regardless of interval since diagnosis) • Previous malignancy not affecting the pelvis (except basal cell carcinoma of the skin) where disease free interval is less than 10 years • Positive lymph nodes (imaging or histological) above the aortic bifurcation* • Hydronephrosis which has not undergone ureteric stenting or nephrostomy except where the affected kidney is non-functioning • Evidence of distant metastasis i.e. any non-nodal metastasis beyond the pelvis • Previous pelvic radiotherapy • Prior diagnosis of Crohn’s disease or Ulcerative colitis • Uncontrolled cardiac disease (defined as cardiac function which would preclude hydration during cisplatin administration and any contraindication to paclitaxel) • Pregnant or lactating * i.e. PET any size, CT/MRI ≥ 15mm

Sub Specialty:

Gynaecological Cancers Radiotherapy

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An International Field Study to test the Reliability and Validity of the EORTC Anal Cancer Module (the EORTC QLQ-ANL27) and the EORTC QLQ-C30 for assessing Health Related Quality of Life in patients with Anal Cancer

Research Summary

The objective of the study is to carry out international field testing of the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Anal Cancer Health-related Quality of Life (HRQoL) Questionnaire Module (the EORTC QLQ-ANL27). The questionnaire was designed to include all relevant and important HRQoL issues specific to patients with anal cancer treated with chemoradiotherapy (CRT). The questionnaire was developed according to EORTC Module development guidelines over three phases: Phase 1 involved the generation of HRQoL issues relevant to patients undergoing CRT for primary or recurrent (locoregional) anal cancer. Issues were identified from a literature review and interviews with patients and health care professionals. In Phase 2 these issues formed questions which were then pilot tested and reviewed in Phase 3 by a separate group of anal cancer patients. The final version of the questionnaire, the EORTC QLQ-ANL27 is designed to supplement the EORTC QLQ (core questionnaire applicable to patients across cancer types). The EORTC QLQ-ANL27 now requires testing with a larger number of patients across different cultures in order to determine its measurement properties and acceptability and this is the focus of the current study. Patients with anal cancer who have not previously been involved in Phases 1-3 will be interviewed and asked to complete the questionnaire alongside the EORTC QLQ-C30. They will then complete a de-briefing questionnaire asking them to share their thoughts on the questionnaire in terms of whether anything is missing from the questionnaires and whether any of the questions were confusing, difficult to answer, or upsetting. In the debriefing interview, patients will also be asked how long it took to complete the QLQ-ANL27 and whether they needed any help completing it. Some participants will be asked to complete the questionnaire on two occasions to check for consistency or changes in responses.

Inclusion Criteria:

Participants will be recruited if they are aged 16 years or above with a confirmed diagnosis of primary or recurrent (locoregional) anal cancer. Participants must be aware of their diagnosis and have been or currently treated with chemoradiotherapy. Only participants able and willing to give informed consent will be included. Participants will be included if they have not previously been involved in earlier phases (1 and 3) of the study.

Exclusion Criteria:

Participants will not be invited to take part if they have a diagnosis of rectal adenocarcinoma and if they have not been treated with both chemotherapy and radiotherapy. Participants who have already been involved in this study and who do not have an adequate understanding of English in order to complete the questionnaires will not be eligible to be involved.

Sub Specialty:

Colorectal Cancer

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A Multi-centre Prospective Single Arm Intervention Trial Evaluating Focal Therapy using High Intensity Focused Ultrasound (Sonablate 500) for Localised Prostate Cancer

Research Summary

To evaluate medium term cancer control, genitourinary, rectal and overall health-related quality of life outcomes, and to model potential cost effectiveness of focal therapy for localised prostate cancer using HIFU.

Inclusion Criteria:

• Histologically proven prostate cancer on trans-rectal or transperineal template prostate biopsies • TRUS biopsy: up to burden bilateral disease with maximum 3mm one biopsy on non-dominant side is allowable. • Template biopsy: - unilateral disease any burden - bilateral disease presence of clinically significant cancer on only one side (as determined by histological rules described above) Gleason ≤7, OR clinically insignificant disease with a burden of > 50% of biopsy cores taken on that side, OR bilateral clinically insignificant disease and < 50% of biopsy cores positive on any one side but with dominant disease burden on one side • Stage T1-T2cN0M0 disease, as determined by local guidelines (radiological T3a permitted) • Serum PSA <= 15 • Life expectancy of >= 10 years • Signed informed consent by patient • An understanding of the English language sufficient to

Exclusion Criteria:

• Men who have had previous radiation therapy • Men who have had androgen suppression/hormone treatment within the previous 12 months for their prostate cancer • Men with evidence of metastatic disease or nodal disease outside the prostate on bone scan or cross-sectional imaging • Men with an inability to tolerate a transrectal ultrasound • Men with latex allergies as the HIFU probe is covered with a latex condom sheath prior to insertion into the back passage • Men who have undergone prior significant rectal surgery preventing insertion of trans-rectal HIFU probe (decided on the type of surgery in individual cases) • Men who have had previous HIFU, cryosurgery, thermal or microwave therapy to the prostate. • Men who have undergone a Transurethral Resection of the Prostate (TURP) for symptomatic lower urinary tract symptoms within 6 months. These patients may be included within the trial if deferred from consenting and screening until at least 6 months following the TURP. • Men not fit for major surgery as assessed by a Consultant Anaesthetist • Men unable to have pelvic MRI scanning (severe claustrophobia, permanent cardiac pacemaker, metallic implant etc likely to contribute significant artefact to images) • Presence of metal implants/stents in the urethra • Presence of prostatic calcification and cysts (on transrectal ultrasound) whose location will interfere with effective delivery of HIFU therapy • Men with renal impairment with a GFR of

Sub Specialty:

Prostate Cancer

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INTERIM: a randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted combination therapy In patients with BRAFV600 mutant stage 3 unresectable or metastatic Melanoma

Research Summary

Metastatic melanoma has a very poor prognosis: median overall survival is 8 months untreated and around 2 years even with optimal systemic therapies. A gene called BRAF is abnormal in about half of melanomas and biological agents targeting the BRAF pathway have been shown to extend life. They are now routinely available in NHS clinical practice. Giving BRAF and MEK inhibitor drugs together offers the best anti-cancer treatment for these patients. However, treatment is limited by side-effects (often affecting the skin) and secondary resistance (which means the cancer regrows usually after about a year). Laboratory experiments and case reports suggest intermittent dosing of these chronic orally administered drugs makes BRAF pathway inhibitors work for longer, extending life and reducing side effects. In the INTERIM trial, we will test whether less treatment than usual is acceptable to patients and doctors and, potentially, more beneficial. We also aim to develop better tools to monitor skin side-effects. We will recruit 150 patients with advanced BRAF mutant melanoma. All patients will receive BRAF+MEK inhibitor treatment with standard dabrafenib+tremetinib, either taken continuously every day, or with planned treatment breaks in each 28 day cycle. Comparing these 2 groups will determine if it is feasible to recruit patients and deliver intermittent therapy, any impact on patient quality of life, and an initial estimate of how long the drugs work.

Inclusion Criteria:

• Signed informed consent • Age > = 18 years old • Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable or metastatic melanoma • Measurable disease by RECIST • ECOG performance status 0-2 • Minimum life expectancy 12 weeks • Adequate bone marrow, renal and liver function • Received no prior BRAF or MEK inhibitor therapy for metastatic disease • Willing and able to comply with the scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other study procedures • Archival tumour tissue sample available • Women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout treatment

Exclusion Criteria:

• Concomitant immunotherapy being administered to treat advanced melanoma • Other invasive malignancies diagnosed within the last year which are not in complete remission, or for which additional therapy is required • Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial • Women who are pregnant, plan to become pregnant or are lactating during the trial period • Other investigational anti-cancer drugs • Use of strong inducers and inhibitors of CYP3A or CYP2C8

Sub Specialty:

Skin Cancer

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A phase II study of intensity modulated radiotherapy (IMRT) in primary bone and soft tissue sarcoma

Research Summary

Primary bone and soft tissue sarcomas are rare tumours, collectively accounting for 1% of all malignancies diagnosed in the UK. Radiotherapy plays an important role in the local management of these tumours. Cancer cells are damaged by the radiotherapy, and die, because they are unable to repair themselves. Side effects of radiotherapy result from normal tissue in the area around the cancer being damaged by the x-rays. Radiotherapy is always planned to avoid healthy tissue as much as possible. However, cancers can have complicated shapes and it is difficult using the normal techniques to match the shape of the x-ray beams to the shape of the cancer. IMRiS will look at giving radiotherapy in a way that is different to the way it is normally given to patients with sarcoma, using intensity modulated radiotherapy (IMRT). IMRT is a way of shaping the radiotherapy treatment very closely round the tumour. IMRT is a well-established treatment that has been studied a great deal in other cancer types such as head and neck cancer where it has been shown to reduce side effects of radiotherapy, and some hospitals already use it to treat selected sarcoma patients. However, IMRT is not considered a routine treatment for sarcoma because it has not yet been tested properly in sarcoma clinical trials to prove that it is better than the usual way of giving radiotherapy. The aim of the IMRiS trial is to understand the benefits of IMRT for sarcoma patients, because we think that it will allow us to treat tumours more effectively, with fewer side effects.

Inclusion Criteria:

1. Histopathological diagnosis of: Soft tissue sarcoma of the upper or lower limb or limb girdle (cohort 1), OR Ewing's sarcoma of bone arising in the pelvis or spine (cohort 2), OR High grade non-Ewing's primary bone sarcoma or chordoma arising in the pelvis or spine (cohort 3) 2.Patient requires: (neo)adjuvant RT (cohort 1) (neo)adjuvant or primary radical RT (cohort 2) adjuvant or primary radical RT (cohort 3) 3.WHO performance status 0-2 4.Aged ≥ 16 years 5.Patients fit enough to undergo radiotherapy treatment and attend follow up visits as per protocol 6.Women of child-bearing potential must have a negative pregnancy test prior to trial entry. Female patients of childbearing potential and male patients with partners of child-bearing potential must agree to use adequate contraception methods for the duration of the trial treatment and for 3 months after completion of treatment 7.Capable of giving written informed consent

Exclusion Criteria:

1.Previous RT to the same site 2.Patients with bone sarcomas eligible for proton beam radiotherapy (PBRT) 3.Diagnosis of paediatric type alveolar or embryonal rhabdomyosarcomas 4.Pregnancy 5.Patients with concurrent or previous malignancy that could compromise assessment of the primary and secondary endpoints of the trial. Sites must discuss these cases with UCL CTC prior to the patient being approached.

Sub Specialty:

Sarcoma

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A multicentre randomised phase II clinical trial of Inotuzumab Ozogamicin plus Rituximab and CVP (IORCVP) versus Gemcitabine plus Rituximab and CVP (GemRCVP) for the first line treatment of patients with diffuse large B cell lymphoma who are not suitable for anthracycline containing chemotherapy

Research Summary

The aim is to determine the efficacy and safety of adding inotuzumab ozogamicin to R-CVP in the first line treatment ofDiffuse Large B Cell Lymphoma in patients who are not able to receive anthracycline containingimmunochemotherapy. The incidence of DLBCL is increasing and with an expanding elderly population,the incidencewill continue to rise. Given that about 40% of cases of DLBCL occur in patients aged over 70 and the number of co-mobilities increases with age,research to investigate the optimal treatment of DLBCL in this group of patients isneeded. R-CHOP remains the standard of care for the majority of patients with DLBCL,anthracycline use is precludedin a proportion of these patients by a high risk of developing cardiotoxicity,especially congestive cardiac failure.Currently there is no standard of care for patients who are unfit for anthracycline treatment. It has been routine to omitthe doxorubicin from R-CHOP,giving R-CVP instead. However the outcome for patients treated with R-CVP is poor andattempts have been made to replace the doxorubicin with alternative agents. The trial will compare an experimentalarm consisting of Inotuzumab Ozogamicin added to the standard immunochemotherapy regimen of rituximab,cyclophosphamide, vincristine and prednisolone (IO-R-CVP) with the control arm of gemcitabine added to the samecombination (Gem-R-CVP).Patients will be indentified, consented and treated at sites throughout the UK. All patientswill receive a steroid pre-phase. Those patients who have an ECOG performance status 0-2 after steroid pre-phasewill be randomised to either Gem-R-CVP or IO-R-CVP for a maximum of 6 cycles followed by 2 further doses ofRituximab. If demonstrated to be efficacious and safe to deliver, the IO-R-CVP regimen will be tested in a phase III trialto determine whether this should become the standard of care amongst patients with DLBCL not fit for anthracylin

Inclusion Criteria:

Inclusion criteria for randomisation a. Informed written consent for the trial b. Histologically proven diffuse large B cell lymphoma (DLBCL) according to the current World Health Organisation (WHO) classification including all morphological variants. The B cell nature of the proliferation must be verified by demonstration of CD20 positivity. A concurrent (synchronous) diagnosis of low grade lymphoma (e.g. on bone marrow trephine or presence of both low grade and DLBCL in a lymph node biopsy) is permitted. c. Bulky Stage IA (lymph node or lymph node mass ≥10cm in maximum diameter), stage IB, stage II, stage III and stage IV disease d. ECOG performance status 0-2 e. Measurable disease f. Age 18 years g. Adequate contraceptive precautions for all patients of childbearing potential h. No active malignant disease other than non-melanotic skin cancer, superficial bladder cancers or carcinoma in-situ of the uterine cervix in the last 5 years i. No previous chemotherapy, radiotherapy or other investigational drug for this indication – previous corticosteroids up to a dose equivalent to prednisolone 1mg/kg/day for up to 14 days are permitted prior to randomisation j. EITHER Unsuitable for anthracycline-containing chemotherapy due to impaired cardiac function defined by an ejection fraction of ≤50% OR Left ventricle ejection fraction > 50% but in the presence of significant co-morbidities (diabetes mellitus, hypertension or ischaemic heart disease) precluding anthracycline-containing chemotherapy as determined by treating physician. Co-morbidities must be documented on the randomisation form and CIRS score recorded using the Cumulative Illness Rating Scale k. Adequate bone marrow function (Platelets > 100x109/l, WBC > 3.0 x109/l, Neutrophils > 1.5x109/l) at time of study entry unless attributed to bone marrow infiltration by DLBCL l. Life expectancy > 3 months

Exclusion Criteria:

Exclusion Criteria for randomisation a. Symptomatic central nervous system or meningeal involvement by DLBCL b. Previous diagnosis of low grade lymphoma c. Non-bulky stage IA disease d. ECOG performance status 3-4 e. History of chronic liver disease or suspected alcohol abuse f. Serum bilirubin greater than upper limit of normal unless attributable to Gilbert’s syndrome or haemolysis. g. Alanine and/or aspartate aminotransferase levels (ALT and/or AST) and alkaline phosphatase (ALP) greater than 2.5 times the upper limit of normal h. Glomerular filtration rate (GFR) < 30ml/min. GFR calculated by Cockroft-Gault (not eGFR) i. Serological evidence of active hepatitis B or C infection whether acute or chronic (defined as positive anti-HCV serology; positive HBsAg). All positive HBcAb results should also be excluded on safety grounds regardless of HBsAg or HBV DNA status. Antibodies to Hepatitis B surface antigen (anti-HBs) due to a history of past vaccination is acceptable j. Known history of HIV seropositive status k. Patients with a history of Venoocclusive Disease (VOD) and Sinusoidal Obstructive Syndrome (SOS) l. Patients with a screening of QTcF interval > 470msec m. Medical or psychiatric conditions compromising the patient’s ability to give informed consent n. Women who are pregnant or lactating o. LVEF > 50% in the absence of significant co-morbidities that preclude anthracycline use p. Patients with a history of severe allergic/anaphylactic reaction to any humanised monoclonal antibody q. Patients with serious active infection

Sub Specialty:

Lymphoma

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Improving Population Outcomes for Renal Tumours of Childhood - applying P-Medicine tools to improve treatment decisions for Wilms tumour and other renal tumours of childhood and young adults: A SIOP Renal Tumours Study Group prospective clinical study

Research Summary

This project aims to improve short and long term outcomes for children and young people with Wilms (WT) and other childhood renal tumours through the introduction of a more ‘personalised’ approach to risk stratification. This will include biological characterisation of tumour, blood and urine samples to better define the molecular pathways involved, particularly in high risk, ‘blastemal type’ Wilms tumour. There will be central review of tumour pathology and of any imaging studies (scans) performed in ‘real time’, to test the feasibility of integrating all of these complex datasets within a newly developed e-health tool project known as “P-medicine”, that will be used to improve clinical decision making in a future clinical trial. Each patient’s treatment will be according to the currently accepted best practice, that is based on the recently closed phase III clinical trial run by the International Society of Paediatric Oncology (SIOP) Renal Tumours Study Group, in which the UK was a major participant.

Inclusion Criteria:

All children, adolescents or young adults with a primary renal tumour (or extrarenal Wilms tumour) diagnosed and treated at a participating Children’s Cancer and Leukaemia Group (CCLG) treatment centre. There is no strict upper age limit nor requirement for the patient to be a UK resident provided that follow up information is anticipated to be available.

Exclusion Criteria:

Patients who do not give/whose parents do not give consent for inclusion of their clinical/imaging or biological sample data. (note that patients/parents can consent separately to the biological studies so may still be registered if they consent for inclusion of their clinical/imaging data but will be excluded from the biological studies if they so wish).

Sub Specialty:

Children's Cancer and Leukaemia

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Investigating Quality of Care for People with Dementia Undergoing Cancer Treatment in Ambulatory Care (IMPACT)

Research Summary

This study aims to understand how high quality care can be provided for people with dementia undergoing outpatient cancer treatment (radiotherapy, chemotherapy or other anti-cancer treatment). The study uses ethnography, where a researcher conducts fieldwork to better understand a group of people. Fieldwork will take place over 12 months in the outpatient departments of University Hospital Southampton NHS Foundation Trust. It will include observations, interviews and review of patient notes. The people who will be invited to take part are: - People with dementia having cancer treatment; - Friends or family supporting people with dementia having cancer treatment; - Staff involved in the care of people with dementia having cancer treatment. All those who take part in the study will be asked to give consent. The study includes: - Observation. Up to 30 hours of observation will take place in the general clinic areas as well as during doctor appointments and when treatment is being given. The researcher will take detailed notes. - Interviews. Up to 40 interviews will be carried out with patients, carers and staff. Interviews will be digitally recorded. - Patient notes. Researchers will look at patient notes to add to information from observation and interviews. They will look at the notes to find out about diagnosis, treatment and support offered to patients. These methods will help the researchers form a picture of the outpatient setting including how people act (behaviour), the surroundings and conditions (environment), and the way treatment and support is organised (processes). This will show how healthcare organisations might best provide cancer treatment for people with dementia that is person-centred (focused on the needs of the person) and of a high quality.

Inclusion Criteria:

Patient participants: - Adult, aged over 18; - Confirmed diagnosis of any cancer; - Undergoing or due to undergo cancer treatment (radiotherapy, or chemotherapy or other SACT delivered via any route e.g. oral, intravenous, subcutaneous, intrathecal) OR have finished these treatments within the last 6 months; - Treatment administered in ambulatory care setting: hospital treatment centre, outreach clinic or home environment; - Diagnosis of dementia of any type (Alzheimer’s, Lewy body, vascular, fronto-temporal), documented in patient case notes; - Capacity to decide to take part in the study; OR after capacity assessed, enhancements made, consultations carried out, decision made to include participant (following British Psychological Society Practical Guide, Dobson 2008) Non-patient participants: - Adult, aged over 18; - Informal carer of patient participant (relative/spouse/friend/neighbour); OR healthcare professional/ NHS staff involved in care & management of patient participant or other patients with dementia having cancer treatment.

Exclusion Criteria:

Patient participants: - Acute or critical illness; - Inability to communicate choices and preferences either verbally or non-verbally; - No confirmed diagnosis of dementia; - Cognitive impairment as a result of aetiology not related to dementia, such as brain injury, delirium, learning disability or brain metastases.

Sub Specialty:

Psychosocial Oncology and Survivorship Supportive and Palliative Care

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Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in BRCA1/2 mutation carriers and controls - IMPACT

Research Summary

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Inclusion Criteria:

Male carrier of a known pathogenic BRCA1 or BRCA2 mutation OR MSH2, MSH6, MLH1 mutation Male who has tested negative for a known pathogenic BRCA1, BRCA2, MSH2, MSH6 or MLH1 mutation present within their family Age 40-69 years WHO performance status 0-2 No previous history of prostate cancer Informed written consent must be sought according to ICH/EU GCP, and national/local regulations before subject registration.

Exclusion Criteria:

Previous cancer with a terminal prognosis of less than five years. Previous prostate cancer

Sub Specialty:

Genetics Prostate Cancer Surgical Urology

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Improving radical treatment through MRI evaluation of pelvic sigmoid cancers (the IMPRESS trial)

Research Summary

Every year more than 40.000 people in the UK are diagnosed with colorectal cancer, of which about two thirds are localised in the colon. Survival and local recurrence rates are improving at a great rate for rectal cancer but much less so for colon cancers. More than half of colon cancers arise in the left side of the colon and the greatest proportion in the pelvis (sigmoid colon). If patients with a high risk of poor outcome and local recurrence can be identified preoperatively, they can be treated with neoadjuvant treatment to improve their outcome. In rectal cancer this has already been succesfully applied using MRI and has lead to a reduction of pelvic recurrence from 40% to 5-10% (MERCURY Trial). To identify high risk patients, accurate preoperative imaging is needed. We propose that if MRI rather than CT (the current standard of care) is used for staging sigmoid cancer in the same way that has been used for rectal cancer, we will be able to select more patients that would benefit from dedicated surgical road mapping and treatment before surgery. The IMPRESS Trial is a randomized clinical trial that will compare the standard of care for colon cancer (preoperative CT followed by treatment discussion by Multidisciplinary Team) with an interventional arm (combination of preoperative CT and MRI followed by routine treatment discussion by MDT).

Inclusion Criteria:

- All patients with pelvic sigmoid cancer (demonstrated on colonoscopy and biopsy) who are eligible for curative treatment.

Exclusion Criteria:

- Less than 18 years old - Unable to consent - Consent witheld or withdrawn - Unable to have an MRI (e.g. pacemaker, metal implant in major viscera, severe claustrophobia) - A previous history of colorectal cancer - Presence of irresectable distant metastases - Severe comorbidities that prevent the application of eventual chemo/radiotherapy

Sub Specialty:

Colorectal Cancer Other

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A randomised phase I/II study of Intensity Modulated Arc Therapy techniques in abdominal neuroblastoma

Research Summary

Neuroblastoma is the commonest solid tumour of childhood. The majority of cases are high risk disease, and the survival of these patients is only around 30% at five years. Radiotherapy to the primary tumour site is standard practice. It improves local control and may improve survival. However the radiation tolerance of adjacent critical normal structures can limit the dose of radiotherapy that can be delivered. A recently developed way of delivering radiotherapy - Intensity Modulated Arc Radiotherapy (IMAT) offers a potential way to overcome some of the limitations through much better shaping of the volume treated to a high dose, and better avoidance of organs at risk (OAR) of damage This study aims to see if, and to what extent, dose escalation is safely possible in children with abdominal neuroblastoma using both IMAT and conventional radiotherapy techniques. This is an unblinded, multicentre randomised UK trial. 50 patients, aged 18 months or older at diagnosis with high risk abdominal neuroblastoma who require radical radiotherapy will be randomised to receive either the 'intended' standard dose (21Gy) or an 'intended' experimental dose (36Gy). Pre-treatment dosimetry will use established normal tissue constraints to ensure that over-treatment of OAR does not occur and that they are not damaged. This may mean that in some patients the full 36Gy dose is not given, and a lower *actual* dose is therefore the compromise outcome. Radiotherapy plans will be prepared for each patient using both conventional and IMAT techniques and the plan judged to have the best balance between target volume coverage to the randomised dose allocation, and sparing of OAR will be chosen for delivery. Having defined an increased dose which can safely be delivered to the majority (80%) of patients, a randomised phase III trial powered to detect superiority of the increased dose over the standard will be planned.

Inclusion Criteria:

• Any patient with high-risk neuroblastoma of the abdominal or pelvic regions who requires radical radiotherapy • Fit to receive radical radiotherapy • Aged > = 18 months at diagnosis • Informed consent from patient, parent or guardian • Documented negative pregnancy test for female patients of child bearing potential. • Patient agrees to use effective contraception during treatment period (patients of child bearing age).

Exclusion Criteria:

• Pregnant patient

Sub Specialty:

Children's Cancer and Leukaemia

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Tissue based immunometric analysis to guide personalised immunotherapy in solid malignancies

Research Summary

In recent years, many diseases have been found to be affected by how the immune system works and in particular cancer. There are now new treatments, which target the relevant biological mechanisms; these can be used on their own or together with existing treatments. Promising results have been seen in patients with several different types of malignancies and several drugs are now approved for use in clinic with many more in clinical trials. So far only a relatively small proportion of patients with cancer benefit from immunotherapy; the risk of significant toxicity is real and to-date unpredictable for each individual. This is because we still do not fully understand how immunotherapy works and how to choose the right treatment for the right person. The purpose of this project is to improve our knowledge of how the immune system functions in people with malignancies; we would also like to work out what effect any treatments they may receive has on the way their immune system fights cancer. We plan to do this by collecting tissue and blood samples from patients before and after they receive anti-cancer treatment and conducting in depth comprehensive analysis of the immune response – at the genetic, functional and morphologic levels – and cross-reference with clinical outcome data. The ultimate aim is to predict which patients are most likely to benefit from particular drugs and least likely to experience side-effects; further more we would use the information gained to guide us choose which new immunotherapy drugs are worth combining with existing treatments to investigate in future larger scale clinical trials or use in personalised medicine approaches.

Inclusion Criteria:

1. Suspected or confirmed diagnosis of a solid malignancy 2. Aged 18 or over. 3. Ability to understand the study requirements and provide written informed consent. 4. Either of: a. Scheduled to undergo diagnostic procedure – surgical/endoscopical or image guided biopsy b. Scheduled to have elective curative or palliative resection of primary tumour or metastatic deposit c. Patient with a histologically proven diagnosis willing to undergo additional research procedures necessary to acquire fresh tumour samples and/or provide excess material from previously obtained biopsies. 5. Willing to provide additional blood samples.

Exclusion Criteria:

1. Underlying medical conditions that in the opinion of the investigator would pose a contraindication to procedures necessary for tissue sampling. 2. Confirmation of non-cancer diagnosis. 3. Withdrawal of consent

Sub Specialty:

Supportive and Palliative Care

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Phase III randomised trial of immunomodulatory therapy in high risk solitary bone plasmacytoma

Research Summary

Solitary bone plasmacytoma (SBP) is a form of blood cancer, in which abnormal plasma cells collect at a single location in the skeleton. The standard treatment is radiotherapy, however around two-thirds of patients either relapse or go on to develop a more widespread version of the disease called myeloma. Scientists now think these patients relapse because they already have very low levels of disease present in their bone marrow when their plasmacytoma is diagnosed. Using blood and bone marrow tests, they think they are able to identify patients who are most likely to relapse. The IDRIS study will investigate whether progression can be delayed or prevented by giving these patients further treatment with lenalidomide and dexamethasone after radiotherapy. 140 patients with newly-diagnosed SBP will be registered into the trial after radiotherapy. A bone marrow sample will be reviewed to check for 'high risk' features predictive of relapse. Patients with 'high risk' features will be randomised to have either lenalidomide and dexamethasone (group A1) or no further treatment (group A2). Patients with no 'high risk' features (group B) will also have no further treatment. Lenalidomide and dexamethasone treatment consists of up to 9 cycles of treatment, each lasting 4 weeks. Both drugs are taken at home, by mouth, and patients will be seen at their outpatient clinic every four weeks until treatment is finished. Patients on all arms will be followed up for at least 5 years. They will be seen every 3 months until 2 years post radiotherapy, every 6 months in years 3-5 and annually thereafter.

Inclusion Criteria:

INCLUSION CRITERIA FOR REGISTRATION: - Patients with newly-diagnosed SBP - SBP treated with local radiotherapy with curative intent (see appendix 2). - Radiotherapy completed within 28 days of registration - Age ≥18 years - ECOG performance status 0-2 - Written informed consent - Willing to comply with the requirements of the Celgene pregnancy prevention programme INCLUSION CRITERIA FOR RANDOMISATION: - Phenotypically aberrant plasma cells in a BM aspirate taken from a site outside the radiotherapy field and/or - Abnormal serum free light chain ratio at diagnosis (or at time of registration if SFLC not measured prior to radiotherapy)

Exclusion Criteria:

- Multifocal plasmacytoma, solitary extramedullary plasmacytoma or myeloma - ≥10% bone marrow plasma cells - Clinical suspicion of failure to respond to radiotherapy - Receiving or intention to treat with systemic corticosteroid therapy (e.g. dexamethasone or prednisolone) unless otherwise agreed by the TMG - Severe hepatic impairment (bilirubin > 2xULN or AST/ALT > 2xULN) - Creatinine clearance < 30 mL/min - Pregnant or lactating women - Non-haematological malignancy within the past 3 years (exceptions apply – see section 6.2.2) - Patients at a high risk of venous thromboembolism due to: -Treatment with erythropoietic stimulating agents (e.g. erythropoietin, epoetin alpha, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta) -Other risk factors not listed above and unable to receive thromboprophylaxis - Patients with untreated osteoporosis - Patients with uncontrolled diabetes - Patients with a known history of glaucoma - Any other medical or psychiatric condition likely to interfere with study participation - Receiving treatment with an experimental drug or experimental medical device. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study. Any experimental drug treatments must be stopped at least 4 weeks before planned start of lenalidomide and dexamethasone. - Evidence of current or past hepatitis B infection. Patient should test negative for both surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) EXCLUSION CRITERIA FOR RANDOMISATION: - Creatinine clearance < 30 mL/min

Sub Specialty:

Haematological Oncology

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A randomized, open label, multicentre, two-arm phase III comparative study assessing the role of mediastinal radiotherapy after rituximab containing chemotherapy regimens to patients with newly diagnosed Primary Mediastinal Large B-Cell Lymphoma (PMLBCL)

Research Summary

Primary mediastinal Large B-cell lymphoma (PMBL), accounts for less than 5% of non-Hodgkin’s lymphoma's (NHL) occurring predominantly in females with a median age at presentation in the third or fourth decades. It is estimated that of the 12,000 newly diagnosed NHL cases per annum, 500 will be PMBL. Current practice is to give intensive chemotherapy sometimes with the addition of mediastinal radiotherapy (RT). Uncertainty exists however, as to whether consolidation radiotherapy following immunochemotherapy is necessary and given the late effects of such treatment whether PET scanning can be used to discriminate between patients who require radiation from those who do not. Functional imaging with PET scanning has been shown to distinguish between residual masses which contain active lymphoma and those where the lymphoma has been eliminated. Although used to determine treatment options in many other lymphomas, whether it can be used similarly in PMBL has yet to be determined. This trial aims to answer this question by recruiting 752 newly diagnosed patients with PMBL who are due to receive a standard chemotherapy regimen which contains rituximab. Patients will be recruited from 21 countries internationally (including 14 sites in the UK). Patients will receive an initial PET/CT scan before they commence their chemotherapy. Following chemotherapy they will receive a further PET/CT scan. Patients whose PET scans are negative will be randomised to receive either consolidation radiotherapy or observation. Patients with a positive PET or who achieve a partial response will not be randomised but referred back to their clinician for further treatment. The primary endpoint is progression free survival at two years. Randomised patients will be followed up for 10 years to assess overall survival and safety. Those not randomised will be followed up to ascertain their response to the treatment given by the investigator, disease progression and overall survival.

Inclusion Criteria:

Previously untreated primary mediastinal diffuse large Bcell lymphoma, CD20 positive. Patients must have histological confirmation of the diagnosis (it is recommended that the immunohistochemical panel includes: CD45, CD20, CD30, CD15, CD10, BCL6, BCL2, MUM1), and in addition have a dominant mass within the anterior mediastinum. No evidence of extranodal disease outside the chest including spleen and bone marrow Age at least 18 years. Fit to receive chemotherapy and radiotherapy with curative intent. Patients will be eligible if the treatment phase consisting in a Rituximab combined with any anthracycline-containing chemotherapy regimen without consolidation with autologous stem cell support (e.g., 6 cycles of CHOP14-21, DA-EPOCH, Mega-CHOP or 12 weeks of VACOP-B or MACOP-B). At least 6 courses of Rituximab should be administered Able and willing to give informed consent, and to undergo staging including PET scanning Willingness to comply with an appropriate contraceptive method in women of childbearing potential or men. Histological diagnostic material available for review.

Exclusion Criteria:

History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of the cervix within the last 5 years. Evidence of clinically significant cardiac disease at diagnosis, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry. Cardiac impairment due to local extension of lymphoma will not be an exclusion criterion in the absence of other cardiac disease. Known HIV-positive serology. Pregnant or lactating women. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Sub Specialty:

Lymphoma

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An international phase III randomised study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

Research Summary

Ovarian carcinoma is the fifth commonest cause of cancer death in women in the UK. Platinum-based chemotherapy remains the cornerstone of treatment. Despite advances in treatment, about 80% of women with advanced ovarian cancer have a recurrence that is ultimately fatal. Patients who relapse > 6 months after completing first-line platinum-based chemotherapy are retreated with further platinum-based chemotherapy regimens. The median survival after first relapse is about 40 months. Two novel biological agents, cediranib targeting blood vessel growth, and olaparib targeting DNA repair processes, have individually led to an improvements in ovarian cancer control. A combination of these drugs has also demonstrated greater activity than either of them alone. The aim of the ICON9 trial is to improve progression free and overall survival by adding maintenance therapy (treatment used to slow the growth or return of cancer after initial treatment) with cediranib and olaparib in patients who have relapsed > 6 months after completing platinum-based chemotherapy. We also seek to determine the effects of treatment on the quality of life, and to find cancer markers which may help identify which treatments patients are most likely to benefit from. Patients who have responded to a minimum of 4 cycles of platinum based chemotherapy will be randomised for maintenance treatment with either olaparib and cediranib or olaparib alone. The maintenance regimen may be continued even if the disease has worsened, as indicated by CT scan, if the clinician believes the patient is still deriving benefit. Trial treatment must be discontinued if further cancer treatment is started. ICON9 will be undertaken internationally in approximately 70 sites. The target accrual is 618 patients. The trial is funded by Cancer Research UK and AstraZeneca. It is sponsored by University College London and coordinated by the CR UK & UCL Cancer Trials Centre.

Inclusion Criteria:

1. Histologically proven diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with second-line platinum-based chemotherapy. Patients may be included post-surgery for relapsed disease if undertaken more than 6 months after progression from first-line therapy. 2. Patients must have had CT or MRI proven relapsed disease (measureable by RECIST 1.1 or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse. 3. Patients showing response to chemotherapy mid-treatment (post 3 or 4 cycles), either by GCIG CA125 criteria or ‘partial response’ on CT/MRI scan, or no evidence of progression having undergone surgical debulking, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/or somatic). 4. Completed a minimum of 4 cycles (and maximum of 6 cycles) of platinum-based chemotherapy for first relapse (2nd line treatment) with at least a partial response on imaging (CT or MRI) by RECIST 1.1 if measureable disease, or CA125 response by GCIG criteria if non-measurable disease. No CT/MRI or CA125 evidence of progression after surgical debulking and chemotherapy (above). 5. Prior front-line maintenance therapy with bevacizumab is permitted. 6. ECOG performance status 0-1. 7. Adequate bone marrow function, liver and renal function. 8. Availability of archival diagnostic tumour sample or tumour samples at relapse if patient has undergone further biopsy or surgical debulking. 9. Adequately controlled blood pressure (systolic blood pressure [SBP] < = 140 mmHg; diastolic blood pressure [DBP] < = 90mmHg) on maximum of 3 antihypertensive medications.

Exclusion Criteria:

1. Non-epithelial ovarian cancer, carcinosarcoma and mucinous carcinomas, ovarian clear-cell carcinoma. 2. Cerebrovascular accident (including transient ischemic attacks) within last 12 months. 3. Gastrointestinal impairment that could affect ability to take, or absorb oral medicines including sub-acute or complete bowel obstruction. 4. Symptomatic or clinically significant inflammatory bowel disease (Crohn’s disease or ulcerative colitis. 5. Evidence of severe or uncontrolled cardiac disease. 6. Evidence of active bleeding or bleeding diathesis.

Sub Specialty:

Gynaecological Cancers

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Development of an IDEAL framework to standardise the complex intervention of cytoreductive surgery for colorectal peritoneal metastases: a necessary step to phase III trials

Research Summary

Cytoreduction surgery (CRS) followed by hyperthermic intra-operative peritoneal chemotherapy (HIPEC) is a relatively new treatment for selected patients with peritoneal metastases of colorectal origin (PMCR). Data from outside of trials suggest that CRS and HIPEC improves survival compared with the current standard care (chemotherapy). The big challenge is to do trials in this setting – as the intervention is complex, and there are wide variations in the process and recording of outcomes. If trials can confirm the findings from non‐randomised studies there are an estimated 1000 to 2000 patients who may benefit from this intervention in the UK each year. The aim of this study is to develop a framework which can be used to undertake a randomised trial in patients with PMCR suitable for CRS with or without HIPEC. We will address this using the principles of the IDEAL (Idea, Development, Evaluation, Assessment & Long term study) framework. Here, we will perform a pre‐trial feasibility study between the two national peritoneal tumour treatment centres (Manchester and Basingstoke). This is a 12 month study that is designed as such that it will take place over the following four stages: Stage 1. Comparing the treatment data from 50 operations from each of the two centres to identify which of the key components of the intervention differ Stage 2. Identifying sources of these differences by selecting up to 25 patients and investigating the variation in the way surgeons score key aspects of the procedure Stage 3. Development of a ‘trial manual’ with standardised definitions (to minimise any differences) Stage 4. Test how well people follow the manual in practice. After this study is complete, it will be possible to use the resulting trial manual to design future randomised trials to test the most suitable clinical question.

Inclusion Criteria:

• Adults aged 18 or over • Diagnosis of histologically proven peritoneal metastasis of colorectal origin • Undergone Cytoreductive Surgery with or without Heated Intra-Peritoneal Chemotherapy (HIPEC) at either The Christie NHS Foundation Trust or Basingstoke and North Hampshire Hospital • Curative surgery

Exclusion Criteria:

• Unable to give informed consent • Diagnosed with distant metastasis • Treatment with palliative intent

Sub Specialty:

Colorectal Cancer Colorectal Surgery

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HORIZONS: a cohort study to explore recovery of health and well-being in adults diagnosed with cancer

Research Summary

HORIZONS is a cohort study to explore recovery of health and well-being in adults diagnosed with cancer. Experiences and outcomes of cancer treatment and care are changing. A growing number of people are experiencing cancer not as a life-limiting disease, but as a life-changing and long-term condition. There is a growing imperative to understand the changing landscape of cancer and its consequences: as we do so, we will be better able to inform the design and delivery of cost effective interventions that make possible supported self-management, as well as service organization and delivery. The key research questions are: What impact does cancer and its treatment have on the lives of people diagnosed with cancer in the short, medium and long term? What are the health outcomes, experiences and self-management activities over the life-course across different cancer types and who and what influence these? HORIZONS is a series of prospective cohort studies of adults treated for non-metastatic cancer to capture their health outcomes and experiences from before they begin active treatment and regularly over their life-course. Our initial cancer cohorts will be breast cancer (diagnosed under age 50), non-Hodgkin lymphoma, and gynaecological cancers (ovarian, cervical, uterine). We will start recruitment with three pilot sites in NHS Trusts before rolling out full recruitment to approximately 50 NHS secondary care Trusts. Questionnaires will be completed before treatment (baseline), and followed up at regular intervals. We will maintain and develop HORIZONS as a national and international resource to explore consequences of different cancer diagnoses and treatments from the individual perspective across the life-course

Inclusion Criteria:

To be included, patients must: • Have a new diagnosis of one of the selected cancer types or • Have new/second primary cancer at a site previously treated for cancer • Have no distant metastases • Be awaiting primary curative intent treatment (or soon after diagnosis for those not undergoing immediate treatment) • Be ≥16 years old • Be able to complete questionnaires in English (use of an interpreter may support reduced consent and allow collection of medical details) • Be able to provide written, informed consent Have the ability to complete questionnaires

Exclusion Criteria:

Disease is recurrence/progression (either locally advanced or metastatic) at an existing cancer site They are having treatment for a potentially curative recurrence of disease e.g. locally advanced disease (i.e. they have been previously treated for the same cancer) They have metastatic disease from a cancer at another site (Previous diagnosis of cancer at any other site would not be grounds for exclusion unless disease was metastatic)

Sub Specialty:

Psychosocial Oncology and Survivorship

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ICON8: A phase III randomised trial of dose-fractionated chemotherapy compared to standard three-weekly chemotherapy, for women with newly diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer and ICON8B: A phase III randomised trial investigating the combination of dose-fractionated chemotherapy and bevacizumab for the first-line treatment of women with newly diagnosed high-risk stage II wstage III-IV epithelial ovarian, fallopian tube or primary peritoneal cancer

Research Summary

ICON8 Standard first line chemotherapy for ovarian cancer is a combination of two drugs: carboplatin and paclitaxel, given once every 3 weeks for 18 weeks. However, giving these agents weekly may be more effective; this is called dose-fractionated chemotherapy. In the original ICON8 study, two dose-fractionated chemotherapy regimens were compared with standard carboplatin-paclitaxel. The ICON8 study completed recruitment in November 2014. The main outcome measures of ICON8 are whether dose-fractionated chemotherapy extends the time until ovarian cancer relapses and whether women who receive it live longer. Secondary outcome measures are comparative toxicity, impact on quality of life and cost-effectiveness. Two interim-analyses are planned: the first looking at feasibility and safety of the dose-fractionated regimens; and the second at their activity. ICON8B Recent studies have suggested that outcomes for women with advanced disease can be improved by adding a third drug called bevacizumab to three-weekly carboplatin-paclitaxel. Bevacizumab, and weekly dose dense paclitaxel have markedly different economic implications for healthcare providers, and place distinct burdens on patients with respect to treatment-related toxicity and duration of therapy. Hence there is an urgent need to compare these treatment approaches in a randomised trial. In ICON8B standard 3-weekly carboplatin-paclitaxel and bevacizumab will be compared to dose fractionated chemotherapy with or without bevacizumab in a randomised controlled trial. The main outcome measures are to determine whether dose-fractionated chemotherapy with bevacizumab extends the time until ovarian cancer relapses and whether women who receive it live longer. Secondary outcome measures are comparative toxicity, impact on quality of life and cost-effectiveness. One interim analysis is planned to establish the safety of neo-adjuvant bevacizumab in delayed primary surgery patients.

Inclusion Criteria:

ICON8 1. Females aged 18 years and above 2. Signed informed consent and ability to comply with the protocol 3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis): • Epithelial ovarian carcinoma • Primary peritoneal carcinoma of Müllerian histological type • Fallopian tube carcinoma • Ovarian carcinocarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary) 4. FIGO stage IC or above, which may be based on clinical and radiological assessment in patients who have not undergone immediate primary surgery 5. Confirmed high-risk histological subtype for patients with FIGO stage IC/IIA disease, namely • High grade serous carcinoma • Clear cell carcinoma • Other histological subtype considered poorly differentiated/grade 3 6. ECOG Performance Status (PS) 02 7. Life expectancy > 12 weeks 8. Adequate bone marrow function • Absolute Neutrophil Count > 1.5 x 10^9/l • Platelets (Plt) > 100 x 10^9/l • Haemoglobin (Hb) > 9g/dl (can be post transfusion) 9. Adequate liver function (within 28 days prior to randomisation) • Serum bilirubin ≤ 1.5 x ULN • Serum transaminases ≤ 3 x ULN in the absence of parenchymal liver metastases or ≤ 5 x ULN in the presence of parenchymal liver metastases 10. Adequate renal function as defined by GFR (Glomerular Filtration Rate) ≥ 30ml/min 11. Able to start chemotherapy within 8 weeks of after immediate primary surgery (where applicable) ICON8B 1.Females aged 18 years 2.Signed informed consent and ability to comply with the protocol 3.Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis): •Epithelial ovarian carcinoma •Primary peritoneal carcinoma of Müllerian histological type •Fallopian tube carcinoma •Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary). 4.High-risk disease defined as •FIGO (2013) Stage IIIA1(ii), IIIA2 with positive retroperitoneal lymph nodes > 10mm in diameter, IIIB or IIIC disease i.With > 1cm residual disease following IPS or ii.Planned to undergo primary chemotherapy with or without DPS •FIGO Stage IV disease i.With any volume of residual disease following IPS or ii.Planned to undergo primary chemotherapy with or without DPS. NB. The FIGO 2013 staging system should be used for women entering ICON8B. Stage may be based on clinical and radiological assessment in patients who have not undergone IPS. 5.ECOG Performance Status (PS) 0-2 6.Life expectancy > 12 weeks 7.Adequate bone marrow function: •Absolute Neutrophil Count (ANC) 1.5 x 109/l •Platelets (Plt) 100 x 109/l •Haemoglobin (Hb) 9g/dl (can be post transfusion). 8.Adequate liver function: •Serum bilirubin (BR) 1.5 x ULN •Serum transaminases 3 x ULN in the absence of parenchymal liver metastases or ≤5 x ULN in the presence of parenchymal liver metastases. 9.Adequate renal function as defined by: •Directly measured GFR (Glomerular Filtration Rate) ≥ 30 ml/min, or •Calculated creatinine clearance ≥ 60 ml/min. NB. If the calculated creatinine clearance is < 60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation. 10.Adequate coagulation profile: •International normalised ratio (INR) ≤1.5 •Activated prothrombin time (APTT) ≤1.5xULN. 11. Able to start chemotherapy within 8 weeks after IPS (where applicable).

Exclusion Criteria:

ICON8 1. Non-epithelial ovarian cancer 2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology 3. Borderline tumours (tumours of low malignant potential) 4. Prior systemic anticancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy) 5. Previous malignancies within 5 years prior to randomisation apart from: adequately treated carcinoma insitu of the cervix, breast ductal carcinoma insitu, nonmelanomatous skin cancer; or previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion 6. Preexisting sensory or motor neuropathy grade ≥2 7. Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at highrisk of treatment-related complications or prevent compliance with the trial protocol 8. Planned intraperitoneal cytotoxic chemotherapy 9. Planned maintenance treatment with systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression. 10. Any previous radiotherapy to the abdomen or pelvis 11. Sexually active women of childbearing potential not willing to use adequate contraception (eg. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards 12. Pregnant or lactating women 13. Treatment with any other investigational agent prior to protocol defined progression 14. Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor) 15. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible ICON8B 1.Non-epithelial ovarian cancer 2.Peritoneal cancer that is not of Müllerian origin, including mucinous histology 3.Borderline tumours (i.e. tumours of low malignant potential) 4.Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy) 5.Previous malignancies within 5 years prior to randomisation apart from: a.adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or b.previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion. 6.Pre-existing sensory or motor neuropathy CTCAE grade ≥2 7.Proteinuria at baseline: •> 1gm protein/24h by a 24-hour urine collection. NB. Proteinuria should be initially assessed by urine dipstick. If urine protein is ≥2+ on urine dipstick, a 24-hour urine protein collection must be performed. 8.Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including: a.Cerebrovascular disease, including transient ischaemic attacks (TIAs), cerebrovascular accident (CVA; i.e. stroke) and intracranial bleeds (i.e. intra-cerebral haemorrhage, sub-arachnoid haemorrhage or sub-dural haemorrhage) within 6 months before trial entry b.Cardiovascular disease as follows: i.Uncontrolled hypertension, defined as sustained BP> 150/100mmHg while receiving anti-hypertensive medication NB. Patients with a BP> 150/100 mmHg prior to randomisation should be commenced on a calcium-channel blocker or other anti-hypertensive agent; or in the case of patients already on anti-hypertensives, medical therapy should be optimised. The BP should then be re-checked a few days later, if BP is controlled to ≤150/100mmHg the patient may be entered into the trial ii.Myocardial infarction or unstable angina within 6 months prior to randomization iii.New York Heart Association (NYHA) grade ≥2 congestive heart failure iv.Poorly controlled cardiac arrhythmia despite medication NB. Patients with rate-controlled atrial fibrillation are eligible v.Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision c.History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication) d.Recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis) e.Previous gastrointestinal perforation. 9.Chronic daily use of high-dose aspirin, > 325mg/day, within 10 days prior to study entry 10.Surgery (including open biopsy) or significant traumatic injury within 28 days prior to anticipated date of first dose of bevacizumab NB. If IPS was performed within 28 days of planned start of treatment, patients are eligible but bevacizumab must be omitted from cycle 1. 11.Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1 12.Active ulcer or bone fracture 13.Anticipated to require extensive dental work during protocol treatment 14.Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at high-risk of treatment-related complications or prevent compliance with the trial protocol 15.Clinical symptoms or radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive recto-sigmoid involvement on imaging related to ovarian cancer 16.Evidence of intra-abdominal free air not explained by paracentesis or recent surgical procedure 17.Symptomatic abdominal fistulae 18.History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible 19.Sexually active women of childbearing potential not willing to use adequate contraception (e.g. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards 20.Pregnant or lactating women who are currently breastfeeding 21.Known hypersensitivity to carboplatin, paclitaxel, bevacizumab or their excipients (including cremophor) 22.Planned intraperitoneal cytotoxic chemotherapy 23.Planned treatment with any other systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression 24.Any previous radiotherapy to the abdomen or pelvis 25.Treatment with any other investigational agent prior to protocol defined progression.

Sub Specialty:

Gynaecological Cancers

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Head & Neck 5000 Follow-up Study

Research Summary

Head & Neck 5000 is a large observational study of people with head and neck cancer from across the United Kingdom. The overall aim of the Head & Neck 5000 Follow-up Study is to describe the social, lifestyle and clinical outcomes in people with head and neck cancer and relate these to information gained from the original Head & Neck 5000 study. In order to achieve this, participants who have taken part in Head & Neck 5000 for at least three years will be sent an invitation to complete the Follow-up Study questionnaire. Data will be collected from the medical notes and through linkage to national databases for all participants who consented to this.

Inclusion Criteria:

1. Participants recruited to the original Head & Neck 5000 cohort 2. Participants who have been in the Head & Neck 5000 study for a minimum of 3 years

Exclusion Criteria:

1. Participants who did not consent to be approached regarding further research 2. Participants withdrawn from the H&N5000 study 3. Participants who are now considered to meet the criteria for mental incapacity or vulnerability set out in the Mental Capacity Act 2005

Sub Specialty:

Head and Neck Cancer Head and Neck Surgery

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Investigation of the molecular and genetic mechanisms promoting oral cancer development and progression

Research Summary

Oral cancer (OSCC) is the 8th most common cancer worldwide, representing about 4% of all malignancies. In the UK, the incidence has increased dramatically over the last 20 years, particularly in young non-smokers, with around 5,000 new cases each year. Compared with many cancers, OSCC remains a relatively understudied disease. And despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained unchanged for decades, with a 5-year survival rate of around 50%. Oral cancer may be preceded by a premalignant, histologically dysplastic lesion, usually presenting clinically as a white or red patch in the mouth. However, only around 10-15% of patients diagnosed with oral dysplasia will develop oral cancer.

Inclusion Criteria:

- Clinical suspicion of premalignant oral/oropharyngeal/laryngeal lesion and/or condition. - Clinical and histopathologic diagnosis of oral/oropharyngeal/laryngeal cancer.

Exclusion Criteria:

N/A

Sub Specialty:

Head and Neck Cancer Head and Neck/Oncology Oral and Maxillofacial Surgery

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Targeted therapy with or without dose intensified radiotherapy for oligo-progressive disease in oncogene-addicted lung tumours

Research Summary

Treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR (epidermal growth factor) mutations or ALK (anaplastic lymphoma kinase) rearrangements has developed significantly with tyrosine kinase inhibitor (TKI) therapies. Higher response rates and progression free survival (PFS) are seen compared to comparator chemotherapy; however disease progression will ultimately occur in all patients due to acquired resistance to TKI. A proportion of patients progress initially at a limited number of sites (< = 3), termed oligo progressive disease (OPD). Optimal management of these patients is uncertain and further systemic options are limited in the UK. Stereotactic body radiotherapy (SBRT) delivers high dose radiation to small, well-defined tumour targets whilst limiting doses received to surrounding tissue. The benefit of SBRT treatment prior to change in systemic treatment is an important question to be addressed. HALT aims to assess whether SBRT treatment to OPD sites increases time patients benefit from TKI therapy until further disease progression. HALT is a phase II, randomised multi-centre study with integrated seamless continuation to phase III trial following acceptable safety and feasibility assessment. HALT aims to recruit 110 patients with mutation positive advanced NSCLC with OPD following initial response to TKI. Patients will continue on background TKI and will be randomisation (2:1) to receive SBRT or not. Patients will be seen 8 weeks post randomisation, then 3 monthly in line with routine care. Tumour imaging and toxicity assessment will be 3 monthly until disease progression. Quality of Life will be assessed at baseline, 8 weeks and at the first 3 month visit. Research bloods will be collected a baseline, after the first SBRT fraction (treatment group), 8 weeks and 3 monthly until change in systemic therapy. PFS defined as time from randomisation to ‘poly’-progression (> 3 progressing lesions) or death will be the primary endpoint.

Inclusion Criteria:

1. Male or female, > = 16 years of age 2. Established histological diagnosis of advanced NSCLC, not suitable for radical treatment, with defined actionable mutation receiving targeted TKI therapy 3. Clinical and/or radiologically confirmed response to TKI therapy (assessed locally usually 2-3 months post commencing TKI) 4. Confirmed OPD defined as < = 3 extracranial sites of progressive disease. All sites must be visible, imaging defined targets and suitable for treatment with SBRT. 5. Adequate baseline organ function to allow SBRT to all relevant targets 6. Predicted life expectancy > = 6 months 7. Karnofsky Index > = 60% or ECOG 0-2 8. Provision of written informed consent

Exclusion Criteria:

1. > 3 extracranial sites of progressive disease 2. Progressing or newly diagnosed brain metastases not amenable to radical surgery or SRS. Treated brain metastases which have remained clinically and radiologically stable for ≥ 6 months are permissible. 3. Prior radiotherapy near the oligoprogressive lesion precluding ablative SBRT 4. Co-morbidities considered clinically to preclude safe use of SBRT e.g. IPF in patients with an oligoprogressive lung lesion, inflammatory bowel disease in patients with an oligoprogressive pelvic lymph node 5. Any psychological, sociological or geographical issue potentially hampering compliance with the study 6. Pregnancy

Sub Specialty:

Lung Cancer

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Therapeutic HPV vaccine trial +/- anti-CD40 in HPV-driven squamous cell carcinoma.

Research Summary

Human papillomaviruses (HPV) causes about 5% of cancer worldwide. High-risk subtypes cause cervical, anogenital and head and neck cancer. Conventional treatments for these cancers include surgery, radiotherapy and chemotherapy: each of these has significant side effects, and new treatment modalities are clearly required. Immunotherapy offers the option of long term disease control by activating the patient’s own immune system to destroy the cancer. This study aims to combine a vaccine (specific for HPV) and an antibody (to stimulate the patient’simmune system), to generate an immune response against HPV. HARE-40 is a phase I/II vaccine and immunostimulatory antibody dose escalation study with two different parts: Part1 comprises three arms in which we will test the HPV mRNA vaccine as monotherapy. Part 2 comprises three arms in which we will test the HPV mRNA vaccine in combination with anti-CD40 IS Ab. Initially, we will undertake a multi-centre phase I, open label study in patients with previous HPV16+ HNSCC without current clinical evidence of disease (Arm 1A) and in patients with HPV16+ advanced disease (Arm 1B). Once a safe and tolerable dose has been established the trial will be opened to patients in the neoadjvant setting following ethical and regulatory review and approval. We will further seek approval for part 2 of the trial which will be added to the protocol via substantial amendment. The HPV16 antigen‐specific immune response will be evaluated before and after treatment in circulating blood and, where possible, in tumour and skin biopsies.

Inclusion Criteria:

Arm 1A: • Previous HPV16+ head and neck squamous cell carcinoma. • At least 12 months after completion of treatment. • Within 5 years of treatment completion. • Currently no clinical evidence of disease. • ECOG performance status 0 or 1. • Able to provide written informed consent. Arm 1B: • HPV16+ head and neck, cervical, anogenital and penile carcinoma patients with recurrent disease. • Intention to treat is palliative. • Patient willing to have repeated tumour biopsies and re-biopsy deemed safe and feasible clinically. • Tissue samples available confirming HPV16+ disease to send to Central Laboratory.

Exclusion Criteria:

• Patients unable to consent. • Any patient who has been previously vaccinated in any Arm of the trial. • < 18 years • Systemic steroids (prednisolone > 10 mg/day or equivalent) or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. Replacement steroids for adrenal insufficiency/failure are allowed. • Major surgery in the preceding three to four weeks, which the patient has not yet recovered from. • Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection. • Patients with clinically relevant autoimmune disease will be excluded. • Patient with a history of anaphylactic reactions or severe allergies are excluded. • Patients with any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease. • Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study.Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing. • Patients who have a positive pregnancy test or who are breast feeding. • Fertile males or females who are unable or unwilling to use an effective method of birth control (eg. condom with spermicide, diaphragm with spermicide, birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until end of treatment +28 days (day 113). • Elevated Liver Function Tests – ALT > 3.0 x ULN, AST > 3.0 x ULN, Bilirubin > 3.0 x ULN. • Arm 1B patients with the presence of liver metastasis only: Elevated Liver Function Tests – ALT > 5.0 x ULN, AST > 5.0 x ULN, ALP > 5.0 x ULN. Patients who are likely to have rapid disease progression may not be good candidates for the trial. In such cases, please discuss with the Chief Investigator. • Any other investigational drug within 28 days or 5 half-lives depending on what gives the longer range before the first treatment of this study.

Sub Specialty:

General Surgery Gynaecological Cancers Head and Neck Cancer Head and Neck/Oncology Skin Cancer

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Development of an EORTC disease or domain specific quality of life questionnaire Phases I/II & III (Subtitle: Specific Module Name and Phase)

Research Summary

The protocol describe a generic three step process to develop and validate a tumour specific or domain specific quality of life questionnaire. Phase I involves a literature search and patient interviews to identify relevant issues. Phase II generates items/questions from the issues. Phase III involves pilot testing the items in a larger patient sample. As the study is conducted on behalf of the EORTC Quality of Life Group cross cultural acceptability is key and at all phases patients from at least 3 European countries are recruited. A final step is field study to validate the measure but that is not covered by this protocol. Amendments will be submitted detailing the specific tumour or domain to be tested as the process is independent of the topic of the questionnaire.

Inclusion Criteria:

All patients will be aged 18 or over. For disease questionnares patients will all have a confirmed diagnosis of the specific cancer (e.g. thyroid). For domain specific questionnaires (e.g. communication) all patients will have a confirmed diagnosis of cancer, but a range of sites will be sampled. For each questionnaire a grid will be prepared for stage of disease x treatment. Exact details of the eligibility criteria will be specified in the protocols which will be submitted as an amendment.

Exclusion Criteria:

Patients under 18 will be excluded. Patients unable to speak or read English will be excluded. (As this is an international study the questionnaires will be simultaneously developed in other languages in other countries.)

Sub Specialty:

Psychosocial Oncology and Survivorship

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Can genomics predict dysphagia after head and neck radiotherapy?

Research Summary

A retrospective case controlled cohort study using Genome Wide Association (GWAS) to compare genomic differences between head and neck cancer patients who do and do not suffer from severe swallowing and mouth opening difficulties after radiotherapy or chemoradiotherapy.

Inclusion Criteria:

Patients who have been treated for first head and neck cancer with radiotherapy or chemotherapy Patients who are between 1 and 6 years post treatment

Exclusion Criteria:

Those patients not deemed able to give informed consent Patients who have had thyroid cancer Patients who have had head and neck surgery

Sub Specialty:

Cardiothoracic Surgery Head and Neck Cancer

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FOCUS-4 – Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trial programme

Research Summary

FOCUS4 is an umbrella, or platform, for testing novel agents in biomarker-defined subpopulations of first-line advanced disease colorectal cancer patients who are not considered candidates for potentially curative surgery. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type. See Trial Schema in the Trial Protocol. • The backbone of the platform is 16 weeks of treatment with any standard first line colorectal cancer treatment, after which, as is frequently standard practice in the UK and Europe, there is a programmed treatment break for responding and stable patients. During that break, either new agent(s) or placebo is administered. The primary outcome measure for assessing the activity of the new treatment is progression free survival in the interval (time to death or progression requiring resumption of chemotherapy). • At present, four coherent biomarker-stratified groups can be identified and trials will be established in each of these cohorts as follows: - BRAF mutant - PIK3CA mutation or complete loss of PTEN on IHC - KRAS or NRAS mutant - All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS) - Unclassified biomarker results • For each of these subgroups, a relevant novel agent or combination is to be tested in an adaptive double blind randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity (the principles are derived from the Multi-Arm, Multi-Stage (MAMS) design). FOCUS4 will open with one molecularly stratified trial (FOCUS4-D) testing AZD8931 (a HER 1,2 3 inhibitor) against placebo in patients stratified into the All wild-type cohort. In addition, a non-stratified trial (FOCUS4-N) will be open for patients whose biomarker results are unclassified or who are unable or unwilling to participate in the molecular trial available to them.

Inclusion Criteria:

Registration Inclusion Criteria (please refer to the protocol for eligibility for randomisation) 1. Male/female patients at least 18 years old 2. Formalin fixed paraffin embedded (FFPE) tumour block taken prior to the commencement of standard chemotherapy and available for biomarker analysis 3. Histologically confirmed adenocarcinoma of the colon/rectum 4. Inoperable metastatic or locoregional disease (synchronous or metachronous) 5. WHO performance status 0, 1 or 2 6. Unidimensionally measurable disease RECIST 1.1 classification 7. Have had an electronically accessible CT scan performed within 4 weeks prior to start of standard chemotherapy 8. Platelet count < 400 x 109/L prior to start of standard chemotherapy 9. For women of childbearing potential, a negative pregnancy test and acceptable contraceptive precautions 10. Effective contraception for male patients if the risk of conception exists 11. Consent for screening of an archival FFPE tumour block for biomarker analysis (PIS1 & CF1) 13. Patients should have sufficient capacity for informed consent and provided signed informed consent

Exclusion Criteria:

Registration Exclusion (please refer to the protocol for eligibility for randomisation) 1. Previous systemic palliative chemotherapy using a different regimen for established advanced or metastatic disease 2. Adjuvant chemotherapy given in the last 6 months 3. Patients with brain metastases 4. Pregnant and lactating women

Sub Specialty:

Colorectal Cancer

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Case­-control study of individuals with increased risk of inherited women's cancer

Research Summary

Every day, 20 women are diagnosed with ovarian cancer in the UK. Of those, less than 7 will survive beyond 5 years. Similar figures exist for triple negative breast cancers, which in fact share similar expression and copy­-number variation profiles (The Cancer Genome Atlas Research Network, Nature, 2013). About 5-­10% of all breast and ovarian cancers, in particular those that are difficult to treat (high grade serous ovarian and triple-­negative breast cancers and serous endometrial cancer), arise in women with a germline mutation in the BRCA1/2 gene. Only about half of these women would be identified due to their family history. We aim to recruit a cohort of volunteers with confirmed BRCA/Lynch Syndrome mutation carrier status (with confirmed non-carriers as controls) in order to contribute substantially to the elucidation the process of cancer development in women with inherited risk of ovarian and breast cancer in order to identify minimally invasive biological markers that would aid the diagnosis of individuals at risk of breast, endometrial and ovarian cancer; and to identify molecular targets to prevent the development of inherited women's cancer.

Inclusion Criteria:

All women attending the Familial Cancer Clinic in gynaecological oncology at UCLH, UCL Partner Clinics, Barts and the London Hospital Clinics, as well as women at risk of cancer due to documented gene mutations, who we aim to recruit from the community. Included in the study would be BRCA1/2 carriers, women with confirmed Lynch Syndrome mutation (LH1, MSH2, MSH6 and/or PMS2), as well as women who have not undergone genetic testing but have a significant family history of ovarian or breast cancer. Control subjects would be women who have tested negative for the above mutations.

Exclusion Criteria:

Women who have undergone previous hysterectomy or who have undergone recent cancer treatment (within 2 years of recruitment) would not be suitable for the study.

Sub Specialty:

Breast Cancer Gynaecological Cancers

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(FAK-PD1) A Phase I/IIA study to assess safety, tolerability and preliminary activity of the combination of FAK (defactinib) and PD-1 (pembrolizumab) inhibition in patients with advanced solid malignancies

Research Summary

Assess the safety and tolerability of combination treatment with defactinib (VS-6063) and pembrolizumab - Determine the recommended doses of the two agents to be used in combination - Preliminary assessment of clinical anti-tumour activity as assessed by imaging - Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on the cell types making up the tumour, by evaluation of tissue samples for changes in immune cell infiltrate on treatment - Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on FAK signalling (defactinib is a FAK inhibitor), by evaluation of phosphorylated FAK

Inclusion Criteria:

All parts of study 1. Informed, written consent 2. Male or female, aged 18 years or older at the time consent is given 3. ECOG performance status 0 or 1, with no deterioration over the previous 2 weeks 4. Life expectancy of at least 3 months 5. Measurable disease according to irRECIST criteria, with at least one measurable lesion that has objectively progressed since (or on) any previous therapy 6. Adequate bone marrow, liver and renal function on blood investigations within 7 days prior to treatment initiation: a. Creatinine ≤ 1.5 x ULN OR GFR ≥ 60 mls/min for patients with creatinine levels > 1.5 x ULN. (using the standard methodology at the investigating centre - i.e Cockcroft-Gault, Wright, MDRD or CKD-EPI formulae, EDTA clearance or 24 urine collection) b. Total bilirubin ≤ 1.5 x ULN c. Alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x ULN (if both measured, both must meet criteria) d. White blood cell count ≥ 3.0 x 109/L e. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L f. Platelets ≥ 100 x 109/L g. Haemoglobin ≥ 90 g/L h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN, UNLESS patient is receiving anticoagulation therapy, in which case INR or PT must be within the intended therapeutic range. 7. Patients must have been offered all appropriate standard-of-care treatments (or all those indicated before anti-PD- 1/PD-L1 therapy, if licensed) 8. Patients must agree to use adequate contraceptive measures for the course of the study through 120 days after the last dose of study medication 9. Women of child-bearing potential must have a negative pregnancy test within 72 hours prior to start of dosing 10. Consent to supply any available archival tissue Dose escalation (Phase I) 11. Pathological diagnosis of any advanced solid tumour type, with confirmation that a tissue sample (core biopsy or resected specimen) is available Pancreatic expansion (Phase IIa) 12. Pathological diagnosis of pancreatic ductal adenocarcinoma, with confirmation that a tissue sample (core biopsy or resected specimen) is available NSCLC expansion (Phase IIa) 13. Pathological diagnosis of non-small cell lung cancer (NSCLC) 14. Lesion suitable for repeat biopsy 15. Baseline biopsy containing tumour material during eligibility 16. Consent for paired biopsies on study Mesothelioma expansion (Phase IIa) 17. Pathological diagnosis of mesothelioma 18. Lesion suitable for repeat biopsy 19. Baseline biopsy containing tumour material during eligibility 20. Consent for paired biopsies on study

Exclusion Criteria:

All parts of study 1. An additional invasive cancer in the last 5 years (other than treated and controlled localised non-melanoma skin cancer or cervical carcinoma-in-situ, or indolent prostate cancer that has been stable for > 1 year) 2. Any central nervous system metastases unless treated and asymptomatic, as well as stable on imaging and not requiring steroids in the preceding 4 weeks 3. Any interventional studies, systemic cancer therapies or monoclonal antibodies in the preceding 4 weeks (6 weeks for mitomycin C and nitrosureas) 4. Any live vaccines in the preceding 4 weeks 5. Systemic immunosuppressive agents in the preceding 2 weeks. Immunosuppressive agents include steroids NHS R&D Form IRAS Version 5.4.2 17 200488/1095978/14/206 such as prednisolone (doses ≥ 15 mg daily) or dexamethasone (doses ≥ 2 mg daily) Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment. 6. Diagnosis of immunodeficiency 7. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment 8. Known interstitial lung disease or active, non-infectious pneumonitis 9. Known history of Tuberculosis (TB), Human Immunodeficiency Virus (HIV) or active Hepatitis B or C 10. Other severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, recent myocardial infarction, organ failure or active infection) 11. Baseline (non-laboratory) toxicities greater than grade 1 (CTCAE v4.03) despite optimal supportive therapy, including fatigue, anorexia, nausea or diarrhoea, but with the exception of alopecia 12. Pregnancy or lactation 13. Limited ability to swallow or absorb oral medications 14. Hypersensitivity to defactinib (VS-6063), pembrolizumab or excipients (including L-histidine, L-histidine hydrochloride monohydrate, sucrose or polysorbate 80) 15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

Sub Specialty:

Bladder Cancer

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Randomised comparison of two remotely delivered diet and physical activity weight loss programmes vs written diet and physical activity advice amongst overweight women attending a Family History Clinic at increased risk of breast cancer: A phase 3 efficacy study

Research Summary

Being a healthy weight, taking regular physical activity and limiting alcohol intake can reduce risk of breast cancer by about 30 – 40% amongst women in the general population and amongst women at increased risk who attend family history clinics. We and others have shown that many high risk women who come for regular mammograms in family history clinics who are overweight and have unhealthy lifestyles will be increasing their risk of BC, other cancers, heart disease, stroke, diabetes and dementia. Unfortunately weight and lifestyle risk factors are not currently addressed in these clinics. Women receive general written advice which has a minimal effect on behaviour. This project aims to find the most effective type of programme to help women to lose weight to reduce their risk of breast cancer and other diseases. 209 overweight/ obese women in 3 UK NHS family history clinics will be randomly assigned to one of 2 different 12 month weight loss / lifestyle programmes or a group receiving written advice : 1. A written advice group (n= 35): Women receive their personal breast cancer risk and are given written diet and physical advice for weight loss. 2.A breast cancer prevention programme (n= 87): Women receive their personal breast cancer and a 6 month health care professional supported telephone, web based and e-mail programme followed by 6 months of web support. 3.A multiple disease prevention programme(n= 87): Women receive their personal risks of breast cancer , heart disease stroke , from an NHS health check followed by a 6 month health care professional supported telephone, web based and e-mail programme followed by 6 months of web support. All participants have their weight and diet and physical activity behaviours assessed at baseline, six and twelve months.

Inclusion Criteria:

1. Receiving annual or 18 monthly mammograms in the FHC (aged > 30 years) 2. Have previously received information on their risk of developing breast cancer within the FHC 2. Overweight / obese (BMI > = 25 kg/m2). 3. Access to the internet and telephone 4. Ability to understand English and complete trial paperwork as successful participation requires engagement with weekly tailored e mails and an interactive patient forum. 5. Participants must be willing to follow a diet and physical activity plan with the aim of losing weight 6. Agree that results of any NHS health checks conducted in the study can be communicated back to their GP. This is a requirement of NHS health checks to allow patients with undiagnosed CVD or T2DM or high risks of these diseases to receive appropriate follow up tests and medical management. 7. Assessed as safe to undertake a home based moderate intensity physical activity programme according to the physical activity readiness questionnaire (PAR-Q) +/- clearance from GP where appropriate. 8. Women taking chemoprevention for breast cancer i.e. tamoxifen, raloxifine or aromatase inhibitors are eligible to join the trial.

Exclusion Criteria:

1.Only one woman per family is able to join the study to avoid contamination between the groups. 2.Previous diagnosis of cancer with the exception of previous non-melanoma skin cancer or cervical intra-epithelial neoplasia. 3.Previous diagnosis of cardiovascular disease i.e. stroke, transient ischaemic attack (TIA), angina, heart attack, heart failure or ventricular or aortic aneurysm 4.Currently prescribed statins for raised cholesterol. 5.Current diagnosis of T2DM. 6.Current physical co-morbidity or hypertension which makes the patients unsuitable for a home based moderate physical activity programme as assessed with a positive PAR-Q score and opinion of the patients general practitioner for example; unstable angina, resting systolic BP > 160 resting diastolic BP > 100 mmHg with or without medication, a significant drop in blood pressure during physical activity, uncontrolled tachycardia> 100 bpm at rest, uncontrolled arrhythmia. 7.Previous diagnosis of borderline personality disorder, bipolar psychotic disorder, or self-harm. 8.Currently prescribed antipsychotics i.e. Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone as these can cause excessive weight gain 9.Current alcohol or drug dependency. 10.People requiring highly specialist medical diets which cannot be adjusted to fit with a weight loss diet i.e. phenylketonuria, maple syrup urine disease, glycogen storage diseases, and urea cycle disorders advanced kidney disease, advanced liver disease. 11.Currently pregnant, breast feeding or planning pregnancy in the next 12 months. 12.Patients who are currently on treatment with Orlistat for weight loss or who have previously had bariatric surgery for weight loss including gastric bypass and sleeve gastrectomy. 13.Current diagnosis of kidney disease. 14.Patients with a diagnosis of an eating disorder (e.g. binge eating or bulimia) 15.Currently successfully following a diet and/or physical activity plan and have lost more than 2 lb (1 kg) of weight in the last 2 weeks 16.Currently or previously on the PROCAS (Predicting Risk of Breast Cancer at Screening) Study

Sub Specialty:

Breast Cancer Public Health

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FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab

Research Summary

This is a phase III, multicentre, randomised, controlled, open, parallel group trial in patients with previously untreated CLL.

Inclusion Criteria:

At least 18 years old. • Maximum age of 75 years old. • B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma • Binet’s Stages C, B or Progressive Stage A • Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. 4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30x10^9/L 5. A minimum of any one of the following disease-related symptoms must be present: (a) Unintentional weight loss more than or equal to 10% within the previous 6 months. (b) Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities). (c) Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection. (d) Night sweats for more than 1 month without evidence of infection. • Considered fit for treatment with FCR as determined by the treating clinician. • World Health Organisation (WHO) performance status (PS) of 0, 1 or 2 • Able to provide written informed consent • Biochemical values must be within the following limits within 14 days prior to randomization and at baseline: - Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤3 x ULN. - Total bilirubin ≤1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non hepatic origin

Exclusion Criteria:

• Prior therapy for CLL • History or current evidence of Richter’s transformation • Major surgery within 4 weeks prior to randomisation • Active infection. • > 20% P53 deletion, determined by FISH • Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies. • Concomitant warfarin or equivalent vitamin K inhibitor or other oral anticoagulant. • Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction. • Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile. • CNS involvement with CLL. • Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) • Respiratory impairment (bronchiectasis or moderate COPD) • Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study. • Inability to swallow oral medication • Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc) • Known HIV positive • Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded. • Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result. • History of prior malignancy, with the exception of the following: - Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician - Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. - Adequately treated cervical carcinoma in situ without current evidence of disease. • Persisting severe pancytopenia (neutrophils < 0.5 x 10^9/l or platelets < 50 x 10^9/l) unless due to direct marrow infiltration by CLL • Current treatment with prednisolone of > 10mg/day. • Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10mg or less per day can be entered into the trial) Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula). • History of stroke or intracranial hemorrhage within 6 months prior to enrollment. • Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer •Cardiac event (e.g. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment.

Sub Specialty:

Haematological Oncology

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Extended follow up of the TARGIT-A trial

Research Summary

All UK patients who participated in the TARGIT-A Trial were initially treated for early breast cancer between 2000-2012. A total of 3451 patients from 33 hospitals in 11 countries participated in the trial and a comparison was made between traditional radiotherapy given over several weeks (external beam radiotherapy, EBRT) with TARGeted Intraoperative radioTherapy (TARGIT-IORT) as a single dose given during the operation to remove the breast cancer. The trial was funded by the Health Technology Assessment (HTA) programme of the Department of Health, UK and sponsored by University College London. The results from this trial have been published in major medical journals and have already started changing the way breast cancer in treated around the world; please see www.targit.org.uk for more details. We would like to continue to collect data about the health status of all patients to enable us to learn about longer term differences in the effects of these treatments on health. An analysis of this information could improve treatment for patients with breast cancer. For this, HTA have granted us further funding.

Inclusion Criteria:

All patients who participated in the TARGIT-A trial.

Exclusion Criteria:

1. Any patient who has withdrawn consent for further follow-up, or died. 2. Any patient who is unable to give formal written consent.

Sub Specialty:

Breast Cancer

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Evaluation of a Non-Endoscopic Immunocytological Device (Cytosponge) for Barrett's Esophagus Screening in a Case-Control Study (BEST2)

Research Summary

A case: control study design in which the cases will be patients with known Barrett’s Oesophagus (BE) and controls individuals with reflux or indigestion (dyspepsia) symptoms referred for endoscopy. Four centres with expertise in Barrett’s oesophagus will recruit patients. All participants will swallow the Cytosponge device prior to having an endoscopy. The Cytosponge will be processed for a number of different biomarkers. The results will be compared with the endoscopy findings.

Inclusion Criteria:

Any patient clinically fit for an endoscopy with Barrett’s oesophagus (for the cases) and (or) with upper GI symptoms of reflux or dyspepsia as