List of studies


Study Results

  • A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Relatlimab and Nivolumab Fixed-dose Combination versus Nivolumab Monotherapy after Complete Resection of Stage III-IV Melanoma

    • Research Summary

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    • Inclusion Criteria:

      1) Signed Written Informed Consent a) Participants must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol -related procedures that are not part of normal patient care. b) Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study. c) Participant Re-enrollment: This study permits the re-enrollment of a participant that has discontinued the study as a pre-treatment failure (ie, participant has not been randomized/has not been treated). If re-enrolled, the participant must be re-consented. 2) Type of Participant and Target Disease Characteristics a) All participants must have been diagnosed with either Stage IIIA (> 1 mm tumor in lymph node)/B/C/D or Stage IV melanoma by AJCC v8 and have histologically confirmed melanoma that is completely surgically resected (free of disease) with negative margins in order to be eligible. All melanomas, except uveal melanoma, regardless of primary site of disease, will be allowed. b) Participants are eligible if central nervous system (CNS) metastases have been resected and participants are neurologically stable. i) Prior resected CNS metastases must be without evidence of recurrence, as determined by magnetic resonance imaging (MRI) performed at least 4 weeks after resection is complete and within 35 days prior to randomization. ii) Participants must be off immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 14 days prior to study drug administration and must have returned to neurologic baseline post-operatively. iii) For CNS lesion(s), a pathology report indicating that there has been complete resection of CNS lesion(s) will suffice as confirmation of negative margins. c) Complete resection must be performed within 12 weeks prior to randomization. Management of residual lymph nodes after positive sentinel lymph node biopsy (SLNB) (ie, completion lymph node dissection) will be as per local standards and recommendations for the individual participant. d) All participants must have disease-free status documented by a complete physical examination within 14 days prior to randomization and imaging studies within 35 days prior to randomization. Imaging studies must include CT scan of the chest, CT or MRI scans of the abdomen, pelvis, and all known sites of resected disease, and brain MRI or CT (brain CT allowable if MRI is contraindicated or if there is no history of resected CNS lesions). e) A FFPE tissue block (strongly preferred) containing 20 mm3 of tumor tissue or 20 positively charged unstained slides (minimum of 15) of tumor tissue obtained from surgical specimen or biopsy during resection (core biopsy, punch biopsy, or excisional biopsy) collected within 3 months prior to randomization, with no intervening systemic anti-cancer treatment between time of acquisition and enrollment, with an associated pathology report, must be submitted to the central laboratory prior to randomization. Fine needle aspirates or other cytology samples are not acceptable. Biopsies of bone lesions that do not have a soft tissue component are not acceptable. If insufficient tumor tissue content is provided for analysis, acquisition of additional tumor tissue (block and/or slides) for the biomarker analysis will be requested. Please refer to Section 9.8 for additional details on tumor tissue requirements. f) Participants must have an ECOG performance status of ≤ 1 (Appendix 6). 3) Age of Participant Participant must be ≥ 18 years of age inclusive at the time of signing the informed consent. 4) Reproductive Status Investigators shall counsel women of child bearing potential (WOCBP) on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention to a developing fetus. The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. Local laws and regulations may require the use of alternative and/or additional contraception methods. a) Female Participants: i) Female participants must have documented proof that they are not of childbearing potential. ii) Women who are not of childbearing potential are exempt from contraceptive requirements. iii) WOCBP must have a negative highly sensitive negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study intervention. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window. (1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. iv) Additional requirements for pregnancy testing during and after study intervention are located in Section 2, Schedule of Activities. v) The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. vi) WOCBP must agree to follow instructions for method(s) of contraception defined in Appendix 4 and as described below and included in the ICF. vii) WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4). viii) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: (1) Is not a WOCBP OR (2) Is a WOCBP and using a contraceptive method that is highly effective as described in Appendix 4 during screening and for the duration of treatment for a total of 5 months after the last dose and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. b) Male Participants: i) No additional contraceptive measures are required to be used.

    • Exclusion Criteria:

      1) Medical Conditions a) History of uveal melanoma. b) Untreated/unresected CNS metastases or leptomeningeal metastases. c) Participants with an active, known or suspected autoimmune disease. Participants 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. d) Participants with serious or uncontrolled medical disorder. e) Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have resolved and based on investigator assessment, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. f) Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (i.e. participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization and the patient has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible. g) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. h) Woman who are breastfeeding. 2) Prior/Concomitant Therapy a) Prior immunotherapy treatment for any prior malignancy: No prior immunotherapies are permitted (such as, but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways). b) Prior treatment with LAG-3 targeted agents. c) Participants treated with anti-cancer therapy directed against the resected melanoma (for example, but not limited to, systemic, local, radiation, and radiopharmaceuticals) except: i) Surgery for the melanoma lesion(s) ii) Adjuvant radiation therapy after neurosurgical resection for CNS lesions iii) Prior adjuvant interferon completed ≥ 6 weeks prior to randomization d) Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks prior to randomization. Such medications are permitted if they are used as supportive care. Refer to Section 7.7.1 for prohibited therapies. e) Treatment with any live/attenuated vaccine within 30 days of first study treatment (inactivated vaccines are permitted). f) Participants currently in other interventional trials, including those for COVID-19, until the protocol specific washout period is achieved. If a study participant has received an investigational COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 prior to screening, enrollment must be delayed until the full dosing schedule of the vaccine has been completed and the biologic impact of the vaccine or investigational product is stabilized, unless the delay would compromise the patient’s health or suitability for enrollment as determined by discussion between the investigator and the Medical Monitor/designee. 3) Physical and Laboratory Test Findings a) Positive pregnancy test at enrollment or prior to administration of study medication. Note: May not use transfuse, use growth factors, and/or coagulation factors within 14 days of randomization to meet criteria 3b to 3e. b) White blood cell count < 2000/μL c) Neutrophils < 1500/μL d) Platelets < 100*103/μL e) Hemoglobin < 9.0 g/dL f) Serum creatinine > 1.5 × upper limit of normal (ULN), unless calculated creatinine clearance (CrCl) ≥ 40 mL/min (using the Cockcroft-Gault formula) g) Aspartate transaminase (AST) / alanine aminotransferase (ALT) > 3.0× ULN h) Total bilirubin > 1.5 × ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0x ULN) i) Any positive test result for hepatitis B virus (HBV) indicating presence of virus (eg, Hepatitis B surface antigen [HBsAg, Australia antigen]) positive. j) Any positive test result for hepatitis C virus (HCV) indicating presence of active viral replication (detectable HCV-ribonucleic acid [RNA]). Note: Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enroll. k) Known human immunodeficiency virus (HIV) positive with an AIDS defining opportunistic infection within the last year, or a current CD4 count < 350 cells/uL. Participants with HIV are eligible if: i) they have received antiretroviral therapy (ART) for at least 4 weeks prior to randomizations as clinically indicated while enrolled on study ii) they continue on ART as clinically indicated while enrolled on study iii) CD4 counts and viral load are monitored per standard of care by a local health care provider. NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive participants must be excluded where mandated locally.(see Appendix 9). l) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital sign, electrocardiograms, or clinical laboratory determinations beyond what is consistent with the target population. 4) Allergies and Adverse Drug Reaction a) Participants with history of allergy or hypersensitivity to study treatment components. b) History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hypothyroidism). 5) Other Exclusion Criteria a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply, and BMS approval is required.) b) Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infection illness).

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  • A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate the Efficacy, Safety,and Tolerability, and Effects on Tumour Biomarkers of the NOX1/4 Inhibitor Setanaxib, when Administered with the PD-1 Inhibitor Pembrolizumab, in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck(SCCHN)

    • Research Summary

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    • Inclusion Criteria:

      1. Male or female patients aged ≥ 18 years, inclusive, at the time of informed consent. 2. Willing and able to give informed consent and to comply with the requirements of the study. 3. Histologically-or cytologically-confirmed diagnosis of SCCHN(ie, primary tumour arising from the oral cavity [including tongue], nasal cavity, paranasal sinuses, oropharynx, hypopharynx, or larynx) that is recurrent or metastatic(including both HPV+ve and HPV-ve SCCHN), with or without nodal involvement, and with or without metastatic spread. 4. Candidates for first-line treatment for pembrolizumab for recurrent or metastatic SCCHN, at the discretion of the investigator. 5. A positive CAFs level (defined as CAFs level in tumours ≥ 5%), performed at a central laboratory, with fresh tumour biopsy taken during the Screening Period. Suitable archival tissue, if available, can be used to assess tumour CAFs level and determine patient eligibility. 6. Measurable disease, in accordance with RECIST v1.1, and with tumour accessible and of sufficient volume for pre-treatment and on-treatment biopsy. 7. Combined positive score (CPS) ≥ 1, as determined on the archival or fresh tumour biopsy taken at Screening. 8. HPV status known at Randomisation. 9. Life expectancy of at least 6 months in the judgment of the investigator. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 11. Adequate organ and bone marrow function within 28 days of starting study treatment. Criteria “a” to “c” cannot be met in patients with ongoing or recent (within 14 days of screening test) transfusions or who require ongoing growth factor support: a. Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 × 109/L). b. Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L). c. Haemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks. Patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9g/dL are not eligible. d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤ 3 × ULN). e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN. f. Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min (measured or calculated according to the method of Cockcroft and Gault). 12. Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥ 4 weeks before randomisation and must agree to continue strict contraception up to 120days after the last dose of IMP or pembrolizumab, whichever is the later. a. For the purposes of this study, women of childbearing potential are defined as “All female patients after menarche unless they are postmenopausal for at least 2 years or are surgically sterile.” b. For female patients ≤ 55 years of age who are considered postmenopausal and who are not on concomitant oestrogen replacement therapy, confirmation of postmenopausal status will be required with follicle-stimulating hormone (FSH) test results in the postmenopausal range for age at Screening. c. Highly effective contraception is defined as use of 2 barrier methods (eg, female diaphragm and male condoms) or use of at least 1 barrier method in combination with spermicide, an intrauterine device or hormonal contraceptives (eg, implant or oral). 13. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomisation before dosing. 14. Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the investigator, such as an established form of hormonal contraceptive, a diaphragm or cervical/vault cap, or intrauterine device. This requirement begins at the time of informed consent and ends 120 days after receiving the last dose of IMP or pembrolizumab, whichever is the later. 15. Male patients must be willing to not donate sperm, and female patients must be willing to not donate eggs, from Baseline until 120days after the last dose of IMP or pembrolizumab, whichever is the later.

    • Exclusion Criteria:

      1. Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at doses not to exceed 10 mg/day of prednisone or equivalent. Steroids as premedication for hypersensitivity reactions due to radiographic contrast agents are allowed. 2. Anti-cancer monoclonal antibody treatment within 4 weeks prior to study Day 1. 3. Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 (radiation therapy can be allowed for palliative therapy of bone metastasis only). 4. Not recovered from AEs Grade 2 or greater (except for alopecia) due to previously administered agents. 5. Treatment with any investigational agent within 12 weeks of Screening Visit or 5 half-lives of the IMP (if known), whichever is longer, or current enrolment in an interventional clinical study. 6. Prior treatment with setanaxib or participation in a previous setanaxib clinical study. 7. Prior treatment with pembrolizumab. 8. Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, or malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of IMP and of low potential risk for recurrence. 9. Known active central nervous system metastases and/or carcinomatous meningitis. 10. Active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents. The following are exceptions to this criterion: a. Patients with vitiligo or alopecia. b. Any chronic skin condition that does not require systemic therapy. c. Patients with coeliac disease controlled by diet alone. 11. Any evidence of current interstitial lung disease or pneumonitis, or a prior history of interstitial lung disease or non-infectious pneumonitis requiring high-dose glucocorticoids. 12. Active infection requiring systemic therapy. 13. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Patients with a past or resolved hepatitis B virus infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]) are eligible provided the hepatitis virus DNA test is negative. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction (PCR) is negative for hepatitis C virus RNA. Patients with ongoing anti-viral therapy with potent inhibitors of cytochrome P450 (CYP) 3A4 are not eligible. Testing for HIV is only required if clinically indicated and is not mandatory for this study. 14. Serious chronic gastrointestinal conditions associated with diarrhoea. 15. History of significant haematological problems, such as blood dyscrasias requiring treatment, aplastic anaemia, myelodysplastic syndrome, or leukaemia. 16. Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the investigator). 17. A positive pregnancy test or breastfeeding for female patients. 18. Evidence of any of the following cardiac conduction abnormalities: a QTc Fredericia interval > 450milliseconds for male patients or > 470milliseconds for female patients. Patients with a second- or third-degree atrioventricular block are to be excluded. 19. TSH > ULN at Screening. 20. Unstable cardiovascular disease as defined by any of the following: a. Unstable angina within 6months prior to Screening. b. Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6months prior to Screening. c. Cerebrovascular accident within 6months prior to Screening. d. New York Heart Association Class III or IV heart failure. 21. Presence of any laboratory abnormality or condition that, in the opinion of the investigator, could interfere with or compromise a patient’s treatment, assessment, or compliance with the protocol and/or study procedures. 22. Any other condition that, in the opinion of the investigator, constitutes a risk or contraindication for the participation of the patient in the study, or that could interfere with the study objectives, conduct, or evaluation. 23. Use of medications known to be potent CYP3A4 inhibitors or inducers, or uridine diphosphate (UDP)-glucuronosyltransferase (UGT) inhibitors or inducers, within 21 days prior to IMP administration. 24. Legal incapacity or limited legal capacity. 25. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. 26. Patients who are unable to provide informed consent, are incarcerated or unable to follow protocol requirements. 27. Previous randomisation in this study.

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  • A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib + Docetaxel Versus Placebo + Docetaxel as Treatment for Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)

    • Research Summary

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    • Inclusion Criteria:

      1. Patient must be ≥ 18 years of age (≥ 20 years of age in Japan), at the time of signing the informed consent. 2. Histologically-confirmed prostate adenocarcinoma. Note: adenocarcinoma must be the predominant histological pattern in previous biopsies and patients with neuroendocrine or small cell cancers in any previous prostate biopsies are not eligible. 3. Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable). Note: Local lymph node involvement is not considered metastatic disease. 4. Patient must have been previously treated with a next generation hormonal agent (NHA), ie, abiraterone, enzalutamide, apalutamide or darolutamide, for prostate cancer for at least 3 months and shown evidence of disease progression (radiological or via PSA assessment) while receiving the NHA. 5. Evidence of mCRPC with progression of disease despite androgen deprivation therapy (ADT) and after anti-androgen withdrawal, if applicable, as documented by one or more of the following: a. Progression of measurable soft tissue disease b. Bone scan progression (appearance of ≥ 2 new lesions on bone scan, attributable to prostate cancer) c. Rising PSA, as defined by increasing levels on at least two consecutive assessments, following a prior assessment taken as a reference value, where all of the following are met: • The assessments are at least 1 week apart, with the first assessment at least 1 week later than the reference value • Progressive increase of at least 50% in each of the 2 assessments after the reference value, without an intervening decrease between assessments. The last value prior to study entry is ≥ 2 ng/mL 6. Serum testosterone level ≤ 50 ng/dL. 7. Candidate for docetaxel and steroid therapy. 8. Ongoing ADT with LHRH agonist, LHRH antagonist, or bilateral orchiectomy. 9. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 and anticipated minimum life expectancy of 12 weeks. 10. Able and willing to swallow and retain oral medication. 11. Confirmation that archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample which meets the minimum pathology and sample requirements is available to send to the central laboratory (see Section 8.7.2). (Patient consents to provision of this tissue sample; this inclusion criterion does not apply to patients in China). 12. Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm: • Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). • Patients should use barrier contraception (ie, condoms) during sexual intercourse from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the pre clinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if patients wish to father children, they should be advised to arrange for collection of sperm samples prior to the start of study treatment; refer to Section 5.3.4. Female partners of childbearing potential should be advised to use a highly effective form of contraception during their partner’s participation on the trial and for 16 weeks after discontinuation of study treatment. 13. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and CSP. 14. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.

    • Exclusion Criteria:

      1. Radiotherapy with a wide field of radiation (affecting ≥ 30% of the bone marrow) within 4 weeks before the start of study treatment. • Samarium must have been completed 4 weeks prior to the first dose of therapy. • Strontium and lutetium Lu 177 therapy must have been completed at least 12 weeks prior to the first dose of therapy. • Radium-233 must have been completed at least 6 weeks prior to the first dose of therapy. 2. Major surgery (excluding placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, or internal stents) within 4 weeks of the start of study treatment. 3. Brain metastases, or spinal cord compression (unless spinal cord compression is asymptomatic, treated, and stable and not requiring steroids for at least 4 weeks prior to start of study treatment). 4. Investigator judgment of 1 or more of the following cardiac criteria: • Mean resting corrected QT corrected by Fridericia’s formula (QTcF) interval > 470 ms, obtained from triplicate electrocardiograms (ECGs) performed at screening. • Medical history significant for arrhythmia (eg, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study. • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relative, history of QTc prolongation associated with other medications that required discontinuation of the medication. See Appendix D for guidance on patients receiving any concomitant medication known to prolong the QTc interval and with the potential to interact with capivasertib. • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥ 2. • Uncontrolled hypotension: systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg. • Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) as measured by echocardiogram (ECHO) (or multiple-gated acquisition [MUGA] scan if an ECHO cannot be performed or is inconclusive). 5. Clinically significant abnormalities of glucose metabolism as defined by any of the following: • Diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment. • HbA1c ≥ 8.0% (63.9 mmol/mol). 6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: • Absolute neutrophil count < 1.5 x 109/L (If sites only collected % differential of neutrophils, the absolute neutrophil count will need to be calculated for eligibility, based on leukocytes [white blood cell] (WBC) and % of neutrophils). • Platelet count < 100 x 109/L. • Haemoglobin < 9 g/dL (< 5.59 mmol/L). [Note: any blood transfusion must be > 14 days prior to the determination of a haemoglobin ≥ 9 g/dL (≥ 5.59 mmol/L)] (If anaemia is present, it must be able to be managed by standard supportive care). • Alterations in hepatic function tests defined as any one of the following: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases - Total bilirubin > 1.5 x ULN (> 3 x ULN in the presence of documented Gilbert's syndrome) - Serum alkaline phosphatase (ALP) levels > 6 x ULN, plus either bilirubin > ULN or AST and/or ALT > 3.5 × ULN. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastases and liver function is otherwise considered adequate in the investigator’s judgement. • Creatinine clearance (CrCL) < 50 mL/min per the Cockcroft-Gault formula (using actual body weight) without the need for chronic dialysis therapy. 7. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant and active bleeding diseases), which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol. Screening for chronic conditions is not required. 8. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib. 9. Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contra indicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. Evidence of dementia, altered mental status, or any psychiatric condition that would prohibit understanding or rendering of informed consent. 10. Previous allogeneic bone marrow transplant or solid organ transplant. 11. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥5 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy. 12. Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the medical monitor. 13. Known to have active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody at screening. Known to have human immunodeficiency virus (HIV) with a CD4+ T-cell count < 350 cells/uL or a history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). Known history of drug or alcohol abuse within 1 month of screening. Note, please see Appendix D for restricted concomitant medications with capivasertib, including select antiretroviral therapy. 14. Treatment with any of the following: • Prior chemotherapy for CRPC. Chemotherapy for metastatic or localized HSPC (including docetaxel) is allowed provided that chemotherapy was completed ≥ 6 months before randomisation and progression of the prostate cancer occurred ≥ 6 months after the completion of therapy. • Prior exposure to AKT inhibitors or PI3K inhibitors • Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment. • Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT) within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologics) as agreed by the sponsor. • Strong inhibitors or inducers of cytochrome P450 (CYP)3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort), or drugs that are sensitive to inhibition of CYP3A4 within 1 week prior to the first dose of study treatment (See Appendix D for details). • Due to the important potential risk of QT prolongation derived from the capivasertib non-clinical development programme, it is recommended that administration of any drugs, other than ADT (at screening or during study conduct), considered essential for patient management which are known to prolong the QT interval is discussed with the medical monitor and that consideration should be given for close monitoring of QT interval prolongation through frequent ECG and electrolyte monitoring. See Appendix D for additional guidance regarding drugs known to prolong the QT interval and that are at risk for a potential PK interaction with capivasertib. 15. Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer. 16. History of hypersensitivity to active or inactive excipients of capivasertib, docetaxel, or drugs with a similar chemical structure or class. 17. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 18. 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. 19. Any restriction or contraindication based on the local prescribing information that would prohibit the use of docetaxel.

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  • A Randomised, Open-Label, Parallel-Group, Pre surgical Study to Investigate the Biological Effects of AZD9833 in Women with ER-positive, HER2-negative Primary Breast Cancer

    • Research Summary

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    • Inclusion Criteria:

      Informed Consent 1. Provision of signed and dated, written informed consent prior to any mandatory study specific procedures, sampling, and analyses. Patients are also required to provide consent for the provision of archival tumour biopsies. 2. For patients who consent, provision of signed and dated written genetic informed consent prior to collection of samples for genetic analysis. Age and Gender 3. Female patients aged at least 18 years. Menopausal Status 4. Post-menopausal status defined as meeting at least one of the following criteria: (a) Have undergone a bilateral oophorectomy (b) Age ≥ 60 years (c) Age ≥ 50 and < 60 years and with cessation of menses ≥ 12 months and FSH and oestradiol levels in the post-menopausal range (utilising ranges from the local laboratory facility) and with an intact uterus in the absence of oral contraception or hormone replacement therapy prior to the diagnosis of breast cancer. 5. Pre-menopausal status (Stage 2 only) defined as patients who are naturally pre-menopausal (ie without concurrent ovarian suppression) (a) Women of childbearing potential must: (i) Not be breastfeeding (ii) Have a negative pregnancy test prior to the start of dosing. (iii) Agree to use one highly effective barrier method of contraception (as defined in Section 5.4.1 Contraceptive Measures) from the time of screening until 4 weeks after discontinuing study treatment. Disease Characteristics 6. Female patients with newly diagnosed primary breast cancer scheduled to undergo treatment with curative intent by surgery and irrespective of clinical node status: (a) Patients who are scheduled to start neoadjuvant therapy can still participate in the study but must have their core tumour biopsies performed before commencing neoadjuvant therapy. 7. Histologically confirmed invasive breast cancer involving a palpable tumour of any size, or a tumour with an ultrasound assessed diameter of ≥ 1.0 cm. 8. Multifocal tumours (including bilateral tumours) are allowed, assuming one lesion is designated as the ‘target lesion’ (at the Investigator’s discretion) and tumour evaluations and pre- and on-treatment biopsies are performed on that lesion. 9. Patients with adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 3 months can be considered for the study: (a) Any endocrine or other anti-cancer therapies must have been received at least 12 months prior to enrolment. 10. According to the local laboratory parameters and where those laboratory parameters are in accordance with accepted diagnostic guidelines (eg, American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer [Hammond et al 2010]) patients must have (where available, assessment of ER and HER2 status should be based on the most recent tumour biopsy sample): (a) ER positive breast cancer (b) HER2-negative breast cancer, defined as an IHC Score 0 or 1+ or negative by in situ hybridisation (ISH; FISH/CISH/SISH); if IHC 2+, ISH negativity is required. 11. ECOG performance status 0 to 1.

    • Exclusion Criteria:

      Prior/Concomitant Therapy 1. Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments). 2. Intervention with any of the following: (a) Use of sex-hormone-containing drugs within 6 months prior to the first dose of study treatment (including oral contraceptive pills, hormone replacement therapy,oestrogen-containing vaginal creams or other topical preparations, and controlled-release vaginal rings and sex hormone-containing intra-uterine systems) (b) Medications or herbal supplements known to be strong inhibitors/inducers of CYP3A4/5, sensitive CYP2B6 substrates (commonly prescribed drugs are listed in Appendix A), and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin or inability to stop use within the washout period as specified in Appendix A, prior to receiving the first dose of study treatment (c) Drugs that are known to prolong QT and have a known risk of torsades de pointes, as indicated in Appendix A. Medical Conditions 3. Inflammatory breast cancer. 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or eg, infection requiring intravenous antibiotic therapy, which in the Investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C, and HIV. Note: Active viral infection is defined as requiring antiviral therapy. Screening for chronic conditions is not required. 5. Any of the following cardiovascular criteria: (a) Mean resting QTcF > 470 msec obtained from screening triplicate ECG (b) Resting heart rate of < 50 bpm, obtained from central review of the average of triplicate ECGs taken at screening (c) Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, second- and third-degree heart block), or clinically significant sinus pause, or sick sinus syndrome. Patients with controlled atrial fibrillation can be enrolled (d) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as symptomatic heart failure, congenital long QT syndrome, immediate family history of long QT syndrome, or unexplained sudden death at < 40 years of age; hypertrophic cardiomyopathy and clinically significant stenotic valve disease; clinically significant hypokalaemia, hyperkalaemia, hypo- and hypermagnesaemia, hypo- and hypercalcaemia (e) Known left ventricular ejection fraction < 50%, and/or experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥ 2, cerebrovascular accident, or transient ischaemic attack.(f) Uncontrolled hypertension. Hypertensive patients may be eligible, but blood pressure must be adequately controlled at baseline. Patients may be re-screened regarding the blood pressure requirement (g) Symptomatic hypotension. 6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: (a) ANC < 1.5 × 109/L (b) Platelet count < 100 × 109/L (c) Hb < 90 g/L (d) ALT > 2.5 × ULN) (e) AST > 2.5 × ULN (f) TBL > 1.5 × ULN or > 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) (g) eGFR < 50 mL/min. 7. Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833. Other Exclusions 8. History of hypersensitivity to active or inactive excipients of AZD9833 or drugs with a similar chemical structure or class to AZD9833. History of hypersensitivity to active or inactive excipients of fulvestrant for Stage 2 if relevant. 9. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 10. Previous randomisation in the present study. 11. 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. 12. Male patients are excluded from this study. Women of childbearing potential are excluded from Stage 1.

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  • A Randomized Phase 3 Study of MRTX849 in Combination with Cetuximab Versus Chemotherapy in Patients with Advanced Colorectal Cancer with KRAS G12C Mutation with Disease Progression On or After Standard First-Line Therapy

    • Research Summary

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    • Inclusion Criteria:

      Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study. 1. Histologically confirmed diagnosis of colorectal carcinoma with KRAS G12C mutation in tumor tissue. 2. Prior receipt of first-line treatment in the advanced disease setting with a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan, and radiographically documented progression of disease on or after treatment. Notes: - Maintenance therapy given in the metastatic setting will not be considered a separate regimen. - Patients experiencing disease relapse during adjuvant treatment or within 6 months following completion of adjuvant therapy are eligible. Patients with relapse more than 6 months after completion of adjuvant therapy are not eligible. - Source documents for historical disease evaluations to allow Investigator certification of disease progression on or after first-line treatment must be available. 3. Candidacy to receive treatment with cetuximab in accordance with the local product label, with the exception that patients must have documented KRAS G12C mutation and may or may not have demonstrated tumor positivity for EGFR-expression. 4. Presence of evaluable or measurable disease per RECIST 1.1. 5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory testing of KRAS G12C mutation status (minimum of 5 slides, preferably 15 slides). 6. Age ≥ 18 years. 7. Life expectancy of at least 3 months. 8. Recovery from the adverse effects of prior therapy to baseline or Grade 1 (any grade alopecia and Grade ≤ 2 peripheral neuropathy are eligible). 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Laboratory values within the screening period: a. Absolute neutrophil count ³1,500/mm3 (³1.5 × 109/L) b. Platelet count ³100,000/mm3 (³100 × 109/L) c. Hemoglobin ≥ 9.0 g/dL. Note: Transfusions will be allowed to achieve this provided the patient has not received more than 2 units of red blood cells in the prior 4 weeks d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); if associated with liver metastases, ≤ 3 × ULN. e. Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase ≤ 2.5 × ULN; if associated with liver metastases, ≤ 5 × ULN. f. Creatinine clearance ≥ 60 mL/min or glomerular filtration rate ≥60 mL/min/1.73 m2 calculated using a validated prediction equation (e.g., Cockcroft-Gault, MDRD, or 24-hour urine CrCl). g. Electrolyte levels within the screening period: corrected serum calcium ≥ 8.0 mg/dL or ionized calcium ≥ 1.0 mmol/L; magnesium ≥ 1.2 mg/dL; phosphorus ≥ 1.8 mg/dL. 11. Able to take oral medications. 12. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment. 13. Completed informed consent process, including signing IRB/EC-approved informed consent form. 14. Willing to comply with clinical trial instructions and requirements.

    • Exclusion Criteria:

      Patients presenting with any of the following will not be included in the study: 1. Prior treatment with both an oxaliplatin- and irinotecan-based regimen for CRC in the adjuvant and/or later treatment settings. 2. Prior treatment with a therapy targeting KRAS G12C mutation (e.g., AMG 510). 3. Prior treatment with an anti-EGFR antibody (e.g., cetuximab or panitumumab). 4. Most recent prior anticancer therapy (e.g., chemotherapy, antiangiogenic therapy or radiation therapy) discontinued within 2 weeks before the date of randomization. 5. Known contraindication to receive cetuximab, 5-FU or folinic acid at the planned doses. 6. Active brain metastases or carcinomatous meningitis. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable for at least 2 weeks prior to randomization without the use of corticosteroids or are on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). 7. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Note that the following are permitted: • Patients treated for hepatitis C (HCV) with no detectable viral load; • Patients treated for HIV with no detectable viral load for at least 1 month prior to randomization while on a stable regimen of agents that are not strong inhibitors of CYP3A4; and • Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of hepatitis B (either [HBsAg-positive with normal ALT and HBV DNA < 2,000 IU/mL or < 10,000 copies/mL] or [HBsAg-negative and anti-HBcpositive]). 8. Major surgery within 4 weeks prior to randomization. 9. History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications. 10. Any of the following cardiac abnormalities: a. Unstable angina pectoris or myocardial infarction within 6 months prior to randomization. b. Symptomatic or uncontrolled atrial fibrillation within 6 months prior to randomization. c. Congestive heart failure ≥NYHA Class 3 within 6 months prior to randomization. d. Prolonged QTc interval > 480 milliseconds or family or medical history of congenital Long QT Syndrome. 11. History of stroke or transient ischemic attack within 6 months prior to randomization. 12. Ongoing need for treatment with concomitant medication known to cause prolonged QTc interval or known as strong inhibitor or inducer of CYP3A enzyme and that cannot be switched to alternative treatment prior to study entry. 13. Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments. 14. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented prior to randomization. 15. Breast-feeding or planning to breast-feed during the study or within 6 months after the last dose of study treatment. 16. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical condition or history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s capacity to provide informed consent, with the patient’s participation in the study, or with the interpretation of the results.

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  • A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton’s Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies

    • Research Summary

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    • Inclusion Criteria:

      1. Each patient must sign an ICF indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient’s disease. 2. Patients must be ≥ 18 years of age. 3. Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, DLBCL, FL, MCL, MZL, or WM. 4. Patients in Phase 1a must meet the following: a. Received at least 2 prior systemic therapies (or 1 prior therapy for WM) and have no other therapies known to provide clinical benefit. 5. Patients in Phase 1b (Cohort Expansion) must have one of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment, and must have failed 2 prior lines of therapy (or 1 prior line of therapy for patients with WM, PCNSL, or secondary CNS involvement): a. Cohort A: CLL or SLL without a BTK C481 mutation with disease progression on a BTKi. Patients who stopped BTKi due to side effects must have subsequent progression. b. Cohort B: CLL or SLL with a BTK C481 mutation with disease progression on a BTKi. c. Cohort C: i. DLBCL with disease progression on an anthracycline and an anti-CD20 mAbbased regimen, including transformed indolent lymphoma, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphomas NOS, or ii. MCL with disease progression on a BTKi and an anti-CD20 mAb-based regimen. d. Cohort D: i. FL with disease progression on an anti-CD20 mAb-based regimen, or ii. MZL with disease progression on an anti-CD20 mAb-based regimen, or iii. WM with disease progression on a BTKi. e. Cohort E: i. PCNSL with disease progression on 1 prior therapy, or ii. Any of the indications listed above with CNS involvement, with disease progression on 1 prior therapy (see Section 5.1.3 for rationale). 6. Patients must have radiographically measurable disease per response criteria specific to the malignancy (i.e., iwCLL, Lugano Classification of Lymphoma response criteria, WM response criteria, or International PCNSL Collaboration Group criteria) by CT, CT/PET scan, or MRI. Target lymph nodes must be > 1.5 cm and extranodal lesions must be ≥1.0 cm in longest diameter. Evaluable disease in bone marrow or compartment (pleural effusion) is also allowed. 7. ECOG performance status of 0 or 1. 8. Adequate organ and bone marrow function, in the absence of growth factors and without platelet transfusions, as defined by the following laboratory parameters (see table in attachment section) 9. WOCBP must agree to use highly effective contraception (failure rate of < 1% per year) during the study from Screening through 6 months after the last dose of study drug. WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe. WOCBP and contraception methods are defined as per the 2020 CTFG recommendations (CTFG 2020). 10. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception (condom) (defined as per CTFG 2020) during the study from Screening through 3 months after the last dose of study drug. Men must agree to not donate sperm during the same timeframe. 11. Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

    • Exclusion Criteria:

      1. Prior treatment for the indication under study that includes: a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation). b. Prior chemotherapy within 4 weeks of planned start of study drug. c. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug. d. Prior small molecule therapy within 4 weeks or 5 half-lives (whichever is shorter) of planned start of study drug. e. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug. f. CAR-T therapy within 100 days prior to start of study drug (30 days for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR-T therapy. g. Use of systemic corticosteroids outside of dosing limits described below and within the 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with CNSL: no greater than 40 mg/day prednisone, or equivalent, CNSL patients using greater than 20 mg/day prednisone, or equivalent must be clinically stable at that dose for 14 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent. h. Use of immunosuppressive drugs other than systemic corticosteroids within 30 days, prior to first dose of study drug. 2. Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. 3. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study drug. 4. Patients with active GVHD or on anti-GVHD treatment or prophylaxis. 5. History of known or suspected uncontrolled seizure disorder not related to CNSL involvement. 6. Patient has any of the following: a. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study drug. b. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or NYHA class III or IV heart failure within 6 months of planned start of study drug. c. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug. d. Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease, or persistent uncontrolled hypertension defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management) within 6 months of planned start of study drug. 7. Bleeding diathesis, or other known risk for acute blood loss. 8. History of Grade ≥2 hemorrhage within 28 days. 9. Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 7 days prior to first dose of study drug or patients treated with dual anti-platelet therapy and vitamin K antagonists. 10. Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy, or hematologic parameters meeting inclusion criteria). 11. Active known second malignancy with the exception of any of the following: a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer. b. Adequately treated Stage I cancer from which the patient has been disease-free for ≥2 years. c. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL. 12. Patient has known allergies, hypersensitivity, or intolerance to components of study drug. 13. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug; for WOCBP, negative pregnancy status must be confirmed by pregnancy test at Screening and within 24 hours of first dose of study drug. 14. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug. 15. Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of study drug, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 4 weeks after the last dose of study drug. Note: patients with minor planned surgical procedures to be conducted under local anesthesia may participate. 16. Active, significant bacterial, fungal, parasitic, viral, or COVID infection including: a. Current active liver disease from any infectious cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), and hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by detectable HCV ribonucleic acid). Exceptions: Patients with hepatitis B virus (HBV) who are negative for HBV deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) are eligible irrespective of serology findings; as are, patients with a history of Hepatitis C with undetectable viral levels following treatment. b. Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible. c. Active viral reactivation (e.g., CMV or EBV) 17. Any other medical or psychiatric condition or social situation that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives or the protocol or completion of treatment per protocol. 18. Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or completion of COVID-19 vaccinations within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period. 19. Administration of any strong or moderate CYP3A inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (See Section 6.8.2.2). 20. Administration of any sensitive substrates or inhibitors of P-glycoprotein, BCRP, or OATP1B1/1B3 transporters within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (see Section 6.8.2.3). 21. Administration of a proton pump inhibitor within 14 days for 5 half-lives, whichever is longer, prior to first dose of study drug. See Section 6.8.2.4 for allowed use of alternative agents. 22. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg within 3 days prior to Screening and during study treatment (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry).

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  • A Phase 2, randomized, open-label three-arm clinical study to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) versus standard of care chemotherapy and lenvatinib monotherapy in participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have progressed after platinum therapy and immunotherapy (PD-1/PD-L1 inhibitors)

    • Research Summary

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    • Inclusion Criteria:

      1. Be male or female and at least 18 years of age on the day of signing informed consent. 2. Have histologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies. 3. Have experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab. 4. Have disease progression on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Anti-PD-1/PD-L1 treatment progression is defined by meeting all the following criteria: • Most recent treatment with an anti-PD-1/PD-L1 mAb. • Has received at least 2 doses of an anti-PD-1/PD-L1 mAb. • Has demonstrated disease progression after an anti-PD-1/PD-L1 mAb as defined by RECIST 1.1. • Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb. Note: Eligible participants may have received anti-PD-1/PD-L1 mAb and platinum-containing therapy concomitantly. 5. Have submitted pre-study imaging that confirmed evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor. • Note: These pre-study images must be submitted to the iCRO for confirmation that they are of acceptable diagnostic quality. The iCRO must have received these images and confirmed that they are of acceptable diagnostic quality before randomization. • Note: The pre-study imaging submitted to the iCRO will be from disease progression on treatment with an anti-PD-1/PD-L1 mAb; NOT from images associated with disease progression on platinum-containing chemotherapy given sequentially. 6. Have documentation of results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using the CINtec® p16 Histology assay and a 70% cutoff point. Refer to Section 8.8.2 for details. If HPV status has previously been tested using this procedure, no retesting is required. 7. Have provided tissue for biomarker analysis from a core or excisional biopsy (fine needle aspirate is not adequate). Repeat samples may be required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior to start of study treatment) is strongly preferred, but an archival sample is acceptable. 8. Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) based on RECIST 1.1 as confirmed by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 9. Have an ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention. 10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least: • 30 days after the last dose of pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3). • 180 days after the last dose of SOC chemotherapy (Arm 2), and agree to the following: • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5]) as detailed below: - Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration. • Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex. Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed. 11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a WOCBP. OR - Is a WOCBP randomized to pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with lower user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. - A WOCBP randomized to SOC chemotherapy is eligible to participate if she is using a contraceptive method that is highly effective with low user dependency or abstinent from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate or freeze/store eggs during the intervention period and for at least 180 days after the last dose of SOC chemotherapy. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum; as required by local regulations) within 24 hours before the first dose of study intervention. - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 5. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 12. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. 13. Have adequately controlled BP with or without antihypertensive medications, defined as BP ≤ 150/90 mm Hg with no change in antihypertensive medications for at least 1 week prior to randomization. 14. Have adequate organ function as defined in Table 1. • Note: Specimens must be collected within ≤ 10 days prior to the start of study intervention.

    • Exclusion Criteria:

      1. Has carcinoma of the nasopharynx, salivary gland, unknown primary origin, or nonsquamous histologies as primary tumors. 2. Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer. 3. Has disease that is suitable for local therapy administered with curative intent. 4. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain), in the opinion of the treating investigator. 5. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to randomization. 6. Has ulceration and/or fungation of disease onto the skin surface. 7. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates > 90 degree abutment or encasement of a major blood vessel. • Note: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy. 8. Has a history of (noninfectious) pneumonitis that required systemic steroids, or current pneumonitis/interstitial lung disease. 9. Has an active infection requiring systemic therapy. 10. 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. 11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated metastases may participate provided 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 study intervention. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study intervention. 12. Has a known additional malignancy that is progressing or has required active systemic treatment within the past 3 years. • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study enrollment. Other exceptions may be considered after consultation with the Sponsor. 13. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). • Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 14. Has had an allogeneic tissue/solid organ transplant. 15. Has a known history of human immunodeficiency virus (HIV) infection. • Note: No HIV testing is required unless mandated by local health authority. 16. Has a known history of hepatitis B (defined as hepatitis B surface antigen (HbsAg) reactive or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection. • Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority. 17. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥ Grade 3), lenvatinib or SOC chemotherapy. 18. Has pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula. 19. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption. 20. Has had major surgery within 3 weeks prior to first dose of study interventions. • Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. • Note: Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy. 21. Has clinically significant cardiovascular impairment within 12 months of the first dose of study drug, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident /transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability. • Note: Medically controlled arrhythmia that is stable with medication is permitted. 22. Has active tuberculosis. 23. Has difficulty swallowing capsules or ingesting a suspension either orally, by a nasogastric (NG) tube, or by a gastrostomy tube. Note: Gastrostomy tube (PVC, greater than or equal to 6 Fr) can be used to administer lenvatinib. 24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) or 180 days after the last dose of SOC chemotherapy. 25. Patients previously treated to one of the 5 SOC agents in this trial (ie, docetaxel, paclitaxel, capecitabine, methotrexate, or cetuximab) may not receive the same agent if randomized to the SOC chemotherapy arm. 26. Has had prior treatment with lenvatinib as monotherapy or in combination with an PD 1/PD-L1 inhibitor or other therapies. 27. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered (ie, ≤ Grade 1 or baseline) from AEs due to a previously administered agent. Note: Events of ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or laboratory values listed in Table 1 are allowed. Note: Participants must have recovered from all radiation-related toxicities and not have had radiation pneumonitis. 28. Has received a live vaccine within 30 days of planned start of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 29. Was previously treated with 4 or more systemic regimens given for recurrent and/or metastatic disease. 30. Is currently participating in or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device. 31. Has urine protein ≥ 1 g/24 hours Note: Participants with proteinuria > 1+ on urine dipstick testing/urinalysis will undergo 24 hour urine collection for quantitative assessment of proteinuria. 32. Has prolongation of QTc interval (calculated using Fridericia’s formula) to > 480 msec. 33. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO). 34. Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: In the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study treatment. 35. Has a history or current evidence of any condition, therapy, or laboratory abnormality that may confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant, in the opinion of the treating investigator. 36. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

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  • A Phase III, Multicenter, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone (B-Pd) versus Pomalidomide plus Bortezomib and Dexamethasone (PVd) in Participants with Relapsed/Refractory Multiple Myeloma (DREAMM 8)

    • Research Summary

      This research study is being done to learn more about multiple myeloma (MM). The study will test if the investigational study treatment, called belantamab mafodotin (also referred to as GSK2857916), can help patients who have already received at least one other treatment and whose MM has worsened. This type of MM is called relapsed/refractory MM or RRMM. In this study, belantamab mafodotin will be given in combination with two other drugs that are currently approved to treat MM, pomalidomide and dexamethasone (abbreviated to pom/dex). Adult patients with Relapsed/Refractory Multiple Myeloma will be eligible to participate in this study if they meet all of the inclusion criteria and none of the exclusion criteria as listed in the study Protocol. The study will include about 450 study participants and will last for approximately 5 years. The study will include a screening period, study treatment period, and follow-up. During screening participants will be evaluated for study eligibility per protocol as defined in the Inclusion and Exclusion criteria. Following screening, eligible participants will be divided into 2 treatment arms (referred to as Arm A and Arm B). Arm A participants will receive the investigational study treatment, belantamab mafodotin. Arm B participants will receive the comparator study treatment bortezomib plus pom/dex. The effects of the drugs will be compared between the two treatment arms. The study assessments will be performed during Screening, prior to the first dose of Cycle 1, and during each cycle of treatment. Upon completion of study treatment, participants will enter the follow-up phase.

    • Inclusion Criteria:

      Please refer to Protocol for full Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria are met: • Capable of giving signed informed consent • Male or female, 18 years or older • Have a confirmed diagnosis of multiple myeloma • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 • Have been previously treated with at least 1 prior line of MM therapy including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles) and must have documented disease progression during or after their most recent therapy. • Note Participants intolerant or refractory to bortezomib at 1.3 mg/m2 dose twice weekly dosing schedule are not eligible. • Must have at least ONE aspect of measurable disease, as defined in the protocol inclusion criteria • Have undergone autologous stem cell transplant (SCT) or are considered transplant ineligible. Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met: a. Autologous SCT was > 100 days prior to the first dose of study medication. b. No active bacterial, viral, or fungal infection(s) present • All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0) must be < = Grade 1 at the time of enrolment, except for alopecia. • Adequate organ system functions as defined by the laboratory assessments listed in Table 2 in the inclusion criteria in Protocol. • Meet the contraception requirements of the inclusion criteria in the Protocol

    • Exclusion Criteria:

      Please refer to Protocol for full Exclusion criteria A participant will not be eligible for inclusion in this study if any of the following criteria are met: Prior or Concomitant Therapies • Active plasma cell leukemia at the time of screening. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes). • Participants after prior allogeneic SCT. NOTE: Participants who have undergone syngeneic transplant will be allowed only if no history of or no currently active graft versus host disease (GvHD). • Systemic anti-myeloma therapy (including chemotherapy and systemic steroids) or 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 drug within 30 days of receiving the first dose of study drugs. • Plasmapheresis within 7 days prior to the first dose of study drug. • Received prior treatment with or intolerant to pomalidomide. • Received prior BCMA targeted therapy. • Intolerant to bortezomib or refractory to bortezomib (i.e., participant experienced progressive disease during treatment, or within 60 days of completing treatment, with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly). Prior- or Concomitant Diseases or Conditions • Evidence of cardiovascular risk including any of the detailed criteria listed in the exclusion criteria in the protocol. • Any major surgery within the last 4 weeks. • Previous or concurrent invasive malignancy other than multiple myeloma, except; The disease must be considered medically stable for at least 2 years; or The participant must not be receiving active therapy, other than hormonal therapy for this disease. • Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment. • Evidence of active mucosal or internal bleeding. • Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria). • Active infection requiring treatment. • Known human immunodeficiency virus (HIV) infection. • 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). • 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. Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. • Intolerance or contraindications to anti-viral prophylaxis. • Presence of active renal conditions (e.g. infection, severe renal impairment • requiring dialysis or any other condition that could affect participant’s safety). • Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in Table 4 of the Protocol. • Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain • Active or history of venous thromboembolism within the past 3 months. • Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis • Current corneal disease except for mild punctate keratopathy (as per Section 10.9 Protocol). • 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. • Pregnant or lactating female.

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  • A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO EVALUATE A DOSING REGIMEN WITH TWO STEP-UP PRIMING DOSES AND LONGER DOSING INTERVALS OF ELRANATAMAB (PF-06863135) MONOTHERAPY IN PARTICIPANTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

    • Research Summary

      -

    • Inclusion Criteria:

      1. Participants age ≥18 years (or the minimum country specific age of consent if > 18). - A female participant is eligible to participate if she is not pregnant or breastfeeding. Refer to Appendix 4 for all reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants. 2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. 3. Prior diagnosis of MM as defined according to IMWG criteria.1 4. Measurable disease based on IMWG criteria as defined by at least 1 of the following: a. Serum M-protein > 0.5 g/dL by SPEP; b. Urinary M-protein excretion > 200 mg/24 hours by UPEP; c. Serum immunoglobulin FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (< 0.26 or > 1.65). 5. Refractory to at least 1 IMiD. 6. Refractory to at least 1 PI. 7. Refractory to at least 1 anti-CD38 antibody. 8. Relapsed/refractory to last anti-MM regimen. Note: Refractory is defined as having disease progression while on therapy or within 60 days of last dose in any line, regardless of response. 9. ECOG performance status ≤1. 10. LVEF ≥40% as determined by a MUGA scan or ECHO. 11. Adequate hepatic function characterized by the following: a. Total bilirubin ≤2 x ULN (≤3 x ULN if documented Gilbert’s syndrome); b. AST ≤2.5 x ULN; andc. ALT ≤2.5 x ULN 12. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or according to local institutional standard method). 13. Adequate BM function characterized by the following: a. ANC ≥1.0 × 109/L (use of granulocyte-colony stimulating factors is permitted if completed at least 7 days prior to planned start of dosing); b. Platelets ≥25 × 109/L (transfusion support is permitted if completed at least 7 days prior to planned start of dosing); and c. Hemoglobin ≥8 g/dL (transfusion support is permitted if completed at least 7 days prior to planned start of dosing). 14. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1. 15. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

    • Exclusion Criteria:

      1. Smoldering MM. 2. Active plasma cell leukemia. 3. POEMS syndrome. 4. Amyloidosis. 5. Stem cell transplant within 12 weeks prior to enrollment or active GVHD. 6. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment: a. Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion); b. Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); c. Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism); d. Prolonged QT syndrome (or triplicate average QTcF > 470 msec at screening).7. Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. 8. Known or suspected hypersensitivity to the study drug or any of its excipients. 9. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. 10. Other surgical (including major surgery within 14 days prior to enrollment), medical or psychiatric conditions including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 11. Previous treatment with a BCMA targeted therapy. 12. Live attenuated vaccine within 4 weeks of the first dose. 13. Previous administration with an investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). 14. A participant may be eligible even if they are in the follow-up phase of an investigational study as long as they meet the criteria for time elapsed from previous administration of investigational product. Cases must be discussed with sponsor’s medical monitor to judge eligibility. 15. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

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  • A Phase III, Double-Blind, Placebo-Controlled, Randomized, Multicenter, International Study to Determine the Efficacy of Durvalumab Plus Oleclumab and Durvalumab plus Monalizumab in Patients With Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer (NSCLC) who Have Not Progressed Following Definitive, Platinum-Based Concurrent Chemoradiation Therapy.

    • Research Summary

      -

    • Inclusion Criteria:

      1. Participants must have histologically- or cytologically-documented NSCLC who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]). Initial staging procedures performed prior to initiation of any component of definitive treatment should include: - Whole-body Positron Emission Tomography – Computed Tomography (PET-CT) scan performed up to 42 days prior to the first dose of concurrent chemoradiotherapy (CRT). Brain imaging must be obtained to allow for appropriate staging. o - Except for overt cT4 disease, biopsy strongly preferred to prove nodal status N2 or N3 via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. 2. Tumour sample requirements as follows: Provision of a tumour tissue sample (≤ 3 months old is preferred; ≤ 6 months old is acceptable). An FFPE block sufficient for sectioning 20 slides (5 micron thickness) is the preferred sample type. 3. Tumour PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a central laboratory, must be known prior to randomization. Patients with unknown PD-L1 status are not eligible for the study. “Unknown” refers to (1) insufficient sample which is not able to be analysed, or (2) sample could be analyzed but results not interpretable. 4. Documented EGFR and ALK status (locally or centrally). If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used. If performed locally, negative EGFR and ALK tests will be confirmed by central laboratory. EGFR and ALK status must be available prior to randomisation. Participants with sensitizing EGFR (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 insertion or S768I mutation) or ALK rearrangements are excluded from the study. 5. Tumours harbouring mutations in any of the following genes, as determined by existing local test results: ROS1, RET, MET, BRAF, NTRK1, NTRK2, ERBB2 and KEAP1/NRF2 are excluded. 6. Patients must have not progressed following definitive, platinum-based, concurrent chemoradiation therapy as demonstrated by the following imaging studies performed after completion of CRT: - Screening baseline RECIST imaging of chest and abdomen by CT (preferred) or MRI (see schedule of assessments Table 1) - Brain magnetic resonance imaging (MRI, preferred) or high-quality brain CT with IV contrast (See schedule of assessments Table 1). 7. Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 28 days prior to first dose of investigational product in the study (one cycle is defined as 21 or 28 days). . Sites are strongly encouraged to complete screening within the first 14 days of the 28 day screening period. 8. The platinum-based chemotherapy regimen must contain one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. Gemcitabine is not permitted. 9. The last dose of chemotherapy must be administered prior to, or concurrently with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted. Up to 2 cycles of induction chemotherapy prior to cCRT is permitted. 10. Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique. Sites are encouraged to adhere to the following organ dosimetric specifications: - Mean lung dose must be < 20 Gy and/or V20 must be < 35% - Mean oesophagus dose must be < 34 Gy - Heart V45 < 35% or V30 < 50%. 11. WHO/ECOG PS of 0 or 1 at randomization. 12. Adequate organ and marrow function. 13. Minimum life expectancy of 12 weeks at randomization.

    • Exclusion Criteria:

      1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active interstitial lung disease/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol. 2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy, adequately treated carcinoma in situ or Ta tumors treated with curative intent and without evidence of disease. 3. Mixed small cell and non-small cell lung cancer histology. 4. Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced, unresectable NSCLC. 5. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy (excluding alopecia). Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead. 6. Participants with ≥ grade 2 pneumonitis from prior chemoradiation therapy. 7. Any prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1. 8. Investigator judgment of 1 or more of the following: a. Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening. b. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP). c. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives. 9. History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead. 10. Subjects with a history of MI, TIA, stroke, or pulmonary embolism diagnosed in the past 6 months or venous thrombosis diagnosed in the past 3 months. 11. Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies, anti-CD73 antibodies, and anti NKG2A antibodies, excluding therapeutic anticancer vaccines.

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  • An open-label, randomized, controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab with or without chemotherapy, versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer

    • Research Summary

      Urothelial cancer is estimated to kill nearly 200,000 patients globally each year. Patients with metastatic urothelial cancer represent a population with significant unmet medical need, as the 5-year mortality rate exceeds 85%. After the current standard first-line treatment for locally advanced and metastatic urothelial cancer most patients are not cured and long-term survival is poor. The aim of this trial is to evaluate the efficacy and safety of the study drug enfortumab vedotin when combined with other drugs to treat patients with previously untreated locally advanced or metastatic urothelial cancer. The sponsor, Seattle Genetics, aims to find out if using the study drug with other cancer drugs works better or worse than the standard treatment for urothelial cancer. The Phase II data has shown promising results. Approximately 1095 people will take part across 17 countries. There will be approximately 9 sites in the UK. Participants will be randomised with equal chance to 1 of 3 treatment arms: Group A will receive the study drug plus pembrolizumab. Group B will receive gemcitabine plus either cisplatin or carboplatin (which is the standard of care). Group C will receive the study drug plus pembrolizumab plus either cisplatin or carboplatin. Group A can get pembrolizumab for up to about 2 years/35 cycles. There’s no limit on the length of time they could get the study drug. Group B can get gemcitabine and either carboplatin or cisplatin for up to about 4 months/6 cycles. Group C can get either carboplatin or cisplatin for up to about 4 months and pembrolizumab for up to about 2 years. There’s no limit on the length of time they could get the study drug. All treatments will be given via IV infusion.

    • Inclusion Criteria:

      1. Participants must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible. 2. Participants must have measurable disease by investigator assessment according to RECIST v1.1 (Appendix J in protocol). a. Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy. 3. Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a. Participants that received neoadjuvant chemotherapy with recurrence > 12 months from completion of therapy are permitted. b. Participants that received adjuvant chemotherapy following cystectomy with recurrence > 12 months from completion of therapy are permitted. 4. Participants must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgement. a. Participants will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria: i. Glomerular filtration rate (GFR) < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine) • Participants with a GFR ≥ 50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement ii. Eastern Cooperative Oncology Group (ECOG) or World Health Organization (WHO) performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects) iii. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 audiometric hearing loss iv. New York Heart Association (NYHA) Class III heart failure 5. Participants must be age 18 years or older. 6. Archival tumour tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomisation. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed (see Section 7.5 of protocol). 7. Participants must have an ECOG Performance Status score of 0, 1, or 2 (see Appendix B in protocol for conversion of performance status using Karnofsky, if applicable). a. Participants with ECOG performance status of 2 must additionally meet the following criteria: i. Hemoglobin ≥ 10 g/dL ii. GFR ≥ 50 mL/min iii. May not have NYHA Class III heart failure 8. Participants must have adequate haematologic and organ function as defined by the baseline laboratory values in Table 5 in the protocol. 9. A female participant of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilisation (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes. Female participants of childbearing potential must meet the following conditions: • Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug. • Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 3 days prior to Day 1. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation. • If heterosexually active must consistently use highly effective methods of birth control with a failure rate of less than 1% (as described in Appendix L of protocol) starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug. • Female participants must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. For the remaining inclusion criteria please see protocol pages 40-41.

    • Exclusion Criteria:

      1. Participants who have previously received enfortumab vedotin or other Monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs). 2. Participants who have received prior treatment with a Programmed death-ligand 1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). 3. Participants who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists). 4. Participants who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment (ongoing hormonal/anti hormonal treatment, e.g., for breast cancer, is allowed, provided that the participant is eligible per exclusion criteria 14). 5. Participants with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 6. Participants with an estimated life expectancy < 12 weeks. 7. Participants with ongoing sensory or motor neuropathy Grade 2 or higher. 8. Participants with active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the subject is on a stable dose of ≤ 10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease. 9. Participants with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to baseline. 10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomisation. Routine antimicrobial prophylaxis is permitted. 11. Participants who have known hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by local country authority. 12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority. 13. Participants with conditions requiring high doses of steroids (> 10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency. 14. Participants with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Participants with nonmelanoma skin cancer or carcinoma in situ of any type (if complete resection was performed) are allowed. A history of prostate cancer (T2NXMX or lower with Gleason score ≤ 7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry is acceptable, provided that the subject is considered prostate cancer-free and the following criteria are met: a. Participants who have undergone radical prostatectomy must have undetectable PSA for > 1 year and at screening. b. Participants who have had radiation must have a Prostate-specific antigen (PSA) doubling time > 1 year (based on at least 3 values determined > 1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir). Participants with untreated low-risk prostate cancer (Gleason score ≤ 6) on active surveillance with PSA doubling time > 1 year (based on at least 3 values determined > 1 month apart) are also eligible. 15. Participants with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomisation (Appendix D in protocol). 16. Participants who have received radiotherapy within 2 weeks prior to randomisation. Participant must have recovered adequately from the toxicity from the intervention prior to starting study treatment. For the remaining exclusion criteria please see protocol pages 42-43.

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  • A PHASE III, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY AND SAFETY OF GDC-0077 PLUS PALBOCICLIB AND FULVESTRANT VERSUS PLACEBO PLUS PALBOCICLIB AND FULVESTRANT IN PATIENTS WITH PIK3CA-MUTANT, HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER

    • Research Summary

      Breast cancer is the most commonly diagnosed cancer in women. Hormone receptor (HR)-positive, HER2-negative breast cancer accounts for 60%–70% of all breast cancers. For most patients, endocrine therapy alone or in combination with a targeted therapy is the treatment of choice in the metastatic setting. Not all HR-positive breast cancers respond optimally to endocrine therapy. Multiple mechanisms may lead to primary and/or secondary resistance to endocrine therapy. The addition of targeted therapies to endocrine therapy may be able to overcome mechanisms of resistance to endocrine therapy. GDC-0077 is an experimental drug and has not been approved for the treatment of HR-positive advanced or metastatic breast cancer. GDC-0077 blocks a signal that cancer cells commonly use to grow and multiply. This signal is called the PI3K pathway. Clinical studies have demonstrated significant improvements in progression-free survival with the addition of targeted therapies to endocrine therapy and support giving GDC-0077 to patients whose breast cancer carries a mutation in the gene that controls the PI3K pathway, this gene is called PIK3CA. Because standard treatment for this type of cancer outside of a clinical trial may include a targeted therapy (palbociclib) in combination with an endocrine therapy (fulvestrant), this study will test the combination of GDC-0077 with palbociclib and fulvestrant. This study will evaluate the efficacy, safety, and pharmacokinetics of GDC-0077 in combination with palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant. The patient population will be those with PIK3CA-mutant, HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease has progressed during treatment or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease. Approximately 400 participants will take part in the study worldwide. The total length of the study will be approximately 6 years. The study is sponsored by F. Hoffman La Roche

    • Inclusion Criteria:

      Participants must meet the following criteria to take part in the study: • Signed Informed Consent Form • Women or men ≥ 18 years of age at time of signing Informed Consent Form • If female, patients must meet at least one of the following definitions: Postmenopausal, as defined by at least one of the following criteria: – Age ≥ 60 years – Age < 60 years and 12 months of amenorrhea plus follicle-stimulating hormone and plasma estradiol levels within postmenopausal range – Documented bilateral oophorectomy (≥ 14 days prior to first treatment on Day 1 of Cycle 1 and recovery to baseline) Premenopausal or perimenopausal (i.e., not meeting the criteria for postmenopausal) and meeting the following criterion: – Treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment. If male, recommendation of treatment with LHRH agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment. • Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent • Documented ER-positive and/or progesterone receptor-positive tumour according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, defined as ≥ 1% of tumour cells stained positive based on the most recent tumour biopsy and assessed locally • Documented HER2-negative tumour according to ASCO/CAP guidelines, defined as a HER2 immunohistochemistry (IHC) score of 0 or 1+, or an IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification, or a HER2/CEP17 ratio of < 2.0 based on the most recent tumour biopsy and assessed locally • Confirmation of biomarker eligibility: valid results from either central testing of blood or local testing of blood or tumour tissue documenting PIK3CA-mutant tumour status. All patients are required to submit a freshly collected pre-treatment blood sample, whether patients are enrolled by local or central test results. Local tests of blood or tumour tissue may only be performed using a Sponsor pre-approved PCR- or NGS-based assay at a CLIA-certified or equivalent laboratory. The full laboratory report of the PIK3CA mutation result must be available and submitted for confirmation. o Local test results reported from blood should be from a blood specimen representative of patient’s metastatic disease state, collected after conclusion of patient’s most recent anti-cancer therapy. o Local test results reported from tumour tissue should be from the patient’s metastatic disease state whenever possible. • Consent to provide fresh (preferred) or archival tumour tissue specimen. It is preferred that the specimen be from the most recently collected and available tumour tissue, and whenever possible, from a metastatic site of disease. See the laboratory manual for specimen requirements. • Patients must have progressed during adjuvant endocrine treatment or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. If a CDK4/6 inhibitor was included as part of neoadjuvant or adjuvant therapy, progression event must be > 12 months since completion of CDK4/6 inhibitor portion of neoadjuvant or adjuvant therapy. • Measurable disease per RECIST v1.1 Patients with bone-only disease are not eligible, even if a bone lesion qualifies as a measurable lesion. • Treatment with endocrine-based therapy (e.g., palbociclib and fulvestrant) is recommended at time of entry into the study, as per national or local treatment guidelines • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm. For the remaining inclusion criteria please refer to the protocol.

    • Exclusion Criteria:

      Participants who meet any of the following criteria will not be able to take part in the study: • Metaplastic breast cancer • Any history of leptomeningeal disease or carcinomatous meningitis • Any prior systemic therapy for metastatic breast cancer • Prior treatment with fulvestrant or any selective estrogen-receptor degrader • Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway • Appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per national or local treatment guidelines (e.g., patients with visceral crisis) • Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes • Inability or unwillingness to swallow pills or receive intramuscular injections • Malabsorption syndrome or other condition that would interfere with enteral absorption • Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: – Measurable disease outside the CNS – No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for > 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases – Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic assessments – Screening CNS radiographic assessments ≥ 4 weeks since completion of radiotherapy – No history of intracranial haemorrhage or spinal cord hemorrhage • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved, and has prior approval from the Medical Monitor. • Serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1 • Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition • Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye • Requirement for daily supplemental oxygen • Symptomatic active lung disease, including pneumonitis • History of or active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazines) are considered to have active disease and are therefore ineligible. • Any active bowel inflammation (including diverticulitis) • Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy. Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed. • Clinically significant and active liver disease, including severe liver impairment (Child Pugh Class B/C), viral or other hepatitis, current alcohol abuse, or cirrhosis • Known HIV infection Sites should include an HIV test during screening, as allowed per local regulations. • Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, or infectious disease) or any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that renders the patient at high risk from treatment complications • Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before randomisation • Investigational drug(s) within 4 weeks before randomisation • Prior radiotherapy to ≥ 25% of bone marrow, or hematopoietic stem cell or bone marrow transplantation • Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and Grade ≤ 2 peripheral neuropathy • History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer • History of or active clinically significant cardiovascular dysfunction, including the following: – History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment. For the remaining exclusion criteria please refer to the protocol.

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  • A Phase 3 Study of Pembrolizumab (MK-3475) in Combination with Concurrent Chemoradiation Therapy Followed by Pembrolizumab with or without Olaparib vs Concurrent Chemoradiation Therapy Followed by Durvalumab in Participants with Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer (NSCLC)

    • Research Summary

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    • Inclusion Criteria:

      1. Has previously untreated, unresectable, histologically or cytologically confirmed stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8 that is considered candidate for definitive concurrent chemoradiation. Note: Sites are encouraged to obtain tissue confirmation of mediastinal nodal involvement if this is safely accessible by endobronchial ultrasound (EBUS)/endoscopic ultrasound (EUS) or mediastinoscopy. However, mediastinal nodal involvement can be declared by imaging when the nodes have distinct margins and the size of the shortest axis of at least 1 node is ≥2.0 cm (positron emission tomography [PET]/magnetic resonance imaging [MRI]/computed tomography [CT] scan). Cases in which the distinct nodes all have short axis of < 2.0 cm must have pathologic confirmation of disease presence for participants to be declared eligible. 2. Participants with cervical nodal involvement are not permitted. Participants with supraclavicular nodal involvement may be entered into the study. The upper border of supraclavicular nodes must not extend above the upper border of the lateral end of the clavicle, extended medially. 3. Has no evidence of metastatic disease by protocol-approved imaging studies. The process for image collection and transmission to the central imaging vendor can be found in the Site Imaging Manual. NOTE: The presence of pleural/pericardial fluid is presumed indicative of metastatic disease unless proven otherwise. A pleural effusion fluid that is present on both a CT chest scan and routine chest x-ray requires a pleuracentesis to confirm the effusion is cytologically negative. Participants with effusions that are exudates are excluded even if the effusions are cytologically negative. Participants with effusions that are not visible on routine chest x-ray or are too small to be tapped safely may be entered on this study, provided the remaining inclusion/exclusion criteria are met. 4. Has at least 1 lesion that meets the criteria for being measurable as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review. Lesions that appear measurable, but have undergone palliative irradiation, cannot be target lesions. 5. Has not received prior systemic treatment for their Stage III NSCLC. Participants who received systemic therapy for earlier stages are eligible if the therapies were completed at least 12 months prior to the development of stage III NSCLC. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 6. Has provided tumor sample (tissue biopsy [core, incisional, or excisional]). Formalin-fixed, paraffin embedded (FFPE) blocks are preferred to slides. Newly obtained tumor sample is highly preferred over archival tissue. Note: If submitting unstained cut slides, newly cut slides must be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual). 7. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status assessed within 7 days prior to the first administration of study intervention. 8. Has a life expectancy of at least 6 months. 9. Has adequate pulmonary function test (PFT) defined as a forced expiratory volume in 1 second (FEV1) > 50% of predicted normal volume and the carbon monoxide lung diffusing capacity (DLCO) > 40% of predicted normal value. Participants for whom DLCO measurements are not available will be deemed to have adequate oxygen transfer if their resting capillary/arterial blood gas on room air reveals an oxygen pressure (PO2) > 60 mmHg. 10. Has adequate organ function as defined in Table 1; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment. Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological ANC ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La Renal Estimated creatinine clearance using the Cockcroft-Gault equation testb or a 24-hour urine test ≥51 mL/min Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin within normal limits for participants with total bilirubin levels > 1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN Endocrine TSH Within normal limits. Note: If TSH is not within normal limits at baseline, the participant may still be eligible if T3 and free T4 are within the normal limits Coagulation INR OR PT aPTT OR PTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulant Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. Demographics 11. Is male or female of at least18 years of age inclusive, at the time of signing the informed consent. Male Participants Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 12. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days following the last dose of study treatment. Note: Male participants should refrain from donating sperm during the treatment period and for at least 180 days following the last dose of study treatment. Female Participants Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 13. A female participant is eligible to participate if she is not pregnant (Appendix 5), not breastfeeding, and at least 1 of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5. OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 180 days following the last dose of pembrolizumab, olaparib, placebo or durvalumab or at least 180 days following the last dose of cytotoxic chemotherapy. Informed Consent 14. Has (or legally acceptable representative if applicable) provided written informed consent/assent for the study. The participant may also provide consent/assent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.

    • Exclusion Criteria:

      Medical Conditions 1. Has small cell lung cancer or a mixed tumor with presence of small cell elements. Note: Participants with squamous NSCLC are not eligible to receive pemetrexed based chemotherapy. 2. Has history, current diagnosis, or features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). 3. Has had documented weight loss > 10% in the preceding 3 months. Prior/Concomitant Therapy 4. Has a radiation treatment plan that is likely to encompass a volume of whole lung receiving > 20 Gy in total (V20) of more than 35% of lung volume. 5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer. 6. Completed palliative radiotherapy within 7 days of the first dose of trial treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids for at least 7 days prior to the first dose of study intervention, and not have had radiation pneumonitis. The radiated lesion must not be included as a target lesion for RECIST 1.1 measurements. 7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 8. Has received prior therapy with olaparib or with any other PARP inhibitor 9. Had major surgery < 4 weeks prior to the first dose of study drug (except for placement of vascular access). Note: If participants received major surgery, or underwent placement of vascular access, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention. 10. Is expected to require any other form of antineoplastic therapy, including radiation therapy, while on study. 11. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 12. Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention. 13. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for pentobarbital and 3 weeks for other agents. Note: a current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 14. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm Pemetrexed-specific 15. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents [for example, piroxicam]) before, during, and for at least 2 days after administration of pemetrexed. 16. Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone. Prior/Concurrent Clinical Study Experience 17. 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 intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Diagnostic Assessments 18. Has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or participant has congenital long QT syndrome. 19. 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 the first dose of study drug. Note: ocular, intranasal, or topical steroids or inhaled corticosteroids for management of asthma or chronic obstructive pulmonary disease are permitted. 20. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 21. Has severe hypersensitivity (≥ Grade 3) to study treatment and/or any of its excipients. 22. Has an active autoimmune disease 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) is not considered a form of systemic treatment and is allowed. 23. Has a known history of, or active, neurologic paraneoplastic syndrome. 24. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 25. Has an active infection requiring systemic therapy. 26. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 27. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority 28. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis). 29. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary. 30. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 31. In the opinion of the treating Investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome. 32. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. Other Exclusions 33. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g. gastrectomy, partial bowel, obstruction, malabsorption). 34. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study intervention.

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  • A randomized, double-blind placebo-controlled, phase 3 study of Debio 1143 in combination with platinum-based chemotherapy and standard fractionation intensity modulated radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy (TRILYNX).

    • Research Summary

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    • Inclusion Criteria:

      1. Willing and able to sign written informed consent prior to study screening. 2. Male or female ≥ 18 years of age (or based on the country legal age limit for adults) on day of signing the Informed Consent Form (ICF). 3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 4. Histologically confirmed diagnosis in previously untreated LA-SCCHN patient (stage III, IVA or IVB according to the American Joint Committee on Cancer [AJCC]/TNM Staging System, 8th Ed.) suitable for definitive CRT, of at least one of the following sites: oropharynx, hypopharynx and larynx. Note: Archival tumor sample to be provided, if available. 5. Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on RECIST v 1.1. 6. For OPC patients, primary tumors must be HPV-negative as determined by p16 expression using immunohistochemistry (pathological report should be available). Note: If the site is not able to perform HPV testing by p16 IHC, it will be evaluated by a central laboratory. 7. Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or jejunostomy placed. 8. No hearing loss by clinical assessment; in case of doubt an audiogram should be performed. 9. Peripheral neuropathy < grade 2. 10. Adequate hematologic, renal and hepatic function as indicated by: • Estimated glomerular filtration rate ≥ 60 mL/min/1.73m² (using the Chronic Kidney Disease - Epidemiology Collaboration [CKD -EPI] creatinine formula). • Absolute neutrophil count ≥ 1 500 cells/μL. • Platelets ≥ 100 000 cells/μL. • Hemoglobin ≥ 9.0 g/dL (transfusions during screening are permitted). • AST and ALT ≤ 3.0 × upper limit of normal (ULN). • Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if the direct bilirubin level is normal and the elevation is limited to indirect bilirubin). 11. Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group) must have a negative serum pregnancy test at screening and must not be breastfeeding. Women of childbearing potential must agree to use highly effective contraceptive method(s) (see Section 8.1.3) from ICF signature to 6 months after the last administration of chemotherapy or 3 months after last dose of Debio 1143/matched placebo, whichever is the latest. Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use condom and spermicide from ICF signature to 6 months after the last administration of chemotherapy or 3 months after the last dose of Debio 1143/matched placebo, whichever is the latest. Because male condom and spermicide is not a highly effective contraception method, it is strongly recommended that female partners of a male study subject use highly effective contraceptive method(s) (see Section 8.1.3) throughout this period. Male subjects must refrain from donating sperm during the clinical study and for 6 months after the last administration of chemotherapy or 3 months after the last dose of Debio 1143/matched placebo, whichever is the latest.

    • Exclusion Criteria:

      1. Primary tumor of nasopharyngeal, paranasal sinuses, nasal or oral cavity, salivary, thyroid or parathyroid gland pathologies, skin or unknown primary site. 2. Metastatic disease (stage IVC as per AJCC/TNM, 8th Ed.). 3. Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents (please refer to Section 6.1.1). 4. Use within 14 days prior to randomization or requirement for ongoing treatment with any drug(s) on the prohibited medication list (provided in Section 6.5.3). 5. Treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment. 6. Known history of infection with HIV. If unknown history of HIV, an HIV screening test is to be performed and subjects with positive serology for HIV-1/2 must be excluded. 7. Known chronically active HBV or HCV infection. If unknown status, the following tests are to be performed and subjects with positive serology must be excluded: • HBV screening tests: both HBV sAg and Anti-HepB core IgG. • HCV screening tests: both HCV-antibody and positive viral load HCV-RNA by PCR. 8. Other infections (viral and/or bacterial and/or mycotic) requiring systemic treatment. 9. Live-attenuated vaccinations within 30 days prior to first investigational treatment administration. 10. Ongoing uncontrolled infection requiring intravenous antibiotic therapy within 1 week prior to randomization. 11. Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery that may limit oral absorption. 12. Documented weight loss of > 10% during the last 4 weeks prior to randomization (unless adequate measures are undertaken for nutritional support), OR plasmatic albumin < 3.0 g/dL. 13. Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to randomization. 14. Active uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, severe extensive psoriasis) requiring ongoing treatment with anti-TNF medication. 15. Any concomitant medication known to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication within 7 days prior to start of treatment. 16. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: • Ongoing or history of uncontrolled or symptomatic ischemic myocardiopathy within 6 months prior to randomization. • Known left ventricular ejection fraction < 50%, left ventricular hypertrophy, ventricular arrhythmias, bradycardia (heart rate < 50 bpm). • History of myocardial infarction, or severe/unstable angina, within 6 months prior to randomization. • New York Heart Association grade ≥ 3 congestive heart failure. • Congenital long QT syndrome. • Family history of long QT syndrome. • Symptomatic pulmonary embolism within 6 months prior to randomization. • Ongoing or known history of transient ischemic attacks or stroke within 6 months prior to randomization. • QTc using Fridericia’s formula (QTcF) interval > 450 ms for males and > 470 ms for females. 17. Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply. 18. History of another malignancy within the last 3 years prior to randomization, with the exception of completely resected non-melanoma cell skin cancer outside the head and neck area or completely resected stage I breast cancer, or completely resected in-situ non-muscular invasive bladder, cervix and/or uterine carcinomas. 19. Known contraindication to undergoing positron emission tomography with 2-deoxy-2 [fluorine-18] fluoro-D-glucose (18F-FDG-PET) scans, contrast-enhanced MRI or contrast enhanced CT scans. 20. Known allergy to Debio 1143, cisplatin or any excipient known to be present in Debio1143 or in the placebo formulation. 21. Non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C). 22. Any ongoing condition or disorder, before randomization, including drug(s) or alcohol abuse, which in the judgment of the Investigator would make the patient inappropriate for entry into the study or precluding his/her ability to comply with study procedures.

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  • A Randomized Open-Label Phase III Study of Sacituzumab Govitecan Versus Treatment of Physician’s Choice in Subjects with Metastatic or Locally Advanced Unresectable Urothelial Cancer

    • Research Summary

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    • Inclusion Criteria:

      Subjects meeting all of the following inclusion criteria at Screening/C1D1 of treatment will be eligible for participation in the study: 1. Female or male subjects, ≥ 18 years of age, able to understand and give written informed consent. 2. Subjects with histologically documented metastatic or locally advanced unresectable UC defined as [Tumor (T) 4b, any node (N) or Any T, N 2-3]. Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology. 3. ECOG performance status score of 0 or 1. 4. Subjects with progression or recurrence following receipt of platinum-containing regimen (cisplatin or carboplatin) and anti PD-1/PD-L1 therapy for metastatic or locally advanced unresectable disease will be enrolled. a. Subjects with recurrence or progression ≤ 12 months following completion of platinum-containing chemotherapy and/or anti PD-1/PD-L1 therapy given in neoadjuvant/adjuvant setting may utilize that line of therapy to be eligible for the study. The 12-month period is counted from completion of platinum therapy or surgical intervention. b. Subjects who received only concurrent chemoradiation for bladder preservation without further systemic therapy are not eligible to enroll in the study. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen and no progression was noted prior to the change in platinum. 5. Subjects with previously treated brain metastases may participate in the study provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and stabilization of all neurologic symptoms, have no evidence of new or enlarging brain metastases, and are not using steroids > 20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to first dose of the study drug. 6. Adequate hematologic counts without transfusion or growth factor support within 1 week of study drug initiation [hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 1,500/mm3, and Platelets ≥ 100,000/μL]. 7. Adequate hepatic function (Bilirubin ≤ 1.5 x institution upper limit of normal (IULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin > 3 g/dL). Docetaxel will only be option in TPC arm for subjects with a total bilirubin ≤ 1 x IULN, and an AST and/or ALT ≤ 1.5 x IULN if alkaline phosphatase is also > 2.5 x IULN. 8. Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (e.g. Modification of Diet in Renal Disease [MDRD] equation). 9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 10. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years. 11. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study therapy.

    • Exclusion Criteria:

      Subjects meeting any of the following exclusion criteria at Screening/C1D1 of treatment will not be enrolled in the study: 1. Women who are pregnant or lactating. 2. Have had a prior anti-cancer mAb/ ADC within 4 weeks prior to C1D1 or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to C1D1. Subjects participating in observational studies are eligible. 3. Have received prior chemotherapy for UC with all available SOC therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy). 4. Have not recovered (i.e., ≤ Grade 1) from AEs due to previously administered chemotherapeutic agent. • Note: Subjects with ≤ Grade 2 neuropathy or any grade of alopecia are an exception to this criterion and will qualify for the study. • Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy. 5. Have previously received topoisomerase 1 inhibitors. 6. Have an active second malignancy. • Note: Subjects with a history of malignancy that have been completely treated and with no evidence of active cancer for 3 years prior to enrollment, or subjects with surgically cured tumors with low risk of recurrence are allowed to enroll in the study after discussion with the medical monitor. 7. Have active cardiac disease, defined as: a. Myocardial infarction or unstable angina pectoris within 6 months of C1D1. b. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. c. New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%. 8. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal (GI) perforation within 6 months of enrollment. 9. Have an active serious infection requiring anti-infective therapy (Contact medical monitor for clarification). 10. Have known history of Human Immunodeficiency Virus (HIV)-1/2 with uncontrolled viral load and on medications that may interfere with SN-38 metabolism. 11. Have active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In subjects with a history of HBV or HCV, subjects with a detectable viral load will be excluded. 12. Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations. 13. Have inability to tolerate or are allergic to any potential TPC agent or sacituzumab govitecan or unable or unwilling to receive the doses specified in the protocol. 14. Have inability to complete all specified study procedures for any reason.

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  • A Phase 1 open-label, first-in-human, multi-centre study to evaluate the safety, tolerability, pharmacokinetics and anti-tumour activity of thorium-227 labelled antibody-chelator conjugate BAY 2701439, in participants with advanced HER2-expressing tumours

    • Research Summary

      In this study, researchers want to learn about the safety of drug BAY 2701439 and how well the drug works in patients with advanced cancer that has the protein HER2 (Human Epidermal growth factor Receptor 2) and cannot be cured by currently available treatment options. The study will include patients with HER2 expressing breast, gastric (stomach) or gastroesophageal (stomach and esophagus) cancer, as well as other cancers that have HER2. Researchers want to find the best dose of BAY 2701439 for patients and look at the way the body absorbs, distributes and excretes the drug. The study drug is a type of therapy called a ‘targeted alpha therapy’ which uses an antibody to deliver a radioactive particle to cancer cells. BAY 2701439 contains thorium-227 which emits radiation (a lot of energy that moves from one place to another with damaging effects). The thorium-227 in the drug is attached to an ‘antibody’ (large protein) that specifically binds to HER2 on the cancer cells and will emit its radiation in the form of alpha particles. The alpha particles are expected to damage the tumor cells and cause them to die, but spare surrounding tissue as alpha particles travel only very short distances in the body. This is the first study in humans for drug BAY 2701439. Patients participating in this study will receive the drug by injection every 6 weeks a maximum 6 times. Observation after treatment will last up to 3 years.

    • Inclusion Criteria:

      1. Male or female participants at least 18 years of age on the day of signing informed consent. 2. Participants must meet the study phase-specific disease requirements: Dose escalation: Pathologically documented, HER2-expressing (IHC3+, 2+, or 1+ and/or ISH+), unresectable locally advanced or metastatic gastric, gastroesophageal or breast cancer that has relapsed after standard treatment options or for which no standard treatment is available. Participants with gastric or gastroesophageal cancer must not have had prior radiotherapy. Participants in the dose escalation cohorts must have evaluable disease by RECIST 1.1, assessed by local imaging. Dose expansion: Group A: Pathologically documented unresectable, locally advanced or metastatic breast cancer with HER2 overexpression or amplification (IHC3+ or IHC2+/ISH+) that has relapsed that has relapsed after standard treatment options, or for which no standard treatment is available. Group B: Pathologically documented unresectable locally advanced or metastatic breast cancer with HER2 low expression (IHC2+/ISH-, IHC1+/ISH-, or IHC1+/ISH untested) that has relapsed after standard treatment options, or for which no standard treatment is available. Group C: Pathologically documented, unresectable locally advanced or metastatic carcinomas other than breast cancer with HER2 overexpression or amplification/mutation (IHC3+ or IHC2+/ISH+), that has relapsed after standard treatment options or for which no standard treatment is available. Participants in the dose expansion cohorts must have measurable disease by RECIST 1.1, assessed by local imaging. 3. Availability of fresh or archival tumour samples – archival tumour samples obtained after disease progression on the most recent anti-cancer treatment may be accepted; those obtained prior to the last anti-cancer treatment may be accepted, upon agreement between the Sponsor and the Investigator. 4. ECOG PS of 0 or 1. 5. Life expectancy of at least 6 months, as estimated by the Investigator. 6. Adequate bone marrow, hepatic, and renal function, as assessed by the following laboratory requirements, to be conducted within 28 days before start of BAY 2701439 administration: a. Hemoglobin ≥ 9.0 g/dL b. Absolute neutrophil count (ANC) ≥ 1500/mm3 c. Platelet count ≥ 100,000/mm3 d. Total bilirubin ≤ 1.5 X the upper limit of normal (ULN), except if confirmed history of Gilbert’s disease e. ALT and AST ˂ 2.5 x ULN (≤ 5 x ULN for participants with liver involvement) f. Participants on a stable dose of anti-coagulation therapy will be allowed to participate if they have no sign of bleeding or clotting, and PT/INR and aPTT test results are compatible with the acceptable benefit-risk ratio at the Investigator’s discretion g. Serum creatinine ≤ 1.5 x ULN and glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2, according to the Modified Diet in Renal Disease (MDRD) abbreviated formula. 7. A negative serum pregnancy test in women of childbearing potential, performed within 7 days before the start of BAY 2701439 administration. Women and men of reproductive potential must agree to use highly effective methods of contraception, when sexually active, during the time period between signing the informed consent form until at least 6 months after the last administration of BAY 2701439. 8. Male and/or female who meet the requirements for contraception and breastfeeding as follows: Male participants: A male participant must agree to use highly effective contraception during the intervention period and for at least 6 months after intervention and refrain from donating sperm during this period. Female participants: A female participant is eligible to participate if she is not pregnant (confirmed by a negative serum pregnancy test within 7 days of first study treatment), not breastfeeding, or is not a woman of childbearing potential. Women of childbearing potential must agree to use highly effective contraception during the intervention period and for at least 6 months after the last dose of study treatment. 9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

    • Exclusion Criteria:

      1. Impaired cardiac function or clinically significant cardiac disease. 2. Unstable angina, new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before the start of study treatment. 3. Clinically significant arrhythmias, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 4. Participants who have Fridericia-corrected QT (QTcF) interval > 480 ms (CTCAE Grade > 1). 5. Uncontrolled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg, despite optimal medical management). 6. LVEF < 50% (as measured at screening by echocardiogram). 7. History or concurrent condition of interstitial lung disease/pneumonitis or severely impaired pulmonary function. 8. Participants known to be affected by genetic defects linked to radiation hypersensitivity (see protocol section 5.2 for examples). 9. Known brain, spinal or meningeal metastases. 10. History of Myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML. 11. Concurrent or active cancer within the last 3 years with a distinct primary site or histology from the cancer being evaluated in this study (see protocol section 5.2 to exceptions to this exclusion criteria) 12. Infections of CTCAE version 5.0 Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade > 2. 13. History of anaphylactic reactions to monoclonal antibody therapy. 14. Serious, infected non-healing wound, ulcer or bone fracture. 15. Known HIV infection or positive HIV test during screening. 16. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Participants with chronic HBV or HCV infection are eligible at the Investigator’s discretion provided the disease is stable and sufficiently controlled under treatment. 17. Major surgery, open biopsy, or significant trauma within 4 weeks before start of study treatment. 18. Known substance abuse, medical, psychological, or social conditions that may interfere with the participant’s participation in the study or evaluation of the study results. 19. History of hypersensitivity or severe infusion related reaction to any Trastuzumab-containing drug or any other ingredients contained in BAY 2701439. 20. For Cardiac MRI substudy: participants with a contraindication to MRI scanning (claustrophobia, certain imbedded metallic foreign bodies [e.g., shrapnel], certain implanted metallic devices [e.g., some pacemakers, some tattoos] or who are deemed unable to tolerate the MRI procedure by the site investigator) are excluded from the cardiac MRI substudy. 21. Chemotherapy, experimental cancer therapy, biologic therapy or immunotherapy within 4 weeks before start of BAY 2701439 administration. Previous high-dose chemotherapy needing hematopoietic-stem-cell-rescue is prohibited. 22. Participants who have received a cumulative dose of anthracyclines above the maximum levels recommended by the London Cancer Centre Maximum Anthracycline Doses Guidelines. 23. Prior investigational anti-HER2 therapy within 4 weeks before start of BAY 2701439 administration. 24. Prior definitive therapy completed less than 6 weeks before start of BAY 2701439 administration. See protocol section 5.2 for details of when palliative radiotherapy completed less than 6 weeks before the start of BAY 2701439 administration will be allowed. 25. Toxic effects (CTCAE Grade ≥ 2) of previous anti-cancer chemotherapy or immunotherapy that have not yet stabilised or if significant post-treatment toxicities have been observed (toxic effects of CTCAE Grade ≤ 2 from previous anti-cancer therapy considered as chronic and for which further resolution is not expected. 26. Live vaccines within 30 days prior to the first dose of trial treatment. See protocol section 5.2 for examples of live vaccines and exception criteria for seasonal influenza vaccines for injection. 27. Biological response modifiers within 3 weeks before start of study treatment. See protocol section 5.2 for examples and exception for chronic use of erythropoietin. 28. Previous autologous or allogeneic stem-cell transplantation. 29. Participants who are on long-term, chronic steroid therapy are not acceptable for at least 4 weeks before the first administration and during treatment with BAY 2701439. 30. Previous treatment with radium-223 dichloride or other radiopharmaceutical, including but not limited to strontium-89 or samarium-153. 31. Concurrent participation in the active part of another clinical study with investigational medicinal product(s). 32. Any condition which, in the opinion of the Investigator, would preclude participation in this trial.

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  • An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 in Combination with Acalabrutinib in Subjects with Relapsed/Refractory Diffuse Large B-cell Lymphoma or Relapsed/Refractory Chronic Lymphocytic Leukemia

    • Research Summary

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    • Inclusion Criteria:

      The inclusion criteria mentioned below are applicable to all cohorts unless otherwise specified. 1. Adults ≥ 18 years of age. 2. Patient population Cohort 1 (R/R DLBCL) a) Histologically confirmed diagnosis of de novo TP53wt ABC (non-GCB) or GCB DLBCL based on 2016 WHO Classification (Beham-Schmid 2017). i. Phase 2: 25 or more subjects with non-GCB and 10 or more subjects with double-expressor lymphoma will be enrolled as described in Section 10.2. b) R/R DLBCL after treatment with at least 2 prior lines of systemic therapy or at least 1 prior line of systemic therapy in subjects who are ineligible for hematopoietic stem cell transplantation (autologous or allogeneic) for reasons other than active disease. c) At least 1 measurable site of disease on computed tomography (CT) (defined as > 1.5 cm in longest transverse diameter of a lesion [LDi]) and clearly measurable in 2 perpendicular dimensions). Cohort 2 (R/R CLL) d) Histologically confirmed diagnosis of TP53wt CLL according to iwCLL criteria.. e) Previously treated with at least 1 prior regimen according to current guidelines. f) Active disease meeting at least 1 of the iwCLL 2008 criteria for requiring treatment (Appendix 6). 3. ECOG performance status of 0 to 2. 4. Adequate hematologic function independent of growth factor support for at least 7 days with the exception of pegylated G-CSF and darbepoetin which require at least 14 days, defined as: a) Absolute neutrophil count (ANC) ≥ 1,000/mm3 b) Platelet count ≥ 50,000/mm3. 5. Adequate hepatic function within 28 days prior to first dose defined as: a) Total bilirubin within normal limits (WNL); if total bilirubin is > upper limit of normal (ULN) then patients are eligible if the direct bilirubin is ≤ 2.0 x ULN b) Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 ULN. 6. Adequate renal function within 28 days prior to the first dose defined as an estimated creatinine clearance ≥ 30 mL/min by Cockcroft Gault. 7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, both male and female subjects must continue to use contraception for 6 months after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion or ligation; (e) vasectomized partner; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the prescribing information (PI) or summary of product characteristics (SmPC) must be followed for all concomitant drugs administered in this study.

    • Exclusion Criteria:

      1. Subjects with a history of CNS involvement. 2. Any recent prior therapy meeting one or more of the following criteria: a) Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy: i. DLBCL: Within 14 days prior to the first dose of study treatment. ii. CLL: Within 28 days prior to the first dose of study treatment. b) Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within 3 months prior to the first dose of study treatment. c) Subjects who have received immunosuppressive therapy for graft-versus-host disease within 6 months prior to first dose of study treatment. 3. Subjects previously treated with MDM2 antagonist therapies. 4. Subjects previously treated with a BTK inhibitor. 5. Subjects with a history of bleeding diathesis or major hemorrhage within 6 months prior to first dose of study treatment. 6. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug. 7. Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure, unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements. 8. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0]). 9. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach; or extensive small bowel resection that is likely to affect absorption; symptomatic inflammatory bowel disease, or partial or complete bowel obstruction; or gastric restrictions and bariatric surgery, such as gastric bypass. 10. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of enrollment. 11. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV). See Section 7.5.9 for additional details. 12. Known history of HIV. 13. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, preprohormone) within 7 days of first dose of study drug. 14. Phase 1 only: Requires treatment with a strong and/or moderate CYP3A inhibitor/inducer within 7 days prior to first dose of study drug. 15. Phase 2 only: Requires treatment with a strong CYP3A inhibitor/inducer within 7 days prior to first dose of study drug. 16. 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 provided the proton pump inhibitor is discontinued at least 5 days prior to first dose of study drug. 17. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma. 18. Subjects who have had major surgery within 28 days prior to the first dose. 19. Women who are pregnant or breastfeeding.

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  • SERENA-6: A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitors (Palbociclib or Abemaciclib) vs Continuing NSAI + CDK4/6 Inhibitors in HR+/HER2- MBC Patients with Detectable ESR1 Mutation Without Clinical or Radiological Progression During 1L Treatment with NSAI + CDK4/6 Inhibitor A ctDNA Guided Early Switch Study

    • Research Summary

      -

    • Inclusion Criteria:

      These criteria are to be checked to confirm eligibility of an ESR1m positive patient prior to randomisation for entry into the Study Treatment Phase of the study. Informed Consent 2.1 Evidence of a personally signed and dated informed consent document (ICF2) indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed. ICF2 must be signed and dated prior to initiation of the interventional study screening activities and randomisation outlined in Table 4. For those patients that wish to participate, provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative. This consent should be signed at Treatment Phase screening. If for any reason these samples are not collected at Treatment Phase screening, they may be taken at any time until the post treatment/disease relapse follow-up visit. For those patients that wish to participate, provision of signed and dated written Optional Pre-treatment and/or At Progression Tumour Sample Collection informed consent prior to collection of sample for optional translational research. This consent should be signed at the second screening for the Treatment Phase. Consent for tumour samples at disease progression could occur during the Treatment Phase. Weight 2.2 Minimum body weight of 35 kg. Type of Patient and Disease Characteristics 2.3 Patients who have ESR1m positive disease irrespective of concurrent mutation(s) detected by ctDNA during screening or surveillance. Qualifying ESR1m status (see Section 8.7.1.1) will be assessed by a prespecified Sponsor-selected assay at a central laboratory (see Section 8.7.1.1). 2.4 Confirmation that the patients are currently on treatment and have received ≥ 6 months (ie, 24 weeks) of AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib or abemaciclib) ± LHRH agonist treatment as their initial endocrine based treatment for their advanced disease in accordance with local palbociclib and abemaciclib label or treatment guidelines (a) Confirmation the patient has had no change in therapy since the start of STEP 1. Please note: (b) Dose modifications of the ongoing therapy are acceptable. 2.5 Documented absence of disease progression (by investigator assessment) prior to randomisation. (a) Clinical progression defined as unequivocal evidence of disease progression on clinical grounds in the absence of radiological progression, including development of new sites of disease or significant increase in tumour burden. (b) Radiological progression defined as unequivocal progression compared to previous imaging obtained during or prior to initiation of CDK4/6 inhibitor + AI. 2.6 Patients must be willing to provide archival radiological images (CT, MRI or bone scan, if not available, then available PET-CT scan is acceptable) used for tumour assessment at the initiation and/or during CDK4/6 inhibitor + AI for their metastatic disease treatment that support the non-PD assessment. 2.7 Eastern Cooperative Oncology Group performance status of 0 to 1. 2.8 Patients must have at least one evaluable lesion (defined as one lesion non previously irradiated, measurable and/or non-measurable, that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment). Patients with bone disease only must have at least one non previously irradiated lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. Bone scan at baseline is required. 2.9 Adequate organ and marrow function as follows: (a) Haemoglobin ≥ 9 g/dL (90 g/L). (b) Absolute neutrophil count ≥ 1000/mm3 (1.0 × 109/L) or documented institutional normal range for restarting palbociclib. (c) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia). (d) Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN; for patients on abemaciclib treatment, ALT and AST ≤ 5 × ULN. (e) Alkaline phosphatase ≤ 2.5 × ULN (≤ 5.0 × ULN if bone or liver metastases present) (f) Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight). (i) Males: CrCL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL) (i) Females: CrCL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL) Reproduction 2.10 For those female or male patients who are not abstinent (in line with their preferred and usual lifestyle choice), and intend to be heterosexually active with a partner: Female patients must be using 2 highly effective non-hormonal contraceptive measures from the time of screening until 4 weeks after discontinuation of study treatment, and must have a negative serum pregnancy test (with a test sensitivity of at least 25 mIU/mL) before first dose of any study treatment if they are of childbearing potential; or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: (a) Post-menopausal, defined as women with (i) Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (ii) Cessation of regular menses for at least 6 consecutive months with no alternative pathological or physiological cause AND with serum oestradiol and follicle stimulating hormone level within the laboratory's reference range for post-menopausal females (iii) Previous bilateral surgical oophorectomy Non sterilised male partners of a patient who is a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period (see Appendix G for complete list of highly effective birth control methods). Male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and the drug washout period (6 months after the last dose of study treatment) to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period. Concurrent Treatment 2.11 Pre-menopausal females and males who are currently receiving concurrent LHRH agonist (goserelin or leuprorelin) treatment while on CDK4/6 inhibitor + AI must be willing to continue to be treated with monthly LHRH agonists during the entire STEP2 treatment phase of the study. If the patients are currently receiving inhibition of LHRH treatment with alternative drugs or schedule other than monthly goserelin or leuprorelin, they must be willing to switch at the earliest practical time within STEP 2. 2.12 Male patients not currently receiving concurrent LHRH agonist treatment whilst on CDK4/6 inhibitor + AI must be willing to be treated with monthly LHRH agonists (goserelin or leuprorelin) unless the patients have clear orchiectomy medical history. Tumour Sample Requirements 2.13 Willingness and ability to provide an archived tissue tumour sample (Blocks or 12 unstained slides) to assess the correlation between genes, proteins, and RNAs relevant to the ER pathways and sensitivity/resistance to the investigational agents’ status/expression prior to enrolment as described in Section 8.7. Tissue from the most recent biopsy in the metastatic setting is preferred. If not available (for example bone only disease patients), then archival samples from the primary breast cancer will be required for patient participation. 2.14 Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

    • Exclusion Criteria:

      Patients are excluded from the study if any of the following criteria apply: Type of Patient and Disease Characteristics 2.1 No evidence of disease, or bone only disease with sclerotic/osteoblastic bone lesions only at the screening for STEP 2. Medical Conditions 2.2 Have advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal]), pulmonary lymphangitis. 2.3 Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of brain or other CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before the screening phase of the study. 2.4 Any evidence of severe or uncontrolled systemic diseases which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol. 2.5 Chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of CDK4/6 inhibitor and/or study (AI or AZD9833) treatment. 2.6 History of another primary malignancy except for the following: (a) Malignancy treated with curative intent with no known active disease ≥ 3 years before the first dose of study treatment, and of very low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease (c) Other exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has undergone potentially curative therapy. 2.7 Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss) after consultation with the AstraZeneca study physician. 2.8 Patients with CDK4/6 inhibitor treatment-induced symptomatic interstitial lung disease (Grade ≥ 2). 2.9 Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV (known positive HBsAg result), and HCV. 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. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required. 2.10 Known to have tested positive for HIV. Patients with HIV may be enrolled if they fulfil the criteria recommended by FDA and ASCO guidelines (FDA Guidance, Uldrick et al 2017): (a) CD4+ T-cell (CD4+) counts ≥ 350 cells/uL, AND (b) No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND (c) On established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment. Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load. 2.11 Unexplained syncope, symptomatic hypotension or asymptomatic hypotension with systolic blood pressure < 90 mmHg. 2.12 Second- and third-degree heart block, or clinically significant sinus pause or sinoatrial block. Patients with pacemakers or medically controlled atrial fibrillation are not excluded. 2.13 Left ventricular ejection fraction < 50% with heart failure NYHA Grade ≥ 2. 2.14 Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions (eg, cardiac valve repair or replacement surgery or transcatheter valve intervention), severe aortic regurgitation (Grade 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischaemic attack. 2.15 Untreated electrolyte abnormalities with potential QT-prolonging effect including serum/plasma potassium*, magnesium* and calcium* below the LLN. *Correction of electrolyte abnormalities to within normal ranges can be performed during screening. 2.16 Mean resting QTcF interval > 480 ms, obtained from triplicate ECGs performed at screening. 2.17 Resting heart rate < 60 beats per minute. 2.18 Uncontrolled hypertension. Blood pressure systolic > 160 and diastolic > 90 mmHg. Hypertensive patients may be eligible, but blood pressure must be adequately controlled at baseline. Patients may be rescreened regarding blood pressure requirement. Prior/Concomitant Therapy 2.19 Any concurrent anticancer treatment not specified in the protocol. Concurrent use of non-topical hormonal therapy for non cancer-related conditions (eg, hormone replacement therapy) is not allowed. 2.20 Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study treatment. 2.21 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days of the first dose of study treatment or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study. 2.22 Patients treated: (a) Within the last 2 weeks before randomisation: medications or herbal supplements known to be strong inhibitors/inducers of CYP3A4/5, sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin. (b) Within the timeframe indicated in Table I29 with drugs that are known to prolong the QT interval and have a known risk of TdP, as indicated in Appendix I 1. 2.23 Previous treatment with AZD9833, investigational SERDs/endocrine agents or fulvestrant. Prior/Concurrent Clinical Study Experience 2.24 Previous randomisation in the present study. 2.25 Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to randomisation or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 2.26 Patients with known hypersensitivity to anastrozole, or any of its excipients, or history of hypersensitivity to active or inactive excipients of AZD9833/placebo or drugs with a similar chemical structure or class to AZD9833 or known hypersensitivity to palbociclib and its excipients. In pre/perimenopausal female and male patients, known hypersensitivity to LHRH agonists or any of its excipients, that would preclude the patient from receiving any LHRH agonist. Note for patients who are receiving LHRH agonists. - Female patients with undiagnosed vaginal bleeding will be excluded. - Patients who are anticoagulated (INR > 2) and at higher risk of vascular injury and subsequent bleeding will be excluded. Other Exclusions 2.30 Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding. 2.31 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site or relative of those site staff members). 2.32 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.

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  • Prospective collection of donor tissue and blood or leukapheresis product from patients with solid tumours to enable development of methods for the manufacturing of clonal neoantigen T cell products (cNeT).

    • Research Summary

      -

    • Inclusion Criteria:

      1. Patient must be at least 18 years old at the Screening Visit. 2. Patient has given informed consent to participate in the study. 3. Suspected or confirmed diagnosis of Non-Small Cell Lung Cancer, melanoma or renal cancer with either primary, recurrent or metastatic disease scheduled for surgical excision and/or collection of multiple tissue samples via image or device guided biopsy. 4. Haemoglobin ‚â• 10g/dL. 5. White cell count ‚â• 3 x 109/L. 6. Negative laboratory test for blood borne pathogens (see exclusion criterion 5).

    • Exclusion Criteria:

      1. The patient is an employee of Achilles Therapeutics. 2. Clinical status precludes surgical removal of, or collection of multiple biopsies from, accessible tumour tissue. 3. Inadequate peripheral venous access precluding collection of blood. 4. Known pregnancy. 5. Known/laboratory confirmed diagnosis of an infectious disease preventing inclusion of tissue into cell manufacturing suite. As a minimum, the patient will undergo specific screening for the following infections: HIV 1 and 2, HTLV I/II, Hepatitis B, Hepatitis C, Syphilis (Appendix 1). 6. Patients who are currently participating in a clinical trial involving an unlicensed medical product. 7. Any medical reason why, in the opinion of the investigator, the patient should not participate in this study.

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  • A Phase 3 randomized, open label, multicenter study of isatuximab (SAR650984) in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma.

    • Research Summary

      Smoldering multiple myeloma is an asymptomatic PC disorder with a heterogenous risk of progression to MM . Customarily, not to treat and remain in observation until the onset of myeloma related events have been considered the standard of care for SMM, particularly for patients at low risk of early progression. However, the improvement in risk assessment and the availability of new drugs, among other achievements, have provided increasing evidence that question of whether early treatment is beneficial in SMM patients at higher risk of progression. CD38 is the most strongly and uniformly expressed antigen identified on the malignant clonal populations of myeloma cells, compared to its pattern of expression on normal cells. Therefore, this antigen may be a useful target for the in vivo depletion of tumor cells while sparing normal cells Isatuximab (SAR650984) is a mAb that binds selectively to a unique epitope on the human surface antigen CD38. Isatuximab kills tumor cells via multiple biological mechanisms, antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct induction of apoptosis (pro-apoptosis) without crosslinking, and inhibition of CD38 enzymatic activity. In conclusion: encouraging single agent activity in high-risk SMM was observed with isatuximab as single agent. This phase 3 study is addressing question of the benefit of adding isatuximab to the backbone lenalidomide and dexamethasone.

    • Inclusion Criteria:

      I 01. Participant must be at least 18 years of age inclusive or older, at the time of signing the informed consent. or country’s legal age of majority if the legal age is more than 18 years. I 02. Participant who are diagnosed within 5 years with SMM (per IMWG criteria, Appendix 5 [Section 10.5]) defined as: · Serum M-protein ≥ 30 g/L or urinary M-protein ≥ 500 mg per 24 hour or both, · and/or clonal BMPCs 10% to 60%. · And absence of myeloma defining events or other related conditions. I 03. High-risk SMM including at least 2 of 3 following abnormalities: a) Serum M-spike > 2 g/dL b) Serum involved/uninvolved FLC ratio > 20 c) BMPC > 20%. Or Presence of ≥ 10% BMPC and at least one of the following: · Serum M-protein ≥ 30g/L (If IgA; IgA ≥ 20g/L) · Serum involved/uninvolved FLC ratio ≥ 8 (but ≤ 100) · Progressive increase in M-protein level (evolving type of SMM; increase of serum Mprotein ≥ 10% on 2 successive evaluations within a 6-months period. · Abnormal PC immunophenotype (≥ 95% of BMPCs are clonal) and reduction of ≥ 1 uninvolved immunoglobulin isotype. (Only IgG; IgA and IgM will be considered). I 04. ECOG Performance Status 0 or 1 or 2. I 05. Absolute neutrophil count (ANC) ≥ 1000/mL. No G-CSF is permitted in order to reach this value before screening period. I 06. Platelets ≥ 50,000/mL (not permissible to transfuse a participant within 2 weeks prior to the screening platelet count to reach this level). I 07. Total bilirubin ≤ 3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be ≤ 5 mg/dL). I 08. Alanine aminotransferase ≤ 3 × upper limit of normal (ULN), aspartate aminotransferase ≤ 3 × ULN.

    • Exclusion Criteria:

      E 01. Evidence of any of the following CRAB criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to the participants SMM involvement): a) Increased calcium levels: Corrected serum calcium > 1 mg/dL above the ULN or > 11 mg/dL. b) Renal insufficiency: Determined by GFR < 40 mL/minute/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serum creatinine > 2 mg/dL. c) Anemia (hemoglobin 2 g/dL below lower limit of normal or < 10 g/dL or both) transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted. d) Clonal BMPCs ≥ 60%. e) Serum involved/uninvolved FLC ratio ≥ 100. f) WB-MRI or PET-CT with more than 1 focal lesion (> 5 mm in diameter by MRI). E 02. Primary systemic AL (immunoglobulin light chain) amyloidosis, MGUS, standard risk smoldering myeloma, symptomatic myeloma. E 03. Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study intervention administration in safety run-in. E 04. Clinically significant cardiac disease, including: a) Myocardial infarction within 6 months with left ventricular dysfunction or uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV). b) Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 5.0) or clinically significant electrocardiogram (ECG) abnormalities. E 05. Known acquired immunodeficiency syndrome (AIDS)-related illness or known human immunodeficiency virus (HIV)disease requiring antiviral treatment or active hepatitis A (defined as positive hepatitis A antigen or positive IgM), hepatitis B (defined as either positive hepatitis B surface antigen or positive hepatitis B viral DNA test above the lower limit of detection of the assay), or C infection (defined as a known positive hepatitis C antibody result or known quantitative hepatitis C [HCV] RNA results greater than the lower limits of detection of the assay). HIV serology at screening will be tested for German participants. E 06. Malabsorption syndrome or any condition that can significantly impact the absorption of lenalidomide. E 07. Any of the following within 3 months prior to randomization (or first study intervention administration in safety run-in cohort): treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event. E 08. Any severe acute or chronic medical condition which could impair the ability of the participant to participate to the study or interfere with interpretation of study results (eg, systemic infection unless anti-infective therapy is employed), or participant unable to comply with the study procedures. Prior/concomitant therapy. E 09. Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3 years of randomization (or first study intervention administration in safety run-in cohort). E 10. Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, immunomodulatory imid drugs, or Proteasome inhibitors). Concurrent use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab is not permitted; however, prior bisphosphonates or once a year IV bisphosphonate given for the treatment of osteoporosis is permitted. E 11. Ongoing treatment with corticosteroids with a dose > 10 mg prednisone or equivalent per day at the time of randomization (or first study intervention administration in safety run-in cohort).

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  • Predicting responsiveness in oncology patients based on host response evaluation during anti cancer treatments

    • Research Summary

      -

    • Inclusion Criteria:

      Target population 1. Patients with newly diagnosed stage IV NSCLC treated with Immunotherapy or Immunotherapy + Chemotherapy. 2. Patients with NSCLC stage IV treated with Immunotherapy at 2nd line or consecutive lines. 3. Patients with stage IV malignant melanoma treated with Immunotherapy with or without targeted therapy. 4. Patients with stage IIIb-d malignant melanoma treated with Immunotherapy as adjuvant therapy. 5. Patients with stage IV SCLC treated with Immunotherapy or Immunotherapy + Chemotherapy. Inclusion criteria 1. Provision of informed consent prior to any study-specific procedures. 2. Male or female aged at least 18 years. 3. ECOG PS – 0/1-2. 4. Normal hematologic, renal and liver function: • Absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, haemoglobin > 9 g/dL; • Creatinine concentration ≤ 1.4 mg/dL, or creatinine clearance > 40 mL/min; • Total bilirubin < 1.5 mg/dL, ALT+ AST levels ≤ 3 times above the upper normal limit. 5. The patient must have at least one measurable lesion and the relevant images in order to enable the assessment of the response.

    • Exclusion Criteria:

      1. Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of study drug. 2. Generalized impairment or mental incompetence that would render the patient unable to understand his/her participation in the study.

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  • A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB WITH OR WITHOUT TIRAGOLUMAB (ANTI-TIGIT ANTIBODY) IN PATIENTS WITH UNRESECTABLE LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

    • Research Summary

      -

    • Inclusion Criteria:

      Patients must meet the following criteria for study entry: ● Signed Informed Consent Form. ● Age ≥ 18 years at time of signing Informed Consent Form. ● Ability to comply with the study protocol, in the investigator's judgment. ● ECOG performance status of 0 or 1. ● Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus in locally advanced disease. ● Prior systemic treatment for esophageal cancer, with the following criteria: Patients must have received at least 2 cycles of platinum-based chemotherapy definitive with radiation therapy (50 to 64 Gy) without evidence of disease progression on treatment with enrollment within 1-42 days after last dose Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization. ● Stage II-IVa (NCCN v2.2019; CSCO 2019). ● Representative FFPE tumor specimens (either an archival specimen or fresh pre-treatment tissue from relapsed disease) in paraffin blocks (preferred) or at least 15 unstained slides. Patients with fewer than 12 unstained slides available at baseline may be eligible upon discussion with the Medical Monitor. Tumor tissue should be of good quality based on total and viable tumor content and must be evaluated for PD-L1 expression prior to enrollment. Patients whose tumor tissue is not evaluable for PD-L1 expression are not eligible. If multiple tumor specimens are submitted (e.g., an archival specimen and tissue from relapsed disease), patients may be eligible if at least one specimen is evaluable for PD-L1. For the purpose of stratification, the PD-L1 score of the patient will be the maximum PD-L1 score among the samples. A tumor specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must also be submitted, if clinically feasible. Acceptable samples include core needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. FFPE tumor specimens in paraffin blocks are preferred Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. ● Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization: - ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support - Lymphocyte count ≥ 0.5 x 109/L (500/µL) - Platelet count ≥ 100 x 109/L (100,000/µL) without transfusion - Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion. - INR or aPTT ≤ 1.5 x ULN This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. - AST, ALT, and ALP ≤ 2.5 x ULN, with the following exceptions: Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN Patients with documented liver or bone metastases: ALP ≤ 5 x ULN - Bilirubin ≤ 1.5 x ULN with the following exception: Patients with known Gilbert disease: bilirubin ≤ 3 x ULN - Creatinine ≤ 1.5 x ULN - Albumin ≥ 25 g/L (2.5 g/dL). ● Negative HIV test at screening. ● Patients with hepatitis B virus (HBV) and patients with inactive/asymptomatic carrier, chronic, or active HBV will be allowed if they have HBV DNA < 500 IU/mL (or 2500 copies/mL) at screening. NOTE: Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for > 2 weeks prior to enrollment and should continue treatment for 6 months after study drug treatment. ● Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test. ● For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below: Women must remain abstinent or use contraceptive methods with a failure rate of  1% per year during the treatment period and for 5 months after the final dose of study drugs. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of  1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. ● For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of study drugs to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

    • Exclusion Criteria:

      Patients who meet any of the following criteria will be excluded from study entry: ● Prior treatment with CD137 agonists, T-cell co-stimulating or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies. ● Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy. ● Evidence of complete esophageal obstruction not amenable to treatment. ● Those with the pathology of small cell esophageal carcinoma, esophageal adenocarcinoma or mixed carcinoma. ● Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 criteria. ● High risk for developing esophageal fistula by clinical assessment or imaging, such as prior history or associated symptoms of esophageal fistula or T4 classification by endoscopic ultrasound. ● No prior esophagetomy. ● Active EBV infection or known or suspected chronic active EBV infection at screening. Patients positive for EBV IgG and/or EBV nuclear antigen (EBNA) are eligible only if EBV IgM and/or EBV polymerase chain reaction (PCR) are negative. ● History of leptomeningeal disease. ● Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). ● Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, total serum calcium  12 mg/dL, or corrected calcium  ULN). ● Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse. ● Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone therapy are eligible for the study. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: - Rash must cover  10% of body surface area - Disease is well controlled at baseline and requires only low-potency topical corticosteroids - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. ● History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. ● Active tuberculosis. ● Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina. ● Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction  50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. ● Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of chemoradiation. ● History of malignancy other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. ● Patients with illnesses or conditions that interfere with their capacity to understand, follow, and/or comply with study procedures. ● Severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. ● Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to randomization. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. ● Prior allogeneic stem cell or solid organ transplantation. ● Any other diseases, metabolic dysfunction, physical examination finding, 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 render the patient at high risk for treatment complications. ● Treatment with any other investigational agent with therapeutic intent within 28 days prior to randomization. ● Has received any Chinese herbal medicine or Chinese patent medicines used to control cancer within 14 days of the first study drug administration. ● Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study. Patients must not receive live, attenuated influenza vaccines (e.g., FluMist®) within 4 weeks prior to randomization, during treatment, and for 5 months following the last dose of study treatment. ● Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to randomization. ● Treatment with systemic immunosuppressive medications (including, but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor confirmation has been obtained. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose mineralocorticoids for orthostatic hypotension or low-dose mineralocorticoids and corticosteroids for adrenal insufficiency are eligible for the study. ● History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. ● Known hypersensitivity to Chinese hamster ovary cell products or to any component of the tiragolumab or atezolizumab formulations. ● Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab or tiragolumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to randomization. End of Study The end of study will occur when both of the following criteria have been met: ● The required number of deaths for the final analysis of OS has been observed. ● The last patient, last visit has occurred. Additionally, the Sponsor may decide to terminate the study at any time. If the Sponsor decides to terminate the study, patients who are still receiving study treatment or undergoing survival follow-up may be enrolled in an extension study.

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  • A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants Whose Disease has Remained Stable or Responded to First-Line Platinum-Based Chemotherapy with Pembrolizumab for Stage IIIB or IV Non-Small Cell Lung Cancer

    • Research Summary

      Niraparib (GSK3985771) is a therapy being developed for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. Niraparib is approved in the UK for the treatment of some types of Ovarian cancer. The purpose of this study is to determine whether Niraparib is effective in treating NSCLC. Niraparib is a PARP (Poly (ADP-ribose) polymerase) inhibitor. PARP is a protein that helps all cells repair damaged DNA (DeoxyriboNucleic Acid). Cancer cells rely on PARP proteins to keep their DNA healthy, to continue growing and dividing. Niraparib stops the PARP protein from working, so the cancer cells die. Approximately 650 patients will be enrolled in the study globally, with 15 patients recruited from UK hospitals. The study has 3 parts: Screening, Treatment and Follow up. Screening: If the cancer has shrunk or stopped growing following standard of care first line treatment, the patient will undergo several tests to check whether they are suitable for the study. Treatment: Patients are assigned to treatment randomly. Half of the study-enrolled patients will receive Niraparib alongside an approved treatment called Pembrolizumab, the other half will receive placebo alongside Pembrolizumab. Neither the patient nor study doctors will know what treatment the patients are receiving. Pembrolizumab will be given as an infusion on Day 1 of each 21-day treatment cycle. Niraparib/placebo will be given as a tablet once daily throughout each treatment cycle. Follow-up: Once criteria for discontinuation of treatment is reached an end of trial visit is scheduled followed by safety follow up visits at 30 and 90 days after last dose. Survival follow up will continue every 90 days after last dose. Tests undertaken will include but are not limited to blood tests, imaging (CT /MRI) Scans, vital signs, medical history review and questionnaires.

    • Inclusion Criteria:

      1. Participants must be ≥ 18 years of age. 2. Participants must have a histologically or cytologically confirmed diagnosis of NSCLC without known targetable driver alteration (either non-squamous or squamous histology; mixed histology is allowed). 3. Participants must have advanced (Stage IIIB not amenable to definitive hemoradiotherapy) or metastatic (Stage IV) NSCLC as defined by the AJCC 8th Edition Staging Manual. 4. Participants must have completed at least 4 but no more than 6 cycles of platinum-based first-line induction chemotherapy with pembrolizumab (according to standard of care defined by NCCN and/or ESMO Clinical Practice Guidelines for NSCLC). 5. Participants must have SD, PR, or CR of their NSCLC per Investigator’s assessment after completion of 4 to 6 cycles of pembrolizumab plus platinum-based first-line induction chemotherapy. Note: Baseline imaging may be done as part of first-line induction period so long as imaging is within 28 days of randomization. If baseline imaging falls outside of this 28-day window, then new imaging will be needed (CT [preferred] or MRI scan [if clinically indicated] of the chest and abdomen, and MRI [preferred; CT if MRI not possible] of the CNS). 6. Participants must have an ECOG performance status of 0 or 1. 7. Participants must have a life expectancy of at least 12 weeks. 8. Participants must have adequate organ and bone marrow function defined as: Absolute neutrophil count: ≥ 1,500/μL Platelets: ≥ 100,000/μL Hemoglobin: ≥ 9 g/dL or 5.6 mmol/L Serum creatinine: < 2 × ULN Total bilirubin: ≤1.5 × ULN (except in participants with Gilbert’s syndrome. Participants with Gilbert’s syndrome: isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) AST and ALT: ≤ 2.5 × ULN (unless liver metastases are present, in which case they must be ≤ 5 × ULN). 9. Participants must submit FFPE tumor specimens preferably collected after being diagnosed with metastatic disease and prior to initiating induction therapy (chemotherapy or radiation) (ie, collected at time of diagnosis of advanced [Stage IIIB] or metastatic [Stage 4] NSCLC), from location(s) not irradiated prior to biopsy. Either tissue block or freshly cut slides (minimum of 5 slides; < 30 days from the date of sectioning) are acceptable. 10. Participants with toxicity from induction therapy must have recovered to Grade (A participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study.) 11. Participants must be able to swallow and retain orally administered study treatment. 12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a WOCBP. OR • Is a WOCBP and using a contraceptive method that is highly effective as defined in the protocol. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours before the first dose of study treatment. • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 13. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study treatment: • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception/barrier as detailed below: − Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a WOCBP who is not currently pregnant. 14. Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent.

    • Exclusion Criteria:

      1. Participants have mixed small cell lung cancer or sarcomatoid variant NSCLC. 2. Participants have received prior PARP inhibitor(s) in prior lines of treatment. 3. Participants have systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg. 4. Participants have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. 5. Participants have leptomeningeal disease, carcinomatous meningitis, symptomatic BM,or radiologic signs of CNS hemorrhage. Note: Participants with asymptomatic BM (ie, off corticosteroids and anticonvulsants for at least 7 days) are permitted. 6. Participants have received colony-stimulating factors (eg, granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment. 7. Participants have active or previously documented autoimmune or inflammatory disorder, including: a. Active infection b. Known diagnosis of immunodeficiency (including known history of human immunodeficiency, HIV, or infection) or is receiving chronic systemic steroid therapy (eg, > 30 days) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment c. Active autoimmune disease that has required systemic treatment in the 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) is not considered a form of systemic treatment. d. History of organ transplant. 8. Participants are receiving chronic systemic steroids (prednisone > 20 mg per day). 9. Participants have previously or are currently participating in a treatment study of an investigational agent within 4 weeks of the first dose of first-line induction therapy preceding the study. 10. Participants have received prior systemic cytotoxic chemotherapy (IV or intraperitoneal), biological therapy (including checkpoint inhibitor), or hormonal therapy for cancer, or received thoracic radiation therapy of > 30 Gy within 6 months of the first dose of the start of first-line induction therapy. 11. Participants have received live vaccine within 30 days of planned start of study randomization. 12. Participants have known hypersensitivity to the components of niraparib, placebo, or pembrolizumab or their formulation excipients. 13. Participants have undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery. 14. Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy. 15. Participants have any clinically significant concomitant disease or condition (such as transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the participants in this study. 16. Participants have any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures. Those conditions should be discussed with the participants before study entry. 17. Participants have high medical risk due to a serious, uncontrolled medical disorder; non-malignant systemic disease; or active, uncontrolled infection. 18. Participant is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment. 19. Participants have presence of hepatitis B surface antigen or a positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.For potent immunosuppressive agents, participants with presence of hepatitis B core antibody should also be excluded. 20. Participants have a known history of Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML). 21. Participants have a known history of active tuberculosis. 22. Participants have current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment.

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  • A randomized phase I trial in patients with newly-diagnosed, locoregionally advanced, HPV-negative, squamous cell carcinoma of the head and neck (SCCHN) evaluating a mutanome-directed immunotherapy initiated at completion of primary treatment or at time of recurrence.

    • Research Summary

      TG4050 is an investigational medicinal product manufactured specifically for each patient based on identification of tumour specific mutations. Tumour specific mutations expressed in the tumour tissue are detected by comparing the tumour and healthy tissue. In the following, mutated sequences are used to design a synthetic gene which is then cloned in a modified vaccinia Ankara viral vector. When administered to the patient TG4050 aims training the immune system to recognize the abnormal proteins coded by the mutated genes as foreign and then to destroy cancer cells that bear any of these proteins. In the TG4050.02 clinical trial the safety and activity of TG4050 are evaluated in patients with newly-diagnosed, locoregionally advanced, HPV-negative, squamous cell carcinoma of the head and neck (SCCHN). TG4050.02 consists of two distinct parts: • A screening phase starting at or just before surgery when patients’ samples (blood and tumour) are collected to manufacture a TG4050 individualized product. During this phase, the patients receive their primary treatment (chemotherapy and/or radiotherapy) per usual medical practice. • A treatment phase when patients receive TG4050 treatment. Patients in Arm A will receive TG4050 upon completion of primary treatment and radiological documentation of complete response. Patients in Arm B will receive TG4050 at the time of recurrence in combination with standard of care. Patient will receive TG4050 injections as long as not showing progressive disease and treatment is well tolerated for a maximum of 20 administrations. Arm A patients will receive a second round of TG4050 injections at the time of relapse if the first round has been well tolerated. Thirty patients will be enrolled in France and UK. In UK, patients will be enrolled in clinical centers located in Liverpool, London and Southampton.

    • Inclusion Criteria:

      Inclusion criteria for the screening period: 1. Signed written informed consent in accordance to ICH-GCP and national/local regulation before undertaking any protocol-specific procedures. 2. Newly diagnosed stage III or IVA squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx excluding HPV-positive oropharynx primaries. 3. Patients must have undergone gross total resection of the primary tumor. 4. Patients must be eligible for adjuvant therapy. 5. Tumor tissue from surgery and peripheral blood sample must be available for exome and transcriptome sequencing. 6. Female or male patients, aged at least 18 years. Inclusion criteria for the treatment period: 7. Patient must have completed adjuvant therapy and have a post-treatment CT or MRI of the head and neck and CT-scan of the chest documenting CR. Imaging has to be performed 3 months after completion of adjuvant therapy and within 6 weeks prior to randomization. 8. Patients must have recovered from the toxicities of adjuvant therapy. 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 10. Adequate hematological, hepatic and renal functions: • Hemoglobin ≥ 9.0 g/dL • Neutrophils count ≥ 1.5 x 109/L • Platelets count  100 x 109/L • Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome who may be included if total bilirubin ≤ 2.5 x ULN) • Serum transaminases: alanine aminotransferase [ALT] and aspartate aminotransferase [AST])  2.5 x ULN • Calculated creatinine clearance  40 mL/min using the Cockroft & Gault formula • Serum albumin ≥ 30 g/L. 11. No locoregional relapse or occurrence of distant metastases within 6 weeks prior to randomization. 12. No active infection. 13. Highly Effective contraception (i.e. methods with a failure rate of less than 1% per year) during the study period and for 3 months after the last study treatment administration for female patients of childbearing potential (WOCBP) and for male patients who are sexually active with WOCBP (See Appendix II for WOCBP definition and details on highly effective contraception methods). Highly effective contraception methods are defined as: • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, intrauterine devices (IUDs) such as Mirena and Nonhormonal IUDs such as ParaGard for WOCBP patient or male patient’s WOCBP partner • Tubal ligation • Vasectomy In addition to highly effective contraception, participating male patients must use a condom during the study period and for 3 months after the last study treatment administration. 14. Negative blood pregnancy test for female patients of childbearing potential.

    • Exclusion Criteria:

      Exclusion criteria for the screening period: 1. Patients with carcinoma of the nasopharynx, squamous cell-carcinoma of unknown primary, squamous cell carcinoma that originates from the skin and salivary gland or paranasal sinus, non-squamous histologies. 2. Prior exposure to cancer immunotherapy including anti-cancer vaccines, any antibody targeting T-cell co-regulatory proteins such as anti-PD1, anti-PDL1 or anti-CTLA4 antibodies. 3. Other active malignancy requiring concurrent systemic intervention. 4. Patients with previous malignancies other than the target malignancy to be investigated in this trial (exceptions: non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry. Additional therapy must not be planned or required during the study period. 5. Patients with any organ transplantation, including allogeneic stem cell or bone marrow transplantation. 6. Any known allergy or reaction to eggs or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products. 7. Known history of positive testing for Human Immunodeficiency Virus (HIV) or known Acquired Immune Deficiency Syndrome (AIDS). 8. Clinical or laboratory history or evidence of Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) indicating acute or chronic infection. 9. Any psychological, familiar, 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. 10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL). Exclusion criteria for the treatment period: 11. Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to TG4050 treatment initiation, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed. 12. Vaccination with a live vaccine for the prevention of infectious diseases in the four-week period prior to TG4050 treatment initiation. 13. Treatment with another investigational agent within 30 days prior to TG4050 treatment initiation. 14. Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social circumstances that could limit compliance with study requirements.

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  • A Randomized, Open-Label, Phase 3 Trial of Epcoritamab vs Investigator’s Choice Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma

    • Research Summary

      This is an open-label (participant and doctor know which medication will be given), global, Phase 3 trial of epcoritamab versus pre-specified investigator’s choice of chemotherapy in subjects with Relapsed (reappeared) or Refractory (no response to treatment) (R/R) diffuse large B-cell lymphoma (DLBCL) who failed or are ineligible for autologous stem cell transplant (ASCT). Every participant has either the chance to receive epcoritamab or investigator’s choice of chemotherapy; sites will choose 1 of 2 chemotherapy options in advance: Rituximab+ Gemcitabine and Oxaliplatin (R-GemOx) or Bendamustine-Rituximab (BR). Approximately 480 subjects (240 in each arm) will be enrolled in the trial with a primary endpoint of Overall Survival. In the epcoritamab arm, treatment will be administered as subcutaneous (Under the skin) injections using a step-up dosing method: priming dose at 0.16 mg on Cycle 1 Day 1, followed by intermediate dose at 0.8 mg on C1D8, and then full doses at 48 mg on C1D15 and C1D22. Each treatment cycle is 28 days. Full doses (48 mg) will be then given on Days 1, 8, 15, 22 of C2 and 3, D1 and D15 of C4-9, and D1 of cycles thereafter (C10+), with treatment until progressive disease or unacceptable toxicity. In the Investigator’s choice arm, subjects will receive one of the following: o R-GemOx: rituximab 375 mg/m2 IV on D1 and D15 and gemcitabine 1000 mg/m2 IV followed by oxaliplatin 100 mg/m2 IV on D2 and D16 of each 28-day cycle for up to 4 cycles (8 doses) o BR: rituximab 375 mg/m2 IV on Day 1 and bendamustine 90 mg/m2 IV on D1 and D2 of each 21-day cycle for up to 6 cycles

    • Inclusion Criteria:

      • Must be at least 18 years of age (≥ 20 years of age in Japan); • Subject [(or their legally acceptable representative)] must sign an ICF indicating that the purpose of the trial and the procedures required for the trial are understood, and indicating that the subject is willing to participate in the trial prior to initiating any other trial-related assessments or procedures; • ECOG PS score of 0-2; • Histologically confirmed CD20+ DLBCL, NOS (according to the WHO 2016 classification) and including: o Subjects with de novo or histologically transformed (including Richter’s transformation) o Subjects with “double-hit” or “triple-hit” (technically classified in WHO 2016 as high-grade B-cell lymphoma (HGBCL), with MYC and BCL2 and/or BCL6 translocations) Note: other double-/triple-hit lymphomas and those classified in WHO 2016 as HGBCL, NOS are not eligible o Subjects with follicular lymphoma Grade 3B; • CD20-positivity at most recent (previous or current) representative tumor biopsy based on the pathology report; • Relapsed or refractory disease and previously treated with at least 1 line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy o Relapsed disease is defined as disease that has recurred ≥ 6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (< 6 months) of completion of therapy. • Failed previous HDT-ASCT or not eligible for HDT-ASCT at screening. If ineligible for HDT-ASCT, the decision must have been based on age, performance status, and/or comorbidity, and/or insufficient response to prior treatment; • Has measurable disease: o A FDG- PET scan demonstrating positive lesion compatible with CT or MRI-defined anatomical tumor sites o ≥ 1 measurable nodal lesion (long axis > 1.5 cm and short axis > 1.0 cm) or ≥ 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI; • Absolute neutrophil count ≥ 1.0 × 109/L (growth factor permitted); • Platelet count > 75 x 109/L (or > 50 x 109/L if bone marrow involvement or splenomegaly); • Alanine aminotransferase level ≤ 3 times the upper limit of normal (xULN); • Total bilirubin level ≤ 2 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin; • Estimated GFR ≥ 40 mL/min/1.73m2; • PT/INR/aPTT ≤ 1.5 xULN, unless receiving anticoagulation. NOTE: An exhaustive list of Inclusion Criteria is listed in the study protocol.

    • Exclusion Criteria:

      • Primary CNS tumor or known CNS involvement as assessed by brain MRI at screening; • Any prior therapy with a bispecific antibody targeting CD3 and CD20; • History of severe allergic or anaphylactic reactions to anti-CD20 antibody therapy; • Contraindication to any component of SOC regimen selected by site; • Radiation therapy, or major surgery within 4 weeks prior to randomization; • Chemotherapy within 4 weeks or 5 half-lives (whichever is shorter) prior to randomization; • Non-investigational antineoplastic agents or any investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to randomization; • ASCT within 100 days of randomization; • Treatment with CAR-T therapy within 30 days prior randomization; • Cumulative dose of corticosteroids more than the equivalent of ≥ 140 mg of prednisone within 2-week period prior to randomization; • Vaccination with live vaccines within 28 days prior to the first dose of epcoritamab; • Clinically significant cardiac disease, including: O Myocardial infarction within 1 year prior to the first dose of epcoritamab, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV) cardiac arrhythmia (CTCAE Version 5 Grade 2 or higher), or clinically significant ECG abnormalities; • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec; • Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results; • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment at time of randomization; • Known history of or positive test results confirming Human Immunodeficiency Virus (HIV) infection; • Active HBV (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection). Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy. Subjects who received treatment for HCV that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. • Has known past or current malignancy other than inclusion diagnosis, except for: O Cervical carcinoma of Stage 1B or less O Non-invasive basal cell or squamous cell skin carcinoma O Non-invasive, superficial bladder cancer O Prostate cancer with a current prostate specific antigen (PSA) level < 0.1 ng/mL O Any curable cancer with a complete response of > 2 years duration; • Has known or suspected allergies, hypersensitivity, or intolerance to epcoritamab or its excipients (refer to the Investigator's Brochure for more information); • Contraindication to all uric acid lowering agents; • A woman of childbearing potential with a positive serum or urine pregnancy test at screening or lactating females; • Clinically significant liver disease, including active hepatitis, current alcohol abuse, or cirrhosis; • Suspected active or latent tuberculosis; • Positive test results for the HTLV-1. NOTE: An exhaustive list of Exclusion Criteria is listed in the study protocol.

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  • Long-Term Follow-up Protocol for Subjects Treated with Gene-Modified T cells

    • Research Summary

      -

    • Inclusion Criteria:

      Patients who received at least one dose of JCAR017 in a previous treatment protocol, and have discontinued, or completed the post-treatment follow-up period in a previous JCAR017 protocol, as applicable.

    • Exclusion Criteria:

      There are no exclusion criteria.

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  • An Open-Label, Multi-Centre Phase I/IIa Study Evaluating the Safety and Clinical Activity of Neoantigen Reactive T cells in Patients with Metastatic or Recurrent Melanoma (THETIS)

    • Research Summary

      Published literature indicates that tumours arise as a consequence of a series of mutations in normal tissue, and that most tumour growth stems from the original clonal mutations within the tumour. This is a clinical study evaluating the safety and clinical response of a novel personalised therapy (termed ATL001) designed to attack patient specific clonal mutations that are hypothesised to occur solely within all cancer cells. This clinical study will treat adult patients (aged 18 and over) with metastatic or recurrent melanoma in selected hospitals who have experience handling this type of product and treating this stage of disease. The study will begin with the collection of patient material used to manufacture the therapeutic product. This will involve a surgical procedure and collection of blood samples. Whilst the product is being made patient will undergo standard treatment. Following successful manufacture of the product and as per protocol criteria, patients will be eligible to receive their personalised treatment. This will involve approximately 2 weeks of treatment which includes chemotherapy followed by administration of ATL001, and a product to help ATL001 kill the cancer cells. After this period of treatment, patients will be asked to visit the hospital a number of times over the next 2 year period to give blood samples and to have a scan to see if ATL001 has killed the cancer cells. Each patient will continue to be followed up for a further 5 years, as part of a separate protocol. If this clinical trial shows that ATL001 is safe and shows a level of effectiveness in treating melanoma, it will likely enable further development of ATL001 for more patients with melanoma and also patients with different cancers all based on the ability to target individual specific clonal mutations within the cancer cells.

    • Inclusion Criteria:

      Inclusion criteria will apply at multiple timepoints. Inclusion criteria 1. Patient must be at least 18 years old at the screening visit. 2. Patient must have given written informed consent to participate in the study. 3. Histologically confirmed diagnosis of melanoma. 4. Patients must have received a PD-1 inhibitor prior to treatment with ATL001. 5. Patients whose tumour is known to have a BRAF V600 mutation must have received BRAF targeted therapy (as well as a PD-1 inhibitor) prior to treatment with ATL001. 6. Patient is considered medically fit enough to undergo all study procedures and interventions: procedures to procure blood and tumour tissue, including a general anaesthetic if required, and to receive fludarabine, cyclophosphamide and IL-2 at protocol doses and schedules. 7. Patient is considered, in the opinion of the investigator, capable of adhering to the protocol. 8. ECOG Performance Status 0-1. 9. Adequate organ function, indicated by the following laboratory parameters: a. Haemoglobin > = 10.0 g/dL. b. White Blood Cell Count (WBC) > = 3.0 x10⁹/L. c. Absolute Neutrophil count (ANC) > = 1.5 x 10⁹/L. d. Platelets > = 100 x 10⁹/L. e. PT and APTT < 1.5 x ULN (unless receiving therapeutic anticoagulation). f. AST or ALT < = 2.5 x ULN. g. Bilirubin < 1.5 x ULN (or < 3 x ULN in Gilbert’s Syndrome). h. Creatinine clearance/estimated GFR > = 50 ml/min. 10. Female patients who are of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 12 months after the ATL001 infusion. Patients with female partners of childbearing potential must agree to use adequate contraception for at least 6 months after the ATL001 infusion. See Section 4.3 of the protocol for details of acceptable methods of contraception. In addition to 1-10, the following inclusion criteria must be met prior to tissue procurement: 11.To be eligible for this study a patient must fall into one of the following groups: a) Patients with unresectable metastatic disease (newly diagnosed or recurrent) who have had no prior systemic therapy for advanced disease and who have accessible sites of disease suitable collection of adequate tissue for ATL001 manufacture. b) Patients with high risk locally advanced resectable disease (i.e. palpable Stage III) who are scheduled to undergo surgery. These patients are not candidates for immediate treatment with ATL001 but may be treated in this protocol if the disease recurs. In these patients the tumour samples will be stored in compliance with the appropriate regulations to enable future manufacture and treatment with ATL001. c) Patients with unresectable metastatic disease who are on or have completed first line systemic therapy and have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. d) Other patients with unresectable advanced stage disease for whom no other alternative approved treatments are available, may be considered on a case-by-case basis and should be discussed with the Sponsor prior to enrolment. 12. Anticipated life expectancy > = 6 months at the time of tissue procurement. In addition to 1-10, the following inclusion criteria must be met prior to lymphodepletion and treatment with ATL001: 13. Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. (If patients have no measurable disease following standard therapy, lymphodepletion and ATL001 treatment may be delayed until there is evidence of measurable disease). 14. Patient is considered well enough to receive ATL001 treatment.

    • Exclusion Criteria:

      Exclusion criteria will apply at multiple timepoints. Exclusion criteria: 1. Patients with known leptomeningeal disease or CNS metastases. 2. Patients with ocular melanoma. 3. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection. 4. Patients with active autoimmune disease requiring immunosuppressive therapy. 5. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day (or equivalent). 6. Patients with a current or recent history, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease. 7. Patients who are pregnant or breastfeeding. 8. Patients who have undergone major surgery in the previous 3 weeks. 9. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except for in situ carcinomas, early prostate cancer with normal PSA or non-melanomatous skin cancers). 10. Patients with a history of organ transplantation. 11. Patients who have previously received any investigational cell or gene therapies. 12. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses (see Investigator Brochure for details). In addition to 1-12, the following exclusion criteria apply to patients who completed first line therapy prior to study entry: 13. Patients who have received any anti-cancer therapy within the 3 weeks prior to blood and tumour tissue procurement. In addition to 1-12, the following exclusion criteria apply to all patients prior to lymphodepletion and treatment with ATL001: 14. Patients who have received a live vaccination within the 28 days prior to lymphodepletion. 15. Patients with an active infection requiring antibiotics. 16. Patients who have received any anti-cancer therapy within the 3 weeks prior to lymphodepletion.

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  • A Post-Authorisation Safety Study Patient Registry of patients with high-risk neuroblastoma being treated with the monoclonal antibody dinutuximab beta

    • Research Summary

      This study is a multi-national,observational, prospective registry of patients with high-risk neuroblastoma treated with dinutuximab beta. The study is non-interventional. All investigations and treatment decisions are made according to normal clinical practice and are not mandated by the protocol. Data collection will occur at baseline, during treatment and during the 10 year follow-up period.During the treatment phase, data will be collected on dose, total cumulative amount of dinutuximab beta per course, dose interruptions, dose discontinuations, prophylactic treatment, use of all concomitant analgesia, assessments of pain, and occurrence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions and other AEs. The study will have a 10 year follow-up period and the data will be collected from the subject approximately 14 times during this 10 year period. The doctor will collect information from the subject four times in the first year (approximately every three months in Year 1), two times in the second year (six monthly in Year 2) and once a year after that up until Year 10. Countries participating in this study may include (but is not restricted to) Austria, France, Spain, Italy, Germany, Poland and the United, Kingdom.

    • Inclusion Criteria:

      Patients meeting the following criteria will be considered for inclusion into the registry: 1. Patients diagnosed with high-risk neuroblastoma and starting treatment with commercially available dinutuximab beta OR 2. Patients diagnosed with high-risk neuroblastoma and starting treatment with dinutuximab beta in a clinical trial where dinutuximab beta is provided according to the country/regional marketing authorisation AND 3. Appropriate consent/assent has been obtained for participation in the registry with a willingness to be followed up for up to 10 years.

    • Exclusion Criteria:

      Patient will not be eligible for inclusion if the following criterion applies: 1. Patients commencing dinutuximab beta within a clinical trial where the product is being provided outside of the country/regional marketing authorisation OR 2. Appropriate consent/assent has not been obtained for participation in the registry or patient/legal representative is not willing for the patient be followed up for up to 10 years.

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  • An open-label Phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy in patients with advanced haematological malignancies.

    • Research Summary

      CCS1477 is a new experimental medication (sponsored by CellCentric Ltd) for a group of cancers that effect the blood and/or bone marrow. These include Acute Myeloid Leukaemia (AML), high-risk Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL). It is aimed at tumours that are not responsive to, or have become resistant to, existing medications used in late stage disease. The purpose of this study is to examine the safety, tolerability, pharmacokinetics (PK) and efficacy of CCS1477 when treating patients with the above disorders. It is expected that approximately 90 patients will be recruited from up to 10 hospitals in the UK. The study has 5 parts consisting of dose escalation and expansion cohorts. Patients will have regular clinic visits for various safety and clinical benefit assessments, to monitor any side effects and to find out how CCS1477 is handled by the body and affects this group of cancers. The information gained in this study will help the sponsor to determine whether CCS1477 is suitable for further studies in humans.

    • Inclusion Criteria:

      1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. 2. Willing and able to participate in all required evaluations and procedures in this study protocol. 3. Men and women ≥ 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (NHL, MM and AML). Patients will include but are not limited to the following: • B-cell non-Hodgkin lymphoma (including Richter’s Syndrome) • T-cell non-Hodgkin lymphoma • Multiple myeloma • AML/secondary AML (patients with acute promyelocytic leukemia (APL) (FAB subtype M3) will be excluded). • High-risk MDS; according to revised International Prognostic Scoring System (IPSS-R). 6. Must have received standard therapy (for the majority of therapeutic indications - at least 2 prior lines of therapy) - refer to relevant disease guidelines, such as European Society for Medical Oncology (ESMO), International Myeloma Working Group (IMWG) or National Comprehensive Cancer Network (NCCN) guidelines. In circumstances where there may be no standard of care, or intensive treatment would not be tolerable or is refused, patients may be considered eligible for the study upon consultation and agreement between the medical monitor and the treating Investigator. 7. Adequate haematologic function defined as: • Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 10^9/L). • Platelet count without requiring ongoing blood product support ≥ 75,000 cells/mm3 (75 x 10^9/L). Platelet transfusions are not permitted within 3 days of screening. • Haemoglobin level ≥ 80 g/L. This criterion does not apply to AML/MDS patients. Patients with other malignancies involving bone marrow with parameters below the threshold may be considered eligible following discussion with the medical monitor. • For AML, WBC must be < 10,000/µl. 8. Adequate organ function at screening defined as: • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), or AST/ALT ≤ 5 x ULN (with underlying liver involvement following discussion with the medical monitor). • Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, patients with borderline elevation due to underlying liver involvement may be eligible following discussion with the medical monitor). • Serum creatinine < 1.5 x ULN, OR creatinine clearance ≥ 50 mL/min as measured or calculated by Cockcroft and Gault equation, or ≥ 30 mL/min in patients with kidney function affected by the underlying malignancy • Serum albumin > 2.5 g/dL.

    • Exclusion Criteria:

      Patients must not enter the study if any of the following exclusion criteria are fulfilled 1. Treatment with any of the following: • Any investigational agent, chemotherapy, immunotherapy or anticancer agents from a previous clinical study within 14 days or 5 half-lives of first dose of study treatment. Shorter wash-out may be considered for immunotherapies after discussion with medical monitor. • Strong inducers of CYP3A4 taken within 4 weeks of the first dose of study treatment or whilst on study treatment. • Strong inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment or while on study treatment. • CYP2C8 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment or while on study treatment. • Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment; palliative radiotherapy to ≤ 30% of the bone marrow within 2 weeks of the first dose of study treatment. • Herbal medications taken within 7 days of the first dose of study treatment (4 weeks for St John’s wort) or while on study treatment. • Statins; patients should discontinue statins prior to starting study treatment. • Steroids use > 10mg daily prednisolone or equivalent within 2 weeks of the first dose of study treatment. • Major surgery within 4 weeks of the first dose of study treatment. 2. With the exception of alopecia, and CTCAE Grade 2 neuropathy, any unresolved toxicities from prior therapy > Grade 1 at the time of starting study treatment. 3. Presence of, or history of, CNS lymphoma, symptomatic leptomeningeal disease, or spinal cord compression. 4. History of prior non-haematologic malignancy except for the following: • Adequately treated carcinoma in situ or non-melanomatous skin cancer • Malignancy treated with curative intent or in remission for > 6 months after the last therapy may be eligible after discussion with medical monitor. Maintenance treatment (eg. hormonal therapy) is allowed. 5. Any evidence of severe or uncontrolled systemic disease (e.g. current unstable or uncompensated respiratory or cardiac conditions; history of, or active, bleeding diatheses; uncontrolled active systemic infection, including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)*), which in the investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol. *Active viral infection is defined as requiring antiviral therapy. Screening for chronic conditions is not required. 6. Repeatable QTcF prolongation (> 480 msec). 7. History of severe allergic or anaphylactic reactions or history of hypersensitivity to active or inactive excipients of CCS1477. 8. Female patients who are pregnant or breast-feeding at study entry. 9. 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.

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  • A Pivotal Phase 2 Trial of Antibody Naxitamab (hu3F8) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients with Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow.

    • Research Summary

      Patients will be invited to take part in this study if they have neuroblastoma which has either not responded adequately to treatment or has relapsed in the bones and/or bone marrow. Neuroblastoma is one of the most common childhood cancers and accounts for a high proportion of childhood cancer deaths. The majority of patients have 'high risk' disease, with metastatic bone/bone marrow disease. Outcome in patients who don't respond well to frontline treatment, or who relapse after treatment, is extremely poor. The purpose of this research is to find out about the treatment effects of an antibody called humanized 3F8 (hu3F8/Naxitamab). In the last decade, antibody therapy has become part of the standard care for children with high risk neuroblastoma. Antibodies are proteins produced by the immune system to fight infections, but can also potentially be used to attack tumour cells. In order to enhance the positive effect of Naxitamab, the treatment will be combined with granulocyte-macrophage colony stimulating factor (GM-CSF). Granulocytes are white blood cells that are able to destroy cancer cells and GM-CSF increases the ability of granulocytes to more effectively kill cancer cells. The only treatment that is being tested in this trial is Naxitamab (hu3F8) in combination with GM-CSF, and all enrolled patients will receive both. Patients can receive treatment for up to 101 weeks following first administration via infusion of Naxitamab- hu3F8 and injections of GM-CSF. Depending on how the participant responds it is up to the treating investigator to decide how many cycles of treatment is required. After treatment has completed, patients will undergo long term follow up of 3 years during which patients will attend visits twice a year to monitor post treatment effects. This study will take place across 6 countries (UK, Spain, Denmark, United States Canada and Hong Kong.

    • Inclusion Criteria:

      1. Documented diagnosis of NB as defined per INRC as a. histopathology of tumor biopsy, or b. BM aspirate or biopsy indicative of NB by histology, plus high blood or urine catecholamine metabolite levels or Myelocytomatosis Viral-Related Oncogene, Neuroblastoma derived (MYCN) amplification, or c. MIBG-avid lesion(s) 2. High-risk NB patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including SD, MR and PR) evaluable in bone and/or BM as defined in section 6.7 in the protocol. 3. Life expectancy > = 6 months 4. Age > = 12 months 5. Acceptable hematological status, (hematological support is allowed if administered > = 1 week before first infusion of naxitamab), defined as: a. Hemoglobin > = 8 g/dL (5.0 mmol/L) b. White blood cell count > = 1000/μL c. Absolute neutrophil count (ANC) > = 500/μL d. Platelet count > = 25,000/μL 6. Acceptable liver function defined as: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < = 5 times upper limit of normal (ULN) b. Bilirubin < = 1.5 x ULN 7. Acceptable kidney function defined as: a. Estimated Glomerular Filtration Rate (eGFR) > 60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation 8. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations.

    • Exclusion Criteria:

      1. Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks before 1st dose of GM-CSF 2. Evaluable NB outside bone and BM 3. Actively progressing disease at trial entry 4. Existing major organ dysfunction > Grade 2, with the exception of hearing loss, hematological status, kidney and liver function. 5. Active life-threatening infection 6. Prior treatment with naxitamab 7. Karnofsky/Lansky score < 50% 8. Pregnancy or a woman who is breast-feeding (women of child-bearing potential must have a negative pregnancy test at screening). A woman of child-bearing potential is excluded if she does not agree to use adequate contraception for a period of 40 days after the last naxitamab infusion: intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections). In certain cases, it is accepted to use double barrier methods (a condom combined with a diaphragm). A sterilized or infertile woman is exempt from the requirement to use contraception after naxitamab treatment: she must have undergone surgical sterilization (hysterectomy, or bilateral ovariectomy) 9. Inability to comply with protocol requirements, including PK studies, as determined by the investigator 10. History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of the product.

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  • Pan Tumor Study for Long Term Follow-up of Cancer Survivors Who Have Participated in Trials Investigating Nivolumab

    • Research Summary

      The purpose of this study is to collect the long-term safety and survival information in participants with different tumour types who will be provided nivolumab or have finished treatment and are now in or have completed follow-up on a Bristol-Myers Squibb (BMS) clinical research study (parent study). The Sponsor for this clinical research study is Bristol-Myers Squibb (BMS) There is not a specific number of patients participating. Enrolment in the study is on a rolling basis and is dependent on the patient’s status in the BMS clinical trial (parent study). Their participation may be either: • as a participant who is being treated with nivolumab from a previous BMS clinical trial. The study doctor will continue to assess long-term safety and survival information. • as a participant who is being followed for survival or has completed follow-up from a previous BMS clinical study, having completed, discontinued, or progressed on treatment, and/or on another therapy. The study doctor will continue to assess long-term safety and survival. This study is being conducted at multiple clinical sites in the United Kingdom and Europe.

    • Inclusion Criteria:

      Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal participant care. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. Participants who have completed treatment with nivolumab, progressed on prior nivolumab treatment or discontinued nivolumab due to toxicity, in the Parent Study are not eligible to receive nivolumab in this study. These participants may be enrolled for safety and survival follow-up only. Participant is eligible for nivolumab treatment as per the Parent Study, and/or Investigator assessed clinical benefit, or Participant is in or has completed the follow-up phase of the Parent Study i) Participant has completed or discontinued treatment, or ii) Participant has progressed on treatment, and/or iii) Participant is on subsequent therapy. Male and female participants ages 18 and older.

    • Exclusion Criteria:

      Participant is not eligible for nivolumab treatment as per the Parent Study. Participants not receiving clinical benefit as assessed by the Investigator (participant is still eligible for study if entering survival follow-up only). Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the opinion of the Investigator, indicates that participation in the study is not in the best interest of the participant. History of allergy or hypersensitivity to study drug components. Prisoners or participants who are involuntarily incarcerated (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.) Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. Dementia or serious psychiatric condition that may compromise the informed consent process and increase the risks associated with study participation. Participants with any condition which, in the judgment of the Investigator, may pose a significant risk to the subject. Participants in survival follow-up have no exclusion criteria. Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.

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  • An international field study for the reliability and validity of the EORTC PATSAT-C33 core questionnaire and the EORTC OUT-PATSAT7 module

    • Research Summary

      The European Organisation of Research and Treatment of Cancer’s Quality of Life Group (EORTC QLG) has developed a four-phase framework that can be used to develop and validate quality of life questionnaires for individuals with cancer. These are developed as modules to supplement their existing EORTC core quality of life questionnaire, the ‘QLQ-C30’. For example, modules have previously been developed for endometrial cancer (QLQEN24), bone metastases (QLQ-BM22), and cancer-related fatigue (QLQ-FA12). The four-phase approach comprises a literature review followed by interviews with patients and clinicians (Phase 1), construction of a questionnaire (Phase 2), refinement of the questionnaire (Phase 3), and finally administration of the questionnaire to an international sample in a full validation study (Phase 4). The present study aims to contribute to the development of a module designed to measure cancer patient satisfaction with care (PATSAT-C33 and OUT-PATSAT7). The study aims to undertake Phase 4 of the above module development process.

    • Inclusion Criteria:

      • Provision of written informed consent to participate in the study • Histological diagnosis of cancer • Aged > = 18 years • Patients have had a sufficient experience of the cancer out-patient treatment setting, i.e. - between 3 to 6 cycles of chemotherapy - at least 2 cycles of other cancer treatment (e.g., biological oral therapy) - 2 to 6 weeks of radiotherapy - within the 3rd to 24th month post-cancer treatment - at least 3 days of hospital stay

    • Exclusion Criteria:

      • Unable to speak English • Participated in Phase 3b of the module development • Cognitive impairment which presents an obstacle to the completion of questionnaires or an interview • The documentation of an ongoing psychiatric condition in the patient’s medical notes to which the researchers have access • Patient is participating in another patient-reported outcome investigation that may interfere with this study

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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

      The purpose of this study is to evaluate efficacy of erdafitinib versus chemotherapy or pembrolizumab in participants with advanced urothelial cancer harboring selected fibroblast growth factor receptor (FGFR) aberrations who have progressed after 1 or 2 prior treatments, at least 1 of which includes an anti-PD-(L) 1 agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2).

      A study of erdafitinib versus standard of care, consisting of chemotherapy (docetaxel or vinflunine) or anti-PD-(L) 1 agent pembrolizumab, in participants with advanced urothelial cancer and selected FGFR aberrations who have progressed on or after 1 or 2 prior treatments, at least 1 of which includes an anti-PD-(L) 1 agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2). It will consist of screening, treatment phase (from randomization until disease progression, intolerable toxicity, withdrawal of consent or decision by investigator to discontinue treatment, post-treatment followup (from end-of-treatment to participants death, withdraws consent, lost to follow-up, or end of study, whichever comes first). Efficacy, pharmacokinetics, biomarkers, patient reported outcomes, medical resource utilization and safety will be assessed.

    • 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 (b-human chorionic gonadotropin [bhCG]) 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.

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  • An open-label Phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination, in patients with advanced solid/metastatic tumours.

    • Research Summary

      CCS1477 is a new experimental medication (sponsored by CellCentric Ltd) for a type of prostate cancer called metastatic castration resistant prostate cancer (mCRPC). It is aimed at tumours that are not responsive to, or have become resistant to, existing medications used in late stage disease. CCS1477 may also be used for other cancers with specific gene mutations, again where existing treatments are no longer working. The purpose of this study is to examine the safety, tolerability, pharmacokinetics (PK) and efficacy of CCS1477 when treating patients with mCRPC, when given alone or in combination with other standard mCRPC therapies, and in treating patients with other solid tumour cancers which have a gene mutation in p300 or CBP. It is expected that approximately 150 patients will be recruited from up to 20 hospitals in the UK and US. The study has 5 parts consisting of dose escalation and expansion cohorts. Patients will have regular clinic visits for various safety and clinical benefit assessments, to monitor any side effects and to find out how CCS1477 is handled by the body and affects the tumour. The information gained in this study will help the sponsor to determine whether CCS1477 is suitable for further studies in humans.

    • Inclusion Criteria:

      All Patients: o Provision of consent. o ECOG performance status 0-1. o Assessable disease (by CT, MRI, bone scan or X-ray). o Adequate organ functions defined as: AST/ALT < = 3 X ULN (upper limit of normal) or AST/ALT < = 5 X ULN [with underlying liver metastasis] Total bilirubin < = 1.5 X ULN Serum creatinine < = 1.5 X ULN ANC > = 1.5 x 109/L Platelets > = 100 x 109/L Haemoglobin > = 9g/dL o Highly effective contraception measures for duration of study. Additional inclusion criteria for mCRPC patients only: o Previously received abiraterone and/or enzalutamide (or equivalent anti-androgen), and docetaxel (unless ineligible or refused). o Progressive disease documented by one or more of the following: Biochemical progression defined as at least 2 stepwise increases in a series of any 3 PSA values. Progression as defined by RECIST v1.1 guideline for assessment of malignant soft tissue disease. Progression defined as two or more new metastatic bone lesions confirmed on bone scan from a previous assessment. o PSA at screening > = 2 μg/L. o Serum testosterone concentration < = 50 ng/dL. o Serum albumin > 2.5 g/dL. Additional inclusion criteria for patients in CCS1477 plus abiraterone combination arm: o Patients must have previously progressed on abiraterone treatment. o Patients whose last dose of abiraterone is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with abiraterone to confirm refractoriness to abiraterone treatment. Additional inclusion criteria for patients in CCS1477 plus enzalutamide combination arm: o Patients must have previously progressed on enzalutamide treatment. o Patients whose last dose of enzalutamide is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with enzalutamide to confirm refractoriness to enzalutamide treatment. Additional inclusion criteria for p300/CBP mutation expansion only: o Patients must have histological or cytological confirmation of malignancy that is advanced and not considered to be appropriate for further approved/standard of care treatment. o Confirmation that the tumour harbours one or more p300 or CBP mutations (identified locally or by a central laboratory in tumour or blood circulating free DNA).

    • Exclusion Criteria:

      All Patients: o Intervention with any of the following: o Any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives (whichever is longer of these two) of the first dose of study treatment. o Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment. o Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study treatment. o Strong inducers or inhibitors of CYP3A4, or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment. Herbal medications cannot be taken within 7 days of the first dose of study treatment (3 weeks for St John’s wort) or while on study treatment. o Statins; patients should discontinue statins prior to starting study treatment. o Any unresolved reversible toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia. o Patients who are pregnant or breast-feeding at study entry. o Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). o Patients with any known uncontrolled inter-current illness including ongoing or active clinically significant infections, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. o QTcF prolongation (> 500 msec). o Prior malignancy that could affect compliance with the protocol or interpretation of results. o Primary brain tumours or known or suspected brain metastases. Additional exclusion criteria for patients in CCS1477 plus abiraterone combination arm: o Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not limited to) recent myocardial infarction (< = 6 months) or unstable angina (< = 3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is > = 50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension. Additional exclusion criteria for patients in CCS1477 plus enzalutamide combination arm: o History of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases and leptomeningeal disease, or alcoholism. o Use of substrates with a narrow therapeutic index metabolised by CYP2C9 or CYP2C19 within 2 weeks of the first dose of study treatment. o Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not limited to) recent myocardial infarction (< = 6 months) or unstable angina (< = 3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is > = 50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension.

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  • An open label, multi-centre, phase I/IIa study evaluating the safety and clinical activity of neo-antigen reactive T cells in patients with advanced non-small cell lung cancer

    • Research Summary

      Published literature indicates that tumours arise as a consequence of a series of mutations in normal tissue, and that most tumour growth stems from the original clonal mutations within the tumour. This is a clinical study evaluating the safety and clinical response of a novel personalised therapy (termed ATL001) designed to attack patient specific clonal mutations that are hypothesised to occur solely within all cancer cells. This clinical study will treat adult patients (aged 18 and over) with a type of lung cancer called advanced non-small cell lung cancer in selected hospitals who have experience handling this type of product and treating this stage of disease. The study will begin with the collection of patient material used to manufacture the therapeutic product. This will involve a surgical procedure and collection of blood samples. Whilst the product is being made patient will undergo standard treatment. Following successful manufacture of the product and as per protocol criteria, patients will be eligible to receive their personalised treatment. This will involve approximately 2 weeks of treatment with chemotherapy followed by administration of ATL001, and a product to help ATL001 kill the cancer cells. After this period of treatment, patients will be asked to visit the hospital a number of times over the next 2 year period to give blood samples and to have a scan to see if ATL001 has killed the cancer cells. If this clinical trial shows that ATL001 is safe and shows a level of effectiveness in treating non-small cell lung cancer, it will likely enable further development of ATL001 for more lung cancer patients and also patients with different cancers all based on the ability to target individual specific clonal mutations within the cancer cells.

    • Inclusion Criteria:

      Inclusion criteria will apply at three timepoints. Inclusion criteria: 1. Patient must be at least 18 years old at the screening visit. 2. Patient must have given written informed consent to participate in the study. 3. Histologically or cytologically confirmed diagnosis of non-small cell lung cancer. 4. Patient is considered medically fit enough to undergo all study procedures and interventions: procedures to procure blood and tumour tissue, including a general anaesthetic if required, and to receive fludarabine, cyclophosphamide and IL-2 at protocol doses and schedules. 5. Patient is considered, in the opinion of the investigator, capable of adhering to the protocol. 6. ECOG Performance status 0-1 7. Adequate organ function, indicated by the following laboratory parameters: a. Haemoglobin > = 10.0 g/dL b. White Blood Cell Count (WBC) > = 3.0x10⁹/L c. Absolute Neutrophil count (ANC) > = 1.5x10⁹/L d. Platelets > = 100x10⁹/L e. PT and APTT < 1.5x ULN (unless receiving therapeutic anticoagulation) f. AST, ALT < = 2.5 x ULN g. Bilirubin < 1.5 x ULN h. Creatinine clearance / estimated GFR > = 50ml/min 8. Patients who are of childbearing potential or have partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 6 months after the last dose of IL-2. See Section 4.3 of the protocol for details of acceptable methods of contraception. In addition to 1-8, the following inclusion criteria must be met prior to tissue procurement: 9. To be eligible for the study the patient must fall into one of the following groups: a. Operable locally advanced disease (stage IIIA) who are scheduled to undergo surgery. These patients are not candidates for immediate treatment with ATL001 but may be treated in this protocol at relapse. In these patients the tumour samples will be stored in compliance with regulations to enable future manufacture and treatment with ATL001. b. Relapsed disease following previous primary surgery +/- adjuvant therapy and either sufficient stored tissue for manufacturing of ATL001 or accessible site s of disease suitable for collection of adequate tissue for ATL001 manufacture. c. Late stage (IIIB/IV) newly diagnosed disease who have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. d. Late stage (IIIB/IV) disease who have completed first line chemotherapy, have achieved disease control, and have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. e. Late stage (IIIB/IV) disease who are undergoing or have completed treatment with PD-1/PD-L1 inhibitor, have achieved disease control and have accessible sites of disease suitable collection of adequate tissue for ATL001 manufacture. 10. Anticipated life expectancy > = 6 months at the time of tissue procurement In addition to 1-8, the following inclusion criteria must be met prior to lymphodepletion and treatment with ATL001: 11. Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. (If patients have no measurable disease following standard therapy, lymphodepletion and ATL001 treatment may be delayed until there is evidence of measurable disease). 12. Patient is considered will enough to receive ATL001 treatment.

    • Exclusion Criteria:

      Exclusion criteria will apply at two timepoints. Exclusion criteria: 1. Patients with known CNS metastases. 2. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection. 3. Patients who are non-smokers (have smoked < 100 cigarettes in their lifetime). 4. Patients with active autoimmune disease requiring immunosuppressive treatments. 5. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day (or equivalent). 6. Patients with superior vena cava syndrome. 7. Patients with a current or recent history, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease. 8. Patients who are pregnant or breastfeeding. 9. Patients who have undergone major surgery in the previous 3 weeks. 10. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except for in situ carcinomas or non-melanomatous skin cancers). 11. Patients with a history of organ transplantation. 12. Patients who have previously received any investigational cell or gene therapies. 13. Patients with contraindications for cyclophosphamide, fludarabine or IL-2 at protocol doses. In addition to 1-13, the following exclusion criteria apply to patients who completed first line therapy prior to study entry: 14. Patients who have received any anti-cancer therapy within the 3 weeks prior to blood procurement. 15. Patients with evidence of disease progression at the first scan after commencing standard first line therapy. In addition to 1-13, the following exclusion criteria apply to all patients prior to lymphodepletion and treatment with ATL001: 16. Patients who have received a live vaccination within the 28 days prior to lymphodepletion. 17. Patients with an active infection requiring antibiotics. 18. Patients who have received any anti-cancer therapy within the past 3 weeks prior to lymphodepletion.

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  • Atezolizumab in patients with urinary tract squamous cell carcinoma:a single arm, open label, multicentre, phase II clinical trial

    • Research Summary

      AURORA is a single arm,open label,multicentre,phase II clinical trial of atezolizumab immunotherapy,in immunotherapy naive patients with urinary tract squamous cell carcinoma (UTSCC). Recruitment is intended to occur over approximately 2 years and will follow a two-stage statistical design (see section 7). However,the intention is to allow continuous recruitment between Stage 1 and Stage 2. Following a Screening Phase of up to 28 days,eligible patients will be registered and will then commence atezolizumab immunotherapy,every 28 days,within a Treatment Phase of up to 1 year. On treatment discontinuation,patients will be reviewed in an End of Treatment Visit,and then 12 weekly (timed such as to continue with the 12 weekly schedule of CT scans from the Treatment Phase) until disease progression. Following disease progression,patients will revert to routine local follow up processes. Consent will be obtained for long term collection of overall survival status.

    • Inclusion Criteria:

      Histologically confirmed cancer of the urinary tract with squamous cell carcinoma histology and without any TCC component. Mixed non-TCC histology is allowed if squamous cell carcinoma is the predominant histology. Newly diagnosed or progressive measurable disease as defined by RECIST version 1.1. To be considered measurable (and to be designated as a target lesion),a lesion must not have been treated with prior radiotherapy or focal ablation techniques. Suitable,in the judgment of the local investigator,for treatment with atezolizumab,with palliative intent. Adequate haematologic and end-organ function within 28 days prior to the first study treatment including: a. Absolute neutrophil count ≥ 1.5 x109/L,b. Platelet count ≥ 100 x109/L,c. Haemoglobin ≥ 90 g/L,d. Aspartate transaminase (AST),alanine transaminase (ALT),and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN),e. Total bilirubin ≤ 1.5 times ULN (or ≤ 3 ULN in patients with Gilbert’s syndrome),f. Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula). Up to one prior line of systemic chemotherapy for UTSCC. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 7. Life expectancy ≥ 12 weeks. 8. Representative formalin-fixed paraffin embedded (FFPE) tumour sample with an associated linkedanonymised pathology report that is available for central use in translational studies. 9. Able to comply with all trial procedures and processes. 10. Age ≥ 18 at time of signed inform consent form. 11. Provision of written informed consent.

    • Exclusion Criteria:

      Any component of TCC histology. Planned for treatment with curative intent. Prior systemic immunotherapy (prior intra-vesical treatments are allowed) AURORA Protocol Version 2 03-MAY-2022 Page 21 of 51. Major surgery within 30 days prior to enrolment. History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation. Use of oral or IV steroids for 14 days prior to enrolment. 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 or attenuated vaccine within 4 weeks prior to enrolment (COVID-19 vaccination is allowed). Treatment with any other investigational agent within 4 weeks prior to enrolment. Coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,unstable arrhythmias,unstable angina or congestive cardiac failure (New York Heart Association ≥ grade 2) within 6 months prior to enrolment. Patients with known HIV infection or with active tuberculosis. Patients with known active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody and the absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Autoimmune disease including myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone or with controlled Type I diabetes mellitus on a stable dose of an insulin regimen are eligible for this study. History of idiopathic pulmonary fibrosis,organizing pneumonia (e.g.,bronchiolitis obliterans),drug-induced pneumonitis,idiopathic pneumonitis,or evidence of active pneumonitis on screening chest CT scan. A history of radiation pneumonitis in the radiation field (fibrosis) is permitted. Prior allogeneic stem cell or solid organ transplant. Patients who are pregnant or breast feeding. Patients of child-bearing potential who are not able to use a highly effective method of contraception (as detailed in section 3.7). A recent or current other cancer. Current non-melanoma skin cancer,cervical carcinoma in situ or localized prostate cancer not requiring current treatment are permissible,as is a history of a separate other malignancy having completed all active treatment ≥2 years previously.

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  • An open-label, prospective Phase III clinical study to compare polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)

    • Research Summary

      The study will look at the effect of the combination of polatuzumab vedotin and R-ICE vs R-ICE alone in patient with relapsed or refractory DLBCL who are eligible for stem cell transplant following salvage therapy. The study is a Phase III,randomised controlled trial with 2 arms. Patients will be randomised at a 1:1 ratio to receive either polatuzumab vedotin + R-ICE or R-ICE alone. For all patients,the visit schedule consist of a screening visit up to 3 weeks before first treatment,cycle 1 at week 1,cycle 2 and week 4-5,interim re-staging at week 6-7,cycle 3 at week 7-8,final restaging at week 1—12 and quarterly follow-up visits for at least 12 months,or until the last patient on the trial has their last follow-up.

    • Inclusion Criteria:

      (1) The informed consent form (ICF) must be signed before any study specific tests or procedures are done (2) Adult male and female patients ≥ 18 years (≥16 years in the UK*) at the time of inclusion in the study * In the UK an “adult” means a person who has attained the age of 16 years,according to The Medicines for Human Use (Clinical Trials) Regulations 2004,Part 1 Point 2. (3) Ability to understand and follow study-related instructions,in the investigator’s judgement (4) Risk group: All patients with one of the following histologically defined entities: Histological diagnosis of primary refractory or relapsed aggressive B-NHL,confirmed by a biopsy of involved nodal or extranodal site. Patients with any of the following histologies can be included: • DLBCL not otherwise specified (NOS) • T-cell/histiocyte-rich large B-cell lymphoma • Primary cutaneous DLBCL,leg type • EBV-positive DLBCL,NOS • DLBCL associated with chronic inflammation • Primary mediastinal (thymic) large B-cell lymphoma • High-grade B-cell lymphoma,with MYC and BCL2 and/or BCL6 rearrangements • High-grade B-cell lymphoma,NOS Refractory disease is defined as no complete remission to first line therapy; subjects who are intolerant to first line therapy are excluded. Three groups of patients are eligible: • PD as best response to first line therapy (biopsy not mandatory if diagnostic sample available). • SD as best response after at least 4 cycles of first line therapy (e.g.,4 cycles of R-CHOP) (biopsy not mandatory if diagnostic sample available). • PR as best response after at least 6 cycles,and biopsy-proven residual disease or disease progression after the partial response. Relapsed disease is defined as complete remission to first line therapy followed by biopsy proven disease relapse. (5) Performance Status ECOG 0-2 at time of randomization or ECOG 3 at screening if this is DLBCL-related and has improved to ECOG 2 or less with a 7-day steroid treatment during the screening phase (e.g. 1 mg/kg prednisone). (6) Information on all 5 IPI factors (7) Staging (PET-CT based-staging according to Lugano criteria 2014 [36]). Patients must have PET-positive lesions. (8) Subjects must have received adequate first line therapy including at a minimum: i) anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative,and ii) an anthracycline containing chemotherapy regimen (9) Intent to proceed to HDT and SCT if response to second line therapy (10) Adequate hematological function,as defined by: hemoglobin ≥ 8 g/dL,ANC ≥ 1.0 x 109/L OR ≥ 0.5 x 109/L if neutropenia is attributable to underlying disease and before the administration of steroids,and platelet count ≥ 75 x 109/L OR ≥ 50 x 109/L if thrombocytopenia is attributable to underlying disease (11) Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first study drug administration (12) For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures,and agreement to refrain from donating eggs,as defined below: • Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 12 months after the final dose of study medication. Women must refrain from donating eggs during this same period. • A woman is considered to be of childbearing potential if she is post-menarcheal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause),and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation,male sterilization,hormonal contraceptives that inhibit ovulation,hormone-releasing intrauterine devices and copper intrauterine devices • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar,ovulation,symptothermal,or postovulation methods) and withdrawal are not acceptable methods of contraception (13) For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures,and agreement to refrain from donating sperm,as defined below (the patient should receive advice on the possibility of opting for cryoconservation of sperm prior to start of study treatment due to the possibility of irreversible infertility following therapy with study medication): • With a female partner of childbearing potential who is not pregnant,men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of study medication. Men must refrain from donating sperm during this same period • With a pregnant female partner,men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of study medication to avoid exposing the embryo • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar,ovulation,symptothermal,or postovulation methods) and withdrawal are not acceptable methods of contraception.

    • Exclusion Criteria:

      (1) Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. In particular,patients with the following organ dysfunction caused by accompanying disorders are to be excluded: • Heart failure with LVEF < 45% • Impaired pulmonary function with VC or FEV1 < 50% of normal (only in case of history of significant pulmonary disease) • Impaired renal function with GFR < 50 ml/min (calculated) • Impaired liver function with ALAT,ASAT,bilirubin > 1.5 x ULN. If elevation is caused by the disease,threshold of 2.5 x ULN is accepted • Peripheral neuropathy > Grade II (2) HIV-positivity with detectable viral load and/or a CD4+ count below 0.3/nL (3) Hepatitis B and C as defined by seropositivity (HBsAG and anti HBe / anti HBc; anti-Hc); in case of false positive serology (transfused antibodies) negative PCR-results will allow patient inclusion. Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable,provided that they are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment (4) Known active bacterial,viral,fungal,mycobacterial,parasitic,or other infection (excluding fungal infections of nail beds) at study inclusion or any unresolved major episode of infection (as evaluated by the investigator) within 1 week prior to Cycle 1 Day 1 (5) Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay (6) Primary or secondary CNS lymphoma at the time of recruitment (7) Richter’s transformation or prior CLL (8) Vaccination with a live vaccine within 4 weeks prior to treatment (9) Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis (10) Treatment with radiotherapy,chemotherapy,immunotherapy,immunosuppressive therapy,or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1 (11) Received more than one line of therapy for DLBCL (12) Received polatuzumab vedotin as part of the first line therapy (13) Any other diseases,metabolic dysfunction,physical examination finding,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 render the patient at high risk from treatment complications (14) Ongoing treatment or study procedures within any other IMP clinical trial with the exception of follow-up. In case of a preceding clinical trial,last application of the respective IMP(s) must have been done more than five elimination half-lives before start of study medication in this trial. (15) History of severe allergic or anaphylactic reactions to human,humanized,chimeric,or murine monoclonal antibodies (16) History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure (17) Contraindications according to the IB of polatuzumab vedotin or the local SmPCs of the used rituximab,ifosfamide,carboplatin or etoposide products (18) Criteria which in the opinion of the investigator preclude participation for scientific reasons,for reasons of compliance,or for reasons of the subject’s safety (19) Pregnancy or breastfeeding,or intending to become pregnant during the study or within 12 months after the last dose of study drug (20) Close affiliation with the investigator (e.g. a close relative) or persons working at the study site (21) Subject is an employee of the sponsor or involved Contract Research Organization.

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  • Update of the EORTC QLQ-PAN26 questionnaire for the assessment of health-related quality of life (HRQoL) in patients with pancreatic adenocarcinoma

    • Research Summary

      The measure for Health-Related Quality of Life (HRQoL) in pancreatic cancer (EORTC QLQ-PAN26), was developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group in 1996. As new treatments are now available for pancreatic cancer new symptoms and side-effects are being reported. A review is needed to see if the EORTC QLQ-PAN26 needs to be updated. We will invite people diagnosed with Pancreatic Duct Adenocarcinoma (PDAC; n= 95), and senior Health Care Professionals (HCP) with PDAC expertise (n= 20) for interviews in an international study. Patients will be purposely recruited by a member of the local research or clinical team while visiting the hospital as an inpatient or outpatient or they will be contacted by their clinician. Interviews will be carried out at the hospital, over the telephone, video conference or at home. In phase I, patients will be asked to talk about how PDAC has affected their HRQoL. Patients will be asked about their experience of PDAC, treatments, symptoms, side effects, their functioning and well-being. HCPs will be asked to share their experience of treating patients with PDAC and HRQoL issues. Both patients and HCPs will be asked to rate the content of the EORTC QLQ PAN26 for importance and relevance, and comment on issues on the more general cancer HRQoL questionnaire EORTC QLQ-C30. In phase II, any new content that has been proposed from phase I will be written in a style and format that fits with the EORTC QLG assessment system. This new content will then be presented in form of a list that will be reviewed by the project team and a patient panel, who decide in agreement what content will be included and how it they will be put together to form an updated questionnaire.

    • Inclusion Criteria:

      Patient participants inclusion criteria a.Adults aged > = 18 years b.Histologically proven as adenocarcinoma of the pancreas (head, body, tail) with disease stages I-IV. c.Patients receiving treatment (either currently or within the last 12 months) including a systemic treatment (chemotherapy, radiotherapy or chemoradiotherapy), biological and immunotherapy), surgical resection, and radiotherapy or receiving supportive or palliative care. d.Patients who are willing and able to give fully informed consent to participate. e.Patients who are currently enrolled in a clinical trial of a therapeutic agent (phase I-II) whose enrolment in this study is permitted under the trial eligibility criteria AND where any concurrent quality of life assessment (e.g., as part of the trial endpoint) will not affect the results of the current study. For example, inclusion would include a trial where the EORTC QLQ-C30 and QLQ-PAN26 are being formally used for the assessment of quality of life. Health Care Professional inclusion criteria a.Adults aged > = 18 years b.Clinician, nurse, or other HCP (e.g., advanced practitioner) with specific senior expertise and experience (> 2 years) in the treatment and care of patients with PDAC (e.g., oncology, surgery, radiotherapy, specialist nurse, palliative care). c.Willingness to undertake an interview or written questionnaire in English.

    • Exclusion Criteria:

      Patient participants exclusion criteria a.Patients under 18 years of age. b.Patients with a concurrent malignancy. c.Patients enrolled in other quality of life studies which will affect the results of the current study. Health Care Professional exclusion criteria a.HCPs under 18 years of age. b.HCPs with limited experience (< 2 years).

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  • Neoadjuvant Pembrolizumab stratified to tumour mutation burden for High Risk Stage 2 or Stage 3 MMR-deficient Colorectal Cancer

    • Research Summary

      The NEOPRISM-CRC study is a phase II clinical trial. The purpose of the trial is to evaluate the efficacy and safety of pembrolizumab (Study IMP) in patients with high risk Stage 2 or Stage 3 MMR-deficient colorectal cancer stratified with tumour mutation burden status. Pembrolizumab is a type of immunotherapy that has demonstrated excellent results in clinical trials for patients with advanced colorectal cancer who have certain genetic characteristics (mismatch repair deficiency (MMR-d) / high microsatellite instability (MSI-H)). There are previous studies providing evidence that checkpoint inhibitors when given before surgery have shown better local and systemic anti-tumour responses in melanoma and glioblastoma than surgery alone. The main question the researcher wants to investigate is whether pembrolizumab given prior to having surgery improves pathological complete response rate in advanced colorectal cancer patients with MSI-H or MMR-d. The trial will investigate whether the treatment is safe,and whether it improves the chances of the tumour being removed completely,and whether this delays or prevents the cancer from coming back. The trial will also investigate whether pembrolizumab causes any delay to surgery due to side effects. The trial will also measure post-surgery complications and impact of the treatment on patient's quality of life. Once patients have consented to the NEOPRISM-CRC trial,a trial colonoscopy will be performed and tissue samples taken during the procedure will be shipped to the FoundationOne Medicine testing Laboratory and analysed to determine the TMB (tumour mutation burden) status assessed by the FOUNDATIONONE®CDx (FM1) test. In addition,a PCR (Polymerase Chain reaction) test or Microsatellite testing will be done to confirm the Microsatellite Instability (MSI) status. Patients will receive one of two pre-operative regimens depending upon their TMB status/MSI status. All patients will have one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the FM1 result should be available and patients will continue their treatment as follows: If results is TMB-high or medium (or MSI-h if FM1 test is not evaluable): A further two cycles of pembrolizumab 200 mg IV every 21 days and then will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab. If result is TMB-low (or if FM1 test and MSI result are not evaluable): No further cycles of pembrolizumab; will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab. Following surgery,patients will receive standard of care adjuvant treatment which may include post-operative chemotherapy in accordance with investigators clinical decision. Patients will continue to be followed up according to routine standard of care for a maximum of 5 years after surgery. Target recruitment is 32 patients and recruitment is expected to take place over a 24 month period.

    • Inclusion Criteria:

      - Histologically proven adenocarcinoma of the colon or rectum which is MMR-d by IHC or MSI-H by PCR (or Microsatellite testing). - Patient is fit (ECOG 0-1) and eligible for planned curative surgery in keeping with NICE guidelines and considered fit/suitable for adjuvant chemotherapy as per local site investigator’s discretion based on: a) Radiological node positive T1-4 CRC or b) high risk T3 defined as EITHER ≥ 5mm of extramural depth of invasion OR unequivocal EMVI on imaging (regardless of depth) or T4 disease - Patients with rectal cancer are eligible if it is determined that neoadjuvant chemo-radiotherapy is not required to achieve a R0 resection. - Patients presenting with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma/stent,and when recovered to a fitness level consistent with the other eligibility criteria - Adequate bone marrow function: White Blood Cell > 3.0 x 109/L; Absolute neutrophil count ≥1.5 x 109/L; Platelets ≥100 x 109/L; Haemoglobin ≥90 g/L (Note Anaemia (Hb < 100 g/L) is not an exclusion,but should be corrected by transfusion prior to surgery and chemotherapy) - Adequate renal function: GFR > 50 mL/min estimated using validated creatinine clearance calculation (e.g. Cockroft-Gault) - Adequate liver function: Total bilirubin < 1.5 times Upper Limit of Normal (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels > 1.5 × ULN; AST and ALT ≤ 2.5 × ULN - Adequate coagulation: International normalized ratio (INR) OR prothrombin time (PT) and Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants - Aged ≥18 years - Able and willing to provide written informed consent - Willing to use highly effective contraception for the duration of trial treatment and for 120 days after last dose of pembrolizumab

    • Exclusion Criteria:

      - Any patient for whom radiotherapy is advised by the MDT - Strong evidence of distant metastases or peritoneal nodules (M1) - Prior therapy with an anti-PD-1,anti-PD-L1 or anti-PD-L2 agent,or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4,OX 40,CD137) - Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration. (NB: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline,with the exception of alopecia. Participants with ≤Grade 2 neuropathy may be eligible.) (NB: If participant received major surgery,they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.) - Has received a live vaccine or live-attenuated vaccine within 30 days prior to registration (seasonal flu vaccines that do not contain live virus are permitted). Examples of live vaccines include,but are not limited to,the following: measles,mumps,rubella,varicella/zoster (chicken pox),yellow fever,rabies,Bacillus Calmette–Guérin (BCG),and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however,intranasal influenza vaccines (eg,FluMist®) are live attenuated vaccines and are not allowed. - Any investigational agents or investigational devices within 4 weeks prior to registration Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10mg daily of prednisone or equivalent),or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment Note: the use of physiologic doses of corticosteroids may be approved after consultation with UCL CTC. - Patients with concurrent or previous malignancy that could compromise assessment of the primary or secondary endpoints of the trial - Has known active CNS metastases and/or carcinomatous meningitis. 100. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or to any of its excipients. - Has previous severe or life-threatening skin adverse reaction with other immune-stimulatory anticancer agents - Has 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). NB: Replacement therapy (e.g. levothyroxine,insulin,or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,etc.) is permitted. - History of (non-infectious) pneumonitis/interstitial lung disease that required steroids,or current pneumonitis/interstitial lung disease - Active infection requiring systemic therapy - Known history of Human Immunodeficiency Virus (HIV). NB: Testing for HIV for the NEOPRISM-CRC trial is not mandatory,however if this test has been done the result should be known prior to registration. - Known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C (defined as hepatitis C virus [HCV] RNA [qualitative] is detected) Note: Without known history,testing is required to determine eligibility. Hepatitis C antibody testing is allowed for screening purposes in sites where HCV RNA is not part of standard of care. - Known history of active TB (Mycobacterium tuberculosis). - Has had an allogenic tissue/solid organ transplant. - Has peritonitis (secondary to perforated tumour) - Has a colonic obstruction that has not been defunctioned or stented - History or current evidence of any condition,therapy,or laboratory abnormality that might confound the results of the study,interfere with the subject’s participation for the full duration of the study,or is not in the best interest of the subject to participate,in the opinion of the treating investigator. - Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. - Is pregnant or breastfeeding,or expecting to conceive or father children within the projected duration of the trial,starting with the prescreening or screening visit through 120 days after the last dose of pembrolizumab

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  • A double-blinded feasibility study of intraoperative electron radiotherapy in patients with locally advanced or locally recurrent rectal cancer

    • Research Summary

      Rectal cancer is a cancer that occurs in the pelvis from the rectum. Locally advanced rectal cancer outgrows the rectum and attaches to other body parts in the pelvis and locally recurrent rectal cancer is a rectal cancer that comes back after surgery, and usually attaches to many different pelvic structures. They are both difficult to manage. The standard of care treatment involves chemotherapy and radiotherapy, followed by what is known as an extended margin operation to remove all cancer affected organs and not leave any cancer cells behind. If cancer cells reach the edge of the removed tissue, there is a high chance of leaving cancer cells behind. This is a key predicter of negative outcome in patients. Intraoperative electron beam radiotherapy (IOERT) was developed to help improve patient outcomes. Once the cancer has been removed, the surgeon and a cancer radiotherapy specialist examine the patient’s scans, the cancer specimen and the area the cancer was in, and if there is concern about small numbers of cancer cells being left behind they treat the area with radiotherapy to destroy these cells. Patients that are due to receive treatment for these subsets of rectal cancer will be approached to take part. If eligible on the day of surgery the patient will be randomised to one of three arms: Arm A – standard of care (No IOERT), Arm B – extended margin surgery plus IOERT (10 Gy), or Arm C – extended margin surgery plus higher dose IOERT (15 Gy). The surgeon, cancer specialist team and patient will be blinded to study treatment. Patients will be followed up at 30 days, 3 months and for a minimum of 12 months post surgery as part of the trial and they will be followed up for 5 years as part of standard care.

    • Inclusion Criteria:

      - Age > = 16 - Non-metastatic/oligo-metastatic (up to three lesions from 2 sites predicted to be radically treatable) – locally advanced or locally recurrent disease involving the posterior or lateral compartment of the pelvis and predicted to be resectable but with close margins from MRI as determined by a specialist MDT (sMDT) - Specialist colorectal MDT review with experience in pelvic exenteration, which has proposed IOERT as an option for treatment - Patient suitable for IOERT as a component of treatment in view of the responsible Clinical Oncologist - Performance status < = 1 as defined by the Eastern Cooperative Group (ECOG) - Deemed medically fit for surgery - Written informed consent

    • Exclusion Criteria:

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  • Niraparib Efficacy in patients with unresectable mesothelioma: A randomised phase II trial of Niraparib versus active symptom control in patients with previously treated mesothelioma

    • Research Summary

      Mesothelioma is a cancer that is caused by exposure to asbestos,an environmental contaminant. This cancer is incurable and lacks effective treatment,particularly after initial chemotherapy. There has not been a licenced therapy for mesothelioma since 2003,and no treatment has yet demonstrated an improvement in survival following initial chemotherapy. There is an urgent need to explore more effective approaches to therapy. Targeted treatments offer potential hope for the treatment of mesothelioma. A class of drugs called PARP (Poly Adenosine Diphosphate-ribose polymerase) inhibitors have already been proven to improve the survival of patients with breast and ovarian cancers,that carry specific mutations. Mesothelioma has been shown in a recent trial to respond to this class of agent. Further investigation is warranted to test whether PARP inhibitors could be a new treatment option for patients. As with ovarian cancer studies of the past,we intend to test a PARP inhibitor (niraparib) after successful treatment with chemotherapy in the NERO trial. Patients whose tumours shrink or stabilise following chemotherapy are expected to have a greater chance of benefit from niraparib. We do not know if niraparib will be able to improve survival of patients with mesothelioma,or indeed whether or not toxicity could occur without benefit. For that reason,patients will be randomised with a 2:1 chance of receiving the drug. Those patients who do not receive niraparib will be closely monitored for signs of early tumour growth so that they can go on to receive an alternative treatment if necessary. If the NERO trial is positive,this study will lead to the approval of a new medicine for use around the world,one that would extend the life expectancy of patients for the first time following initial chemotherapy. NERO will recruit 84 patients over 18 months. Those randomised to receive niraparib will receive a daily dose of 200 mg or 300mg for up to 24 weeks within the trial.

    • Inclusion Criteria:

      • Patients must have signed and dated a REC-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care. • Patients must be willing and able to comply with scheduled visits,treatment schedule,laboratory tests,and other requirements of the study. • Histologically confirmed diagnosis of mesothelioma. Any histological subtype (epithelioid,biphasic or sarcomatoid) and any site (e.g. pleural or peritoneal) with an available tissue block. Tissue blocks will be requested at the time of screening. • Patients must have received prior systemic therapy (any number of lines) for pleural or peritoneal mesothelioma • Disease progression must be confirmed per Investigator’s assessment prior to screening. • Any prior treatment must be completed at least 14 days prior to receiving study treatment,with no ongoing toxicity of CTCAE Grade 3 or above. • Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 (see appendix 1). • Radiologically assessable disease by modified RECIST (pleural mesothelioma) or RECIST 1.1 (non-pleural mesothelioma or where measurements for modified RECIST cannot be obtained). • Age ≥ 18 years old • Consent to provide mandatory diagnostic tissue blocks and blood samples for translational research,including an optional rebiopsy at progression. • Adequate organ function,including suitable bone marrow reserve and creatinine clearance. • Screening laboratory values must meet the following criteria within 48 hours prior to commencement of treatment: a. White blood cells ≥ 2 x 109/L b. Neutrophils ≥ 1.5 x 109/L c. Platelets ≥ 100 x 109/L d. Haemoglobin ≥ 90 g/L e. Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl) > 50 mL/minute (using Cockcroft/Gault formula) i. Female CrCl= [(140 - age in years) x weight in kg x 0.85) ÷ (72 x serum creatinine in μmol/L)] ii. Male CrCl= [(140 - age in years) x weight in kg x 1.00) ÷ (72 x serum creatinine in μmol/L)] f. AST ≤ 3 x ULN OR ALT ≤ 3 x ULN (if both are assessed,both need to be ≤ 3 x ULN) g. Total bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome,who must have total bilirubin < 51.3 μmol/L) • Reproductive status (refer to section 4.6) a. Women of childbearing potential (WOCBP,as defined in section 4.6) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of Human Chorionic Gonadotropin) at enrolment and within 24 hours prior to the start of study treatment. An extension up to 3 days prior to start of study treatment may be permissible in situations where results cannot be obtained within a 24-hour window. b. Women must not be breastfeeding. c. WOCBP must agree to use a highly effective method of contraception (as outlined in section 4.6) for the duration of treatment and 180 days after the last dose of ASC+Niraparib. d. Men who are sexually active with WOCBP must use the contraceptive methods as outlined in section 4.6 for the duration of treatment and for 90 days after the last dose of ASC+Niraparib. • Expected survival of at least 12 weeks per Investigator’s assessment.

    • Exclusion Criteria:

      Patients with untreated,symptomatic central nervous system (CNS) metastases,including carcinomatous meningitis,leptomeningeal disease,and radiographic signs of CNS haemorrhage are excluded. Patients with untreated third space fluid collection requiring therapeutic drainage are excluded. Second malignancy within 5 years except cancers definitely treated with curative intent (e.g. basal cell carcinoma of the skin,squamous cell carcinoma of the skin,in situ bladder or in situ cervical cancer). Any serious or uncontrolled medical disorder or active infection that,in the opinion of the investigator,may increase the risk associated with study participation,study drug administration,or would impair the ability of the patient to receive protocol therapy. Difficulty swallowing or previous significant resection of the stomach or small bowel. Patients who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment. Prior exposure to PARP Inhibitor or known hypersensitivity to the components of niraparib. New York Heart associated class II or greater heart failure,hepatic [AST > 3xULN,ALT > 3xULN Total bilirubin > 1.5xULN] or renal impairment [Serum creatinine of > 1.5 X ULN or creatinine clearance (CrCl) ≤ 50 mL/minute (using Cockcroft/Gault formula)]. Known alcohol or drug abuse. Patients are not permitted to enter any other interventional studies Any patient not able to give consent. Any pregnant or breastfeeding patient. Patient with known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Patient with known history of active tuberculosis. Patients with uncontrolled hypertension. Participants have current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease,drug-related pneumonitis,or radiation pneumonitis requiring steroid treatment Patients that have received colony-stimulating factors (eg,granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment Live vaccines within 30 days prior to the first dose of study treatment and while participating in this clinical study. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.

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  • Randomised controlled trial evaluating effectiveness of neoadjuvant endocrine treatment in post-menopausal women

    • Research Summary

      RESEARCH QUESTION: In post-menopausal women who will not require chemotherapy for >T1,strongly ER+,HER2- invasive breast cancer,does NET improve global HRQoL over 15 months and increase breast BCS rates? Patients will be randomised 1:1 to either the intervention (NET) arm (6 +/- 1 months of NET followed by surgery and adjuvant ET) or the control arm (2-4 weeks of presurgical NET and surgery within 2-4 weeks [up to 8 weeks permitted for trial purposes] followed by adjuvant ET). Both arms will receive the same treatments (surgery,ET,and radiotherapy where indicated),but the sequencing of surgery will differ; both arms starting ET at randomisation,with 6 months +/- 1 month of the course of ET delivered prior to surgery in the NET arm.

    • Inclusion Criteria:

      • Female,• Clinically post-menopausal; including one of: o amenorrhoea > 12 months and an intact uterus. o bilateral oophorectomy o for those with a history of hysterectomy,or HRT within 12 months,venous FSH levels classified as post-menopausal by the testing laboratory if any doubt. • Unifocal,newly diagnosed breast cancer visible on USS; • Strongly ER+; defined as Allred scores of 7 or 8 or equivalent • HER2- by immunohistochemistry,or 2+ and not amplified by in situ hybridisation • T-stage 2 or 3 (> 2cm); • Axillary N0-1 on diagnostic USS +/- negative FNA or core biopsy; • Suitable for surgery and radiotherapy; • Chemotherapy unlikely to be indicated; • Participant is able and willing to give informed consent for participation in the trial; • In the Investigator’s opinion,is able to comply with all trial requirements.

    • Exclusion Criteria:

      • Bilateral breast cancer; • ER- or HER2+; • Stage IV disease (distant metastasis); • Previous neoadjuvant treatment for breast cancer; • Previous invasive malignancy within 5 years other than basal cell carcinoma; • Concurrent use (at the time of randomisation) of HRT or any other oestrogen-containing medication (including vaginal oestrogens); • Ovarian suppression/ablation for the purposes of trial entry not permitted.

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  • The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

    • Research Summary

      The HER2-RADiCAL study is for patients with HER2-positive breast cancer who: -started their course of drug treatment (chemotherapy + trastuzumab + pertuzumab) before surgery; -have had breast surgery; -and have been found to have the best possible response to treatment (a “pathological complete response” or “pCR”). A pCR means that there were no remaining living cancer cells in tissue removed at surgery. We already know that such patients have good outcomes with only a small chance of the cancer returning, and so it is possible that the side effects and risks of continuing all of these treatments in combination could outweigh any benefit. The study will investigate whether a more personalised treatment plan can be offered, with the aim of allowing patients with a pCR to safely receive less drug treatment after surgery. Study participants will not receive a type of chemotherapy called an anthracycline, they will continue treatment with trastuzumab to complete 9 cycles (rather than 18), including the cycles given before surgery. No more pertuzumab or any type of chemotherapy will be given after surgery. Any other treatment that might have been recommended (like hormone therapy or radiotherapy) will be given as normal. Patients will be asked to donate tissue samples removed during routine biopsy procedures or surgery. No new tissue samples will be taken for research purposes. The HER2-RADiCAL study aims to recruit around 720 patients with HER2-positive breast cancer and a pCR, to test whether these patients can safely receive less trastuzumab, pertuzumab and chemotherapy after surgery. This reduction of drug treatment may not only benefit the patient, but also save NHS resources. Data from routine NHS records on all patients with HER2-positive breast cancer in the UK will be collected in addition to the study data to assess the cost-effectiveness of this response-adapted approach.

    • Inclusion Criteria:

      1. Female or male, age ≥ 16 2. Histologically confirmed invasive breast cancer that is HER2-positive (IHC3+, and/or ISH positive/amplified) as determined by the local laboratory in accordance with national guidelines 3. Has received neoSACT with a non-anthracycline chemotherapy regimen with at least 3 cycles of concomitant trastuzumab and pertuzumab 4. pCR (ypT0/is ypN0) in breast and sampled regional lymph nodes as per local pathology reporting 5. Imaging of breast and axilla prior to initiation of neoSACT and either: a) Breast primary radiological measurement ≤ 20mm prior to neoSACT and limited nodal involvement (cN1) confirmed by axillary core biopsy or FNA (cT1N1) OR b) Breast primary radiological measurement > 20mm but ≤ 50mm and node-negative (cT2N0) or limited nodal involvement (cT2N1) 6. Multiple ipsilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 7. Bilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 8. Pre-treatment diagnostic breast tumour biopsy sample available 9. Study consent ≤6 weeks after completing breast cancer surgery 10. Patient must be fit to continue treatment with trastuzumab and have no concomitant medical, psychiatric or social problems that might interfere with informed consent, adherence to the reduced treatment pathway or follow up 11. Provision of written informed consent to participate in HER2-RADiCAL

    • Exclusion Criteria:

      1. Evidence of metastatic disease at any time since diagnosis 2. Any residual invasive disease following neoSACT. This includes isolated tumour cells in axillary nodes or tissue or evidence of lymphovascular invasion in the breast. Persistent ductal or lobular non-invasive disease (DCIS or LCIS) is permitted. Resection margins must be deemed clear of any residual DCIS according to local MDT protocol. 3. Any planned further resectional surgery for breast cancer (including re-excision, mastectomy, or axillary surgery) 4. HER2-negative invasive breast carcinoma 5. Breast cancer with clinical stage of T≥3 at diagnosis 6. Evidence of scarring (or other pathological features consistent with previous malignant involvement) in > 4 axillary nodes or clinical nodal stage N≥2 at any time 7. Positive SLNB pre-neoadjuvant systemic therapy as this precludes determination of pCR 8. Pregnant and/or lactating women 9. Female patient of child-bearing potential, unwilling to use an effective form of contraception during trastuzumab treatment and for 7 months after their last dose of trastuzumab (NB. See section 5.5 for further guidance) 10. Previous diagnosis of invasive breast carcinoma 11. Previous diagnosis of any other (non-breast) malignancy unless disease-free for at least 5 years and considered to be at low risk of recurrence or treated basal cell or localised squamous cell carcinoma of the skin or cervical intraepithelial neoplasia 12. Chemotherapy administered following surgery (NB. Pertuzumab and/or trastuzumab may have been continued after surgery as per local practice prior to trial entry) 13. Has received > 9 cycles trastuzumab 14. Clinically significant cardiac disease within 12 months of starting trastuzumab, including unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident, or cardiac arrhythmia associated with haemodynamic instability 15. Left ventricular ejection fraction (LVEF) less than 50% on most recent cardiac imaging 16. History of interstitial lung disease 17. Any medical or other contra-indication to continuing trastuzumab

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  • PRiZM+: A phase II platform study of zanubrutinib monotherapy and combination therapy for relapsed and refractory primary CNS lymphoma

    • Research Summary

      Primary central nervous system lymphoma (PCNSL) is a rare type of brain tumour. It is an aggressive type of non-Hodgkin lymphoma that is found only in the brain or spinal cord. PCNSL is often treated with high-doses of chemotherapy. The first treatment doesn’t work for some patients (called ‘refractory’), and the lymphoma can come back (called ‘relapse’). Refractory or relapsed (RR) PCNSL is much more difficult to treat. There is currently no standard treatment for RR-PCNSL and further chemotherapy treatment is often unsuccessful. Radiation treatment to the brain can sometimes be used but can cause significant long-term side-effects. Clinical trials are now focused on testing new drugs that are better at targeting the tumour, and are likely to have fewer side-effects. The treatment being tested in the PRiZM+ trial is a drug called zanubrutinib. Zanubrutinib is a new type of drug (a Bruton’s tyrosine kinase inhibitor), which works by targeting lymphoma cells. Previous studies have shown that similar drugs can cause RR-PCNSL to shrink or disappear. It is thought that zanubrutinib could be a more effective treatment, which can be given safely without too many side effects. The aim of the study is to find out how effective and safe zanubrutinib is for patients with RR-PCNSL. We will be looking at the effects zanubrutinib has against lymphoma, how long these effects last, and what the side-effects of the drug are.

    • Inclusion Criteria:

      •> = 16 years of age •Histologically confirmed CD20+ DLBCL confined to the CNS •Relapsed or refractory PCNSL (defined as disease progression following CR/CRu/PR, or failure to achieve PR after one or more lines of therapy; one therapy line must have included at least 1 cycle of high-dose methotrexate (> = 1g/m2)) •Measurable disease on contrast-enhanced MRI of brain (and/or spinal cord) •ECOG performance status of 0 to 2, or 3 if attributed to lymphoma •Ability to swallow capsules •Adequate renal and liver function defined as: o Creatinine clearance > = 30 mL/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection) o Serum total bilirubin < 3.0 x ULN (unless due to Gilbert’s syndrome) o Up to and including moderate impairment (Child-Pugh class B) • Adequate bone marrow function, defined as unsupported platelets > 50 x109/L, neutrophils > 1 x109/L, haemoglobin > 80 g/L • Patient willing and able to comply with scheduled visits, treatment plan, investigations and other study procedures • Written informed consent for the trial

    • Exclusion Criteria:

      • Current evidence or prior history of systemic lymphoma • Exclusive intraocular involvement • Active infection requiring intravenous antimicrobials • Chemotherapy for lymphoma within 2 weeks of first dose of zanubrutinib • Whole-brain radiotherapy within 4 weeks of first dose of zanubrutinib • Contra-indication to lumbar puncture • Prior exposure to BTK inhibitor • Known bleeding disorder e.g haemophilia or severe Von-Willebrand Disease • Current use of warfarin, or dual anti-platelet therapy o Therapeutic anticoagulation with direct oral anticoagulants or low molecular weight heparin is permitted • Evidence of active HIV, HBV or HCV infection, except o HIV positive patients established on anti-retroviral treatment, with undetectable HIV RNA, after discussion with the patient’s HIV physician o HBV core antibody positive patients who are (i) surface antigen negative and (ii) HBV DNA PCR negative, who take prophylaxis as per institutional guidelines • Patients who are pregnant or breastfeeding (women of childbearing potential must have a negative urine or serum pregnancy test prior to trial entry) • Patients and patients with partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use highly effective contraception (see Section 9.6) during and for 12 months after cessation of therapy • Clinically significant cardiac or respiratory dysfunction that, in the opinion of the investigator, would jeopardise the safety of the patient in the trial • Active malignancy treated in the last 2 years, except o Non-melanoma skin cancer o Carcinoma in situ of the cervix or breast o Incidental finding of prostate cancer (T1a or T1b)

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  • Augmented response of volatile biomarkers in assessment of oesophagogastric cancer (AROMA 1)

    • Research Summary

      Cancer of the stomach and oesophagus (gullet) is among the world's top five cancers. Survival rates are very poor as the disease presents late and early symptoms are non-specific. We have developed a non-invasive test for cancers of the stomach and oesophagus based on the detection of small molecules in exhaled breath that we believe are produced by the cancer as well as gut bacteria that are associated with the cancer. Our proposed innovation is to improve the accuracy of this test by investigating whether the ingredients of simple foods can increase the production of these small molecules. It is expected that cancer and bacteria cells will break down these ingredients to produce larger amounts of the small molecules we have previously measured in the breath, therefore making it easier to detect the cancer. The study will be a prospective multi-centre study, recruiting patients to augment the production of organic compounds in the breath by the consumption of a stimulant drink. Serial breath tests will be performed following this and the collected breath samples will be analysed for organic compounds (associated with cancer and the gut microbiome). In addition to this we aim to establish a comprehensive bioresource of matched samples from patients with oesophageal and gastric cancer as well as controls. Biosamples including breath, urine, saliva, blood, tissue and gastric contents will be collected and analysed to further investigate the metabolic pathways involved in cancer development and organic compound production.

    • Inclusion Criteria:

      1.Male and females aged 18-90 years 2. Patients with biopsy proven oesophageal or gastric adenocarcinoma who have not yet undergone treatment with chemoradiotherapy or surgery 3. Control subjects with symptoms of upper gastrointestinal disease and either a normal upper gastrointestinal tract or benign upper gastrointestinal disease (e.g. gastritis or Barrett’s) as determined at the time of oesophago-gastro-duodenoscopy (± histopathology).

    • Exclusion Criteria:

      1. Oesophageal squamous cell carcinoma 2. Antibiotic therapy within the last 4 weeks 3. Previous oesophageal and gastric resection 4. Allergy to any of the constituents of the nutrient drink 5. Antibiotic allergy 6. Unable or unwilling to provide informed written consent 7. Pregnant women

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  • A multicentre randomised controlled trial of virtual self-help cognitive behavioural therapy to MANage the impact of hot flush and night sweat symptoms in patients with prostate CANcer undergoing androgen deprivation therapy (MANCAN2).

    • Research Summary

      Hormone therapy medication is widely used to treat prostate cancer. It works by blocking or reducing the amount of testosterone in the body. This stops or slows down the cancer's spread. While effective as a medication, 80% of men suffer from Hot Flushes and Night Sweats as a result of taking it. These side effects can occasionally be so troublesome that some men decide to stop taking the medication allowing the cancer to grow. Unfortunately, there are few established effective treatments for men with Hot Flushes and Night Sweats. Our previous research has shown that cognitive behavioural therapy (CBT), a type of talking therapy, can help both men and women manage hot flush and night sweats in a positive way by changing how they think and behave. This study will evaluate how effective a self-help CBT programme is in reducing the impact of hot flushes and night sweats in men taking hormone therapy for prostate cancer. This will be delivered by a trained member of the existing prostate cancer nursing team. We will recruit 150 men with a diagnosis of prostate cancer currently receiving hormone therapy and experiencing problematic hot flushes and night sweats from seven hospitals around the UK. Half will be randomly assigned to a 4-week self-help CBT programme and the others will receive treatment as usual. Participants randomised to the self-help programme will be given a cognitive behavioural therapy booklet to work through consisting of information and exercises to help manage symptoms and improve wellbeing. There will also be two virtual group workshops delivered by the cancer nurse specialist team. Men in this arm will also receive a CD/ audio file demonstrating breathing and relaxation exercises. All participants will complete study questionnaires at baseline, 6 weeks and 6 months.

    • Inclusion Criteria:

      1. A diagnosis of prostate cancer 2. Localised or advanced disease stage. Patients may have had potentially curative treatments including, but not limited to, radiotherapy, brachytherapy or surgery. Patients with advanced disease must have hormone sensitive disease at the point of study entry 3. Currently receiving ADT, having been on this treatment for a minimum of 4 months, and anticipated to require a minimum of 12 months further continuous treatment. Treatment may have been planned for either a fixed duration (for example, but not limited to, 2 years after radiotherapy) or permanent. Treatment may be with either adjuvant (following potentially curative treatment) or palliative intent. LHRH analogues, LHRH antagonists and surgical castration are all acceptable forms of androgen deprivation. Androgen receptor antagonists, including but not limited to, bicalutamide, enzalutamide, apalutamide or darolutamide, or abiraterone, may be given in combination with androgen deprivation according to local practice. 4. Presence of problematic HFNS symptoms defined as a HFNS Rating Scale score of two or more. 5. Ability to read and understand English without assistance 6. 16 years or older 7. Ability to attend virtual group workshops through video conferencing software. If this is not feasible, participants must be able to participate in one-to-one workshops by telephone Concomitant Medications and HFNS interventions: Interventions intended to mitigate HFNS, including but not limited to, medications, herbal remedies, vitamin supplements, yoga and acupuncture are permitted. All other concomitant medications are permitted. Use of HFNS and concomitant medications will be recorded.

    • Exclusion Criteria:

      1. Currently with either uncontrolled biochemical, radiological or clinical disease progression or relapse as determined by the local principle investigator 2. Castration resistant disease status 3. Currently receiving chemotherapy. Prior chemotherapy must have been completed with a minimum of 3 months elapsed between the date of the final dose and confirmation of eligibility. Concomitant use of bone health agents, including zoledronate and denosumab is allowed 4. Currently receiving multi-fraction external beam radiotherapy, brachytherapy or focal ablation techniques. These must have been completed with a minimum of six weeks elapsed between the date of the final fraction/treatment and confirmation of eligibility. Single fraction radiotherapy to sites of painful bony metastatic disease is allowed 5. Intention to receive ADT on an intermittent schedule 6. Use of experimental drugs within other interventional clinical trials. Co-recruitment to observational studies, or studies of surgery or focal ablation techniques where the interventional component is complete, is acceptable 7. Currently receiving androgen deprivation as a neoadjuvant treatment 8. Medical or psychiatric conditions or other factors that, in the view of the local PI, are likely to impact on the ability of the patient to participate in the trial procedures and interventions

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  • IMproving PAtient undeRstanding of GEP TEst Results: Phase 4

    • Research Summary

      Gene Expression Profiling (GEP) tests in breast cancer help determine whether or not adjuvant chemotherapy may help reduce a patient’s risk of recurrence. Two main tests are Oncotype DX and Prosigna. Many breast cancer teams provide patients with information leaflets about these tests but often they are not written as accessible to the general population. To address this, we designed 2 short information films, and compared the ability of these to convey basic information about GEP testing, and recurrence risk results, with that achieved after reading an information leaflet. Results from this study (IMPARTER Phase 3), showed that providing information about Oncotype DX or Prosigna in film format, significantly improved the knowledge of 120 women aged 45-75 (without breast cancer) compared with that achieved after reading the information leaflets. Most participants preferred the films for reasons including clarity, graphics and reassuring tone. The leaflets proved difficult for most participants to understand, often due to the medical terminology used, irrelevant extra information and layout. We now wish to explore breast cancer patients knowledge about GEP testing after receiving standard test information, or standard information plus a GEP patient information film, specific to either Oncotype DX or Prosigna. We aim to do this by comparing the understanding of GEP testing between women with breast cancer (n= 250) randomised to standard information or standard information plus film. We will also explore the impact of certain attitudes to uncertainty on decision making. The outcomes will show if the film and leaflet combination provides additional value to patients, over the standard information alone (usual practice/leaflet), in terms of knowledge and understanding about the test results for patients. Recruited patients will have already consented to GEP testing by their clinical team with their tumour sample sent for GEP analysis.

    • Inclusion Criteria:

      - First presentation of early stage breast cancer with all known disease surgically removed - Oestrogen Receptor (ER+ve) and HER-2 negative (female patients only) - No clear decision as to whether chemotherapy should be given as adjunct based on current prognostic criteria - Consented to GEP tests - Able to give full informed consent to IMPARTER:4 - Good comprehension of the English language - Access to internet connection and compatible devices

    • Exclusion Criteria:

      - Other breast cancer diagnosis e.g. DCIS, metastatic - Unable to give fully informed consent - Under 18 years of age - Unable to understand and speak English - No access to internet connection and/or compatible devices

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  • FOxTROT: Personalising neo-adjuvant Chemotherapy in Locally advanced but operable colon cancer. A randomised trial programme.

    • Research Summary

      The FOxTROT platform is a rolling programme of molecularly stratified,randomised phase II/III,multi-centre,international,open-label studies. FOxTROT 2 is a phase III,multi-centre,open-label,international,randomised-controlled trial of modified dose of OxFp compared to STS,in patients unsuitable for FOLFOXIRI with a left-CC or have a right-CC tumour confirmed to be pMMR or MSS,and not felt to be at risk of bowel obstruction. Patients diagnosed with locally advanced but operable CC will be identified at a CC multidisciplinary team meeting following radiological assessment of the primary tumour and histological assessment of endoscopic biopsy. Potential participants will then be reviewed by a clinician and asked for consent to send their tumour block for biomarker testing (if MMR/MSI status is unknown) and translational research. The clinician will assess whether they are suitable to be treated on a neoadjuvant pathway and which comparison is most appropriate and provide the patient with a PIS. If MMR/MSI status is known at first assessment,or if patients have left primary tumour location (PTL),patients can proceed directly to assessment of suitability for each comparison and consent/ randomisation. Although MMR/MSI status is not a requirement for randomisation for patients with a left-PTL,testing is strongly recommended. If MMR/MSI status is being tested centrally,potential participants will be assessed for eligibility and suitability for each comparison once the results are available,and proceed to consent/randomisation.

    • Inclusion Criteria:

      Patients will have met the following FOxTROT Registration inclusion criteria: • Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high for radiotherapy); high grade dysplasia is acceptable with unequivocal radiological evidence of invasive cancer* • Radiological stage T3-4,N0-2,M0 • Patient being treated with curative intent • Tumour tissue is available for MMR/MSI testing (local or central) • No clinical or radiological evidence of bowel obstruction • Age ≥18 at the time of registration • Patient able and willing to provide written informed consent for the study * Patients with synchronous tumours are eligible,if the most advanced tumour meets the criteria above (please note MMR/MSI testing requirements for randomisation depending upon location of most advanced tumour) Additionally they will meet specific inclusion criteria for FOxTROT 2: • Patients will be unsuitable for mFOLFOXIRI due to oncologist assessed frailty or comorbidity • pMMR/MSS tumour status (for rt sided tumours) • CRC specialist-assessed fit to receive 6 weeks of NAC with OxFp (either full or modified dose) and surgery. • Adequate full blood count: WBC > 3.0 x109/l; Plts > 100 x109/l. Anaemia (Hb < 10.0 g/dl) is not an exclusion,but should be corrected by transfusion prior to surgery and chemotherapy. If Hb remains low despite transfusions,surgery and chemotherapy can be given at the decision of the surgical and oncology teams. • Adequate renal biochemistry: GFR > 50 ml/min as assessed by local standards • Adequate hepatobiliary function: bilirubin < 1.5 ULN (Patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study.) • If female and of childbearing potential,must agree to avoid pregnancy during and for 6 months after study treatment • If male with a partner of childbearing potential,must: - Agree to use adequate,medically approved,contraceptive precautions during and for 90 days after the last dose of study treatment • Signed the Informed Consent Document for randomisation

    • Exclusion Criteria:

      Patients will not have any of the following (as per FOxTROT Registration exclusion criteria): • Any patient for whom radiotherapy is advised by the MDT • Strong evidence of distant metastases or peritoneal nodules (cM1),however patients with lung lesions of uncertain significance (< 5mm) are eligible. • Peritonitis (secondary to perforated tumour) • Colonic obstruction that has not been defunctioned* * Obstructed patients cannot be included in the Foxtrot trials,unless the obstruction has been relieved. This would usually be by defunctioning. Patients may also be stented,but there is more limited safety data on this and these cases should be individually discussed with the TMG. Additionally patients will not have any of the following specific exclusion criteria for FOxTROT 2: • Serious medical comorbidity,as assessed by leading clinician (such as uncontrolled angina) • 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 a recurrence risk < 10% • Known dMMR/ MSI-H tumour status

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  • Perceptions and experiences of abemaciclib and endocrine therapy

    • Research Summary

      This study is looking at the expectations and experiences of women who are receiving abemaciclib (a targeted cancer drug) and hormone (or endocrine) therapy for early breast cancer that is at high risk of recurrence. This treatment is fairly new and little is known about what patients expect, their experiences during treatment and how they manage any possible side-effects. We know for example that diarrhoea (sometimes severe) is a common side effect of abemaciclib and usually starts during the first weeks of treatment. Finding out how people experience treatment, how well they deal with any problems and understanding their needs, is essential to aid the development of helpful information materials that will best inform and support them. In this study, we will invite 25-30 women from the POETIC-A trial to take part in a series of three interviews. The first interview is before or shortly after starting study treatment to find out what their treatment expectations are and what they know about the drugs they have been prescribed. The follow-up interviews will take place 4 and 8 weeks later to find out if their treatment experiences met their expectations. We would like to know especially if they had diarrhoea, what steps they may have taken to reduce it, and how successful this was. We hope that the results of the study can be used to develop materials to help doctors communicate better the side-effects of treatment, and more importantly how effective different ways to deal with these might be. Our work has real potential to benefit patients by changing the way we support people who are receiving abemaciclib, and help them to fulfil their everyday life roles and responsibilities.

    • Inclusion Criteria:

      - diagnosis of ER+, HER2- breast cancer; - postmenopausal; - participating in the POETIC-A trial and randomised to receive abemaciclib and standard adjuvant ET; - aged 18 years or over; - comprehension of the English language.

    • Exclusion Criteria:

      - inability to understand and speak English; - inability to give fully informed consent.

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  • The MARECA study- National study of management of breast cancer locoregional recurrence and oncological outcome

    • Research Summary

      Although the 5 year UK breast cancer survival is favourable at 86.6%, patients continue to develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy. Patients also present with breast cancer recurrence in the nearby lymph glands (under the arms or above/below the collarbone). These recurrences are collectively termed locoregional recurrence (LRR). It is estimated that up to 8% of breast cancer patients are diagnosed with LRR 10 years after their diagnosis. Currently there is a lack of high-quality data and clinical guidance for the optimal management of breast cancer patients diagnosed with LRR. In the UK, breast cancer recurrence is under-reported at individual hospital level to the national cancer registries. As a result, retrospective analysis of existing routine data sources are unlikely to provide data on patient management that is reflective of current national practice. The MARECA study is a prospective observational multicentre longitudinal cohort study which will determine the frequency, current management and prognosis of patients diagnosed with breast cancer LRR +/- distant metastasis in the UK with the aim of establishing best practice and inform future national guidelines. Over 50 UK breast units will participate in the study. We will establish a national prospective cohort of patients newly diagnosed with LRR (+/- distant metastasis) and describe how these patients are managed, and examine any geographical variation in the care received. The study participants will be followed up at two time points (3 and 5 years) in order to determine patient survival outcome (breast cancer related or not), as well as development of any further locoregional re-recurrence or distant metastasis. Patient survival analysis will identify prognostic factors, which will in turn generate hypothesis for future related studies with an aim of improving patient outcome.

    • Inclusion Criteria:

      -Female or male patients more than 18 years old. -Treated for previous unilateral or bilateral breast cancer (invasive cancer including all histological subtypes as well as ductal carcinoma in situ) with curative intent. -No previous evidence of distant metastatic disease. -Recently (within the last 6 months) diagnosed with new ipsilateral locoregional recurrence (biopsy proven invasive cancer including all histological subtypes or ductal carcinoma in situ) +/- distant metastasis. -Able to provide written informed consent. -A minimum of 3 months interval between the resection surgery for the original cancer and the diagnosis of locoregional recurrence. There will be no maximum interval time period.

    • Exclusion Criteria:

      -Patients where the new breast cancer diagnosis is in the contralateral breast. -For patients who present with new bilateral breast cancer, the side with no previous cancer will be excluded. -Patients diagnosed with distant metastatic disease with no evidence of locoregional recurrence. -Patients diagnosed with angiosarcoma. -Patients with previous history of non-breast cancer treatment that was non-curative in intent. -Patients who have had previous ipsilateral surgery for atypia, benign conditions, or phyllodes tumour and other breast sarcomas. -Patients under 18 years old. -Patients lacking capacity to provide written informed consent.

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  • A multi-arm phase II basket protocol testing reduced intensity immunotherapy across different cancers

    • Research Summary

      Immune checkpoint inhibitors are a type of drug used to treat patients with advanced cancers. They help the body’s immune system find cancer cells. The immune system is important in fighting infections and cancer. Immune checkpoint inhibitors can stop cancers growing for many months or years. Immune checkpoint inhibitors are given to patients through an injection into a vein every 3-6 weeks in a hospital or clinic. Blood tests are needed before each injection. This means that patients spend a lot of time (and money) on hospital visits. The drugs are expensive costing many thousands of pounds per month and use a lot of hospital resource. It is likely that immune checkpoint inhibitors work for a longer period of time than originally thought. This means it may be possible to give the drugs less often and still have the same effect on the cancer. The unwanted side effects of these drugs are unlike those of traditional chemotherapy drugs as they may cause auto-immune problems, meaning that the patients’ immune system attacks their normal tissues. The relationship between dose of drug and side-effect is not clear but it is possible that giving the drugs less often might limit the side-effects experienced by patients. REFINE is a clinical trial that tests whether patients can receive immunotherapy drugs less often whilst getting the same benefit in terms of treating their cancer with fewer side effects and improved quality of life. Giving these drugs less often may also allow the NHS to deliver equally effective treatment at a lower cost. The REFINE trial is an initial test of this concept and aims to understand the benefits to patients and to the health service from this approach, and may lead to a larger trial in due course. REFINE will start by testing this in groups of patients with advanced kidney cancer and melanoma but will then test this approach in patients with a range of other tumour types.

    • Inclusion Criteria:

      1. WHO Performance Status 0 or 1. 2. Patients with locally advanced or metastatic cancer whose clinician has determined they are candidates for treatment with standard of care immune checkpoint inhibitor. 3. Patients aged > = 18years. 4. Adequate normal organ and marrow function. a. Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks prior to 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/L (> = 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 < = 3 x ULN. f. Calculated Creatinine Clearance level > 40mL/min by Cockcroft Gault formula (using actual body weight). 5. Resting 12-lead ECG on which QTcF must be < 450 ms. This will usually have been performed prior to commencement of the initial 12 weeks ICI. 6. Both men and women enrolled in this trial must be in agreement with trial policy on contraception during the treatment phase of the study. Egg donation, sperm donation and breastfeeding must be avoided. 7. Evidence of post-menopausal status or negative serum HCG 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). RENAL COHORT SPECIFIC INCLUSION CRITERIA: 1. Patients with un-resectable locally advanced or metastatic renal cell carcinoma (including clear cell and papillary histologies) 2. Intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria 3. Patient has received induction ipilumumab 1mg/kg (all four doses) and nivolumab 3mg/kg as first line treatment 4. Due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease on cross sectional imaging on completion of initial 12 weeks treatment with ICI) MELANOMA COHORT SPECIFIC INCLUSION CRITERIA 1. Patients with locally advanced or metastatic melanoma 2. Patients have received single agent pembrolizumab first line for 3 months, with no evidence of progression (i.e. response or stable disease), and due to commence maintenance Pembrolizumab every 6 weeks; OR induction ipilumumab 1mg/kg and nivolumab 3mg/kg as first line treatment, and due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease) on cross sectional imaging 12 weeks post initiation of ICI.

    • Exclusion Criteria:

      1. Patients who have received immune checkpoint inhibitors in a prior line of treatment 2. Patients whose planned treatment is the combination of anti-PD-1 and tyrosine kinase inhibitor eg, pembrolizumab-axitinib or the combination of traditional cytotoxic chemotherapy and anti-PD-1. 3. Patients with unresolved/untreated immune-related adverse events resulting from the first 3 months of treatment with standard of care immune checkpoint inhibitor 4. History of another previous 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 without evidence of disease. c) Adequately treated carcinoma in situ without evidence of disease. d) Superficial bladder cancer 5. 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 (see co-enrolment section for further details). 6. Current or prior use of immunosuppressive medication within 14 days before starting immune checkpoint inhibitor, 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. 7. 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). 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. c. Hepatitis C. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. d. Human immunodeficiency virus (positive HIV 1/2 antibodies). 8. 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 immune checkpoint inhibitor and up to 30 days after the last dose of immune checkpoint inhibitor. 9. Known allergy or hypersensitivity to immune checkpoint inhibitor 10. Pregnant or breastfeeding patients. 11. Uncontrolled adrenal insufficiency 12. Any serious or uncontrolled medical or psychiatric disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, interfere with participation and/or compliance in the trial, or interfere with the interpretation of study results. 13. Participants who have undergone any prior systemic anti-cancer treatment (previous participation in adjuvant studies allowed, providing the patient was on the observation/ placebo arm – this may require un-blinding of the patient) 14. Untreated brain metastases or brain metastases treated only with whole brain radiotherapy. (Patients are eligible if previous brain metastases treated with complete surgical resection, Stereotactic Brain Radiation Therapy (SBRT), or gamma knife with no subsequent evidence of progression and asymptomatic).

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  • What clinical outcomes are associated with the 'joint care' for teenagers and young adults with cancer?

    • Research Summary

      What is the problem? In England, around 2,100 young people aged 16-24 years are diagnosed with cancer annually. Young people develop rare cancers and are more likely to experience significant impacts on their mental health, education and relationships with friends/family which means they need specialist care. Thirteen cancer hospitals called Principal Treatment Centres (PTCs) specialise in treating young people. Not all patients are treated in PTCs. Young people can have: 1. All care delivered in PTC 2. No care delivered in PTC, all their care is in a children’s or adult hospital. 3. Some care in a PTC and some care in another hospital, this is called ‘joint care’. BRIGHTLIGHT investigated the impact of having all care in a PTC, versus no care and some care in a PTC. Results suggest young people whose care is divided between PTCs and other hospitals (joint care) have lower quality of life than those having all their care in a PTC or no care in a PTC. New NHS commissioning guidance recommends ‘joint care’. It is important to assess whether the findings of BRIGHTLIGHT still hold or, whether now joint care can be as good as those being treated in one type of hospital. What are our aims? To determine if young people in ‘joint care’ have similar quality of life compared to those treated in one hospital. How will we do this? A survey will be sent to 732 young people aged 13-24 years, within seven months of a new cancer diagnosis asking about quality of life and other factors including social support, their experience of their cancer journey and care. We will link patient responses to data collected in the cancer registry and data collected by the NHS to determine whether they have had care in one hospital or if they had ‘joint care’.

    • Inclusion Criteria:

      New cancer diagnosis. Aged 16 – 24 years at the time of diagnosis. Not literate in English or non-English speaking. Resident in the UK at the time of diagnosis and treatment. Recruited within 4-5 months of diagnosis.

    • Exclusion Criteria:

      Young person is not capable of completing the survey (e.g., unconscious, mental incapacity). Current admission is for recurrence of previous cancer. Death is imminent as evaluated by the clinical team. Young person is receiving a custodial sentence. Young person opts out of having details transferred to Quality Health.

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  • VALTIVE1: Validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors: Optimising the design of a subsequent randomised discontinuation trial

    • Research Summary

      Tumours require a blood supply to provide them with oxygen and nutrients and to enable spread of cancer to other organs (metastasis). New blood vessel formation is known as angiogenesis, which is controlled by a growth factor (like a hormone) called Vascular Endothelial Growth Factor (VEGF). Many drugs have been developed that block VEGF and, in most cancers, including ovarian cancer, the addition of VEGF inhibitors (VEGFi) to conventional anti-cancer therapy postpones recurrence of the disease and in some cases improves the overall outcome. VEGFi are widely used in cancer medicine. Yet, until now, there have been no biomarkers (tests) that could be used to tell patients and their doctors whether the drugs were working. In their initial studies in ovarian and bowel cancer, Prof Jayson’s team discovered the first biomarker that tells us whether a VEGFi is working. The test involves measuring a protein in the blood called Tie2, which can be measured from routine blood tests. When Tie2 decreases in the blood, we know that tumour blood vessels are blocked by VEGFi and the treatment is working; when the level increases, we know that the blood vessels have escaped the control of VEGFi and treatment should be changed. However, further research is required to establish the test in the NHS to support clinical decision making. In VALTIVE1 study, we would like to collect blood samples from patients with advanced ovarian cancer who are receiving a specific type of VEGFi called bevacizumab as part of their standard of care. The aim of VALTIVE1 is to generate a comprehensive biomarker data set that describes how Tie2 responds to treatment with bevacizumab. The data set will be used to design VALTIVE2, which will be a randomised trial with the aim of proving conclusively the value of Tie2 test.

    • Inclusion Criteria:

      In order to be eligible for participation in this trial, the patient must: 1. Be willing and able to provide written informed consent for the trial 2. Age 16 years or over on day of signing informed consent 3. Histologically proven ovarian, primary peritoneal or fallopian tube cancer (henceforth referred to collectively as Ovarian Cancer - OC) FIGO stage III with residual disease of more than 1cm; or stage IV; or stage III at presentation treated with neoadjuvant chemotherapy; or stage III with contraindication to debulking surgery chemotherapy 4. Planned to receive treatment with bevacizumab or biosimilar bevacizumab 5. Be scheduled to receive at least 2 successive doses of bevacizumab with 6 or more weeks of follow up blood samples after the first dose of bevacizumab if given pre-operatively; or to start bevacizumab post-operatively 6. Be eligible for receiving treatment with first line, 3-weekly carboplatin and paclitaxel chemotherapy 7. Be willing to provide blood samples and comply with trial-specific procedures

    • Exclusion Criteria:

      The patient must be excluded from participating in the trial if the patient: 1. Is unsuitable for treatment with VEGF inhibitors 2. Is unable or unwilling to comply with study procedures 3. Is participating in a clinical study with an investigational product other than carboplatin, paclitaxel and bevacizumab 4. Is judged by the investigator to be unlikely to comply with study procedures 5. Is pregnant or could become pregnant and is not using adequate contraception 6. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 7. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g. HCV RNA is detected). Testing only required if patient has a history of either of these

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

    • Research Summary

      TRACC C is a prospective, randomised, multi-centre, study enrolling a total of 1681 patients Patients with high risk stage II or stage III colorectal cancer (CRC) whose pre-surgery blood test confirms presence of circulating tumour DNA (ctDNA) will be randomised to 1:1 with 810 patients treated in standard of care arm where patients are offered adjuvant chemotherapy according to national guidelines and 810 patients in the experimental arm, in which patients are treated based on ctDNA results . Patients will be stratified according to: 1. High risk stage II versus stage III 2. Site of primary tumour: right colon versus left colon versus rectum Hypothesis: ctDNA directed adjuvant chemotherapy administration will enable biomarker driven selection of patients who would benefit from adjuvant chemotherapy, thereby reducing the proportion of patients receiving adjuvant chemotherapy without compromising disease free survival. Background: There are 42,000 new cases of CRC, a top four cancer, diagnosed in the UK each year (CRUK Bowel Cancer Statistics, 2017). Approximately half of these cases are curable and include stage II (n= 9600/year) and III (n= 10,500/year). In patients with high risk stage II and stage III colorectal patients, adjuvant chemotherapy is currently determined by pathological features of the tumour resected at surgery. This is not a precise method of risk stratification of relapse and we are undoubtedly over-treating a proportion of patients already cured. Around 15-25% of patients offered standard oxaliplatin containing chemotherapy have permanent peripheral sensory neuropathy which can be quite debilitating and distressing (Grothey, Sem in Onc, 2003). Progress has been made in minimising unnecessary chemotherapy with the landmark UK-led publication (Iverson T et al, Lancet Onc, April 2018), confirmed by international meta-analyses (Grothey A et al, NEJM, March 2018) indicating that 3 months of post-operative chemotherapy was non-inferior to 6 months, without loss of benefit. The 3 year disease-free survival (DFS) in the 3-month group was 76.7% (95% CI 75.1–78.2) and in the 6-month group was 77.1% (75.6–78.6) [HR: 1.006 (0.909–1.114)]. The incidence of peripheral sensory neuropathy was of significantly less magnitude, with the rate being 58% in the 6 month group versus 25% in the 3 month group. The SCOT trial has changed clinical practice and our current standard of care is either 3 months of doublet capecitabine and oxaliplatin (CAPOX) or 6 months of single agent capecitabine chemotherapy in the adjuvant setting for patients with high risk stage II or stage III CRC. Liquid biopsies, in particular ctDNA, are emerging as an indicator of microscopic minimal residual disease following surgery. There is increasing evidence that postoperative ctDNA levels could potentially be a prognostic biomarker, identifying patients with high or low risk of recurrence. This represents the next step in individualising risk stratification and treatment minimisation, thereby truly delivering personalised care to patients. Multiple prospective studies have shown that time to recurrence, relapse free survival and overall survival were significantly shorter in patients who are ctDNA positive post-operatively compared to negative patients in stage II and stage III colon cancer (Tie et al., Science Translational Medicine, 2016; Diehn et al., ASCO 2017; Tie et al., ASCO 2018). Similarly, in patients with locally advanced rectal cancer (T3/T4 and/or N+) receiving chemo-radiotherapy recurrence-free survival was significantly worse in patients in whom ctDNA was detected after after surgery (HR 13.0; p< 0.001). (Tie et al., Gut Feb 2018). The technology for detecting ctDNA has advanced rapidly from the laborious droplet digital PCR (ddPCR) which involves designing individual probes for analysis, to next generation sequencing (NGS) directly in the blood by using suitable cutting edge gene panels. Our amendment now allows us to add TRACC C to the current TRACC protocol to use ctDNA analysis to guide therapy in high risk stage II and stage III patients with standard of care chemotherapy. This study will facilitate rapid implementation of this technology for assessment across the existing network of recruiting centres.

    • Inclusion Criteria:

      Eligibility criteria to be used prior to registration (for all patients, Part A and B): Inclusion Criteria: • New diagnosis of histologically confirmed CRC scheduled to undergo surgery with curative intent, with no radiological evidence of metastatic disease. • Patients with lesions with high degree of suspicion on histology but not confirmed to be an adenocarcainoma and whose imaging is strongly suggestive of colorectal carcinoma (CRC) will be included. This patients will be excluded post-surgery if carcinoma diagnosis is not confirmed • Age≥18 • Ability to give informed consent • Able to adhere to follow up schedule Additional eligibility criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy All patients proceeding to surgery Eligibility criteria at the first post-operative visit: Inclusion Criteria: • Stage I, 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 For patients in the ctDNA guided interventional arm of the study only (Part C) Inclusion Criteria: 1. Subject ≥ 18 years of age 2. Subjects with histologically proven high risk stage II or stage III colon or rectal cancer treated with curative intent with surgery alone (any T, N1 or N2) with no evidence of metastatic disease. Subjects must be due to receive adjuvant chemotherapy following surgery. Subjects with histologically proven stage III rectal cancer are eligible, including patients treated with neoadjuvant chemoradiotherapy (any T, N1 or N2, M0) with no evidence of metastatic disease. Subjects must be due to receive adjuvant chemotherapy following surgery. 3. Fully surgically resected tumour with clear resection margins (i.e., > 1 mm) 4. Patients must have detectable levels of ctDNA (i.e., ctDNA positive) in blood samples at baseline; this is collected pre-operatively if being treated with surgery alone, or before chemoradiotherapy in patients with locally advanced rectal cancer being treated with neoadjuvant chemoradiotherapy before surgery 5. Adequate organ function - Absolute neutrophil function ≥1.0 x 109 / L - Platelet Count ≥ 75 x 109 / L - Haemoglobin ≥80g/L (blood transfusion before randomisation is allowed) - Adequate renal function as calculated by Cockcroft and Gault equation (GFR ≥ 30ml/min if FOLFOX chemotherapy chosen and GFR ≥ 50ml/min if single agent capecitabine or CAPOX chosen) - Aspartate aminotransferase/ Alanine aminotransferase levels ≤ 2.5 upper limit of normal 6. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would not contraindicate adjuvant chemotherapy 7. Patients should be assessed by Oncology team for suitability and assessment for adjuvant chemotherapy, be able to have post-operative ctDNA sample collected and be randomised by week 4-8 after surgery. 8. ECOG performance status 0- 2 9. Able to give informed consent

    • Exclusion Criteria:

      Eligibility criteria to be used prior to registration (for all patients, Part A and B): Exclusion Criteria: • 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 eligibility 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 Eligibility criteria at the first post-operative visit: Patients with no confirmed tissue diagnosis or high grade dysplasia included in the study based on imaging diagnosis but subsequent histopathology of surgical specimen confirms no carcinoma will be excluded • Scheduled to receive post-operative radiotherapy For patients in the ctDNA guided interventional arm of the study only (Part C) Exclusion Criteria: 1. History of concurrent and previous malignancy within the last 3 years, with the exception of non- melanomatous skin cancer and carcinoma in situ 2. Any major post-operative complications or other clinical conditions that in the opinion of the investigator would contra-indicate adjuvant chemotherapy 3. Any subject not due to receive adjuvant chemotherapy will not be eligible for Part C of the study 4. Hypersensitivity or contraindication to the drug(s) associated with the planned choice of systemic chemotherapy (CAPOX, FOLFOX or single agent 5-FU or capecitabine) as stated in the SPC for each of the drugs

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  • ELEVATE: Temozolomide + nivolumab in MGMT deficient oesophagogastric cancer

    • Research Summary

      Surgery is the only curative option for patients with oesophagogastric adenocarcinoma, but despite the use of multimodality therapy which combines it with chemo and/or radiotherapy, more than 50% of patients will relapse and die. Many of the UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab (a checkpoint blockade inhibitor) has been found to work in some advanced cancers. It is proposed for those where it hasn't worked - that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. In this trial we will aim to sensitize the tumour with temozolomide (TMZ) to increase its sensitivity to nivolumab. Patients will be treated for up to 3 months with TMZ prior to commencing nivolumab either in conjuction with TMZ or alone.

    • Inclusion Criteria:

      Patients ≥ 18 years of age • Pathologically confirmed advanced unresectable or metastatic OGA • MGMT methylation on archival tissue • Mismatch repair proficient (MSI-normal or MMR intact) • Previously treated with at least 3 months of platinum and fluoropyrimidine based chemotherapy for advanced disease and without evidence of disease progression. • Measurable disease per RECIST 1.1. • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 • Can swallow TMZ capsules • Adequate organ function assessed within 7 days before randomization: o White blood cell count (WBC) > 1.5 x 109/L o Absolute neutrophil count (ANC) > 1.5 x 109/L o Platelets ≥ 100 x 109/L o Haemoglobin ≥ 90 g/L o Measured/calculated creatinine clearance ≥ 60 mL/min (according to Cockroft-Gault formula). o Total bilirubin within normal limits (if the patient has documented Gilbert’s disease ≤ 1.5 x ULN or direct bilirubin ≤ 1.5 x ULN) o Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 1.5 x ULN • All toxicities (exception alopecia, and grade 2 fatigue, neuropathy and lack of appetite /nausea) attributed to prior anti-cancer therapy must have resolved to grade 1 (NCI CTCAE version 5.0) or baseline before administration of study drug. • Women of childbearing potential (WOCBP) may be included following a confirmed menstrual period and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)). Pregnancy test must be within 24 hours prior to starting treatment. (A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). • WOCBP should use one highly effective and one effective method of birth control during the study treatment period and for at least 5 months after the last dose of the study treatment. • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last dose of the study treatment. • Men who are sexually active with a WOCBP must adhere to contraception during and for a period of 7 months after the last dose of the study treatment. • Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. • Written informed consent

    • Exclusion Criteria:

      - Previous treatment with TMZ • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways • Active central nervous system metastases • Candidate for curative surgery • Previous malignancies are excluded unless a complete remission was achieved at least 5 years prior to study entry. Adequately treated cervical carcinoma in situ, and localized non-melanoma skin cancer are not exclusion criteria, regardless of timepoint of diagnosis. • Active, known, or suspected infectious or autoimmune disease (except for patients with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enrol) • Conditions requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration • Interstitial lung disease • > Grade 1 peripheral neuropathy • Positive test result for HBV or HCV indicating acute or chronic infection • Known history of testing positive for HIV or known AIDS • Known hypersensitivity to the components or excipients of co-trimoxazole, temozolomide or nivolumab. (Please refer to nivolumab IB and SmPC for TMZ and co-trimoxazole). • Known hypersensitivity to dacarbazine (DTIC) • Clinically significant abnormal 12-lead ECG. If clinically indicated, cardiac function assessment using either echocardiography or MUGA Scan, if clinically significant the patient is ineligible. • In the past 6 months serious cardiac illness or medical condition including but not confined to: o History of documented congestive heart failure (CHF) o High-risk uncontrolled arrhythmias o Angina pectoris requiring antianginal medication o Clinically significant valvular heart disease o Evidence of transmural infarction o Poorly controlled hypertension (e.g. systolic > 180mm Hg or diastolic greater than 100mm Hg) • Patients with severe liver parenchymal damage • Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed • Patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides. • Patients with acute porphyria • Patients with severe myelosuppression

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  • Lung Health Checks in Wessex and Yorkshire: Integrated Biomarker Studies

    • Research Summary

      Screening for lung cancer is being carried out in the NHS using low dose CT scans. This study will test whether adding blood or tissue biomarkers (tests that can detect molecules secreted by a tumour, or a specific response of the body to the presence of cancer) will help with screening for lung cancer in addition to a routine low-dose CT scan. This could help to improve the early diagnosis of lung cancer, and thereby survival, in the future. People undergoing a routine NHS Targeted Lung Health Check (TLHC) in Wessex or Yorkshire will be approached by a member of the clinical team, or an appropriately trained member of the research team, and asked if they are willing to participate in this study. If participants consent to the study, they will have a single blood sample taken, and a tissue sample taken from inside the nose with a swab. The blood taken will be analysed to detect biomarkers (antibodies, circulating tumour DNA, or abnormal protein markers in the blood) and the sample from the nose will be analysed to measure the patterns of gene expression in the lining of the air passages. No additional visits for the study will be required. No additional clinical data will be collected for the study beyond the information routinely collected by the NHS. Permission will be sought to enable surplus samples to be stored for future ethically-approved research. One of the blood tests, called EarlyCDT Lung, has a a CE mark for use as an in vitro diagnostic. The results of this test will be fed back to the TLHC clinical team in case it is helpful in deciding whether a person would benefit from further investigation.

    • Inclusion Criteria:

      1. Individuals undergoing a Lung Health Check in Southampton, or a CT scan as part of the Yorkshire Lung Screening Trial in Yorkshire. 2. Ability to understand the study requirements and provide written informed consent

    • Exclusion Criteria:

      1. Deemed medically unfit for sample collection 2. Contraindication for study procedures or sampling

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  • Development of an EORTC Patient-Reported Outcome (PRO) Questionnaire for Quality of Life (QOL) of children with cancer: Phase I & II

    • Research Summary

      The assessment of quality of life (HRQOL) is a critical outcome measure for trials evaluating the risks and benefits of treatments for children with cancer. QOL assessment also plays an important role within clinical practice by facilitating communication between children, their parents and clinicians. It is therefore vital that QOL measures include questions which are of significance to children with cancer. While several paediatric QOL measures exist, previous research has identified shortcomings of those questionnaires when applied to children with cancer. The European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) has an international reputation for the development of cancer QOL questionnaires with a core quality of life questionnaire (EORTC QLQ-C30) and supplementary modules specific to a particular tumour, condition or age group (older adults, adolescents and young adults). There is currently no EORTC QLG questionnaire specific to children. The objective of this multi-centre study is to use EORTC QLG guidelines to develop a measure asking about QOL concerns of relevance and importance to children aged 8-14 years with cancer and identify optimal response options which are appropriate for this age group. The study is led by the Medical University in Innsbruck, Austria and involves two phases: Phase I consists of a literature review as well as qualitative semi-structured interviews with 60 children (8-14 years), 45 parents and 30 health-care professionals (HCPs). In Phase Ib, a further 60 children (8-14 years) will be interviewed to evaluate the best response format (Smiley faces- vs. Likert-Scale) for these age groups. In Phase II, the issues generated in Phase I will be operationalized and transformed into items and a preliminary questionnaire for children with cancer of 8-14 years will be constructed. In the UK a total of 30 children, 20 parents and 5 HCPs will be recruited.

    • Inclusion Criteria:

      The age group above relates to child participants (not parents or HCPs). Inclusion criteria: Diagnosis of any cancer and receiving treatment for cancer or palliative / supportive care Aged between 8 - 14 years No cognitive impairment Fluency in the native language of the local recruiting centre Willingness and ability of parents or guardians to give their fully informed consent Willingness and ability of children to give their assent HCPs: At least 5 years of clinical experience in paediatric oncology

    • Exclusion Criteria:

      Children with cognitive impairment and not able to give their assent or understand the nature of the study. Children / parents who are not willing to give their assent / consent. Children who have finished curative intent treatment and no longer have active disease.

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  • Translational Renal Adjuvant MultiPle Arm Randomised Trial (TransRAMPART)

    • 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. RAMPART is a study looking at two new immunotherapy treatments (durvalumab and tremelimumab) that have shown a benefit in other cancer types. TransRAMPART is a translational research study being run within the RAMPART clinical trial. Translational research is carried out in the laboratory on biological samples that our patients provide. By biological samples we mean samples of tumour, blood and urine. In TransRAMPART study we will carry out research on these samples to gain a better understanding of kidney cancer and how people respond to treatment with the class of medication (immune checkpoint inhibitors) our patients will be taking in RAMPART.

    • Inclusion Criteria:

      The inclusion criteria are the same as the RAMPART study (as copied below). All RAMPART patients at TransRAMPART sites will be offered the opportunity to participate in this study. 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 at UCL 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 their randomisation date. 4. Post-operative scans should be performed within 28 days prior to randomisation. 5. Patients with microscopically positive resection margins after radical nephrectomy at the nephrectomy bed, renal vein or inferior vena cava are eligible provided the post-operative CT scan shows no evidence of residual macroscopic disease. 6. WHO Performance Status 0 or 1. 7. 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 blood sample for future translational research. 8. Adequate normal organ and marrow function a. Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks prior to 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 (using actual body weight). 9. 12-lead ECG on which QTcF must be < 450 ms. In case of clinically significant ECG abnormalities, including a QTcF value > = 450 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. Patients are only eligible if a QTcF of < 450ms is confirmed 10. Subjects must be > = 18 years of age. 11. Written informed consent obtained from the patient. 12. Both men and women enrolled in this trial must be in agreement with trial policy on contraception during the treatment phase of the study and 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided. 13. Evidence of post-menopausal status or negative serum HCG 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:

      The exclusion criteria are the same as the RAMPART study (as copied below). All RAMPART patients at TransRAMPART sites will be offered the opportunity to participate in this study. 1. Previous diagnosis of RCC. 2. Metastatic or macroscopic residual disease. 3. Patients with positive resection margins after partial nephrectomy. 4. 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. 5. Prior anticancer treatment (other than nephrectomy) for RCC. 6. 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. 7. 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. 8. History of leptomeningeal carcinomatosis. 9. 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. 10. 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. 11. 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. 12. Active or prior documented autoimmune or inflammatory disorders. 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 13. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty. 14. History of allogeneic organ transplant. 15. Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection of any kind (patients who are exhibiting symptoms consistent with COVID-19, or who have tested positive, should not be randomised into the study until they are asymptomatic and at least 14 days after a positive test) 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. 16. Active infection including a. Tuberculosis b. Hepatitis B c. Hepatitis C d. Human immunodeficiency virus (positive HIV 1/2 antibodies). Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 17. 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. 18. Pregnant or breastfeeding patients. 19. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 20. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients. 21. Previous investigational medicinal product assignment in the present study. 22. Clinically significant pneumonitis or fibrosis.

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  • Phase 2 study of neoadjuvant immune checkpoint inhibitors in urothelial cancer

    • Research Summary

      This study is being carried out to see if the drug atezolizumab can reduce the size of tumours in patients with types of urothelial cancer before surgery. Atezolizumab is designed to stop a protein called PD-L1 (programmed death-ligand 1) being expressed on the cancer,allowing the immune system to recognise the tumour cells as foreign bodies and attack them. Atezolizumab has been shown to have activity in urothelial cancer which has spread. There two cohorts for this trial. One cohort will investigate the most common histological type of urothelial cancer (transitional cell carcinoma) outside the bladder,for example in the upper urinary tract. The other cohort will investigate rarer histological subtypes (such as such as squamous cell or adenocarcinoma) of urothelial cancer throughout the entire urinary system. This study will be recruiting patients from hospitals in the UK,France and Spain. If a patient is eligible for the study and decides to take part,they will receive up to two 3-weekly cycles of atezolizumab. 4-8 weeks after being enrolled,the patient will have an operation to remove the bladder (cystectomy) or the kidney,ureter and part of the bladder (nephroureterectomy or distal ureteral resection) as per normal practice. Following surgery,they will attend three hospital visits (4,12 and 24 weeks after surgery) and their disease progress/survival will be followed over the next 2 years. The clinical team will compare the patient’s tumour tissue samples,scan results and blood results from before and after treatment with atezolizumab in order to see how well the drug works and if it is safe. Many of the procedures involved in this study are offered as standard care and participation in this trial will not delay surgery.

    • Inclusion Criteria:

      Cohort-Specific Inclusion Criteria • Bladder cohort: Histopathologically confirmed carcinoma of the urothelium (T1 high grade -T4a) in the bladder with mixed or rare histological subtypes such as squamous cell or adenocarcinoma. Patients with mixed histologies are required to have a dominant non- transitional cell pattern. • UTUC cohort: Histopathologically confirmed,high grade or high risk upper urinary tract urothelial carcinoma (renal pelvis and ureter). This cohort includes all patients with upper tract malignancy who in the opinion of the investigators qualify for radical surgery (nephroureterectomy or distal ureter resection). Urothelial carcinoma of the upper urinary tract qualifies as high-risk disease if any of the below factors are present: - Hydronephrosis - Tumour size > 2cm on cross sectional imaging - High grade cytology - High grade biopsy - Multifocal disease - Variant histology - Previous radical cystectomy for urothelial cancer of the bladder All patients undergoing radical surgery with curative intent in the opinion of the investigator are eligible. Radical surgical interventions include nephroureterectomy or distal ureteral resection. General inclusion criteria: 1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Age ≥ 18 years 4. Residual disease after TURBT or URS (surgical opinion,endoscopy or radiological presence). 5. Fit and planned for radical surgery with curative intent in the opinion of the investigator (according to local guidelines). 6. N0 or M0 disease CT or MRI (within 4 weeks of registration) 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin- based therapy is not appropriate. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential. 11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of atezolizumab. 12. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: a) ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1,Day 1) b) WBC counts > 2500/μL c) Lymphocyte count ≥ 500/μL d) Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1,Day 1) e) Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f) AST or ALT,and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled). g) INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h) Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)

    • Exclusion Criteria:

      1. Pregnant and lactating female patients. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. 3. Previously intravenous chemotherapy for urothelial cancer. 4. Patients with prior allogeneic stem cell or solid organ transplantation. 5. Prior treatment with CD137 agonists,anti-CTLA-4,anti−programmed death−1 (PD-1),or anti−PD-L1 therapeutic antibody or pathway-targeting agents. 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids,physiologic replacement doses of glucocorticoids (i.e.,for adrenal insufficiency),and mineralocorticoids (e.g.,fludrocortisone) is allowed. 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g.,for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible). 8. 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. 9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug,whichever is shorter,prior to enrolment. 10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results,including significant liver disease (such as cirrhosis,uncontrolled major seizure disorder,or superior vena cava syndrome). 12. Malignancies other than UC within 5 years prior to Cycle 1,Day 1,with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix,basal or squamous cell skin cancer,or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive). 13. Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection,bacteraemia,or severe pneumonia. 14. 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. 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced pneumonitis,organizing 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 (fibrosis) is permitted). 16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible. 17. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Positive test for HIV 19. Patients with active tuberculosis 20. History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug. 21. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > the institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study. 22. History of autoimmune disease including but not limited to myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis. 23. Patients with a history of autoimmune-related hypothyroidism,unless on a stable dose of thyroid-replacement hormone. 24. History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation

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  • BIOSPECIMEN COLLECTION FOR: PREBIOTIC EFFECT OF EICOSAPENTAENOIC ACID TREATMENT FOR COLORECTAL CANCER LIVER METASTASES

    • Research Summary

      The mechanism(s) by which the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-colorectal cancer (CRC) activity is not understood. Recent experimental data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota (gut bacteria), thereby reducing immunosuppressive mechanisms that allow CRC cells to ‘hide’ from the host anti-tumour immune response. The EMT2 trial is an ongoing randomized, double-blind, placebo-controlled phase 3 trial of the effect of EPA ethyl ester 4 g daily on CRC recurrence and survival after surgery for resectable CRC liver metastases (ClinicalTrials.gov NCT03428477). There is a unique opportunity to collect samples from participants in the trial in order to characterise the intestinal microbiota and immune response to CRC. We will collect biospecimens (faecal [stool] samples, CRC liver metastasis tissue, blood and urine) from EMT2 trial participants in a way that does not interfere with participation in the EMT2 trial. Using stool, blood and urine samples collected 1) after EMT2 trial randomisation, before starting active EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, we will interrogate immune and microbiome pathways in relation to survival in EMT2 trial participants. We will address causality and characterize the mechanisms by which EPA potentiates host anti-tumour immunity and suppresses CRCLM using a novel ‘avatar’ germ-free CRCLM mouse model humanized with faecal material from EMT2 trial participants. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximise the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalised use of EPA, which will be targeted at those most likely to benefit.

    • Inclusion Criteria:

      Only individuals recruited to the EMT2 trial are eligible.

    • Exclusion Criteria:

      There are no specific exclusion criteria. If an individual is recruited to the EMT2 trial, they would be automatically eligible for the biospecimen collection study.

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  • Urine Biomarkers for detecting prostate cancer

    • Research Summary

      Cancer is present in the prostates of around half of all men over 60, however only a very small proportion of these men will die of prostate cancer. There is therefore a need to determine which men have cancer that needs treating and which does not require treatment. The progression of prostate cancer is highly heterogeneous, with risk assessment at the time of diagnosis considered as a critical step in the management of this disease. Sampling issues associated with needle biopsy of the prostate have prompted the development of non-invasive urine tests for aggressive disease which examine prostate-derived material harvested in urine. We are proposing the use of urine to detect aggressive prostate cancer. The prostate constantly produces secretions which naturally flow into the urine. These secretions carry cancer markers and are flushed out of the body on urination. We can collect these markers from urine and examine them for the presence of prostate cancer as well as determining how aggressive the cancer is. Our hypothesis is that urine expression signatures obtained from urine can be used to predict clinical outcome in prostate cancer patients adding clinical benefit in pre-biopsy patients and helping triage active surveillance (AS) patients into groups with high and low risk of progression. We also hypothesis that use of home-sample collection from the first urination of the day without a DRE can substitute for post-DRE collection at the clinic (confirmed in a pilot study). Using a cohort of 537 samples taken from 503 patients we have developed a test called PUR (Prostate Urine Risk), based on NanoString assessment of RNA expression levels in urine extracellular vesicles (EVs), that allows the probability of membership of each D'Amico risk group to be assessed prior to needle biopsy. The test was developed in a Training Cohort (n= 359) and confirmed in a Test Cohort (n= 178). PUR signatures that have shown efficacy in predicting prostate cancer biopsy results. A particularly effective application of the PUR test was in predicting failure in Active Surveillance (AS) patients. In a pilot study of 87 AS men, PUR could dichotomise the men into those that would progress up to 5 years later with a Hazard ratio > 8. There is nothing currently in the clinic that can do this. In AS patients PUR still had predictive value after MRI monitoring was considered. In the proposed study we will (i) validate the use of urine collected by the patient at home from their first urination of the day, (ii) test a simplified method of harvesting EV RNA and (iii) confirm the observations in our initial studies of the predictive value of PUR, including prognosis within AS cohorts. The study will involve the collection of urine from patients, from 8 UK NHS hospitals, 3 EU sites and 1 Canadian. The PUR test was developed as part of the Movember GAP1 Biomarker Initiative. This study is designed to provide information that will progress the future implementation of the PUR test in the clinic as an aid in shared decision making between patients and clinicians.

    • Inclusion Criteria:

      All male patients who are not thought to have prostate cancer in the control arm and all patients who have an established diagnosis of prostate cancer and not on treatment in the cancer arm.

    • Exclusion Criteria:

      Male patient post-prostate cancer treatment such as radical surgery or radiotherapy Patients who are unable to consent for any reason will be excluded.

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  • PRIMROSE TISSUE STUDY: A COLLECTION AND ANALYSIS OF TISSUE AND CSF SAMPLES FROM PATIENTS WITH CNS DISEASE SECONDARY TO BREAST CANCER

    • Research Summary

      PRIMROSE Tissue Study aims to collect and investigate archived tissue, excess CSF samples and related data (all collected as part of standard care) from patients with central nervous system disease secondary to breast cancer. This study does not involve additional procedures or interventions outside of standard care. Patients will be informed of the study and consented to participate in PRIMROSE Tissue. Following consent, arrangements will be made to request available archived FFPE tissue blocks of primary breast cancer tissue, non-cranial metastatic tissue or cranial metastatic tissue if available. CSF samples will be collected only if the patient has been scheduled to undergo a CSF collection procedure as part of their standard care. In this case, an excess 10ml of CSF will be collected for the PRIMROSE Tissue study. Prior to CSF collection, 10ml blood will be collected for the study (which would not otherwise be collected). The study can be carried out by trained clinical staff members, at sites with the appropriate and relevant facilities and this study does not involve experimental treatment or placebo treatment.

    • Inclusion Criteria:

      1.Male or female. 2.16 years of age or above 3.Histologically and/or cytologically confirmed breast cancer with CNS involvement, as defined as having one or more of the following: a)Metastases to the brain parenchyma b)Metastases to the leptomeninges c)Paraneoplastic Neurological Disorders 4.FFPE of biopsied or resected primary breast cancer, non-CNS metastasis and/ or brain metastasis is available or will be available. 5.Informed consent

    • Exclusion Criteria:

      1.Unable to comply with study procedures or give informed consent

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  • Patients’ preferences in the treatment of hormone-sensitive metastatic prostate cancer: a discrete choice experiment

    • Research Summary

      Key Question – What? The main aim of MATTER is to understand what types of treatment men who have been newly-diagnosed with metastatic prostate cancer (mPCa) might prefer. We also want to look at their willingness to accept new treatments that might improve survival but have potential risk of side-effects and worsening quality-of-life. We will do this using a study that looks at trade-offs between the different characteristics of different treatments. Key Question – Why? In the UK, over 14,000 men each year are diagnosed with prostate cancer that has spread beyond the prostate gland. We have improved life expectancy in these men using medication such as new hormone drugs and chemotherapy. Recently, it has been proposed that by treating the main cancer in the prostate and some areas that have spread might improve survival further. This is because the amount of cancer cells in the body is reduced and the signals that encourage more cancer growth can be interrupted. ‘Local’ treatment to the prostate can be given using surgical approaches or radiotherapy. Treatment to areas of spread is given using radiotherapy. These approaches are being tested in trials. More intensive treatments such as these might further improve survival but can carry additional risks of complications and long-term side effects. It is important to know to what extent men will accept these new approaches and whether when choosing, they make trade-offs between the problems caused by treatments and the benefit they give. Key Question – How? We have previously carried out a study called a ‘discrete choice experiment’ (DCE) in men with cancer that has not spread. This showed men are willing to make trade-offs between survival and side-effects. A DCE relies on the fact that patients make complex decisions when faced with a number of options for treatment. Hypothetical treatment scenarios are put to real patients to allow researchers to find out to which factors or ‘attributes’ involved in treatment men value most and which will they ‘trade-off’. e.g a man might be offered surgical removal of his prostate with the potential of 12 months of added life. However, due to the surgery he may suffer urinary incontinence. Whilst this may also occur as a result of his cancer at some stage, by choosing surgery he risks bringing this symptom forward. Therefore, he may decide to have targeted surgery e.g. freezing which has fewer side-effects. A DCE helps understand the trade-offs men make. Using interviews, with 10 men, we will first establish what are the key attributes (e.g. loss of libido, incontinence, pain) associated with treatment. Next we will develop the series of hypothetical scenarios that we can present 300 men across the UK. Men will be asked to choose the treatment they most prefer using the scenarios. The scenarios will be chosen to balance the information needed for statistical analysis and the burden on men. The statistical analysis of men’s choices will allow us to assign a mathematical value to the importance of each attribute and calculate the trade-offs between the attributes. This will allow us to make an overall statement on which attributes are the most important factors to men with mPCa when choosing which form of treatment to consent to.

    • Inclusion Criteria:

      Healthcare Professional: 1. Active clinician member of prostate/uro-oncology multi-disciplinary team meeting (MDT). This would include, but is not limited to, Oncologists, Urologist, Specialist Nurses, Clinical Fellows, Registrars, Radiologists & Research Nurses. Patient: (To be determined at specialist prostate/uro-oncology MDT). 1.Diagnosed with prostate cancer within 3 months of screening visit. 2.Performance status 0-2.

    • Exclusion Criteria:

      Patient: (To be determined at specialist prostate/uro-oncology MDT) 1.Castrate-resistant metastatic prostate cancer. 2.Patient has consented to a form of local cytoreductive treatment to prostate. 3.Patient has consented to a form of metastasis directed therapy.

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  • Precision medicine for liver tumours with quantitative magnetic resonance imaging and whole genome sequencing

    • Research Summary

      This will be a prospective, observational, cohort study to determine the impact of integrated diagnostics using quantitative magnetic resonance imaging, whole genome sequencing and digital pathology on intended patient management for liver cancer patients referred for liver resection. Participants with primary or secondary liver cancer will be recruited from Hampshire Hospitals NHS Foundation Trust in Basingstoke or Oxford University Hospitals NHS Foundation Trust in Oxford. The incidence of treatable liver tumours is on the rise globally, driven by obesity, viral hepatitis and metastases from colorectal cancers. Survival rates can be improved with optimised allocation of treatment options including surgical resection, radiofrequency ablation, embolisation, chemotherapy and targeted molecular therapies (including immunotherapy). The key motivation of this study is to help patients access the most suitable treatment combinations, based on integrating clinical, radiological and genomic data. A similar integrated approach, integrating radiology and pathology, has been shown to improve outcomes in breast cancer care. Detailed pathologic analysis of the surgical specimen from breast carcinoma biopsy provides valuable feedback to the radiologist, establishes the completeness of surgical intervention, and generates predictive information for therapeutic decisions. Whole genome sequencing (WGS) has discovered cancer driver mutations and the complex molecular profile of liver cancer. In many metastatic solid tumours, WGS has been used to identify a significant patient population (31%) who present with a biomarker that predicts sensitivity to a drug and lacked any known resistance biomarkers for the same drug. Identifying which patients possess druggable mutations will allow clinicians to make the optimal treatment decisions. The next challenge is integrating WGS into scalable clinical practice.

    • Inclusion Criteria:

      Male or female 18 years of age and older willing and able to give informed consent to participate in the study. Patients being considered for liver resection for primary or secondary liver cancer.

    • Exclusion Criteria:

      The participant may not enter the study with any known contraindication to magnetic resonance imaging (including but not limited to pregnancy, a pacemaker or other metallic unfixed implanted device, metallic fragments, extensive tattoos, severe claustrophobia). Any other cause, including a significant underlying disease or disorder which, in the opinion of the investigator, may put the participant at risk by participating in the study or limit the participant’s ability to participate.

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  • Validation of the EORTC QLQ-C30 with young people aged 12-17 years with cancer

    • Research Summary

      The European Organisation for Research and Treatment of Cancer Quality of Life Group Core measure (EORTC QLQ-C30) is the most widely used cancer health-related quality of life (HRQoL) questionnaire. We will be recruiting adolescents (12-17 years) (n= 300 minimum) who have been diagnosed with cancer and receiving treatment for curative intent or who are receiving palliative care. We would like to know whether the EORTC QLQ-C30 is acceptable, and if the content is relevant and representative for this age group. We will also be comparing young people and their parents'/ guardians' questionnaire responses. This current study has a target sample size of 300. There will be a good spread of participants according to language, culture (this is an international study), age sub-group (12-14 years and 15-17 years), on treatment and palliative care. For pragmatic reasons, we envisage recruiting fewer patients receiving palliative care compared with those on treatment with curative intent. Participants will be asked to complete the EORTC QLQ-C30 followed by a debrief interview asking about their experience of completing the questionnaire. They will also be asked to complete the 23 item PedsQL teen self-report form designed for adolescents aged 13-18 years. This measures physical, emotional, social and school (role) functioning thus it lends itself for comparison with the EORTC QLQ-C30. The young people will also be invited to complete a 15-item symptom checklist. Socio-demographic and clinical characteristics including the ECOG performance status will be completed. Participants will be recruited by a member of the research or clinical team while visiting the hospital as an inpatient or outpatient or they will be contacted by their clinician. Questionnaire completion will be carried out at the hospital, over the telephone, Microsoft Teams or at the participant’s home.

    • Inclusion Criteria:

      Diagnosis of cancer; awareness of diagnosis and management plan; treatment with curative intent or palliative care; age 12-17 years; comprehension of the language of the questionnaire; willingness and ability to give informed consent / assent (for participants aged 12-15 years), willingness and ability of parent / guardian to give consent.

    • Exclusion Criteria:

      Cancer survivors (i.e., participants who have completed treatment with curative intent and are now cancer free).

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  • International Validation of the Locally Recurrent Rectal Cancer - Quality of Life (LRRC-QoL) Questionnaire and a Longitudinal, Prospective, International Study of Patient Reported Outcomes in Locally Recurrent Rectal Cancer.

    • Research Summary

      Locally recurrent rectal cancer (LRRC) – cancer which returns close to the original site - affects approximately 10% of patients following treatment of rectal cancer. LRRC can cause symptoms, such as pain, bleeding and anal discharge. The only curative treatment for LRRC is extensive surgery in the form of an extended pelvic resection with 5-year survival rates of 43-63% following complete surgical resection, which is associated with high post-operative morbidity of up to 60%. The true extent of the burden of LRRC and its treatments on patients is unknown. The clinical and cancer-related outcomes are well documented, however, the extent of the impact on patients overall quality of life (QoL) is poorly reported. The LRRC-QoL is a questionnaire specifically designed for patients with LRRC to measure QoL. The LRRC-QoL was developed and validated for use in England and Australia. The best way to document outcomes related to QoL in this group is to collaborate with a number of high-volume, specialist centres internationally and to report outcomes related to QoL over a length of time. This study aims to translate and validate the LRRC-QoL into a number of other languages to enable its international use. We will validate the LRRC-QoL questionnaire on an international platform. Validation means checking that the questionnaire is applicable across all the relevant patient groups. The data obtained from the serial measurements will be used to evaluate changes in quality in life over time. Comparisons in scores of quality of life will be examined between patients undergoing different treatments. Survivorship issues represent the healthcare needs experienced by patients who have survived cancer treatment. As survival continues to improve in patients with LRRC and the number of survivors of exenterative surgery improves, it is important to understand the QoL and survivorship issues relevant to this cohort of patients.

    • Inclusion Criteria:

      Inclusion criteria for phase I: • aged > = 18 years; • with radiological and/or histological diagnosis of LRRC; • or have undergone treatment (surgery/chemotherapy/radiotherapy) for LRRC within the last 2 years; • able to provide informed written consent to participate and; • able to read and write in the target language. For phase II: • aged > = 18 years; • with a new radiological and/or histological diagnosis of LRRC; • able to provide informed written consent to participate and; • able to read and write in the target language. For phase III: • aged > = 18 years; • treated for LRRC and are disease-free for more than 3 years; • able to provide informed written consent to participate and; • able to read and write in the target language.

    • Exclusion Criteria:

      For phases I and II: • have cognitive impairment • are in remission from treatment of primary rectal cancer with no evidence of local recurrence • receiving treatment for distant metastatic disease (i.e. liver, lung) following previous treatment of rectal cancer with no evidence of local recurrence. For phase III: • have cognitive impairment • have been treated for LRRC and disease-free for less than 3 years. • diagnosis or treatment for distant metastatic disease (i.e. liver, lung) or locally re-recurrent rectal cancer following previous treatment for LRRC.

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  • A randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma with Acalabrutinib

    • Research Summary

      Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin’s lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP a type of immunochemotherapy), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL. The main aims of this randomised phase II clinical study are: - To determine if combining Acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL. - To compare progression-free survival, overall survival, event free survival, disease free survival, time to progression, response duration and overall response rate between both treatment and molecular groups. - To assess differences in toxicity between the assigned treatments - To assess differences in quality of life in different treatment arms - To explore correlation of molecular characteristics in tumour material to clinical outcomes. - To explore correlation of baseline PET features including metabolic tumour volume, tumour lesion glycolysis, extranodal sites and bone marrow involvement with clinical risk factor and molecular characteristics in tumour material. - To compare metabolic response rates between molecular groups. Up to 558 patients (453 randomised) will be recruited to the clinical trial with 302 patients randomised to the experimental arm and 151 to the control arm in a 2:1 randomisation.

    • Inclusion Criteria:

      1.Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may be included: • DLBCL, not otherwise specified (NOS) • T-cell/histiocyte-rich large B-cell lymphoma • Epstein-Barr virus positive DLBCL, NOS • ALK-positive large B-cell lymphoma • HHV8-positive DLBCL, NOS • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) • High-grade B-cell lymphoma, NOS 2. At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter > 7.5cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be eligible. 5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma. 6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma. 7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault [(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (µmolL)]). 8. Serum bilirubin < 35μmol/L and transaminases < 1.5x upper limit of normal at time of study entry. 9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than institutional normal range. 10. No concurrent uncontrolled medical condition. 11. Life expectancy > 3 months. 12. Aged 16 years or above. 13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.

    • Exclusion Criteria:

      1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of study drug. 15. Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with < 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during the screening phase to control symptoms. 16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Women who can bear children must agree to use two highly effective forms of contraception or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for > = 2 years or which will not limit survival to < 2 years. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial.

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  • PreOperative Endocrine Therapy for Individualised Care with Abemaciclib

    • Research Summary

      In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as endocrine therapy) for at least five years after surgery is very effective at reducing the risk of the cancer returning. However, for some women their cancer may eventually become resistant to these drugs. POETIC-A Registration part will identify those who have a higher risk of developing resistance to standard endocrine therapy (ET). Approximately 8000 women diagnosed with early stage breast cancer and have not yet had surgery to remove the cancer will enter the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a type of ET, to treat the cancer for 2 weeks before surgery. A sample will be taken from the cancer during surgery and the study laboratory will measure a biological marker called Ki67. If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be less sensitive to endocrine therapy, and the study doctor will explore additional treatments after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage (2500 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or Group2: ET plus a new drug called abemacicilib. The first aim of the Treatment stage is to confirm whether abemaciclib given in combination with ET is more effective than giving ET alone in preventing the cancer coming back. The study laboratory will perform a second test on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib. Patients in Group 2 will receive ET plus abemacicilib for 2 years. Patients in both groups will have regular study visits during this period.

    • Inclusion Criteria:

      INCLUSION CRITERIA FOR THE REGISTRATION STAGE 1. Postmenopausal women defined as: 1a. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. or 1b. Documented bilateral oophorectomy. 2. Diagnosed operable invasive breast cancer with a palpable tumour of any size or an estimated invasive tumour size > = 1.5cm by imaging (ultrasound/MRI/mammogram) excluding those who are grade 1 and /or lobular histological type on diagnostic biopsy. 3. Tumour ER positive and HER2 negative. ER positivity is defined as > = 1% cells staining positive (or equivalent Allred Score of ER > = 3 out of 8). HER2 negativity will be defined as per the 2018 ASCO/CAP updated guidelines. 4. Baseline Ki67 and/or clinical pathological factors which predict for a high (20%) 5-year risk of relapse with AI alone (see Appendix 2) 4a. Baseline Ki67 > = 20% measured at the local site or 4b. Presence of clinicopathologic factors that have been previously shown to predict (> 50% chance) patients with Ki67 > = 8% after 2 weeks’ AI, defined as one or more of the following  grade 3  clinical/radiological tumour size > 5cm  PgR negative  PgR unknown AND evidence of Vascular Invasion 5. No evidence of metastatic spread by standard assessment according to local guidelines. 6. Written informed consent to enter the registration stage of the trial and to donation of tissue (fresh tissue and surplus tissue from diagnostic procedures) and blood samples. 7. No medical condition or other factor likely to preclude entry to randomised stage of the study if eligible e.g. patient would not be suitable to receive abemaciclib due to concomitant medications or medical history. 8. The patient has given written informed consent prior to any study-specific procedures and is willing and able to make herself available for the duration of the study and amenable and able to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records. INCLUSION CRITERIA FOR THE RANDOMISATION STAGE 1. Patient previously consented and registered for screening component of POETIC A. 2. Centrally confirmed Ki67 > = 8% following 2 weeks of AI. 3. Aromatase Inhibitor Resistant-CDK4/6 Inhibitor Sensitive (AIR-CIS) signature has been derived in the central laboratory and confirmed to ICR-CTSU. 4. Patient must have undergone definitive surgery for the primary breast tumour with clear radial margins as judged by the multidisciplinary team. 5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection. 6. Adjuvant chemotherapy, if prescribed, must have been completed prior to randomisation and patients must have recovered (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5 ] Grade < = 1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomisation. A washout period of a minimum of 28 days from day 1 of last cycle of treatment is required. 7. Adjuvant radiotherapy, if prescribed, must have been completed prior to randomisation, and patients must have recovered (Grade < = 1) from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomisation. 8. The patient should be randomised within 6 months of commencement of adjuvant endocrine therapy. 9. The patient is able to swallow oral medications. 10. The patient has adequate organ function for all of the following criteria defined as; ANC > / = 1.5 × 109/L (G-CSF / blood tranfusions cannot be administered to meet this ANC eligibility criterion) Platelets > / =  100 × 109 / L Hemoglobin > / = 8g/dL Total bilirubin < / = 1.5 × ULN (Patients with Gilbert’s syndrome with a total bilirubin < = 2.0 times ULN and direct bilirubin within normal limits are permitted) ALT and AST < / = 3 × ULN 11. The patient intends to take adjuvant endocrine therapy for at least 5 years. 12. The patient has given written informed consent prior to any study-specific procedures (for the randomised intervention stage) and is willing and able to make herself available for the duration of the study and amenable and able to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records.

    • Exclusion Criteria:

      EXCLUSION CRITERIA FOR THE REGISTRATION PHASE 1. Men and pre/perimenopausal women. 2. Grade 1 tumours 3. Invasive lobular carcinoma. 4. Concurrent use (defined as use within 4 weeks prior to diagnostic tissue sample being taken) of HRT or any other oestrogen-containing medication (including vaginal oestrogens). 5. Prior endocrine therapy for breast cancer or breast cancer prevention. 4. Evidence of metastatic disease. 6. Locally advanced breast cancer not amenable to surgery. 7. Bilateral breast cancer. 8. Multiple unilateral tumours with different ER/PgR/HER2 status, grade or type (e.g. ductal vs lobular) i.e. anything that suggests two or more different cancers. Multifocal disease with homogenous ER/PgR/HER2 status, grade and type is allowed if at least one lesion is palpable or at least 1.5cm on ultrasound; the largest lesion should be used for sample collection and CRF completion. 9. Previous invasive breast cancer except for ipsilateral DCIS or LCIS treated > 5 years previously by locoregional therapy alone or contralateral DCIS/LCIS treated by locoregional therapy at any time. 10. Any invasive malignancy diagnosed within previous 5 years (other than non-melanoma skin cancer or cervical carcinoma in situ). 11. Any other medical condition likely to exclude the patient from subsequent randomisation stage. (See exclusion criteria: Eligibility for Randomisation). EXCLUSION CRITERIA FOR THE RANDOMISATION STAGE 1. Patient has received prior CDK4 / 6 inhibitor. 2. Any patient with a history of VTE (for example, DVT of the leg or arm and/or PE) will be excluded. Patients with a history of venous catheter occlusion by thrombus that did NOT surround the catheter, and the lumen could be made patent by appropriate measures (for example, saline or thrombolytic agent), are not excluded. 3. The patient has serious/or uncontrolled pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (such as severe renal impairment, [for example, estimated creatinine clearance < 30 mL/min], interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or pre-existing Crohn’s disease or ulcerative colitis or a pre-existing chronic condition resulting in baseline Grade 2 diarrhoea). 4. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: patients with controlled atrial fibrillation diagnosed more than 30 days prior to randomisation are eligible. 5. The patient has active systemic bacterial infections (requiring IV antibiotics at time of initiating study treatment),systemic fungal infection or detectable viral infection ( such as known HIV positivity or with known active hepatitis B or C (e.g. hepatitis B surface antigen positive). Screening is not required for enrolment.

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  • Risk-Adapted therapy Directed According to Response comparing treatment escalation and de-escalation strategies in newly diagnosed patients with multiple myeloma (NDMM) suitable for stem cell transplant (TE).

    • Research Summary

      Myeloma is a cancer of the bone marrow cells. Combining stem cell transplantation (SCT) with new drug treatments has shown to improve outcomes in myeloma patients. Some patients have been found to have genetic abnormalities in the myeloma cells and these ‘high-risk’ patients do not respond well to standard treatment. Some patients without these genetic abnormalities are also known to not respond as well to initial therapy. This study will investigate different treatment combinations for these two groups of patients. It will also investigate whether a third group of patients, who do respond well to initial treatment, can receive treatment for a shorter period of time without coming to harm. This study gives access to new treatments (the unlicensed drug isatuximab) and treatment combinations. All participants will receive the same initial induction treatment and during this time will have genetic tests to determine whether they have ‘standard-risk’ or ‘high-risk’ disease. Following this chemotherapy treatment participants will receive ASCT (A stands for autologous, meaning that the participant's own stem cells are used). After induction treatment participants will be allocated to a second stage treatment group based on their genetic risk, high-risk or standard-risk, and on how well the myeloma has responded to the initial treatment. Each treatment group will then receive different combinations of medication to investigate their benefit. Treatment will comprise of combinations of isatuximab, bortezomib, cyclophosphamide, lenalidomide and dexamethasone. Newly diagnosed myeloma patients, above the age of 18 who are suitable for SCT will be eligible for the study. Patients will be required to have bone marrow, blood and urine tests throughout the trial. Participants will also be asked to complete questionnaires about their quality of life. The study will be conducted in multiple hospitals throughout the UK. RADAR study is funded by Cancer Research UK, Celgene and Sanofi.

    • Inclusion Criteria:

      Inclusion criteria for registration 1.Previously untreated patients with multiple myeloma requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to IMWG diagnostic criteria 2.Eligible for stem cell transplant 3.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression); 4.Total bilirubin < 3 x upper limit of normal (ULN) 5.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 6.adequate marrow function: •neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 109/L is allowed), •haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted, •platelets > = 75 × 10^9/L (in the case of heavy bone marrow infiltration (> 50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of > = 50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted. 7.Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 8.Able to swallow oral medication 9.Aged at least 18 years 10.Agree to follow the pregnancy prevention guidelines 11.Able to provide written informed consent Inclusion criteria for starting isatuximab maintenance, R1, R2 and R3 1.4 cycles of RCyBorD received 2.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression); 3.Total bilirubin < 3 x upper limit of normal (ULN) 4.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 5.Adequate marrow function: •neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed), •haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted, •platelets > = 75 × 10^9/L (in the case of heavy bone marrow infiltration (> 50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of > = 50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted. 6.Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 7.Agree to follow the pregnancy prevention guidelines Additional inclusion criteria for starting isatuximab maintenance 1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q), as confirmed by the CTRU. 2.4 cycles of RCyBorD received 3.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R1 treatment pathway Additional inclusion criteria for R1 1.12 cycles of isatuximab maintenance received 2.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) after 12 cycles of isatuximab Additional inclusion criteria for R2 1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as confirmed by CTRU. 2.4 cycles of RCyBorD received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.MRD-positive (proportion of malignant cells in the bone marrow is > = 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT 5.Received > = 100mg/m^2 high-dose melphalan and ASCT 6.Signed the Informed Consent Document for the R2 treatment pathway Additional inclusion criteria for R3 1.High-risk (participant is confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q)) as confirmed by CTRU 2.4 cycles of RCyBord received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R3 treatment pathway

    • Exclusion Criteria:

      Exclusion criteria for registration (and for starting isatuximab maintenance, R1, R2 and R3) 1.Smouldering MM, monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM) 2.Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160mg dexamethasone. This criteria is not applicable at R1, R2 and R3 when participants will have received previous treatment for MM as part of this trial. 3.Unstable angina or myocardial infarction within 4 months prior to registration (or at any time since registration for participants starting isatuximab maintenance, R1, R2 and R3), NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker 4.Cardiac disorder identified according to local practice (eg left ventricular ejection fraction, LVEF; results from formal measurements acceptable within 28 days prior to registration) 5.Significant neuropathy (Grade > = 3, or Grade 2 with pain) 6.Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to registration. Cancer treated with curative intent for > 5 years previously and without evidence of recurrence will be allowed 7.Pregnant, lactating or breastfeeding female participants (within 28 days prior to starting isatuximab maintenance, R1, R2 and R3 8.Known resistance, intolerance or hypersensitivity to any component of the planned therapies, except in the case of hypersensitivity which is amenable to premedication with steroids or H2 blocker. Intolerance includes hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 9.Major surgery within 14 days before registration (or starting isatuximab maintenance, R1, R2 and R3). This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty. 10.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 11.Active systemic infection 12.Participant is hepatitis B surface antigen positive, hepatitis C antibody positive or HIV positive. Participants must have hepatitis and HIV screening conducted within 28 days prior to registration. 13.Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 14.Receipt of live vaccination within 30 days prior to registration, for the duration of the study and for 3 months after the last dose of study drug. Exclusion criteria for starting isatuximab 1.Disease progression 2.MRD-positive at 100 days post-ASCT 3.Registration exclusion criteria Exclusion criteria for R1 1.Disease progression 2.MRD-positive at 100 days post-ASCT or after 12 cycles of isatuximab 3.Registration exclusion criteria Exclusion criteria for R2 and R3 1.Disease progression 2.Registration exclusion criteria in Section

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  • A prospective cohort study in women at increased life-time risk of developing breast cancer to look for blood-markers that would enable an earlier diagnosis of the disease.

    • Research Summary

      Women at high risk of developing breast cancer often undergo a double mastectomy. Detecting the disease at an earlier stage could be a major step forward to eliminate the need to have risky surgery. There has been considerable interest recently in using blood-markers in the early detection of cancer. ctDNA (circulating tumour DNA) is released by cancer cells into the blood-stream and is now an important blood-marker in advanced disease. The aims of this study are two-fold: (i) to further develop and use sensitive state-of-the-art assays to detect small amounts of ctDNA in the blood with increased sensitivity and (ii) to measure ctDNA over time in women who develop breast cancer. Using these blood-markers it may be possible to detect breast cancer at a much earlier stage. We aim to recruit two cohorts of women: (i) Cohort 1: Approximately 2700 women with a strong family history of breast cancer. These women will be asked to provide annual blood samples and complete some questionnaires for up to 3 years initially or until they receive a clinical diagnosis of breast cancer. For women who develop cancer we will analyse the ctDNA in the blood samples collected at the time closest to diagnosis. We will also obtain mammogram images and tumour samples to guide a more sensitive analysis. Following this, we will analyse the blood samples collected at other time points to establish the earliest point at which ctDNA can be detected in the blood. (ii) Cohort 2: We aim to recruit at least 100 women who have been recalled to the Breast Unit because of abnormalities seen on their recent mammogram (in Cambridge only). We will take blood samples from these women to refine and validate the ctDNA assays in readiness for use with cohort 1.

    • Inclusion Criteria:

      Women who are eligible for and receiving annual mammograms. These may include: Women, aged 40-49 years with a lifetime risk of developing breast cancer > 17% and < 30% (“moderate risk” as defined by NICE CG164) Women aged 40-59 years with a lifetime risk of > 30% of developing cancer (high risk as defined by NICE CG164) Women who have had a previous diagnosis of breast cancer and are at high risk of another. Women that have been classed as high risk through other studies (e.g. BRAID and MyPEBS) and who subsequently attend the Breast Unit for annual mammograms. Inclusion criteria for Cohort 2: Women who presented with an abnormal mammogram image at routine screening and are recalled to the Breast Unit for further investigations.

    • Exclusion Criteria:

      Women who are known carriers of the common pathogenic gene mutations (e.g. BRCA1 and BRCA2).

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  • MOSAICC: an in-depth case-control study of Myeloproliferative Neoplasms

    • Research Summary

      There is a paucity of data on the aetiology of myeloproliferative neoplasms (MPNs). The research group will conduct a UK wide case-control study of 560 patients with classic MPNs and up to 560 non-blood relative or friend controls to investigate the causes (aetiology) of MPNs and to evaluate quality of life2 (QoL). DNA and RNA samples from MPN patients and controls who participate in the case-control study will be collected and retained to evaluate gene-environment interactions upon receipt of additional funding.

    • Inclusion Criteria:

      • Have clinically confirmed MPN diagnosis (PV, ET or PMF); see definitions above. • Have been informed that they have a MPN. • Diagnosed within the previous 24 months. • Aged 18 years and over. • Capable of giving informed consent as determined by the treating clinician. • Physically and cognitively capable of completing the questionnaire as determined by the treating clinician. • Capable of completing the questionnaire in English language as determined by the treating clinician.

    • Exclusion Criteria:

      • Patients under 18 years old. • Where the clinician does not agree to inclusion • Incapable of giving informed consent as determined by the treating clinician. • Physically or cognitively incapable of completing the questionnaire as determined by the treating clinician. • Incapable of completing the questionnaire in English language as determined by the treating clinician. • Too ill to participate. The WHO performance evaluation scale will be used at the stage of participant identification by the clinician and retained. Only those scoring 0-3 will be considered eligible for inclusion in the study. Those scoring 3 are described as “Symptomatic > 50% in bed but not bedbound”. • Patients not expected to live more than 2 months. • Those who do not speak English language.

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  • Impact of abemaciclib on patients’ roles and responsibilities (IMPACTOR)

    • Research Summary

      In this study we will be looking at Quality of Life (QoL) in women starting abemaciclib treatment for locally advanced or metastatic breast cancer. Often QoL is studied as part of a clinical trial but research has shown that the participants in clinical trials are not always like people taking the treatment in the ‘real world’. This is because clinical trials often need to control for lots of factors, such as age or having other medical conditions. In the IMPACTOR study, we will look at the impact of abemaciclib for women outside of a clinical trial; how treatment might affect their QoL and ability to maintain or return to their normal activities, roles and responsibilities. We will ask 150 participants to complete questionnaires measuring general health-related QoL, endocrine symptoms (e.g. hot flushes) and side effects associated with abemaciclib such as diarrhoea. They will also complete a questionnaire measuring ability to maintain or return to normal roles and responsibilities; things like caring for family members, returning to work and managing financial responsibilities. We will ask them to complete these measures before starting treatment and after one, three and six months. This will enable us to track any changes in QoL over time. Participants will also keep a weekly diarrhoea diary, as diarrhoea is a common side-effect of abemaciclib. This will help us track whether or not they experience diarrhoea, what steps they may take to reduce it (e.g. dietary changes, over the counter or prescribed medications), and whether this side-effect improves with time on treatment. We will also invite some participants to take part in an interview study to explore in more depth peoples’ experiences of treatment and side effects, the impact on different areas of their lives, and how they and their healthcare professionals have tried to manage any problems.

    • Inclusion Criteria:

      - Patients with locally advanced or metastatic breast cancer who are prescribed either: - Abemaciclib in combination with fulvestrant (for women who have relapsed after endocrine therapy) Or; - Abemaciclib in combination with an aromatase inhibitor (for women who have not previously been treated). - Patients who are able to give fully informed consent and are able to read and speak in English (please see A33-1). - Patients who are 18 years old and over.

    • Exclusion Criteria:

      - Patients with cancers other than breast or receiving treatments other than abemaciclib. - Patients who are not able to provide fully informed consent or who are not able to read and speak English (please see A33-1). - Patients under 18 years of age. - Patients who are currently inpatients or who are too distressed to participate.

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  • Body composition and chemotherapy toxicity in women with early breast cancer (CANDO-3)

    • Research Summary

      Some patients with early breast cancer are treated with chemotherapy before or after surgery. Chemotherapy is given with the aim of eradicating any cancer cells that may have escaped into the general circulation and reduce the risk of the cancer returning. Chemotherapy treatment in this setting is most effective if patients receive the optimum dose, on time and without delays or reductions in their treatment doses. Chemotherapy doses are calculated from a patient’s height and weight. However, these calculations were designed for normal weight patients which has resulted in uncertainty as to whether patients with different amounts of blood, muscle and fatty tissue (body composition) are being dosed with chemotherapy correctly. For example, obesity is defined by body mass index calculated from height and weight but this does not take into account that people of the same size can have differing body compositions which can affect the behaviour of drugs. Approximately 26% of British women are considered to be obese and obese breast cancer patients have a higher risk of disease recurrence than healthy-weight patients. Our pilot study, CANDO-2, has confirmed that body composition data from early breast cancer patients attending routine chemotherapy out-patients can be collected quickly and easily by asking patients to stand on a sBIA analyser for a few minutes and that these measurements may help predict when patients might need to unexpectedly return to hospital during chemotherapy for side effects or problems. In the Cando-3 study we will be collecting body composition data from over 300 women receiving routine chemotherapy before or after breast surgery across seven UK hospital sites. We will collect information on the chemotherapy drugs and doses each patient receives and the side effects they experience to investigate how different patterns of body composition are associated with intolerance and side effects from chemotherapy.

    • Inclusion Criteria:

      1) Early invasive breast carcinoma 2) Stage I-III disease 3) Tumour grade, ER and HER 2 status available from core biopsy 4) Clinical or pathological tumour size and lymph node status available 5) Neo-adjuvant or adjuvant systemic chemotherapy recommended by local breast multi-disciplinary meeting 6) No prior systemic anti-cancer treatment 7) No evidence of metastatic disease 8) Patient agrees to receive neo/adjuvant chemotherapy 9) Planned to receive 4-6 21 day cycles of anthracycline or taxane based combination chemotherapy 10) Aged> = 18 years and< 80 years 11) Female 12) Able to complete written records in English

    • Exclusion Criteria:

      1) Previous invasive malignancy (with the exception of non-melanomatous skin cancer) 2) Any other medical conditions preventing physical participation in the study procedures 3) Patients receiving single agent or weekly neo/adjuvant chemotherapy regimens eg weekly paclitaxel with trastuzumab

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  • Evaluation of the role of tongue base MucOsectomy and Step sErial Sectioning in the management of the unknown primary squamous cell cancer in the head and neck

    • Research Summary

      Squamous cell carcinoma (SCC) is a cancer that originates from the cells lining the body and can spread into the lymph glands and beyond. Some patients first present with an SCC which has moved to the lymph glands of the neck. Clinical examination and imaging investigations are performed to try and identify the site where the cancer has originated. However, if no original site can be identified, then we call these ‘cancers of an unknown primary’ (CUP) of the head and neck. One region where these cancers could have originated from is the oropharynx. There are two areas in the oropharynx were cancers commonly arise. One area is the palatine tonsils, which can be removed for analysis with an operation called tonsillectomy. The other area is the tissue lining the back of the tongue, known as the tongue base. A relatively new surgical technique called ‘tongue base mucosectomy’ (TBM) allows removal of this tissue to see if the primary cancer is contained within it. This study will then use a histological method called ‘step serial sectioning’ (SSS) to look in more detail at the tonsils and tongue base, hoping to increase the detection rate of the primary cancer. Centres performing TBM will be asked to participate. Patients will be asked to consent to their tissue being used for SSS after it has undergone conventional histology. Anonymised samples will be sent to a central laboratory in Newcastle for processing. Other anonymised data regarding the patients' diagnosis and care will be collated. Patients will be asked to complete questionnaires regarding pain and swallowing recovery following surgery. A smaller cohort of patients will also be interviewed as part of a qualitative research process to establish their views on CUP and the acceptability of the above treatment.

    • Inclusion Criteria:

      • Aged over 18 • Both sexes • Cervical metastatic SCC, confirmed with cytology or biopsy, undergoing TBM for identification of primary site

    • Exclusion Criteria:

      • Primary site identified by any means prior to being indicated for TBM • Patients undergoing targeted biopsies or resections

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  • Phase 2 and 3: Understanding and improving community-based palliative care outside of normal working hours

    • Research Summary

      Background: Provision of community specialist palliative care (SPC) outside of normal working hours (‘out-of-hours’) in the UK is highly variable and inequitable. Service components across the country differ markedly and discontinuity of community-based care is common. Without adequate ‘out-of-hours’ support, patients are at risk of being ‘crisis-managed’ with emergency department (ED) attendances and unplanned admissions. The lack of a consistent method to delineate models of ‘out-of-hours’ care is leading to; poor quality evaluations of services, uncertainty over effectiveness/cost-effectiveness of community-based models of palliative and end-of-life care, and inability to advance the state of the science about these. Aim: To understand different models of ‘out-of-hours’ community based specialist palliative care (SPC), develop a typology for these models, and compare the experience of patients and families from differing models of ‘out-of-hours’ care. Phases/ Objectives: Phase 1: Objective 1. Systematically review the evidence for models of out-of-hours care for patients and families receiving community based SPC and develop a logic model. Phase 2A Objective 2. Establish patient, family and health care professionals’ opinions on the components required for effective and integrated ‘out-of-hours’ community based SPC Phase 2B: Objective 3. Seek expert opinions (Patient and Public involvement members, specialist palliative care and generalists) to rank, refine and reach consensus on service components that are important for providing high quality out-of-hours community based SPC Phase 2C: Objective 4. Understand models of out-of-hours care across the UK using the refined service components Objective 5. Develop a typology for models of out-of-hours community based SPC. Phase 3: 6. Explore and contrast patients’ and families’ experiences of different models of ‘out-of-hours’ community based palliative care and understand their perspectives on drivers of service utilisation (ED attendances and unplanned admissions) and preferred place of care Methods: Mixed methods study; systematic review, focus groups, Delphi study, in depth interview study.

    • Inclusion Criteria:

      Patient and family inclusion criteria for Phase 2A patient and family interviews. Inclusion criteria Patients in receipt of community palliative care OR Informal carers of people who are experiencing community palliative care AND > = 18 years old AND Capacity to consent for participation in interview. Phase 2A healthcare professionals: Inclusion criteria Health professional with experience of working in the community with patients in receipt of specialist palliative care or who facilitate admission/discharge from/into community-based care OR Generalist health care practitioners with experience of providing community-based palliative care Exclusion criteria No experience of providing or facilitating admission/discharge from/into community-based palliative care in the UK. Phase 2B Delphi Study Inclusion criteria Specialist palliative care staff working in community or who facilitate admission/discharge from/into community-based care OR Generalist health care practitioners with an interest in or experience of community palliative care OR Patient and public involvement members who have who have experienced community palliative care including bereaved carers. OR Participants of the focus groups/interviews conducted in phase 2A. Phase 2C Inclusion criteria: Specialist palliative care community clinicians who hold a managerial role for the community service provided. Phase 3: In-depth patient and family experience interviews Inclusion criteria Patients who are currently in receipt of specialist palliative care from one of the three selected study sites. OR Informal carers who have a family member who is currently in receipt of specialist palliative care from one of the three selected study sites. AND > = 18 years old AND Capacity to consent to participate in focus group discussion

    • Exclusion Criteria:

      Patient and family exclusion criteria for Phase 2A patient and family interviews. Lacking cognitive capacity to give informed consent to participate in qualitative interview*. OR Too physically frail/unwell to participate*. OR Too distressed to participate* OR > 18 years old *as judged by the patient’s clinical team. Phase 2A healthcare professionals exclusion criteria: No experience of providing or facilitating admission/discharge from/into community-based palliative care in the UK. Phase 2B Delphi Study exclusion criteria: No experience of community-based palliative care or facilitating admission/discharge from/into community-based providing palliative care in the UK OR < 18 years old Phase 2C: application of criteria structured interviews exclusion criteria: Clinicians who do not hold a managerial role in community specialist palliative care team Phase 3: In-depth patient and family experience interviews exclusion criteria: Not receiving care from our specified study sites OR Lacking cognitive capacity to give informed consent to participate in qualitative interview*. OR Too physically frail/unwell to participate*. OR Too distressed to participate* OR > 18 years old *as judged by the patient’s clinical team.

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  • A phase Ib/II study to assess the safety and activity of DURvalumab (MEDI4736) in combination with S-488210/S-488211 vAccine in Non-muscle invasive bladder CancEr

    • Research Summary

      Bladder cancer is the 9th most common cancer in the world. In about 70% of patients the disease only involves the cells that line the inner layer of the bladder (i.e. the cancer has not invaded the muscular wall of the bladder) and is known as Non-Muscle Invasive Bladder Cancer (NMIBC). Patients with NMIBC that are at risk of the cancer invading the muscular wall usually have surgery to remove as much of their cancer, followed by BCG vaccine administered into the cells lining the bladder. However, in around 40% of patients the cancer returns and they require radical cystectomy (to remove the bladder) which carries significant risk of health issues or death. Immunotherapy has been used to treat bladder cancer for over 40 years and the addition of vaccine to immunotherapy is hoped to improve the way immunotherapy treatment works. Durvalumab is an immunotherapy treatment that works by stimulating the immune system to block cancer growth or other activities needed for cancer growth. S-488210/S-488211 are 2 vaccines that can potentially increase the number of different types of immune cells the immune system needs to stop cancer growth. DURANCE is a trial looking at the safety and activity of combining durvalumab with S-488210/S-488211 in patients with NMIBC whose cancer has returned. The study will be conducted in two parts. Phase Ib will recruit 14 patients to assess if it is safe to combine durvalumab and S-488210/S-488211. If considered safe, will recruit 50 more patients in phase II. Data collected from all 64 patients will be used to look at how the combined treatment works by measuring their disease at 1 year after starting treatment. Patients will receive up to 24 weeks of trial treatment provided the treatment appears to be working and then followed up for 5 years from the start of treatment.

    • Inclusion Criteria:

      1. Histologically proven high-risk non-muscle invasive bladder cancer (high-risk tumours include any of the following features: T1 lesions, high-grade disease, tumours larger than 3 cm, multiple or recurrent lesions, and CIS). 2. Adequate archival tissue sample available for histological assessment. 3. Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma. 4. BCG unresponsive disease (persistent high-risk NMIBC or recurrence of high-risk NMIBC after disease-free period at 6 months despite receiving adequate course of BCG). 5. Refused or deemed clinically inappropriate for radical cystectomy. 6. > = 18 years of age. 7. Body weight > 30 kg. 8.WHO performance status 0-1. 9. Must have undergone each of the following procedures within 8 weeks of registration: • Complete excision of all papillary disease (T1/TaHG) and demonstration of no muscle invasive disease in the resected specimen (muscle must be present in the tumour tissue sample); • Bladder ‘Mapping biopsies’ taken; • CT of the chest; • CT urogram or MRI of the abdomen and pelvis (if CT is not possible). 10. Adequate haematological status: • Haemoglobin > = 9.0 g/dL; • Absolute neutrophil count > = 1.5 x 10^9/L; • Platelet count > = 100 x 10^9/L; • INR and APTT < = 1.5 x ULN. NB: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. 11. Adequate liver function: • Total bilirubin < = 1.5 X ULN (< 3.0 x ULN for patients with Gilbert’s syndrome); • AST or ALT < = 2.5 x ULN. 12. Adequate renal function (measured creatinine clearance or calculated creatinine clearance using Cockcroft-Gault formula of > = 40 mL/min, or by 24-hour urine collection for determination of creatinine clearance). 13. Life expectancy of > = 6 months. 14. Willing and able to give informed consent (which includes compliance with the requirements and restrictions listed in the patient information sheet and in the protocol). 15. Patients of child-bearing potential and male patients with female partners of child-bearing potential must agree to use highly effective contraception methods from date of consent, which must be continued for up to 90 days after last treatment administration. 16. Female patients must not be pregnant. There should be sufficient evidence of post-menopausal status or a negative serum pregnancy test for pre-menopausal female patients. 17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and any other study procedures.

    • Exclusion Criteria:

      1. Any history of autoimmune or inflammatory disease including: inflammatory bowel disease, diverticulitis, SLE, sarcoidosis syndrome, wegener syndrome. Exceptions: thyroid disease on stable treatment, any chronic skin condition that does not require systemic corticosteroid therapy. Patients with a history of an autoimmune condition but without active disease in the last 5 years may be included after consultation with the CI/TMG. 2. Prior allogeneic stem cell or solid organ transplantation. 3. Prior treatment with anti- PD-1, PD-L1 or CTLA-4 monoclonal antibody or other novel immune-oncology agent(s). 4. Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. 5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest CT scan. 6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. 7. QTcF value of > 470 ms. If prolonged, should be confirmed by 2 further ECGs each at least 5 minutes apart. 8. Patients with risk factors for bowel perforation: history of acute diverticulitis or intra-abdominal abcess in the last 3 years, history of mechanical GI obstruction or abdominal carcinomatosis. 9. Any unresolved toxicity Grade > = 2 from previous anti-cancer therapy with the exception of alopecia, vitiligo and laboratory values defined in the inclusion criteria. Patients with any irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the CI/TMG. 10. Receipt of last dose of anti-cancer therapy within 30 days prior to first dose of trial treatment. 11. Treatment with any experimental drug within 30 days or 5 half-lives (whichever is longer) of the first dose of trial treatment. 12. 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. 13. Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial. 14. Received therapeutic oral antibiotics that cannot be discontinued at least 14 days prior to starting treatment or received IV antibiotics within 14 days prior to registration. 15. Any psychiatric or other disorder that impacts the ability to give informed consent or comply with trial treatment and activities. 16. History of leptomeningeal carcinomatosis. 17. Active infection of TB (clinically evaluated in accordance with local guidelines). 18. Patients must not have had systemic corticosteroid therapy (> 10 mg daily prednisone equivalent) within 14 days prior to registration or concomitant use of other immunosuppressive medications. 19. Administration of a live, attenuated vaccine within 4 weeks prior to planned start of treatment or anticipation that such a live, attenuated vaccine will be required during the study. 20. Evidence of significant uncontrolled concomitant disease that could substantially increase the risk of incurring AEs, affect compliance with the protocol or interpretation of results, including significant liver disease, uncontrolled hypertension, serious chronic GI conditions associated with diarrhoea and uncontrolled major seizure disorder. 21. Major surgical procedure within 28 days prior to first dose of treatment. 22. Significant cardiovascular disease (as outlined in the protocol). 23. Uncontrolled Type 1 diabetes (eligible if controlled on a stable insulin regimen). 24. Uncontrolled adrenal insufficiency. 25. Active hepatitis infection or hepatitis C (HCV). Patients with past hepatitis B virus infection or resolved infection are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 26. Known active primary immune deficiency, including uncontrolled HIV (detectable viral load) or AIDS-related illness. 27. Women who are pregnant or breast feeding. 28. Known allergy or hypersensitivity to any of the IMPs or their excipients. 29. Prior randomisation to, or treatment in a previous durvalumab clinical study. 30. Must not donate blood while participating in this study and for at least 90 days following the last dose of trial treatment.

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  • Mammographic Predictors of Cancer Recurrence after Breast Conservation and Adjuvant Endocrine Therapy

    • Research Summary

      Female hormones can help some breast cancers to grow. So most women who have had breast cancer are put on endocrine therapy such as tamoxifen which stops oestrogen from helping the cancer to grow. However in some women the cancer comes back while they are on endocrine therapy. Often we learn too late that the treatment wasn’t working so we need to know much sooner whether it’s effective. We can tell from mammograms how dense a woman’s breast tissue is. For some women their breasts become less dense while they are on endocrine therapy. We think that might mean that the treatment is working. We think if a woman’s breasts remain dense while on treatment, her cancer may be more likely to come back. The aim of this study is to prove whether a reduction in breast density really does mean that the endocrine therapy is keeping the cancer away. We have identified 2500 women who have been recruited into a research project called Mammo50. These women are all over 53 years old, have had a lump removed. 2000 are on endocrine therapy and did not have chemotherapy. We want to transfer their mammograms to a central imaging centre and use a computer and radiologists to assess if the breast tissue has become more or less dense. (We will also look at mammograms from 500 similar women who did not have endocrine therapy as a control group). The progress of these women is then followed so that we will then see if a change in density of the breast tissue is related to the effectiveness of the endocrine therapy

    • Inclusion Criteria:

      Adjuvant Endocrine Therapy (AET) Group • Woman over 50 years at invasive breast cancer diagnosis • Treated by successful breast conserving therapy • Normal 3-year mammogram • On AET at 3 years • Relevant mammograms available. No-AET Group • Woman over 50 years at breast cancer diagnosis (invasive or DCIS) • Treated by successful breast conserving therapy. • Normal 3 year mammogram. • Relevant mammograms available

    • Exclusion Criteria:

      Adjuvant Endocrine Therapy (AET) Group • Bilateral breast cancer • Breast cancer previous to current episode • Chemotherapy either neoadjuvant or adjuvant. • Diagnosed or suspected recurrence at 3 years • Contralateral breast cancer No-AET Group • Bilateral breast cancer • Breast cancer previous to current episode • Chemotherapy either neoadjuvant or adjuvant. • Diagnosed or suspected recurrence at 3 years • Contralateral breast cancer • AET

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  • Microbiome Immunotherapy Toxicity and Response Evaluation (MITRE) An observational study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy

    • Research Summary

      There is increasing evidence that the bacteria that live naturally in our mouth and gut (called our ‘microbiome’) influence our immune system and how it works. The mix of bacteria living in your microbiome is unique to you and this is affected by various factors, including your diet, your medications and where you live. Recently, some small studies have linked the presence of certain bacteria in a patient’s microbiome with the effectiveness of immunotherapy for cancer, particularly immune checkpoint inhibitor drugs that they have taken. Immune checkpoint inhibitor drugs are improving outcomes for cancer patients, these drugs work by reactivating immune cells to recognise and kill cancerous cells. However, these drugs do not work for everyone and they can also cause some people side effects that are difficult to tolerate. We would like to be able to identify patients who are likely to either benefit or experience side effects from these drugs, which we cannot do currently. Previous research has mainly focussed on looking for markers in blood and tumour samples that these drugs are working or causing toxicity. We plan to undertake a detailed study of the mouth and gut bacteria of patients receiving treatment with these drugs by collecting an oral swab sample prior to treatment as well as a series of stool samples prior to and during treatment. We will collect blood samples and also tumour tissue, if it is available to us. After we analyse these samples, we hope to better understand how the microbiome contributes to the effectiveness of immune checkpoint inhibitor drugs as well as potential side effects. We hope we can use this knowledge to tailor patient treatment and potentially develop better treatments in the future. We plan to recruit up to 1800 patients and 360 household controls over a 5 year period.

    • Inclusion Criteria:

      CANCER PATIENT • Signed informed consent and ability to comply with the study protocol • Aged > = 18 years old • Histological or cytological confirmation of invasive malignancy • Due to commence palliative, adjuvant or neoadjuvant systemic therapy including an anti-PD-(L)1 antibody ± anti-CTLA-4 antibody • Patients with unresectable disease must have radiologically and/or clinically measurable disease, by RECIST version 1.1; target lesions must not have been previously irradiated; baseline tumour assessments must be performed within 28 days prior to starting immune checkpoint inhibitor treatment. • Received no prior immune checkpoint inhibitors (previous treatment with other types of anti-cancer therapy is determined by patient cohort; for patients with unresectable disease, prior adjuvant therapy with immune checkpoint inhibitor(s) is allowed if completed at least 6 months previously). • Willingness and ability to comply with scheduled visits, treatment plans, sample collections and other study procedures.

    • Exclusion Criteria:

      CANCER PATIENT • Other invasive malignancies diagnosed within the last year which are not fully resected, or 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 their ability to comply with the study. Examples include, but are not limited to: o Patients with uncontrolled ischaemic heart or other cardiovascular event eg. myocardial infarction, new angina, stroke, transient ischaemic attack, or new congestive cardiac failure within the last 6 months o Presence of active infection o Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C o Current active, severe, or uncontrolled autoimmune condition, including but not limited to Crohn’s disease and ulcerative colitis. • Women who are pregnant, plan to become pregnant, or are lactating during the study period • Requirement for daily non-physiological dose of oral steroids, or regular use of any other immunosuppressive agents; less than 10mg prednisolone or equivalent doses are allowed. Use of inhaled or topical steroids is allowed. HOUSEHOLD CONTROLS Confirmation of suitability to be a household control participant will be determined by completing a self-assessed questionnaire either at home or in clinic. Household controls must: • NOT have had any gastrointestinal infections i.e., parasites, viruses or diarrhoeal episodes during the last 6 months. • NOT have taken antibiotics for at least 6 months • NOT have or be recovering from any chronic intestinal disease such as: o Crohn’s disease o Ulcerative colitis o Coeliac disease o Irritable bowel syndrome o Stomach ulcers • NOT have a chronic autoimmune disease or significant allergies e.g., multiple sclerosis, asthma requiring regular medication, psoriasis. • NOT have and NOT be recovering from any form of cancer. • NOT take proton pump inhibitors, steroids, other non-steroidal anti-inflammatory drugs such as ibuprofen or aspirin. In addition, household controls must sign informed consent and be aged > = 18 years old.

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  • A randomized multicenter clinical trial for patients with multi-organ, colorectal cancer metastases comparing the combination of chemotherapy and maximal tumor debulking versus chemotherapy alone.

    • Research Summary

      Colorectal cancer is the third most common malignancy worldwide and the second leading cause of cancer death in the United Kingdom. In both early stage and metastatic disease, curative treatment is only possible with complete resection of the tumor. In recent years, resection of single organ metastases has improved survival in patients with limited metastatic colorectal cancer. Besides surgical resection, several techniques have become available for local treatment of metastases, including radiofrequency ablation, stereotactic ablative radiotherapy and transarterial chemoembolization. Local treatment of metastases of patients with metastatic colorectal cancer is often technically feasible, but effects on survival and quality of life have not been studied in patients with multi-organ metastatic colorectal cancer. The standard treatment of multi-organ metastasized colorectal cancer is systemic chemotherapy. This study is a randomized multicenter clinical trial for patients with multi-organ metastatic colorectal cancer, comparing the combination of chemotherapy and maximal tumor debulking versus chemotherapy alone. It is hypothesized that adding tumor debulking to chemotherapy will increase overall survival with at least six months. Patients with multi organ mCRC with an indication for first line systemic therapy are eligible for study participation, if tumor debulking of at least 80% is deemed feasible by a multidisciplinary team. After inclusion all patients will receive 3 cycles of chemotherapy, followed by radiological evaluation. Patients with stable disease or response to treatment will be randomized to either continuation of chemotherapy alone, or to additional tumor debulking. Local treatment of the metastases can consist of surgery, radiofrequency ablation, stereotactic ablative radiotherapy and transarterial chemoembolization. Data will be gathered by laboratory analysis, tumor markers, CT or PET CT scans and quality of life questionnaires. If successful, this study may define a new standard of care for most metastatic colorectal cancer patients.

    • Inclusion Criteria:

      Screening must be performed no longer than 14 days prior to study inclusion. Subjects are eligible if they meet the following criteria: • Histological or cytological documentation of cancer is required. • Indication for first line palliative systemic treatment for metastatic colorectal cancer. • Patients with CRC metastases in: • ≥ 2 different organs if at least > 1 extrahepatic metastases or • ≥ 2 different organs including > 5 hepatic metastases not located to one lobe or • ≥ 2 different organs including either a positive para-aortal lymph nodes or celiac lymph nodes or adrenal metastases or pleural carcinomatosis or peritoneal carcinomatosis • The primary tumor is excluded as metastatic site. • Feasible radical tumor debulking. Incomplete tumor debulking is allowed only if at least 80% of metastases can be treated. • To meet the inclusion criteria a cytological analysis should be performed in case of any uncertainty about the presence of a lesion e.g. a false positive or false negative result on imaging. • Age ≥ 18 years. • WHO performance status 0 – 1. • Life expectancy of at least 12 weeks. • Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening: • Hemoglobin ≥ 5.6 mmol/L; o Absolute neutrophil count (ANC) ≥ 1,500/mm3 ; • Platelet count ≥ 100*109 /l; • Total bilirubin ≤ 1.5 times the upper limit of normal; • ALT and AST ≤ 2.5 x upper limit of normal (≤ 5 x upper limit of normal for subjects with liver involvement of their cancer); • Albumine > 30 g/l; • Serum creatinine ≤ 1.5 x upper limit of normal or a MDRD  50 ml/min; • Prothrombin time or INR < 1.5 x ULN, unless coumarin derivates are used. Due to interactions with capecitabine, all patients using coumarin derivates will be treated with LMWH instead. • Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation therapy is allowed if this treatment can be interrupted as judged by the treating physician). • Written informed consent.

    • Exclusion Criteria:

      Subjects who meet the following criteria at the time of screening will be excluded: • Prior (neo-)adjuvant chemotherapy for < 6 months after last treatment and first detection of extrahepatic metastases, except for neoadjuvant capecitabin in the context of chemoradiation for rectal carcinoma. • Candidates for HIPEC. • Patients with liver metastases only. • Evidence of brain metastases. • History of other prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in-situ carcinoma of any organ. Patients with other malignancies are eligible if they have remained disease free for at least 5 years. • History of cardiac disease: • Congestive heart failure >NYHA class 2; • Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to screening); • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted). • Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 3 separate measurements on at least 2 separate days. • Uncontrolled infections (> grade 2 NCI-CTC version 4.0). • Pregnant or breast-feeding women. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must agree to use adequate barrier birth control measures (e.g., cervical cap, condom, and diaphragm) or intrauterine device during the course of the trial. Oral birth control methods alone will not be considered adequate on this study, because of the potential pharmacokinetic interaction between study drug and oral contraceptives. Concomitant use of oral and barrier contraceptives is advised. • Concurrent anticancer chemotherapy, immunotherapy or investigational drug therapy during the study or within 4 weeks of the start of study drug. • Concomitant chronic use of dexamethasone, anti-convulsants and anti-arrhythmic drugs other than digoxin or beta blockers. • Severe allergy for contrast media not controlled with premedication. • Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results. • Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.

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  • A phase III trial of intensity-modulated proton beam therapy versus intensity modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer

    • Research Summary

      The number of cases of cancers arising from the tonsil and back of the tongue is rising worldwide. Even when this type of cancer is large or has spread to lymph nodes in the neck (called locally advanced cancer), it usually responds well to treatment and most people are cured. However, treatment with radiotherapy combined with chemotherapy can cause severe side effects during treatment. In the long-term this has the potential for significant harmful impact on quality of life. This study includes patients with locally advanced cancers of the tonsil and back of the tongue. It will focus on whether proton beam therapy (a newer form of radiotherapy) can reduce side effects and improve patient-reported quality of life compared with standard radiotherapy (called intensity-modulated radiotherapy). Proton beam therapy can be directed more precisely than standard radiotherapy. This reduces the amount of normal tissue receiving radiation that isn’t wanted. We know from international use of proton beam therapy (e.g. the USA) that it is a safe treatment and is thought to cause less damage to normal tissues. About 183 patients will take part in the study. Approximately 122 (two thirds) patients will receive proton beam therapy at an NHS proton centre in Manchester or London. The other 61 (one third) patients will receive intensity-modulated radiotherapy at their recruiting cancer centre. The NHS will provide accommodation for the duration of treatment for patients receiving protons and additional funding has been obtained for patient/carer travel costs. Patients will be asked to complete quality of life questionnaires at baseline, during treatment and during 5 years of clinical follow-up, in keeping with routine practice. There are also optional translational studies that patients will be asked to take part in.

    • Inclusion Criteria:

      • Histologically confirmed oropharyngeal squamous cell carcinoma. • HPV positive TNM8: T1-2 N1-2 (excluding T1-2 with a single ipsilateral node < 3cm), T3-4 N0-2 • HPV negative TNM 8: T1N2, T2N1-N2, T3-4N0-2 • Local MDT decision for concurrent chemoradiotherapy with bilateral neck treatment. • Age > = 18 years. • WHO performance status 0-1. • Adequate renal function, glomerular filtration rate (GFR) > 60ml/min calculated using Cockcroft-Gault formula • Adequate cognitive ability (in the opinion of the local PI) to complete PRO assessments. • Willingness to comply with the protocol, including travel to the proton centre for IMPT treatment. • Written informed consent.

    • Exclusion Criteria:

      • Feeding tube insertion required for nutrition due to dysphagia prior to treatment [Note: patients who have prophylactic feeding tube insertion, with or without tube use to top up nutrition prior to starting treatment, remain eligible for the study]. • N3 disease. • Upfront neck dissection. • Use of induction chemotherapy. • Previous head and neck radiotherapy. • Major surgery within 6 months of trial entry. • Permanent pacemaker or implantable cardioverter defibrillator. • Any invasive malignancy within previous 2 years (other than non melanomatous skin carcinoma or cervical carcinoma in situ). • Previous or concurrent illness (e.g., active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis), which in the investigator’s opinion would interfere with completion of therapy, trial assessments or follow up. • Pregnancy; lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception (male patients should also use contraception if sexually active); • Pre-existing speech or swallowing problems unrelated to the diagnosis of cancer. For patients taking part in the optional DW-MRI study at The Christie Hospital the following additional exclusion criteria apply: • Any contra-indication to MRI scanning, including metallic heart valve replacement, permanent pacemaker, implantable cardiac defibrillator, non-MRI compatible metal implants, neuro-stimulators. • A history of allergy / reaction to Gadolinium contrast.

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  • Primary and Secondary Screening in individuals with Inherited Pancreatic Disease syndromes for Pancreatic ductal adenocarcinoma and complications of other pancreatic diseases.

    • Research Summary

      Pancreatic cancer has one of the worst overall survival of malignancy (five year survival under 10%). The main reason for this is late detection. Symptoms are non- specific and screening of asymptomatic individuals is impractical as no current screening system has adequate specificity to avoid false positives exceeding true positives, treatment for pancreatic cancer involves surgical resection of the organ with very high associated morbidity and even mortality. In order to develop and validate improved screening modalities these need to be applied to high risk individuals. Current guidelines only allow research screening in individuals with an autosomal dominant predisposition for pancreatic cancer. The European Registry for heredity pancreatitis and familial pancreatic cancer (EUROPAC) was established in 1996 in order to identify individuals at high risk of pancreatic cancer. We wish to continue recruitment to this registry and to continue to pilot secondary screening for pancreatic cancer in the individuals registered. The registry has also proved an invaluable resource in order to study pancreatic diseases in general: diabetes, acute and chronic pancreatitis as well as cancer. We also wish to continue this analysis. The screening we propose to carry out will be based on established methods of pancreatic imaging including Endoluminal Ultrasound, Computed Tomography and Magnetic Resonance Imaging. This will be supplemented by use of biomarkers which will at first be purely experimental but following validation will be used to phase subsequent screening. Epidemiological and demographic data as well as clinical reports will be used to stratify cancer risk and to monitor disease progression: acute pancreatitis can progress to chronic pancreatitis with endocrine and exocrine failure; diabetes mellitus can be both an early sign of pancreatic cancer and also a risk factor.

    • Inclusion Criteria:

      Inclusion Criteria for Registry: Cancer families: Two first degree relatives with pancreatic adenocarcinoma. A family with three or more relatives with pancreatic ductal adenocarcinoma. Families with pancreatic cancer and other cancers (e.g. bowel, breast/ovarian, melanoma, gastric) that suggest a known cancer predisposition syndrome: Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Familial atypical mole melanoma (FAMMM). Lynch Syndrome. Breast Ovarian Cancer Peutz-Jegher's syndrome Li Fraumeni syndrome Families with a causative mutation in a gene linked to pancreatic cancer (e.g. PALB2 BRCA2 or genes prospectively discovered to be linked to pancreatic cancers) and at least one case of pancreatic cancer in the family. Pancreatitis families: Families with two or more relatives with idiopathic pancreatitis. Families with at least one case of pancreatitis and a confirmed causative mutation in the PRSS1 gene. Cyst surveillance: Individuals already enrolled on surveillance due to identification of a pancreatic cystic lesion NOD individuals: Individuals over the age of 40 with diabetes mellitus diagnosed in the last 6 months Disease control Individuals with: diagnosed pancreatic ductal adenocarcinoma; acute or chronic pancreatitis of any aetiology; and individuals with long term (over two years) type 2 or 3c diabetes mellitus Inclusion Criteria for Screening: Individuals over 40 years of age from an established pancreatic cancer family where the family is consistent with predisposition with high penetrant autosomal dominant inheritance (for example, at least two first degree relatives with pancreatic ductal adenocarcinoma, where no non-penetrant carriers have to be assumed over the age of 75). Individuals with Peutz-Jeghers syndromes, or individuals with affected relatives under the age of 50 will be considered for inclusion below the age of 40. Unaffected members of a family with an associated cancer syndrome and at least one case of pancreatic cancer, who are over 40 years of age and who have been shown to carry the relevant genetic alteration. Any member of a Hereditary Pancreatitis (HP) family (autosomal dominant predisposition for pancreatitis) who have been confirmed to carry a causative PRSS1 mutation or (where no causative mutation is known) have symptoms of pancreatitis. Individuals incidentally found to have cystic lesions or other clinical features that indicate an increased risk of pancreatic cancer may also be included. There will be adaptation to risk models as the study progresses to fit the needs of the study outcomes.

    • Exclusion Criteria:

      Any individual who is incapable of providing informed consent. For genetic testing: Any individual who does not consent to be informed of clinically significant results. Genetic testing specifically for research purposes at a specific locus with no actionable clinical significance can be carried out (e.g. for a polymorphism that may associate with disease but is not causative), but only with explicit consent from the individual. For screening: Individuals of less than 40 years of age or 10 years younger than the youngest case in the family will be excluded. Risk assessment will be made using progressively developed models any individual deemed to have less than 2% chance of developing PDAC in the next three years will be excluded (this will depend on the evidence supporting the models and the exclusion will only apply if the steering committee agrees on the risk assessment). Any female participant able to bear a child but who has not taken appropriate contraceptive measures.

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  • UK Early Detection Initiative for Pancreatic Cancer

    • Research Summary

      At the time of diagnosis of pancreatic cancer, an estimated 65% of patients have diabetes mellitus (DM). Whilst a small proportion of DM in pancreatic cancer patients is long standing (present more than 3 years) the remainder is new-onset-DM. This often goes undiagnosed, and when it is diagnosed, in the majority of cases this comes within one year prior to pancreatic cancer being identified. In effect, new-onset diabetes can be an early warning sign of the presence of pancreatic cancer, and individuals with new-onset diabetes are a high-risk group for pancreatic cancer. Approximately 1% of individuals (1 in 100) diagnosed with new onset type 2 DM (T2DM) have undiagnosed pancreatic cancer. This group of individuals actually has pancreatic cancer associated DM, although it is mistakenly diagnosed as T2DM. Currently individuals with new-onset DM are not screened for pancreatic cancer as there are no reliable tests to distinguish between T2DM and pancreatic cancer associated DM. Developing methods for pancreatic cancer detection in individuals with new-onset DM will require early-stage, pre-diagnostic samples and corresponding patient data. In this study we aim to recruit 2500 Individuals from hospitals and GP surgeries who are 50 years old or over and newly diagnosed with DM. Blood samples and questionnaire/clinical data will be collected at appointments every six months for two years. We will collect and store samples in a standardised way so that they can be used to identify biomarkers in the blood that will distinguish between DM caused by pancreatic cancer and type 2 DM. This may ultimately enable a screening programme in the future. As part of this study we will also attempt to gain a better understanding of risk factors associated with pancreatic cancer and to determin the cost effectiveness of screening for pancreatic cancer.

    • Inclusion Criteria:

      1. Age > = 50 at time of study entry. 2. New-onset diabetes (defined as HbA1C > = 48mmol/mol (6.5%)) diagnosed within 6 months of study entry. 3. Written informed consent obtained from the participant prior to performing any protocol-related procedures. 4. Participant is willing and able to comply with the protocol for the duration of the study including scheduled follow-up visits.

    • Exclusion Criteria:

      1. Diagnosis of pancreatic cancer within 5 years of study entry. 2. Treatment for digestive or endocrine cancer within 5 years of study entry. 3. Previous Surgical resection of the pancreas. 4. A known history of hyperglycaemia/pre-diabetes (HbA1c: 42-47 mmol/mol (5.9% - 6.4%)) of greater than three years duration. 5. Diagnosis of diabetes > 6 months before study entry. 6. Pregnancy. 7. Condition preventing study investigation and follow-up. 8. Inability or incapacity to give informed consent.

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  • A RANDOMIZED PHASE II TRIAL ASSESSING TRIMODALITY THERAPY WITH OR WITHOUT ADJUVANT DURVALUMAB (MEDI4736) TO TREAT PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER

    • Research Summary

      This study is looking at whether a type of immunotherapy drug called durvalumab can be safely administered after the initial treatment received by patients. Durvalumab has been tested in many different types of cancers and works by allowing the immune system to detect cancer and reactivate the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die. It is unclear if the addition of durvalumab is beneficial in patients with bladder cancer who have completed initial surgery, radiotherapy and chemotherapy (trimodality therapy - TMT). This project sets out to address this question. Following TMT, 238 adult participants, aged 18 years or older, with muscle-invasive bladder cancer will be equally randomized to receive either durvalumab (1500 mg IV on day 1 of 4 week cycle every 4 weeks for 12 months) or surveillance only. During this time, patients will come to hospital for treatment every 4 weeks. During these visits, patients will have some blood tests to make sure they are well enough to receive treatment and will sometimes be asked to complete a questionnaire, asking about their health and quality of life. Patients will have CT scans, every 4-12 weeks to measure changes in the size of their tumour. At the end of the trial, we will compare the two groups of patients to see if there are differences in terms of survival, how long we can stop the disease from getting worse (progressing), quality of life and costs of treatment. Also, we will collect blood and tumour samples which will be sent to a laboratory in Canada. They will be analysed to tell us more about how the treatments work and whether some patients may benefit more from treatment than others. This may help target treatments to those most likely to respond in the future.

    • Inclusion Criteria:

      1) Histologic diagnosis of urothelial carcinoma of the bladder. Patients with mixed histology and focal differentiation are eligible but patients with pure small cell histology will be excluded. 2) Stage T2-T4a N0M0 at time of diagnosis (AJCC-TNM version 8) based on trans-urethral resection of bladder tumour (TURBT), imaging, and/or bimanual examination under anesthesia (EUA). 3) CT scan of the chest/abdomen/pelvis within 8 weeks from enrollment, showing no evidence of metastatic disease. 4) Patients must be > = 18 years of age. 5) Patients must have a life expectancy greater than 6 months. 6) Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix I) and a body weight of > 30kg. 7) Patients must have adequate haematologic reserve: Platelet count > = 75 x 109/L, Absolute neutrophils > = 1.0 x 109/L. Anemia will be corrected to minimum hemoglobin of 90 g/L with red cell transfusions, if necessary. 8) Patients must have an estimated creatinine clearance (Cockcroft-Gault Equation) > = 30 ml/min. 9)Patients must have adequate liver function with a bilirubin < = 1.5 ULN (if confirmed Gilbert’s, eligible providing bilirubin < = 3 x UNL) and AST/ALT (SGOT/SGPT) < 2.5 x the upper normal limit. 10) All patients must have a tumour block from their primary tumour available and consent to release the block/cores/cut slides for correlative analyses and the hospital/pathologist must have agreed to the submission of the specimen(s). 11) Patients have completed prior trimodality therapy (TMT) consisting of surgery, chemotherapy and radiation therapy treatment prior to enrollment on the BL.13 study. *Patients should begin protocol treatment within 42 days after completion of TMT. 12) Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration / randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) 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. 13) 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. 14) Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 15) Protocol treatment is to begin within 2 working days of patient enrollment. 16) Women/men of childbearing potential must have agreed to use a highly effective contraceptive method during and for 3 months following treatment. A woman is considered to be of “childbearing potential” if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 17) Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

    • Exclusion Criteria:

      1) Pre-existing medical conditions precluding treatment. 2) Pregnancy or lactating mothers. 3) Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, including durvalumab anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumour Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 4) 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, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: • Patients with alopecia; • Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years); • Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement; • Any chronic skin condition that does not require systemic therapy. 5) Patients with active or uncontrolled intercurrent illness including, but not limited to: • cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia); • active peptic ulcer disease or gastritis; • active bleeding diatheses; • psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent; • known history of previous clinical diagnosis of tuberculosis; • known human immunodeficiency virus infection (positive HIV 1/2 antibodies); • known active hepatitis B infection (positive HBV surface antigen(HBsAg).Patients with a past or resolved HBV infection (defined as presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible; • known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 6) History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade > = 3 infusion reaction. * Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of prednisone or equivalent dose of an alternative corticosteroid are permissible. 7) Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed. 8) Peripheral neuropathy > = grade 2 (CTCAE v5.0). 9) History of allergic or hypersensitivity reactions to any study drug or their excipients. 10) Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) > = 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome. 11) History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline CT scan. 12) Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy. 13) Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol. 14) Live attenuated vaccination administered within 30 days prior to randomization.

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  • Comparative Evaluation of the computer-adaptive EORTC quality of life measures

    • Research Summary

      Cancer diagnosis/treatment results in unwanted symptoms/toxicity so assessing the risks and benefits of new treatments requires knowledge of both effectiveness against the cancer and impact on quality of life. Several research groups, including the EORTC, have developed questionnaires to measure quality of life so that patients can be monitored and their treatment side effects investigated. These groups are now looking to enhance the use of their questionnaires more efficiently. It would be helpful to pool results from studies using different questionnaires investigating the same symptoms, but because the questions on each questionnaire are subtly different, this is not easy. In this study patients complete several widely used similar questionnaires. Their scores are then compared with those from the EORTC questionnaires. Using statistical analysis we will produce an algorithm (mathematical equation) 'converting' scores between questionnaires. The algorithm could be useful in clinical research when two groups of researchers are investigating a new drug with a side effect of fatigue but are using different questionnaires to assess this e.g EORTC Fatigue Scale versus FACT Fatigue Scale. The algorithm will link the scores by ‘predicting’ the score on one questionnaire using the score on the other. The two studies can then be compared, or their results pooled, giving a larger sample for analysing any effect. Using other statistics we will compare all the questionnaires and see how good (or not) they are at detecting symptoms (validity and reliability) and how sensitive they are to changes over time as the symptoms worsen or improve . Knowing which are the most sensitive questionnaires for different domains of quality of life and side effects is critical because fewer patients would then need to be recruited in future research.

    • Inclusion Criteria:

      Cross Sectional Sample: 1. Any cancer diagnosis and any (previous) treatment 2. > 18 years of age 3. Ability to provide written informed consent 4. Good literacy skills Longitudinal Sample: 1. Any cancer diagnosis 2. Patients about to start first line chemotherapy (Previous treatment e.g surgery/radiotherapy or no prior treatment is acceptable) 3. > 18 years of age 4. Ability to provide written informed consent 5. Good literacy skills Survivorship Sample: 1. Any cancer diagnosis and any (previous) treatment 2. Completed primary curative treatment at least 12 months previously or receiving maintenance therapies (hormonal therapies) 3. > 18 years of age 4. Ability to provide written informed consent. 5. Good literacy skills

    • Exclusion Criteria:

      Cross-sectional sample 1. Patients with brain metastases 2. Patients with serious cognitive impairment 3. Patients participating in other competing quality of life studies 4. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. Longitudinal Sample: 1. Previous chemotherapy 2. Patients not having chemotherapy or whose chemotherapy has already commenced. 3. Patients with brain metastases 4. Patients with serious cognitive impairment 5. Patients participating in other competing quality of life studies 6. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. Survivorship Sample: 1. Patients with brain metastases 2. Patients with serious cognitive impairment 3. Participating in other competing quality of life studies 4. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. 5. Patients currently on treatment

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  • FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

    • Research Summary

      FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS). It is a multi-arm, multi-stage format, involving several different trial questions. FaR-RMS is intended to be a rolling programme of research with new treatment arms being introduced dependant on emerging data and innovation. This study has multiple aims. It aims to evaluate the impact of new agent regimens in both newly diagnosed and relapsed RMS; whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent (in metastatic disease) and timing of radiotherapy improve outcome and quality of life. In addition the study will evaluate risk stratification through the use of PAX-FOXO1 fusion gene status instead of histological subtyping and explore the use of FDG PET-CT response assessment as a prognostic biomarker for outcome following induction chemotherapy. Newly diagnosed patients should, where possible, be entered into the FaR-RMS study at the time of first diagnosis prior to receiving any chemotherapy. However, patients can enter at the point of radiotherapy or maintenance, and those with relapsed disease can enter the study even if not previously entered at initial diagnosis. Patients may be entered into more than one randomisation/registration, dependant on patient risk group and disease status.

    • Inclusion Criteria:

      Inclusion Criteria for study entry 1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS) 2. Written informed consent from the patient and/or the parent/legal guardian Inclusion criteria for all randomisations and registrations: • Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active • Written informed consent from the patient and/or the parent/legal guardian • Medically fit to receive treatment Frontline chemotherapy specific inclusion: • Entered in to the FaR-RMS study at diagnosis • No prior treatment for RMS other than surgery • Documented negative pregnancy test for female patients of childbearing potential • Adequate hepatic function: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome Phase 1b Specific Inclusion • VHR disease • Age > 12 months and ≤25 years • Adequate hepatic function: ALT or AST < 2.5 X ULN for age • Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 • Absolute neutrophil count ≥1.0x 10^9/L • Platelets ≥ 80 x 10^9/L CT1a specific inclusion • VHR disease • Age ≥ 6 months • Available for randomisation ≤60 days after diagnostic biopsy/surgery • Fractional Shortening ≥ 28% • Absolute neutrophil count ≥1.0x 10^9/L (except in patients with documented bone marrow disease) • Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) CT1b specific inclusion • HR disease • Age ≥ 6 months • Available for randomisation ≤60 days after diagnostic biopsy/surgery • Absolute neutrophil count ≥1.0x 10^9/L • Platelets ≥ 80 x 10^9/L Radiotherapy Inclusion • Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) • VHR, HR and SR disease • ≥ 2 years of age • Receiving frontline induction treatment as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen • patients for whom. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible • Documented negative pregnancy test for female patients of childbearing potential • RT1a and RT1b Specific Inclusion • Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy • (6 cycles for metastatic disease) • Adjuvant radiotherapy required in addition to surgical resection (local decision). • Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised • disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease RT1b and RT1c Specific Inclusion • Higher Local Failure Risk (HLFR) based on presence of either of the following criteria: • Unfavourable site • Age ≥ 18yrs RT1c Specific Inclusion • Primary radiotherapy indicated (local decision) • Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease RT2 Specific Inclusion • Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy. • Unfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4 Maintenance specific Inclusion • Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy • regimen • Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible • No evidence of progressive disease • Absence of severe vincristine neuropathy – i.e requiring discontinuation of vincristine treatment) CT2a specific inclusion • VHR disease • Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens) CT2b specific Inclusion • HR disease • Completed 5 cycles of VnC maintenance treatment Relapse CT3 specific Inclusion • Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse) • Age ≥ 6 months • First or subsequent relapse of RMS • No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks • Documented negative pregnancy test for female patients of childbearing potential

    • Exclusion Criteria:

      Phase 1b specific exclusion • Weight < 10kg • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) CT1a and CT1b specific exclusion • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) Radiotherapy specific exclusion • Prior allo- or autologous Stem Cell Transplant • Second malignancy • Pregnant or breastfeeding women • Receiving radiotherapy as brachytherapy CT2a and CT2b specific Exclusion • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter current illness or active infection • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) CT3 specific exclusion • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women

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  • Incorporating the patient voice in sarcoma research: How can we assess health-related quality of life in this heterogeneous group of patients?

    • Research Summary

      -What is the problem? Although sarcoma patients have higher survival rates with different treatments, they often experience side-effects and psychosocial issues that negatively impact health-related quality of life(HRQoL) during and long after treatment. Therefore, it is important to assess treatment effectiveness both in terms of objective outcomes (survival, recurrence) and in terms of subjective patient reported outcomes including HRQoL. Generic HRQoL instruments are available, but questionnaires capturing all of the unique experiences of sarcoma patients is currently lacking. -What are our aims? To be able to develop a HRQoL instrument specifically for sarcoma-patients, this study aims to provide insight into the relevant HRQoL issues in this patient-group. Furthermore, we will investigate how to design the questionnaires: one list for all sarcoma patients or items based on patient and sarcoma-characteristics. -How will we do this? This study has a mixed method design. In the first phase of this study, semi-structured interviews will be conducted with sarcoma patients and health care professionals about the HRQoL issues that they experience. Subsequently, the respondent will be asked to review the EORTC QLQ-C30 and a site-specific module, if available, for topic and item relevance. These results will be combined with data from previous literature to create an extensive issue-list. In the second phase, we will present the list of HRQoL issues to another group of sarcoma patients and health care professionals and ask them to rate the issues on relevance and to prioritize the 10 most important issues. -What can we learn? The results of this study will help to develop a HRQoL instrument that can be used in future studies to assess not only adverse events and efficacy of new treatments, but also their impact on common functional health problems reported by sarcoma patients.

    • Inclusion Criteria:

      A confirmed diagnosis of sarcoma; age 18 years or older; informed consent provided. Although sarcoma is a disease of all ages, we decided to include only those 18 years and older because the EORTC QLQ-C30 is only validated among cancer patients 18 years and older. Age-specific questionnaires are available for those patients under 18 years.

    • Exclusion Criteria:

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  • Molecular analysis of screen detected non-invasive breast cancer and atypical breast hyperplasias identified by the Sloane Project

    • Research Summary

      This ethics application is a continuation of the project titled: Generation of ductal carcinoma in situ prognostic gene signature using retrospective archived paraffin embedded tumour samples. The study was given ethical approval on November 2008 by West Glasgow Ethics Committee 1 ( REF 08/S0703/147) The Sloane Project is a UK wide prospective audit of screen detected non-invasive and atypical breast hyperplasias. Non invasive breast neoplasia accounts for 25% of all ‘breast cancers’ detected through breast screening and includes ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Atypical hyperplasias are high risk benign lesions and are found in 10% of benign biopsies performed through the screening programme. The importance of these lesions rests on the increased risk of subsequently developing invasive breast cancer with DCIS at highest risk ( 20 times greater than the general population) followed by LCIS (2-11 times greater) and atypical breast hyperplasia (4 times greater). The Sloane project data are held by Public Health England (PHE) and provide full and detailed information about the patients' journey from diagnosis to treatment and outcome. The project aims to increase the understanding of these early breast lesions which can lead to breast cancer. All NHS breast screening units in the UK are invited to send in data for the Sloane Project. The objective of this research protocol is the collection of formalin fixed paraffin embedded (FFPE) tissue blocks from women whose data is held within the Sloane Project in order to allow detailed analysis of the genomic changes in cases of in situ and atypical hyperplasia and how these relate to the corresponding annotated clinical, pathological and radiological data collected by PHE in order to identify a particular signature that define which cases are likely to develop invasive disease.

    • Inclusion Criteria:

      Women of screening age identified through the Sloane project with ductal carcinoma in situ, lobular carcinoma in situ or atypical hyperplasia.

    • Exclusion Criteria:

      Women with a previous history of invasive breast cancer

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  • Randomised phase II/III study of Rituximab and Ibrutinib (RI) versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as initial therapy for Waldenström's macroglobulinaemia

    • Research Summary

      Waldenström’s macroglobulinaemia (WM) is a rare type of slow growing lymphoma. It develops when white blood cells grow abnormally. Typically a disease of the elderly, the median age of presentation is > 70 years and the current treatment for WM is unsatisfactory, with incomplete responses and inevitable recurrence. Therefore there is a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. The RAINBOW study is a phase 2-3 trial assessing ‘chemotherapy free’ treatment as primary therapy for WM which can potentially improve response outcome, durability and importantly, reduce toxicity for WM patients. This approach will be done using the drug Ibrutinib, which in combination with rituximab (RI) will be the experimental arm. As there is no agreed standard on first-line therapy for WM, the control arm is the current treatment based on the most recently published clinical trial results. The control arm consists of rituximab, cyclophosphamide and dexamethasone (DCR), and is widely recommended by international consensus as appropriate treatment for first-line therapy for WM. In this study, 148 adults (aged > = 18 years) with treatment naïve WM will be randomised on a 1:1 ratio to either the treatment or control arm. Randomised treatment lasts for a maximum of 6 cycles and response will be assessed following 3 cycles of treatment and completion of randomised treatment at approximately 24 weeks after commencing treatment. RI patients may then have up to 5 years of Ibrutinib monotherapy. Patients will be seen regularly during treatment and then every 3 months for 5 years after treatment discontinuation. Patients will enter annual follow up for survival until the end of trial (including progressed patients). The study will be conducted at NHS hospitals and is expected to last 9 years and 6 months.

    • Inclusion Criteria:

      1.Patients > = 18 years 2.Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein 3.Previously untreated disease at any stage requiring therapy at the discretion of the treating physician. Suggested criteria for initiating treatment include: - haematological suppression to Hb < 10g/dl, or neutrophils < 1.5x109/l or platelets < 150x109/l - clinical evidence of hyperviscosity - bulky lymphadenopathy and/or bulky splenomegaly - presence of B symptoms 4.No previous chemotherapy (prior plasma exchange and steroids are permissible) 5.Eastern Cooperative Oncology Group (ECOG) performance status grade 0 – 2 6.Life expectancy of greater than 6 months 7.Written informed consent 8.Willing to comply with the contraceptive requirements of the trial 9.Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)

    • Exclusion Criteria:

      1. Prior therapy for WM 2. Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein 3. CNS involvement with WM 4. Autoimmune cytopenias 5. Major surgery within 4 weeks prior to randomisation 6. Clinically significant cardiac disease including the following: - Myocardial infarction within 6 months prior to randomisation - Unstable angina within 3 months prior to randomisation - New York Heart Association class III or IV congestive heart failure - History of clinically significant arrhythmias (e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) - QTcF > 480 msecs based on Fredericia’s formula - History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place - Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mm Hg - Cardiac event within 6 months of screening (e.g. coronary artery stent) requiring dual antiplatelet treatment 7. History of stroke or intracranial haemorrhage within 6 months prior to randomisation 8. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (direct oral anticoagulants (DOACs) allowed) 9. History of severe bleeding disorders considered not to be disease related (Haemophilia A, B or von Willebrand’s disease) 10. Requires ongoing treatment with a strong CYP3A inhibitor or inducer 11. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows: - Presence of hepatitis B surface antigen (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 patient will be excluded - Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable 12. Women who are pregnant or breastfeeding or males expecting to conceive or father children at any point from the start of treatment until the end of the “at risk period” 13. Renal failure (creatinine clearance < 30 ml/min as estimated by the Cockroft-Gault equation) 14. Patients with chronic liver disease with hepatic impairment Child-Pugh class B or C 15. Known history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies 16. Inability to swallow oral medication 17. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (e.g. malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease) 18. Active systemic infection requiring treatment 19. Concomitant treatment with another investigational agent 20. Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could compromise the patient’s safety, or put the study at risk 21. Unwilling or unable to take PJP prophylaxis (e.g. cotrimoxazole). 22. 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, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer without current evidence of disease.

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  • Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma: A phase III trial to compare standard and frailty-adjusted induction therapy with ixazomib, lenalidomide and dexamethasone (IRD) and maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I).

    • Research Summary

      Myeloma is a cancer diagnosed in around 5500 patients within the UK, each year. The development of treatments have increased life expectancy in all patients, but these have been less effective in older and frailer patients. There is no evidence to suggest their Myeloma is more aggressive, so it needs to be asked why this is the case. Research is beginning to look at older Myeloma patients who are ineligible for transplants. Myeloma XI, a trial previous to this run at the CTRU, where 1840 of these patients were recruited, has shown that treatment outcomes were not necessarily associated with different combinations of treatment. Frailty-adjusted can potentially show how problems developed during treatment that are not responding effectively so it can be minimised. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomised on a 1:1 basis at trial entry to either frailty score-adjusted treatment vs.standard up-front treatment followed by toxicity dependen dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomisation. In the second phase of the trial, patients will be tested to assess whether lenalidomide and ixazomib is effective as a maintenance treatment. Patients will either receive lenalidomide and ixazomib, or lenalidomide and placebo (something that has a similar taste and appearance to ixazomib but has no effect on the person) to test this. Participants and their treating physicians will be blinded to maintenance allocation. Aims: This trial aims to determine and compare: a) Frailty adjusted dosing induction treatment compared to standard dosing induction treatment with modifications allowed where toxicity is seen b)If there is an improved response rate and overall survival rate when patients receive lenalidomide plus ixazomib vs lenalidomide alone. Methods: A phase III, multi-centre, randomised controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant.

    • Inclusion Criteria:

      Inclusion criteria for Randomisation 1 (R1): 1. Newly diagnosed as having multiple myeloma (MM) according to the updated International Myeloma Working Group (IMWG) diagnostic criteria 2014 (see Appendix 1 in protocol for criteria) requiring treatment. 2. Not eligible for stem cell transplant. 3. Aged at least 18 years. 4. Meet all of the following blood criteria within 14 days before R1: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L, or, in the case of heavy bone marrow infiltration (> = 50%) which in the opinion of the investigator is the cause of the thrombocytopenia and provided appropriate supportive measures and patient monitoring are in place, platelet count > = 30 x 10^9/L is permitted. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN. 5. Meet the pregnancy prevention requirements: Female participants who: a) Are not of childbearing potential (Appendix 8 in protocol), OR b) If they are of childbearing potential, agree to practice 2 effective methods of contraception (Appendix 8 in protocol), 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 participants must consent to) the Celgene-approved Pregnancy Prevention Programme. If female and of childbearing potential (see Appendix 8 in protocol), they must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Pregnancy Prevention Programme. 6. Able to provide written informed consent. Inclusion criteria for Randomisation 2 (R2): 1. Randomised into the FiTNEss (Myeloma XIV) trial and received induction chemotherapy with ixazomib and lenalidomide continued for 12 cycles. 2. Achieved at least MR at the end of IRD induction according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol), with no evidence of progression prior to R2. 3. Meet all of the following blood criteria within 14 days before R2: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN.

    • Exclusion Criteria:

      Exclusion criteria for Randomisation 1 (R1): 1. Smouldering MM, MGUS, solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM). 2. Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160 mg dexamethasone. 3. Known resistance, intolerance or sensitivity to any component of the planned therapies. 4. Prior or concurrent invasive malignancies except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention; ‐ Any cancer from which the subject has been disease-free for at least 3 years. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Any concomitant drug therapy which, in the opinion of the investigator, may lead to an unacceptable interaction with any of the agents ixazomib, lenalidomide, dexamethasone, and that cannot be safely stopped prior to trial entry. Full details of interactions can be found in the SPCs. 9. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 10. > = Grade 2 peripheral neuropathy. 11. Known HIV positive 12. Participant has current or prior hepatitis B surface antigen positive or hepatitis C antibody positive. Participants must have screening conducted within 14 days before R1. 13. Active systemic infection. 14. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. Exclusion criteria for Randomisation 2 (R2): 1. Received any anti-myeloma therapy other than their randomised trial treatment, with the exception of local radiotherapy to relieve bone pain (in the absence of disease progression), or bisphosphonate treatment. 2. SD or disease progression according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol). 3. Known resistance, intolerance or sensitivity to ixazomib or lenalidomide that required cessation of either agent during induction. 4. Developed any malignancy since R1 except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 9. > = Grade 2 peripheral neuropathy, or grade 1 with pain. 10. Known HIV positive 11. Current or known hepatitis B surface antigen positive or hepatitis C antibody positive. 12. Active systemic infection. 13. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s continued participation in this study.

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  • Multi-centre Observational study of maintenance Niraparib in Treatment of Ovarian CanceR: UK routine clinical practice experience

    • Research Summary

      Ovarian cancer is diagnosed in over 7000 women per year and is the cause of over 4000 deaths per year in the UK. Around 70% of patients experience disease recurrence within the first 3 years of diagnosis. Maintenance treatment strategies have been developed to improve patient outcomes. Maintenance treatment with Niraparib slows cancer growth by blocking a group of enzymes called poly [ADP-ribose] polymerase (PARP) that are implicated in DNA repair. The purpose of this study is to improve the knowledge and understanding of the tolerability and incidence and management of treatment emergent adverse events (TEAEs) during Niraparib treatment in patients with advanced ovarian fallopian tube and primary peritoneal cancer. All patients who have already commenced treatment and those who are due to commence Niraparib will be eligible to take part. This is a multicentre observational study which will aim to collect and analyse the records of 200 patients in the UK who have been prescribed Niraparib as maintenance therapy for their cancer in order to determine how best the drug can be used within the British healthcare system. Data will be collected retrospectively for patients who have previously received Niraparib. Information on patients’ Quality of Life will be collected for all patients who have not received Niraparib when they enrol on the trial. They will be asked to complete several questionnaires at regular time points throughout the study. The study will last for 2.5 years and will be funded by TESARO UK.

    • Inclusion Criteria:

      1. Female patients over 18 years of age 2. Patients with histologically confirmed advanced ovarian or primary peritoneal cancer 3. Patients who are planned to receive Niraparib for advanced ovarian fallopian tube and primary peritoneal cancer. 4. Patients who have previously commenced maintenance Niraparib prior to study opening at site. 5. Deceased patients who have previously been prescribed Niraparib. 6. Patients able to give written informed consent, complete questionnaires and comply with study procedures (if applicable).

    • Exclusion Criteria:

      1. Patients unable to give informed consent unless deceased 2. Patients unable to complete questionnaires or comply with study procedures (if applicable).

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  • Oxford Pre-cancerous Lymphoproliferative Disorders: Analysis and Interception study

    • Research Summary

      The purpose of the study is to monitor patients with early stage lymphoproliferative disorders not meeting criteria for treatment, including early stage Chronic Lymphocytic Leukaemia (CLL), Monoclonal B-cell Lymphocytosis (MBL), Monoclonal Gammopathy of Uncertain Significance (MGUS), asymptomatic Waldenstroms Macroglobulinaemia (WM) and Smouldering Myeloma (SM). Each of these disorders has a pre-cancerous phase when abnormalities can be seen in the blood however treatment may not be required. A minority of people with early stage lymphoproliferative disorders will go on to need chemotherapy or other treatment for blood or bone marrow cancer. Currently we do not have a reliable way to predict which of these individuals with these disorders are more likely to develop a blood or bone marrow cancer. By studying a large group of individuals over time we hope to discover more about what factors might predict progression. We may be able to identify markers which identify individuals who are more or less likely to develop blood or bone marrow cancer. These markers might be particular symptoms, gene changes called mutations or levels of particular molecules or cells in the blood or bone marrow. In the longer term this may enable us to identify those people who would benefit from certain types of treatment or from receiving treatment at an earlier stage and also to confidently reassure those who will never progress. Patients will be studied for up to 5 years with blood, bone marrow and saliva samples taken at key time-points to help answer these questions. In addition to looking for these markers we will also collect information about: •What it is like to live with one of these conditions •How many people with these conditions develop other significant medical conditions, such as serious infections, thrombosis (blood clots) or other types of cancer.

    • Inclusion Criteria:

      1.Patients diagnosed within the previous two years with one of the following: a.High count monoclonal B-cell lymphocytosis (MBL) i.e. clonal B-cell population 0.5-4.9 10*9/L b.Low risk Rai Stage/ Binet Stage A Chronic Lymphocytic Leukaemia not meeting the IWCLL criteria for treatment c. IgG or IgA Monoclonal Gammopathy of Uncertain Significance meeting one of the following criteria: i. IgA paraprotein > 10g/L or ii. IgG paraprotein > 15g/L or iii. IgA/IgG paraprotein below these cut-offs but kappa:lambda light chain ratio of < 0.1 or > 3.0 iv. Patients not meeting the cut-offs defined in points i) to iii) but who are referred to secondary care e.g. due to GP concern or for investigation of symptoms d. IgM Monoclonal Gammopathy of Uncertain Significance meeting one of the following criteria: i. IgM paraprotein > 10g/L or ii. IgM paraprotein < 10g/L and difference between the kappa and lambda light chains of > 50mg/L iii. Patients not meeting the cut-offs defined in point i) and ii) but who are referred to secondary care e.g. due to GP concern or for investigation of symptoms e. Asymptomatic smouldering Waldenstroms Macroglobulinaemia not meeting the criteria for treatment f. Smouldering myeloma not meeting the criteria for treatment 2. ECOG performance status of 0,1 or 2 3. Age 16 years and over 4. Signed written informed consent 5. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations. 6. Haematological and biochemical indices within the ranges shown below: Haemoglobin (Hb) > 110g/L Platelet count > 100 x 10*9/L

    • Exclusion Criteria:

      1. Pregnant or breast-feeding women. Pregnant or breast-feeding women may be re-screened following delivery and/or cessation of breastfeeding, as appropriate. 2. Previous chemotherapy or immunotherapy for any haematological cancers 3. Treatment with any other investigational agent, or participation in an interventional clinical trial within 28 days prior to enrolment. 4. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor study candidate or could interfere with protocol compliance or the interpretation of study results. 5. Any other malignancy that requires active surgical or chemotherapeutic treatment. Patients on long term hormone therapies (e.g. tamoxifen) are permitted to enrol at the discretion of the investigator, after considering the overall clinical context. 6. Any significant concurrent medical condition resulting in a life-expectancy of less than 5 years (including but not limited to renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease)

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  • An international multicenter phase II randomised trial evaluating and comparing two intensification treatment strategies for metastatic neuroblastoma patients with a poor response to induction chemotherapy

    • Research Summary

      High-risk neuroblastoma is one of the major challenges in paediatric oncology, as the outcome remains poor, particularly for patients who respond poorly to initial chemotherapy. High-risk neuroblastoma is not cured by a single treatment. All patients who have become long-term survivors have received sequential treatments with various drugs. This trial compares two sequential treatments, each containing treatments successfully used before, in combination with an experimental component. There is no recognised or accepted standard treatment in this very high-risk patient group and no guidelines exist for poor responders. Eligible patients will receive induction chemotherapy (using irinotecan and temozolomide), and will then be randomised to receive either mIBG radiotherapy with topotecan or high dose thiotepa, followed by autologous stem cell transplant (ASCT). Each randomised treatment will be followed by high dose chemotherapy with busulfan and melphalan (BuMel) and a second ASCT. The two consolidation treatments will be evaluated for success and compared to see which is the better treatment.

    • Inclusion Criteria:

      1. Metastatic neuroblastoma (NBL) 2. Previously treated within the SIOPEN High Risk Neuroblastoma study or treated with the current standard treatment for very high risk neuroblastoma off-trial (Rapid COJEC induction chemotherapy) 3. 131I-mIBG scintigraphy positive at diagnosis and after induction chemotherapy (pre BuMel evaluation). 4. Metastatic response after induction chemotherapy lower than the SIOPEN High Risk Neuroblastoma trial criteria to be eligible for high dose chemotherapy (metastatic response worse than partial response (< PR) or SIOPEN score > 3) 5. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on study drug and for one year after stopping the study drug. Acceptable contraception is listed in Appendix 12. Female patients who are lactating must agree to stop breast-feeding. 6. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines. 7. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

    • Exclusion Criteria:

      1. Parenchymal brain metastasis(es) (even one) 2. Progressive disease at study entry 3. Previous high-dose therapy and ASCR 4. Performance status (Karnofsky or Lansky) < 70% 5. Patient having received other therapy for cancer treatment than those allowed as per the SIOPEN High Risk Neuroblastoma trial or as defined in the future frontline protocol (for HRNBL1 trial : after induction + 2 TVD) 6. Impaired organ function (liver, kidney, heart, lungs) according to the following definitions o Shortening fraction < 28%, or ejection fraction < 55%, or clinical evidence of congestive heart failure or uncontrolled cardiac rhythm disturbance o Dyspnea at rest and/or pulse oximetry < 95% in air. o ALT, Bilirubin > 2 ULN o Creatinine clearance and/or GFR < 60 ml/min/1.73m2 and serum creatinine > = 1.5 mg/dl 7. Any uncontrolled inter-current illness or infection that in the investigator’s opinion would impair study participation 8. Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines 9. Patient allergic to peanut or soya 10. Chronic inflammatory bowel disease and/or bowel obstruction 11. Pregnant or breastfeeding women 12. Known hypersensitivity to the active substance or to any of the excipients of study drugs 13. Known hypersensitivity to dacarbazine 14. Concomitant use with St John's Wort

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  • Phase I study of transfer of effector memory T cells (Tem) following allogeneic stem cell transplantation.

    • Research Summary

      Healthy bone marrow produces blood cells, including infection-fighting immune cells. These blood cells originate from stem cells. In cancer, the bone marrow can no longer function properly. To restore healthy blood cell production and to fight the cancer, some patients are given healthy stem cells from a donor’s bone marrow. Although this can cure many patients, it can have serious side effects, including ‘graft versus host disease’ (GvHD). This happens because the bone marrow contains donor immune cells (the ‘graft’) that see the patient’s healthy cells (the ‘host’) as foreign and attacks them. It mainly affects the tissues of the skin, the liver and the gut and can be life threatening. Drugs that prevent GvHD by suppressing the donor’s immune cells in the patient’s body renders the immune system weak and unable to fight infections. These infections are sometimes very severe and can lead to patients dying. This trial aims to find out if giving patients additional infection fighting immune cells from the donor (Tem cells) will reduce their chance of getting an infection without causing GvHD. Patients will receive additional donor immune cells about one month after the transplant. They will also receive the standard GvHD prevention treatment. Different doses of the donor immune cells will be given to individual patients to work out which dose is best. All patients will be closely monitored for signs of GvHD or infection. They will also have blood tests to determine how well and quickly their immune systems recover. Patients will be followed up for 12 months post treatment. The study will recruit a maximum of 18 patients. The study will be conducted at NHS hospitals and is expected to last 22 months.

    • Inclusion Criteria:

      Patient: - Severe aplastic anaemia or - Primary immune deficiency or - Haematological cancer which can be ONE OF the following: o Non-Hodgkin’s lymphoma (NHL) in CR or PR; o Hodgkin’s lymphoma (HL) in CR or PR; o Chronic (Pro-)lymphocytic leukaemia (CLL or PLL) in CR or PR o Plasma cell myeloma (PCM) in CR, VGPR or PR; o Acute myeloid leukaemia (AML) in CR; o Acute lymphoblastic leukaemia (ALL) in CR; o Myelodysplastic syndrome (MDS) < 10 % blasts in bone marrow; o Chronic myelomonocytic leukaemia (CMML) < 10% blasts in bone marrow - Have undergone disease reassessment within 8 weeks prior to registration - Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based conditioning regimen with calcineurin-inhibitor based immunoprophylaxis - Aged > = 16 years, < 70 years - Written informed consent Donor: - Aged > = 16 years - HLA-identical sibling - Have met transplant centre criteria regarding suitability for cell therapy donation - Negative for HIV 1 and 2, hepatitis B, hepatitis C, HTLV-1 and 2, syphilis serology - Written informed consent

    • Exclusion Criteria:

      Patient: - Women who are pregnant or breast feeding - Life expectancy of < 8 weeks - Currently taking part in any other interventional clinical research study (involving any IMP, ATIMP or cellular therapy) - Proposed use of any other method of GvVHD prophylaxis other than alemtuzumab and calcineurin inhibitor - Organ dysfunction: o LVEF< 45% o Glomerular filtration rate (corrected) < 50ml/min o Bilirubin > 50µmol/l o AST or ALT > 2.5 x ULN (NB: If both are performed then both must be < = 2.5 x ULN) Trial Treatment Exclusion Criteria (patient eligibility check 2 days prior to CD62L- Tem Infusion) - Prior or active acute pattern GvHD of any grade - Relapse or progression - Primary or secondary graft failure - Has received other cellular therapies Donor: - Pregnant/lactating women

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  • Improving outcomes through collaboration in osteosarcoma

    • Research Summary

      There has been little improvement in outcome for patients with osteosarcoma (OS) over the last 20 years. There have been only a few clinical trials of new treatments and no major new therapies introduced recently. This is in part because we do not have a good understanding of the biology of osteosarcoma, but also trials have only included subgroups of patients. The more we understand about how and why osteosarcoma arises and grows the better we will be able to decide what treatments are most likely to work best. The purpose of this project is to collect high quality clinical data about patients of all ages with osteosarcoma, such as information about the size of the disease, how it was diagnosed and where it is at diagnosis, what treatments were given and how the disease responded the treatments. We will also collect blood and tissue samples for analysis in research laboratories. By looking at the results of the laboratory findings and the clinical data together, we will start to answer the questions about why osteosarcomas arise and grow, what makes it spread, and why some patients respond to treatment better than others. As time goes on, we plan to use this information to develop clinical trials of new treatments. Alongside this, we want to find out more about how osteosarcoma and its treatments affect the lives of those living with this disease. This information will help us to provide the most appropriate care and support that will meet the needs of each patient. Ultimately, our aim is to improve the care and treatment of osteosarcoma patients so that they may live longer and better lives.

    • Inclusion Criteria:

      • New histological diagnosis of osteosarcoma or in the absence of osteoid seen on biopsy, pathology and imaging supportive of a diagnosis of osteosarcoma. It is well recognised that some patients may present with features suggestive of osteosarcoma (under 40, radiological abnormality compatible) but in whom no osteoid is detected in needle biopsy. Although categorised as spindle cell tumour of bone, such patients are usually treated in an identical approach to osteosarcoma. A definite diagnosis of osteosarcoma is then often possible after surgery when the entire resection specimen is available. • Written informed consent of patient or parent/legal guardian

    • Exclusion Criteria:

      • Osteosarcoma diagnosis more than three months prior to registration

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  • ATRiUM: A phase 1 trial to assess the safety, tolerability, pharmacokinetics and preliminary antitumor activity of ascending doses of combined therapy with ATR inhibitor AZD6738 and gemcitabine, Using a Model based design.

    • Research Summary

      This trial is being carried out to explore the safety, tolerability and anti-tumour activity of a combination of gemcitabine and a new anti-cancer drug called AZD6738 in patients with solid tumours. Gemcitabine is anti-cancer drug which is routinely used as a treatment for various types of cancers. There are 2 parts to this trial. All participants will receive both study drugs. Part 1 is a dose escalation phase. During this phase AZD6738 will be given in combination with gemcitabine. Doses will be increased as participants are recruited. Within part 1 there are 2 treatment schedules, continuous and intermittent. Participants will be allocated to either the continuous administration schedule (AZD6738 once daily for 21 days and gemcitabine administered on days 3, 10 and 17 of every 28 days cycle) or the intermittent administration schedule (AZD6738 once daily on days 1 to 4, 8 to 11 and 15 to 18, and gemcitabine administered on days 3, 10 and 17 of every 28 days cycle). Part 2 is a dose expansion phase and will only recruit patients with inoperable, locally advanced or metastatic pancreatic cancer. The schedule(s) and dose levels determined from Part 1 will be allocated to all participants. Up to 55 evaluable participants will be recruited across approximately 4 participating sites. Up to forty (40) participants will be registered in to the dose escalation phase of the trial, followed by up to fifteen (15) participants in the treatment expansion phase. Participants will undergo routine and research tests and assessments. Participation is expected to last a maximum of 1 year, plus a 28 day screening period. Participants that have withdrawn or completed the study will be referred back to their usual hospital doctor.

    • Inclusion Criteria:

      To be included in the trial the participant must meet all of the following criteria: • Written informed consent to participate. • Aged 18 years and over. • ECOG performance status of 0 or 1. • Dose escalation phase only: Patients with inoperable/unresectable, histologically proven, locally advanced or metastatic solid tumour that has progressed on standard therapy, or patients unwilling to receive standard therapy. • Treatment expansion phase only: Patients with inoperable, histologically proven, locally advanced or metastatic pancreatic adenocarcinoma that has progressed on conventional chemotherapy, or patients unwilling to receive standard therapy. • Documented evidence of progression (radiological or clinical) prior to trial entry. • Estimated life expectancy of > = 12 weeks. • Measurable tumour lesions that can be accurately assessed at baseline by computed tomography (CT) and are suitable for repeated assessment as per RECIST 1.1 and considered accessible for core biopsy. • Women of childbearing potential, male participants and their partners are required, and must be willing, to use 2 highly effective forms of contraception for the duration of the trial and for six (6) months after the completion of the trial treatment. Women of non-childbearing potential must meet one of the following: • Documented postmenopausal (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 sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy with last menses > 1 year ago (excluding tubal ligation, radiation-induced oophorectomy). • Documented amenorrhoeic for 12 months (defined as women under the age of 50 years with serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution). • Patient is willing and able to comply with the protocol for the duration of the trial.

    • Exclusion Criteria:

      • Diagnosis of ataxia-telangiectasia syndrome. • Women who are pregnant or breast-feeding. • Women of child-bearing potential and male participants who are unwilling to use 2 highly effective forms of contraception during the trial and for 6 months after the completion of the trial treatment. • Cytotoxic chemotherapy within 21 days of start of treatment (greater than five half-lives is allowed for washout in patients treated with non-cytotoxic drugs). Exposure to a small molecule IMP within 30 days or 5 half-lives (whichever is longer) prior to the start of treatment. • Palliative radiotherapy within 21 days of start of treatment. • Immunotherapy within 42 days of start of treatment. • New treatment with bisphosphonates or denosumab for bone metastases within 5 days of start of treatment (patients can receive a stable dose of bisphosphonates or denosumab for bone metastases before and during the trial as long as these were started at least 5 days prior to start of treatment). • Major surgery within 2 weeks of start of treatment (patients must have recovered from any effects of major surgery). • Current treatment with steroids (doses of > 10mg of prednisone or equivalent) or other immunosuppressive drugs within 14 days of start of treatment. • Any other malignancy which has been active or treated within the past three years (with the exception of cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively treated with no evidence of disease for > = 5 years prior). • Current treatments with known potent cytochrome P (CYP) 3A inhibitors, potent CYP3A inducers, CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index or Pgp modulators (wash out period of five half-lives, but three weeks for St. John’s Wort, see Appendix 5). The use of herbal supplements or ‘folk remedies’ is not permitted. • Impaired hepatic or renal function defined as: o AST or ALT > 2.5 x ULN (or 5 times if liver metastasis). o Total bilirubin > 1.5 x ULN. o Glomerular filtration rate (GFR) (calculated by Cockcroft-Gault) of < 41 ml/min. • Inadequate bone marrow reserve or organ function defined as: o Absolute neutrophil count < 1.5 x 10*9/L. o Platelet count < 100 x 10*9/L with no blood transfusions in the past 28 days. o Haemoglobin < 90 g/L with no platelet transfusions in the past 28 days. • INR > = 1.25 above the normal range. • Haematuria +++. • Known history of cardiac dysfunction within the last 6 months defined as: o Myocardial infarction o NYHA Class II/III/IV heart failure o Unstable angina pectoris o Unstable cardiac arrhythmias not controlled with a pacemaker or medication (e.g. complete left bundle branch block or third degree heart block). • Any of the following cardiac criteria: o Mean resting corrected QT interval (QTc) > 470 msec for women, and > 450 msec for men obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula. o Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mmHg. o Patients with known reduced LVEF < 55%. o Patients at risk of brain perfusion problems (e.g. medical history of carotid stenosis, pre-syncope, syncope episodes or a history of transient ischaemic attack). o Uncontrolled hypertension (grade 2 or above) requiring clinical intervention. • Patients unable to swallow orally administered medication and with gastrointestinal disorders likely to interfere with absorption of AZD6738. • Any other concurrent severe and/or uncontrolled medical condition that places the patient at unacceptable risk of toxicity or non-compliance (examples include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome, extensive bilateral lung disease on high resolution CT scan, severe Parkinson’s disease, active inflammatory bowel disease, psychiatric condition, or active infection (including any patient known to have hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral drugs)). Screening for chronic conditions is not required. • Prior exposure to an ATR inhibitor. • A known hypersensitivity to AZD6738 or gemcitabine (e.g. excessive myelosuppression), any excipient of the products, or any contraindication to the combination of anti-cancer agents. • Any unresolved toxicities from prior therapy of CTCAE grade > 1 (with the exception of alopecia and CTCAE grade 2 neuropathy). • Spinal cord compression (unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of treatment). •Brain metastases. • Judgment by the Investigator that the patient should not participate in the trial.

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  • PHOENIX Trial: A pre-surgical window of opportunity and post-surgical adjuvant biomarker study of DNA damage response inhibition and/or anti-PD-L1 immunotherapy in patients with neoadjuvant chemotherapy resistant residual triple negative breast cancer

    • Research Summary

      Triple negative breast cancer (TNBC) can have a high/moderate risk of returning (relapsing) after standard treatment; usually within the first 2 years after finishing treatment. In some patients with TNBC who receive chemotherapy before surgery, if there is cancer remaining after chemotherapy (called residual disease) that risk of relapse is higher. PHOENIX aims to investigate the biology of this residual disease in the 2-week time window between completing chemotherapy and surgery to see if giving trial treatment in this window changes the biology of the cancer. TNBC patients who have cancer remaining at their mid-point assessment during chemotherapy will be invited to register for PHOENIX. After registration, a post-chemotherapy MRI scan will confirm presence of residual disease and eligible patients will be randomly allocated into a cohort: Cohort A: standard care (no trial treatment) Cohort B: AZD6738 Cohort C: olaparib Cohort D: durvalumab A pre-treatment research biopsy and blood sample will be collected, followed by trial treatment before surgery. After trial treatment, a second research biopsy and blood sample will be collected. Pre- and post-treatment samples will be compared to see if there is a difference that may provide an early signal that warrants further investigation of the trial treatment. Patients may resume trial treatment after surgery for a period of 12 months (adjuvant treatment) to investigate whether any signals seen in the tumour/blood after short exposure to trial treatment prior to surgery are also seen after longer exposure to trial treatment in the adjuvant setting.

    • Inclusion Criteria:

      INCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Signed Informed Consent Form (ICF) for Trial Registration; 2. Aged > = 18 years old; 3. Histologically confirmed invasive triple negative breast cancer (TNBC). TNBC defined as ER negative, PgR negative (ER and PgR negative as defined by Allred score 0/8, 1/8 or 2/8 or stain in < 1% of cancer cells) or PgR unavailable, and HER2 negative (immunohistochemistry 0/1+ or negative in situ hybridization) as determined by local laboratory and recorded in the patients notes; 4. Planned definitive surgical treatment after at least 6 cycles of neoadjuvant chemotherapy (NACT); 5. Radiographically measurable tumour mass assessable for new distinct radio-opaque marker insertion and repeated biopsies on the NACT mid-assessment standard of care imaging modality; 6. Eastern Oncology Cooperative Group (ECOG) performance status 0-1; 7. Considered fit enough to have breast cancer surgery with curative intent; 8. Considered fit to complete at least 2 weeks of pre-operative trial treatment in the WOP; 9. Patients must be suitable for a mandatory pre-treatment baseline biopsy performed Day -1 or 1 of the window of opportunity (WOP) and a post-treatment biopsy performed on Day 14 of the WOP. Registered patients who are approached for Trial Entry will be required to consent to the pre- and post- WOP treatment biopsy. If it is deemed unsafe to proceed with biopsy upon Trial Entry the patient will not be eligible for participation in the trial. 10. Patients with clinical stage II disease or clinical suspicion of metastatic disease must have staging studies as per standard of care to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 11. Patients with stage III disease must have staging studies as per standard of care at any point after diagnosis but before Trial Registration, to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease), even if asymptomatic. 12. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed > 5 years prior to Trial Registration, and there is no evidence of recurrent disease; 13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before Trial Registration; 14. Patients must be: a) surgically sterile (i.e. if female have undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy; if male have undergone a bilateral orchidectomy); b) have a sterilised sole partner; or c) be post-menopausal; or d) must agree to practice total/true abstinence; or e) use a condom and one highly effective form of contraception in combination during the period of trial treatment and be willing to do so for a period of at least 6 months following the end of trial treatment. Post-menopausal is defined in Protocol Section 6.3.1. INCLUSION CRITERIA FOR TRIAL ENTRY: 1. Signed Informed Consent Form (ICF) for Trial Entry; 2. Residual disease is confirmed as at least one viable disease focus > = 1cm on trial-specific imaging performed at least 1 week following day 1 of the final cycle of NACT. 3. Recovery from all acute adverse events of prior NACT to baseline or NCI CTCAE Grade < = 1, except for alopecia. Patients with irreversible toxicity not reasonably expected to be exacerbated by trial treatment may be included only after consultation with the CI or Coordinating Investigator. 4. Patients must have adequate haematological, renal and hepatic function as defined in Protocol Section 9.1.1. 5. Women of childbearing potential must have a confirmed menstrual period and a negative urinary or serum pregnancy test prior to Trial Entry. This should be repeated as applicable to ensure a negative pregnancy test is performed within 3 days prior to commencing trial treatment (or on the day of planned trial treatment for Cohort C) 6. Confirmation that all Trial Registration inclusion criteria listed in Section 6.3.1 remain satisfied.

    • Exclusion Criteria:

      EXCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Definitive evidence of metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 2. Patients with bilateral tumours; 3. History of another primary malignancy within the last 5 years prior to Trial Registration, except for: a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; b. Adequately treated carcinoma in situ without evidence of disease; 4. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML; 5. Severe concurrent disease, infection or co-morbidity that, in the judgment of the local Investigator, would make the patient inappropriate for Trial Registration; 6. Resting ECG with QTc > 470msec for females and > 450 msec for men on 2 or more time points within a 24 hour period, factors which increase the risk of QTc prolongation or family history of long QT syndrome; 7. A diagnosis of ataxia telangiectasia; 8. Patients unable to swallow orally administered medication; 9. Patients receiving formal anti-coagulation treatment; 10. Patients with gastrointestinal disorder affecting absorption; 11. History of seizure or any condition that may predispose to seizure; 12. Other non-malignant systemic disease that would preclude trial treatment or would prevent required follow-up; 13. Pregnant or breast-feeding; 14. Prior exposure to ATR inhibitor (including AZD6738), PARP inhibitor (including olaparib), anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab); 15. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that in the investigators opinion would cause reasonable suspicion of a disease or condition, that contraindicates the use of trial treatment, that may increase the risk associated with trial participation, that may affect the interpretation of the results, or that would make this trial inappropriate for the patient; 16. Patients with a known hypersensitivity to the trial treatments or any excipients of the products; 17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT); 18. Active or prior documented autoimmune or inflammatory disorders (examples & exceptions are listed in Protocol Section 6.3.1). 19. Active infection including tuberculosis (TB), hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV) as described in Protocol Section 6.3.1. EXCLUSION CRITERIA FOR TRIAL ENTRY: 1. History of clinically significant or uncontrolled cardiovascular disease as described in Protocol Section 9.1.2; 2. History of loss of consciousness or transient ischemic attack within 12 months prior to Trial Entry; 3. Patients with Grade > = 2 neuropathy, as defined by NCI CTCAE v5.0 will be evaluated on a case-by-case basis after consultation with the CI or Coordinating Investigator; 4. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 2 weeks prior to Trial Entry. Patients must have recovered from any effects of any major surgery prior to commencing trial treatment. 5.Use of any investigational agent within 30 days prior to commencing trial treatment. 6. Concomitant use of known strong CYP3A inhibitors. 7. Concomitant use of known strong CYP3A inducers. The required washout period prior to commencing trial treatment is 5 weeks; 8. Whole blood infusion or erythropoietin within 28 days prior to trial entry (packed red blood cells and platelet transfusions are acceptable); 9. Current or prior use of immunosuppressive medication within 14 days prior to commencing trial treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisolone, or an equivalent corticosteroid. 10. Receipt of live attenuated vaccine within 30 days prior to commencing trial treatment. 11. Confirmation that none of the Trial Registration exclusion criteria listed in Section 6.3.2 are met.

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  • A Clinical Pharmacology Study to Investigate the Utility of Therapeutic Drug Monitoring in Challenging Childhood Cancer Patient Populations

    • Research Summary

      It is particularly difficult to treat some groups of children diagnosed with cancer, including very young infants in the first weeks of life and children with poor kidney function. It can be especially difficult to know how much chemotherapy (anti-cancer drugs) to give to these children. Doctors often have to make difficult decisions about the most appropriate dose of drug, without enough scientific information to help them decide. This can mean that patients might not get enough drug or get too much, and this can be harmful in terms of causing long term health problems due to under or over dosing. Our research group is a national centre for carrying out cancer drug trials in children. Over the past 10 years we have gained a reputation for expertise in supporting the treatment of ‘hard to treat’ children through the use of therapeutic drug monitoring. This involves the measurement of drug levels in individual patients following a request from the treating clinician. A limited number of blood samples are collected following drug administration and sent to our laboratory for analysis. The results are fed back to the treating clinician who can use this information alongside information on patient response and side effects to make informed decisions regarding the continued treatment of the individual patient. Based on the positive impact on patient treatment of this approach, we now aim to conduct a study to allow the formal collection of clinical data following the treatment of these challenging patient populations. The findings of this research programme will be made available to doctors treating children with cancer about what doses of drugs to prescribe. This will positively impact on the treatment of future childhood cancer patients by providing data that will inform future dosing guidelines.

    • Inclusion Criteria:

      Inclusion criteria to be utilised for patient recruitment; a) age < 18 years b) confirmed diagnosis of cancer c) patient receiving 'modified' chemotherapy (see below for patients who fall into this category)* d) central venous catheter in place e) willingness to participate and written informed parental/patient consent (signed and dated) f) request from the treating clinical for therapeutic drug monitoring approach to treatment * Patients receiving 'non standard' chemotherapy dosing regimens will include the following groups: - neonates and infants including pre-term infants - anephric patients - patients receiving high dose myeloablative chemotherapy and autologous stem cell rescue - obese patients (BMI at or above the 995th percentile for children of the same age and sex)

    • Exclusion Criteria:

      a) Failure to meet the inclusion criteria

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  • MAESTRO: Molecular stratification profiling protocol in metastatic Castration Resistant Prostate Cancer (mCRPC)

    • Research Summary

      This study is a prospective, observational, molecular stratification profiling study. Patients with mCRPC who have received at least one standard treatment for mCRPC will be approached to participate in MAESTRO. Patients must have archival tumour available and be willing to undergo a fresh tumour biopsy, for molecular analyses. Tumour tissue (archival and fresh), research blood samples and saliva will be sent to the central laboratory for analysis to identify molecular aberrations through targeted or broader molecular analyses (eg exome, transcriptome) and orthogonal assays (eg immunohistochemistry; digital droplet PCR). When the results are available, depending on patients choice, the results will be discussed. If significant results are indicated, patients will be recommended to have follow-up with a cancer geneticist to discuss the implications of these results for their personal and family’s health. There is a safety follow up 30 days after collection of study biopsy or blood samples. Patients will also be followed up for overall survival and subsequent anticancer treatment every 6 monthly via medical notes or telephone calls.

    • Inclusion Criteria:

      1. Male aged > = 18 years. 2. Histologically confirmed metastatic castrate resistant adenocarcinoma of the prostate 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 – 2. 4. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). 5. Confirmed metastatic disease on imaging. 6. Patients with tumour deemed by the designated investigator as safely suitable for fresh biopsy AND who are medically fit (according to local practice) to undergo a biopsy or procedure to acquire tumour tissue AND previously collected tumour specimens from prior surgery or biopsy available for analyses. An mCRPC biopsy collected within 6-months of study entry can be used instead of this fresh biopsy if available and passes laboratory quality control requirements. 7. Willing and able to comply with the requirements of the sample collection including fresh tumour biopsy. 8. The subject is capable of understanding and complying with the protocol requirements and has given written informed consent.

    • Exclusion Criteria:

      1. The presence of any haematological disorders, including coagulation disorders, which would be a contraindication if patient were to undergo a biopsy. 2. Any psychiatric illness/social situations that would limit compliance with study requirements. 3. Presence of any concurrent condition or situation, which, in the investigators opinion, may put the patient at significant risk, may confound the study results or may interfere significantly with the patient’s participation in the study.

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  • ATLANTA - Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms

    • Research Summary

      Men diagnosed with prostate cancer that has spread to other organs are currently treated with drug therapy alone usually androgen deprivation therapy (ADT). ADT suppresses the male hormone, testosterone, which the prostate cells need to grow.Some men also have chemotherapy with ADT Recent evidence shows treating the main cancer in the prostate itself might prolong the time ADT control the cancer and might improve survival.Treatment directed to the metastases has also shown some initial promising data.There are no randomised controlled trials (RCT) that have shown this yet so we need better evidence to see if local treatment to the prostate might be beneficial in combination with treatment to metastases in some men. This is important since local radical therapy(surgery or radiotherapy)can have side-effects.Ablation therapy using heating or freezing has shown to have lower side-effects when used in men whose cancer has not spread so might be a alternative to radical therapy in men with metastatic cancer. Eligible men will be asked to participate in a RCT comparing standard drug therapy to radical therapy (surgery or radiotherapy) or local ablation (heating or freezing) therapy,in combination with metastases directed therapy in select men. 80 men will be approached in 10 UK centre to estimate recruitment rate, acceptability of the trial randomisation, reported toxicities and adherence to trial interventions in a pilot phase. They will also be included into the Main phase where 918 will be recruited. Participants will remain in the study for a maximum of 4 years. Our aims are to see whether men will participate in this trial (pilot) before we continue to run a larger trial (Main), and the impact of these treatments on quality of life. [68Ga]PSMA-11 PET-CT substudy: Embedded within the pilot phase this sub-study assesses the role of [68Ga]PSMA-11 PET in metastatic prostate cancer as this unknown. Blood and urine taken from patients will establish prognostic & predictive factors

    • Inclusion Criteria:

      1. Diagnosed with prostate cancer within 6 months of screening visit 2. Metastatic disease (Tany, Nany, M1+) any grade, stage or Prostate Specific Antigen (PSA) level 3. Fit to undergo standard of care treatment for metastatic disease and both minimally invasive therapy and prostate radiotherapy/prostatectomy. 4. Performance status 0-2 5. Histologically proven local tumour Embedded [68Ga]PSMA-11 PET sub study Patients must meet all the criteria listed in the main protocol and the following criteria for sub-study entry. Signed separate consent for participation in the ATLANTA PET Sub-study is required. Main Inclusion Criteria: 1. Confirmed newly diagnosed metastatic prostate cancer as per PCWG3 guidelines (MPC is defined as extrapelvic disease e.g. retroperitoneal, mediastinal, thoracic), who are due to start ST (physician directed). 2. Age > = 18 years 3. WHO performance status < = 2 4. Clinically acceptable full blood count, renal and liver function (as judged by the investigator)

    • Exclusion Criteria:

      1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest Xray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI. 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 3 months of randomisation. 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above) Embedded [68Ga]PSMA-11 PET sub study: Main Exclusion Criteria 1. Metastatic prostate cancer patients who have had previous surgery and or radiotherapy treatment. 2. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry.

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  • Plasma analysis for response assessment and to direct the management of metastatic prostate cancer

    • Research Summary

      In the UK, prostate cancer is the most common cancer in men and with about 1 in 8 men diagnosed with prostate cancer in their lifetime. Up to a third of prostate cancer deaths occur when cancer spreads to other parts of the body known as metastatic prostate cancer, which is a major healthcare burden. Currently, physicians use a maximum of six cycles of Docetaxel and continue abiraterone until disease progression with long term androgen deprivation therapy (ADT). There is no early test to indicate if treatment is working for patients with metastatic prostate cancer. Currently Prostate Specific Antigen (PSA) is not sensitive enough to guide treatment alone. Studies in colorectal, lung and prostate cancers have started looking at substance called Plasma tumour deoxyribonucleic acid (ptDNA) and correlated presence of ptDNA will early relapse. Therefore, this study will investigate if the detection of ptDNA after initiating treatment is associated a worse clinical outcome. Our ultimate aim, is to identify which of the current treatment options will work best for patients in the future. This research may also identify new targets for the development of new drugs to test in clinical trials in the future. Assessments will include blood taken before and during treatment and at cancer progression. In selected centres, an optional Whole Body Magnetic Resonance Imaging (WBMRI) will be performed before and during treatment for those patients who are eligible. Patients will be followed up for a maximum of 5 years at the time they register onto the study. We expect recruitment duration to be 18 months.

    • Inclusion Criteria:

      1. Able and willing to provide written informed consent 2. Prostate adenocarcinoma confirmed on biopsy obtained in previous 6 months 3. Polymetastatic disease defined as two of the following: i. Gleason score of > = 8, ii. Presence of > = 3 lesions on bone scan, iii. Presence of measurable visceral lesion 4. Eastern Cooperative Oncology Group (ECOG) Performance status 0 to 2 5. No medical contra-indications to abiraterone or docetaxel 6. Patients should be either of the following: A. Planned to start long-term Luteinizing hormone (LH) suppression, or B. within 10 weeks of starting long-term luteinizing hormone releasing hormone (LHRH) antagonist, or C. within 12 weeks of starting LHRH agonist or an anti-androgen when the latter is used in combination with or prior to LHRH agonist for flare protection. 7.Patients should be planned for addition of docetaxel (PARADIGM-D) or abiraterone (PARADIGM-A) 5 to 10 weeks after start of LHRHa (or 7 to 12 weeks if LHRH agonist is started without anti-androgen ) with a target of 6 cycles or continuation until progression respectively. 8.No concomitant medical conditions likely to reduce life expectancy. 9.Patient agrees to be followed up in the recruiting centre and to having sequential plasma samples collected as per the study protocol.

    • Exclusion Criteria:

      1. Medically unsuitable for either abiraterone, prednisolone or docetaxel. 2. Concurrent or planned for (within the first 5 cycles of docetaxel or abiraterone) treatment with any experimental drugs, oestrogen patches radiotherapy or surgery to the primary tumour. Patients randomised to the standard of care (SOC) arm in open-label clinical trials are eligible. Patients who are still to be randomised to STAMPEDE may be included where the randomisation will be limited to SOC or arm K. Patients can participate in other observational studies. 3.Prior systemic therapy for prostate cancer other than for LHRHa +/- anti-androgen (started within the time limits defined in inclusion criterion 6). 4.Metastatic brain disease or leptomeningeal disease. 5.Any surgery planned prior to Cycle 3 Day 1 (C3 D1) 6.Other current malignancy or malignancy diagnosed or relapsed within the past 5 years (other than non-melanomatous skin cancer, stage 0 melanoma in situ and non-muscle invasive bladder cancer) 7.Patients who consent to the whole-body magnetic resonance imaging (WBMRI) translational sub-study should have no contraindications to MRI as per local guidelines.

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  • MITHRIDATE: A phase III, randomised, open-label, Multicenter International Trial comparing ruxolitinib with either HydRoxycarbamIDe or interferon Alpha as first line ThErapy for high risk polycythemia vera

    • Research Summary

      Polycythemia vera (PV) is a rare blood cancer characterised by a high-risk of thrombosis (clotting) and haemorrhage (bleeding). Average survival in high-risk patients receiving contemporary care is 10.9 years. Current treatments include aspirin, venesection (blood drawing) and selected use of standard therapies (hydroxycarbamide (HC) or interferon alpha (IFNa)). The strategies remain less than perfect, with on-going risks of developing blood clots, bleeding, dying early due to either these events or to the disease progressing into leukaemia or a more aggressive form (myelofibrosis). Approximately 9 out of 10 people who have PV have a change in the JAK2 gene. The JAK2 gene makes a protein that controls how many blood cells the stem cells make. Ruxolitinib, the drug being tested in this trial, targets the JAK pathway to stop the JAK2 gene signalling to the stem cells to make blood cells. Ruxolitinib appears to help patients with PV whether they have the JAK2 mutation or not. MITHRIDATE is therefore an important trial as it aims to answer whether ruxolitinib, is better than the Best Available Therapy (BAT) HC or IFNa to improve outcomes for patients with PV. Patients will be randomised between ruxolitinib and BAT. 586 patients with high risk PV who meet the eligibility criteria will be recruited from the UK and France. All patients will be assessed for response throughout and will attend clinic visits seven times in the first year and every 3 months throughout year 2 and 3. Patients on either treatment will continue on the drug until the last patient finishes treatment or until the primary endpoint is reached,or end of study is declared, whichever is sooner. The research is funded mainly by Novartis who will be providing the drug free of charge. There is also some funding from MPN Voice (a charity) and The French National Cancer Institute.

    • Inclusion Criteria:

      1. Patient > = 18 years of age 2. Diagnosis of PV meeting the WHO criteria within the past 10 years 3. Meets criteria of high risk* PV ( High risk PV defined as WBC > 11 x 109/l* AND at least ONE of the following: -Age > 60 years -Prior thrombosis or major haemorrhage related to disease -Platelet count > 1000 x 109/l* -Diagnosed < 10 years -Received treatment for < 5 years) 4. Patients may have received antiplatelet agents and venesection 5. Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy) 6. Able to provide written informed consent.

    • Exclusion Criteria:

      1. Diagnosis of PV > 10 years previously 2. Absence of JAK-2 mutation 3. Patients with any contraindications to any of the investigational medical products 4. Treatment with > 1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy 5. Active infection including hepatitis B, hepatitis C, Tuberculosis 6. Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry) 7. Patients and partners of childbearing potential not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication 8. ECOG Performance Status Score > = 3 9. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (within the last 6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease > NYHA ( New York Heart Association) Class II 10. Patients who have transformed to myelofibrosis 11. Previous treatment with ruxolitinib 12. Previous (within the last 12 months) or current platelet count < 100 x 109/L or neutrophil count < 1 x 109/L not due to therapy 13. Inadequate liver function as defined by ALT/AST > 2.0 x ULN 14. Inadequate renal function as defined by eGFR < 30 mls/min 15. Unable to give informed consent

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  • IRONMAN: International Registry for Men with Advanced Prostate Cancer

    • Research Summary

      IRONMAN is an international registry study of men with advanced prostate cancer. The treatment of advanced prostate cancer has changed significantly over the past 10 years. There are now multiple drug treatments available for men with advanced prostate cancer. The use of these drugs has resulted in improved survival and quality of life for many patients. However a number of questions still remain including the observation that some patients have an excellent and long response to treatment, whilst others do not. We also do not have any biomarkers helping chose the best treatment for an individual patient. The aim of this research study is to learn more about prostate cancer and to describe the use of different therapies for advanced prostate cancer internationally. The study also aims to identify associations between treatment sequences and outcome and investigate biomarkers which could be helpful with deciding which treatment is best for which patient. Finally this study will also investigate the patient experience of men with advanced prostate cancer and identify any unmet needs in their treatment. World wide 5,000 patients will be recruited to IRONMAN, including the UK, US, Canada, Brazil, Australia, and Europe. Patients will be recruited from hospitals treating patients with advanced prostate cancer. This registry study does not involve a new drug or treatment but will focus on collecting real-life information on a patient’s cancer, treatment, symptoms, and quality of life. Hospital visits will be every 3 months and these will coincide with routine visits. Blood samples will be taken for biomarker research and this will take place at study entry, after 1 year and at each point a patient changes prostate cancer treatment. Patients will be followed up for at least 3 years.

    • Inclusion Criteria:

      To be included in the IRONMAN Registry, subjects should meet the following criteria at the time of registration: 1. Willing and able to provide written informed consent and privacy authorisation for the release of personal health information 2. Males 21 years of age and above 3. Histological or cytological confirmed prostate cancer from prostate biopsy, radical prostatectomy or Transurethral Resection of the Prostate (TURP) Or Documented histopathology or cytopathology of prostate cancer from a biopsy of a metastatic site Or Metastatic disease typical of prostate cancer (i.e. involving bone or pelvic/extra pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA > 20ng/mL 4. Metastatic hormone sensitive prostate cancer (mHSPC): a) No more than 1 year of continuous androgen deprivation therapy (ADT) exposure prior to consent, with documented recovery of testosterone as determined by investigator. b) No more than 90 days of active systemic therapy at the time of consent c) Metastatic disease M1a, b, or c stage as defined by the American Joint Committee on Cancer Or Castration resistant prostate cancer (CRPC) a) A rising PSA indicating progressing disease or new metastatic disease as determined by the investigator I. While on ADT (or orchidectomy) or II. With castrate level of testosterone as determined by investigator b) No more than 6 weeks of continuous systemic therapy for CRPC at the time of consent I. NOTE: Prior systemic therapy for any length of time for mHSPC is allowed for patients currently with CRPC 5. No active systemic treatment for a diagnosis of a second, non-prostate malignancy 6. For both mHSPC and CRPC, prior treatment with bisphosphonate or denosumab will be permitted.

    • Exclusion Criteria:

      1. Previous diagnosis of a second, non-prostate malignancy that requires additional systemic therapy. 2. Men with mHSPC who have received active systemic therapy for longer than 90 days prior to consent. 3. Men with CRPC who have received continuous systemic therapy for CRPC for longer than 6 weeks prior to consent.

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  • Identification of genetic factors that predispose to immune checkpoint inhibitor toxicity

    • Research Summary

      THIS STUDY WILL RECRUIT PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS FOR ALL FORMS OF CANCER Immune Checkpoint Inhibitor Genetics Summary Title: Toxicites caused by immune checkpoint inhibitors used to treat cancers: are there differences in the genetic make-up of those patients who suffer side effects and those who do not? All anti-cancer therapies cause toxicity and some individuals appear especially susceptible to the side-effects of particular treatments. This might be because of genes that we inherit. We can find out whether those genes exist by studying the clinical features and blood samples of a large set of cancer patients who have been treated with immune system boosters and looking for differences between those who develop severe toxicity, those who have mild toxicity and those who have no toxicity. We can also look at people with different types of toxicity, for example affecting different parts of the body. We will also study the clinical features and bloods samples of a group of participants who have autoimmune diseases but have not been treated with immune system boosters to assess whether there are any similarities in their inherited genes. If we find genes that affect the chances of toxic side-effects, we may be able to find out who is at greatest risk before they take the drugs and develop ways of preventing or minimising the side-effects. Clinical details will be collected from the participant and clinical team in the form of a questionnaire, blood sampling will occur on a single occasion, either within routine clinical management or at the participants convenience.

    • Inclusion Criteria:

      Patients that have been treated with Immune Checkpoint Inhibitors for any malignancy. Able and willing to provide informed consent and a sample of blood (or saliva). Aged 16 or over. Family members of participants with autoimmune disease.

    • Exclusion Criteria:

      Unable or unwilling to provide informed consent and a sample of blood (or saliva) Aged less than 16 years old

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  • TACE-3: A two-arm multi-stage (TAMS) seamless phase II/III randomised trial of nivolumab in combination with TACE/TAE for patients with intermediate stage HCC

    • Research Summary

      This study is looking to see if adding the drug nivolumab to the current standard treatment will be better for treating patients with liver cancer. The current treatment TACE (Transcatheter Arterial Chemoembolisation) with drug eluting beads puts a large dose of chemotherapy drugs directly into the tumour. Putting the drug directly into the tumour gives less side effects and less damage to other tissues nearby. Current evidence suggests that adding an immunotherapy drug like Nivolumab at the same time as TACE may help increase the time taken until the tumour begins to grow/spread. The study is looking at patients who have liver cancer (Hepatocellular carcinoma (HCC)) which is classified as intermediate. Patients will need to undergo some tests and a biopsy of their Liver to confirm it is safe and they are suitable to be included in the trial. The study will be conducted across NHS hospitals in the UK and in hospitals in France. In this study we will treat half the patients with TACE on its own and the other half with TACE and the new drug nivolumab. Patients will have regular scans to look at their cancer and will be treated until the cancer has grown. Nivolumab will be given once before a patient’s first TACE therapy and then every 4 weeks alongside any further TACE therapy given. Patients will be on study treatment for a maximum of 2 years. We will look at how long it takes for patient’s cancer to grow, how long patients survive, the side effects patients suffer and also Quality of Life. The study is split into two parts. If the first part (phase II) of the study shows that the drug maybe working to control patient’s cancers, we will expand the study to recruit more patients in part two (phase III).

    • Inclusion Criteria:

      1. Histological diagnosis* of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI. 2. Not a candidate for surgical resection or liver transplantation** 3. Aged > = 16 years and estimated life expectancy > 3 months 4. ECOG performance status 0-1 5. Adequate haematological function: • Hb > = 9g/L • Absolute neutrophil count > = 1.0x109/L • Platelet count > = 60x109/L 6. Bilirubin < = 50 μmol/L, AST,ALT and ALP < = 5 x ULN 7. Adequate renal function; Creatinine < = 1.5ULN (Using Cockcroft-Gault Formula) 8. INR < = 1.7 9. Child-Pugh A (score < = 6) (Appendix D) 10. HAP score A, B or C (Appendix E) 11. No contra-indications to T-cell checkpoint inhibitor therapy (use of immunosuppressive drugs including steroids at dose equivalent to prednisolone > 10mg/day unless used as replacement therapy; organ transplantation; 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, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol). 12. Women of child-bearing potential should have a negative pregnancy test prior to study entry. Both men and women must be using an adequate contraception method, which must be continued for 5 months after completion of treatment for women and 7 months for men 13. Written informed consent *All patients are required to under a MANDATORY biopsy prior to entry onto the study. **Criteria which establish ‘intermediate’ HCC

    • Exclusion Criteria:

      1. Extrahepatic metastasis* 2. Prior embolisation, systemic or radiation therapy for HCC* 3. Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis 4. Investigational therapy or major surgery within 4 weeks of trial entry 5. History of variceal bleeding within the past 4 weeks 6. Child-Pugh cirrhosis B or C (score > = 7) 7. HAP score D 8. Hepatic encephalopathy 9. Ascites refractory to diuretic therapy 10. Documented occlusion of the hepatic artery or main portal vein5 11. Hypersensitivity to intravenous contrast agents 12. Active clinically serious infection > Grade 2 NCI-CTC 13. Pregnant or lactating women 14. Known history of HIV infection 15. HBV chronic infection with HBV DNA > 500IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated. 16. History of serious autoimmune disease. 17. History of second malignancy except those treated with curative intent more than three years previously without relapse and non-melanotic skin cancer or cervical carcinoma in situ 18. Evidence of severe or uncontrolled systemic disease, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial 19. Psychiatric or other disorder likely to impact on informed consent 20. Patient is unable and/or unwilling to comply with treatment and study instructions *Criteria which establish ‘intermediate’ HCC

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  • Stratified Medicine Paediatrics: Genomic Characterisation of Relapsed Paediatric Cancers for Diagnostics and Stratified Therapy

    • Research Summary

      Stratified Medicine Paediatrics (SMPaeds) is a UK research study testing tumour (somatic) and normal (germline) DNA and RNA for genetic and gene-expression changes in children, teenagers and young adults with relapsed/refractory cancer. The results of the tests performed will identify patients who may be eligible for new targeted anti-cancer therapies and will aid research that will help us to more precisely diagnose cancer and understand why some patients do not respond to standard treatments. All children, teenagers and young adults with solid paediatric tumours (including brain tumours and lymphoma) whose disease has come back (relapsed) or not responded to treatment (refractory) will be eligible to take part. In addition, the patient must have had a recent biopsy/operation to obtain tumour tissue on which molecular tests can be performed. The results of the testing will be relayed back to the patient’s doctor via an expert group of doctors who will make recommendations on any available treatments. Patients and/or their parents will be asked in advance to consider what information they which to receive in relation to any abnormal genetic results either in the tumour or their normal (germline) genetic code. In addition, the data collected will be used and shared for the purposes of clinical research.

    • Inclusion Criteria:

      Inclusion • Patients with a relapsed or refractory paediatric tumour (all solid tumours, central nervous system (CNS) tumours and Lymphoma) • Formalin fixed paraffin embedded (FFPE) tumour available from a biopsy, resection or other surgical procedure that was taken within 8 weeks of trial entry* • Written informed consent of patient/parent/guardian/legal guardian** * To allow full multi-omic analysis both fresh frozen and Formalin fixed paraffin embedded (FFPE) tumour plus a blood sample for constitutional (germline) and circulating tumour (ct) DNA will need to be available. Original diagnostic slides should be submitted at the same time as block from current relapse/refractory episode either in same shipment or via PathXL (see laboratory manual for further details). ** Some adult patients with brain tumours or brain metastases may be incapable of providing their own consent due to the neurological effects of their disease. In such cases, these patients will be classed as an incapacitated adult and a consultee will be sought.

    • Exclusion Criteria:

      None

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  • PERSEUS1: Phase II Trial of the Immune Checkpoint Inhibitor Pembrolizumab For Patients Suffering from Metastatic Prostate Cancer.

    • Research Summary

      With an increased understanding of the genes involved in metastatic castrate resistant prostate cancer (mCRPC), and with the majority of patients potentially having some faulty genes, also known as mustations, there is a need to run a study to identify patients with specific faulty genes and test new agents that are targeted towards treating cancers with these faulty genes. Pembrolizumab is a useful anticancer treatment in advanced melanoma, metastatic non-small cell lung cancer and metastatic urothelial cancer. Scientists believe that there is a group of prostate cancer patients who may also benefit from this targeted treatment. The study will recruit up to 100 patients with mCRPC that is no longer responding to standard treatment and who have been identified as having specific faulty genes that are anticipated to respond to pembrolizumab treatment. These faulty genes will have been identified through a screening study for patients with prostate cancer that identifies faulty genes from a blood, tumour tissue and saliva samples. The main aim of the study is to assess whether pembrolizumab is effective in treating mCRPC patients with these faulty genes.

    • Inclusion Criteria:

      1. Male, aged 18 years or older. 2. Histologically confirmed adenocarcinoma of the prostate. If the patient does not have a prior histological diagnosis then the planned baseline fresh biopsy may be used for both the purpose of confirming the histological diagnosis prior to trial entry and for subsequent biomarker analysis. All patients must be willing to have fresh biopsies to obtain tumour tissue for biomarker analysis. 3. mCRPC with one of the following: - MMR defective disease by immunohistochemistry; - Tumours with evidence of bi-allelic CDK12 loss; - Tumours with high MSI-NGS with either: o deleterious MMR gene mutation OR; o high CD3 (≥70th centile) OR; o HIMUT (≥11); - Tumours with HIMUT with either high CD3 or a deleterious mutation in a DNA repair gene; - The presence of DNA repair defects (HR, NHEJ, NER) with high CD3 count; 4. Patients with: - Measurable soft tissue disease as per iRECIST criteria (with or without bone disease), OR - Non measurable soft tissue disease as per iRECIST criteria (with or without bone disease), and a CTC count ≥5 cells/7.5 ml and PSA value ≥ 2 μg/L (2 ng/ml) 5. Documented prostate cancer progression as assessed by the investigator with one of the following: - PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1-week between each determination. Patients on systemic glucocorticoids for control of symptoms must have documented PSA progression by PCWG3 while on the same dose of systemic glucocorticoids prior to commencing Cycle1 Day1 of treatment. - Radiological progression of soft tissue disease by iRECIST criteria or of bone metastases by PCWG3 criteria with two or more confirmed new bone lesions on a bone scan/WBMRI with or without PSA progression. 6. Willing and able to comply with the follow-up schedule and the requirements of the biomarker studies including the paired fresh tumour biopsies. 7. Written informed consent. 8. Prior treatment with at least one of the approved treatments for mCRPC (i.e. Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel, Radium 223). 9. At least 28-days washout at trial entry since the completion of prior therapy, including major surgery, chemotherapy and other investigational agents.. For hormonal treatment and radiotherapy refer to the guidelines below: • At least 28-days since the completion of prior flutamide treatment. Patients whose PSA did not decline in response to antiandrogens given as a second line or later intervention will only require a 14-day washout prior to Cycle 1, Day 1. • At least 42-days since the completion of prior bicalutamide (Casodex) and nilutamide (Nilandron) treatment. Patients whose PSA did not decline for at least 3-months in response to antiandrogens given as second line or later intervention will require only a 14-day washout period prior to Cycle 1 Day 1. • At least 14-days from any radiotherapy with the exception of a single fraction of radiotherapy for the purposes of palliation (confined to one field) is permitted. 10. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study. 11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. 12. Albumin > = 25 g/L. 13. Patient and the patient’s partner of reproductive potential who are sexually active, must agree to use adequate methods of contraception during the course of the study and for 120 days after the last dose of study drug (see protocol appendix 3 for accepted methods of contraception). 14. QT interval corrected for heart rate according to Fridericia’s formula (QTcF) < 470 msec or < 480 msec with bundle branch block. 15. Patients with primary hypothyroidism can be considered eligible if thyroid stimulating hormone (TSH) at the screening visit is within normal range while patient is under hormonal treatment. 16. Subjects must have adequate bone marrow, hepatic and renal function documented within 7-days of trial entry defined as: - Hb >= 9.0g/dL, - ANC >= 1.5x10^9/L - Platelet count >= 100x10^9/L - INR or Prothrombin time <= 1.5xULN - Serum bilirubin or Direct bilirubin (for patients with total bilirubin > 1.5x ULN) <= 1.5x ULN - ALT and AST <= 2.5x ULN (for patients with liver metastases <= 5x ULN is permissible) - Serum creatinine <= 1.5 x ULN or Calculated creatinine clearance > 40mL/min for patients with creatinine levels above institutional normal. For GFR estimation, the Cockcroft and Gault equation should be used.

    • Exclusion Criteria:

      1. Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies. 2. Patients who have received any of the following concomitant therapies: IL-2, interferon or other non-study immunotherapy regimens; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses) within 1 week prior to first dose. A dose of 10mg of prednisolone or equivalent will be allowed if clinically indicated. 3. Patients who have received any non-oncology vaccine therapy used for prevention of infectious diseases including seasonal vaccinations for up to 28-days prior to the expected start or after any dose of pembrolizumab. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine. - Administration of killed vaccines is permitted, examples include: • Pfizer-BioNTech (BNT162b2) • Moderna (mRNA-1273) • AstraZeneca (AZD-1222) • Gameleya Research Institute (Sputnik V) • Sinovac (CoronaVac) • Sinopharm (BBIBP-CorV) As other COVID-19 vaccines become approved, they can be utilised with the exception of live/live attenuated replicating vaccines 4. Patients receiving growth factors including, but not limited to, G-CSF, GM-CSF, erythropoietin, within 14-days of study drug administration. Use of such agents while on study is also prohibited. Prior use of growth factors should be documented in the patient’s medical history. 5. Uncontrolled intercurrent cardiovascular disease as symptomatic congestive heart failure (NYHA Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension (defined as systolic blood pressure of >= 150mmHg or diastolic blood pressure of > 100 mmHg based on a mean of three measurements at approximately 2-minute intervals). 6. Any psychiatric illness/social situations that would limit compliance with study requirements. 7. Any acute toxicity due to prior chemotherapy and / or radiotherapy that has not resolved to a NCI-CTCAE v4.0 grade <= 1 with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy. 8. Prior malignancy diagnosed within the previous 2-years with a > 30% probability of recurrence within 12-months, with the exception of non-melanoma skin cancer, and in-situ or non-muscle invasive bladder cancer and germline MMR defect associated cancers that have been completely resected. 9. Patients with myelodysplastic syndrome or acute myeloid leukaemia. 10. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 11. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable and asymptomatic. 12. Any immunological disorder requiring treatment with immunosuppressive treatments: - High dose of steroids (low dose of steroids as 10mg of prednisolone or equivalent are allowed if the patient is not able to discontinue this treatment; patient needs to be on a stable dose for at least 4-weeks before the enrolment); - Cytotoxic agents (such as alkylating agents or antimetabolites); - Antibodies (polyclonal antibodies; monoclonal antibodies different from pembrolizumab); - Drugs acting on immunophilins (cyclosporin, tacrolimus, sirolimus); - Other drugs (interferons, TNF binding proteins, mycophenolate). 13. History of any autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis). Patients with controlled Graves’ disease will be allowed. 14. Known history of HIV 15. Known active Hepatitis B or C 16. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect). 17. Patients with history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease. 18. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible and may continue. 19. Presence of a condition or situation, which, in the investigator’s opinion, may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study.

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  • NOSTRA-Feasibility Study: A prospective non-randomised multi-centre feasibility study to assess if patients with residual cancer following dual-targeted neoadjuvant chemotherapy treatment for HER2-positive, ER-negative early breast cancer can be identified by multiple ultrasound-guided tumour bed core biopsies

    • Research Summary

      Approximately 15% of early breast cancer patients in the UK have HER2-positive tumours. Within the neoadjuvant population HER2-positive cases split roughly 50:50 between ER-positive and ER-negative disease; thus an estimated 6-7.5% of all operable breast cancer patients have tumours with the HER2-positive, ER-negative phenotype. In the UK, this is approximately 3500 patients per year. At least half of these patients would be candidates for a dual-targeted therapy (a combination of neoadjuvant chemotherapy plus two anti-HER2 therapies), which results in consistently high pathalogical Complete Response (pCR) rates in the region of 70-80%, which are linked to good outcome. Patients with operable early stage breast cancer treated with neoadjuvant treatment always undergo surgery, regardless of their response to treatment. These patients are thus an appropriate group in which to initially explore omitting surgery. The NOSTRA-Feasibility study is designed as a prerequisite to the conduct of a randomised phase III study which will determine if it is safe to omit surgery after the planned neoadjuvant chemotherapy plus dual-targeted anti-HER2 treatment. The study is needed to determine whether patients with residual cancer can be identified by histological examination of multiple ultrasound-guided tumour bed core biopsies following dual-targeted neoadjuvant treatment for HER2-positive, ER-negative early primary breast cancer and whether there is concordance between local pathology reporting and central pathology reporting by the trial’s expert pathologists. 150 patients with early breast cancer will enter the study from hospitals around the UK to one of the three National Institute of Clinical Excellence (NICE) approved treatment regimens involving neoadjuvant chemotherapy plus dual-targeted anti-HER2 treatment. The study encompasses an important translational research component, which involves the collection of diagnostic biopsies, tumour bed core biopsies and surgical excision specimens (including axilla biopsy specimen and SLNB specimen). Also incorporated into the study is collection of blood samples for the optional ctDNA substudy.

    • Inclusion Criteria:

      1) Patient with histological diagnosis of operable HER2-positive, ER-negative, early stage invasive breast cancer 2) Tumour size > = 1cm and visible on US (T1c to T4d) 3) Patient fit and willing to receive one of the three planned NICE approved treatment regimens in the opinion of the responsible clinician 4) Eastern Co-operative Group (ECOG) performance status of 0 or 1 5) Women of child-bearing potential, prepared to adopt highly effective contraceptive measures if sexually active for at least 6 months after completion of study medication 6) Female, aged > = 18 years 7) Able to provide written informed consent for the study 8) Availability of embedded paraffin tumour blocks from pre-chemotherapy biopsy

    • Exclusion Criteria:

      1) Previous invasive breast cancer 2) Unequivocal evidence of distant metastatic disease at registration 3) Active malignancy of non-breast origin 4) Previous chemotherapy 5) Prior extensive radiotherapy (as judged by the Investigator) to bone marrow 6) Risk factors precluding the safe administration of the intended cytotoxic chemotherapy regimen 7) Patient unsuitable for the planned dual-targeted anti-HER2 treatment in opinion of the Investigator 8) Prior diagnosis of cardiac failure 9) Uncontrolled hypertension, coronary heart disease or other significant cardiac abnormality 10) Bleeding diathesis 11) Any evidence of other disease which in the opinion of the Investigator places the patient at high risk of treatment related complications 12) Pregnant (female patients of child bearing potential must have a urine or blood Human Chorionic Gonadotropin test performed to rule out pregnancy prior to study entry) 13) Patient lactating 14) Patients who have received live vaccine within 4 weeks of the date of study entry 15) Any concomitant medical or psychiatric problems which in the opinion of the Investigator would prevent completion of treatment or follow-up 16) Patient unfit and/or unwilling to undergo surgery 17) Patient unwilling or unable to comply with scheduled visits, treatment plan and study procedures

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  • STELLAR: A phase II, randomiSed study of CHOP-R in combination with acalabruTinib comparEd to CHOP-R in patients with newLy diagnosed Richter’s Syndrome (RS) and a pLAtfoRm for initial investigations into activity of novel treatments in relapsed/refractory and newly diagnosed RS.

    • Research Summary

      The STELLAR trial will assess the effect of acalabrutinib taken in combination with CHOP-R compared to taking CHOP-R alone in patients with newly diagnosed Richter’s Syndrome (RS). It will also be a platform to test other new drugs that show potential for treating RS. Chronic lymphocytic Leukaemia (CLL) is the most common blood cancer in adults, usually in their 70s or older. In a few patients, CLL can transform from a slow-growing cancer into an aggressive lymphoma called Richter’s Syndrome. RS is very difficult to treat and patients have a short life-expectancy - usually a few months after diagnosis. Treatment for Richter’s Syndrome in the UK is CHOP (four chemotherapy drugs) plus rituximab (‘R’ - an antibody treatment). The CHOP-R treatment is given as a standard of care for RS but has limited benefit - it is often temporary to extend life. Richter’s Syndrome returns in most patients who then die from this disease. The STELLAR trial will investigate if a new drug called acalabrutinib, which is effective used by itself in patients with relapsed CLL and also some with Richter’s Syndrome, will improve outcomes for newly diagnosed patients with RS. Acalabrutinib blocks a protein in CLL which can stop the cancer growing. Participants who have Richter’s Syndrome and are suitable for CHOP-R will be recruited by specialised hospitals across the UK. People with another cancer, heart problems, or recent stroke cannot take part. Participants will have a lymph node biopsy, 3-4 bone marrow biopsies, blood samples, and PET-CT and CT scans. CHOP-R is given in a hospital every three weeks up to 6 times. All participants will receive CHOP-R; half will also receive acalabrutinib. When treatment with CHOP-R ends the patients who had acalabrutinib can continue to take it; patients who had CHOP-R alone may have acalabrutinib if their Richter’s Syndrome returns after CHOP-R.

    • Inclusion Criteria:

      Inclusion criteria for the Randomised Trial -Suitable for anthracycline-containing chemo-immunotherapy. -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures Inclusion criteria Cohort 1 (progressive RS following chemo-immunotherapy) -Patients with relapsed/refractory RS who received anthracycline based chemotherapy with anti-CD20 monoclonal antibody. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures Inclusion criteria Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib) -Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within four weeks of last dose of ibrutinib. -No previous anthracycline treatment and suitable for anthracycline-containing chemo-immunotherapy. -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures

    • Exclusion Criteria:

      Exclusion criteria ALL -Known central nervous system (CNS) involvement of CLL or DLBCL. -Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin. -Chronic or ongoing active infectious disease -Positive serology for Hepatitis B (HBKnown human immunodeficiency virus (HIV) positive. -Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease). -Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenoprocoumon). -Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) > 2 x the upper limit of normal (ULN). -Major surgery within 30 days prior to randomisation and/or inadequate recovery from any prior major surgery, toxicity or complications. -Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function. -Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. -Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. -History of significant cerebrovascular disease in the 6 months prior to randomisation, including intracranial haemorrhage. -Known or suspected hypersensitivity to components of the investigational products -Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment -Current participation in any other interventional clinical study. -Patients known or suspected of not being able to comply with a study -Breast feeding women or women with a positive pregnancy test at screening. -Women of childbearing potential and men not willing to use adequate contraception during study and for 3 months after last dose of study therapy Additional exclusion criteria for the Randomised Trial -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation. -Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop RS are not excluded from the randomised trial component). -Previous acalabrutinib exposure. Additional exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy) -Previous acalabrutinib exposure. Additional exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib) -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation. -Previous acalabrutinib exposure.

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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

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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.

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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.

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  • A Prospective Evaluation of the Management of Sporadic Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤ 2 cm

    • Research Summary

      The study is designed as a prospective international (including also non-European institutions) multicentre cohort study, which will be coordinated by the Pancreatic Surgery Unit of San Raffaele Scientific Institute (Lead Study Centre) under the auspices of the European Neuroendocrine Tumor Society (ENETS) . The study duration is 6 years, patients will be recruited for 5 years from December 2016 to December 2021, with a follow up of 1 year at least (end of the study: December 2022) . After 2 years of recruitment an interim analysis will be performed in December 2018. San Raffaele Scientific Institute will be the lead centre from where the international study will be managed and coordinated. Participating study centres will identify, recruit patients and will send pseudoanonimised data of patients to the lead centre, which is responsible for statistical analysis, storing and controlling data. The research database will be managed and analysed by the Lead Study centre research team. Study participation is voluntary, there will be no reimbursement for patients.

    • Inclusion Criteria:

      -Age > 18 years -Individuals with asymptomatic sporadic NF-PNEN < = 2 cm -Diagnosis has to be proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging technique (CT or MR) that is positive at 68Gallium DOTATOC-PET scan or Octreoscan. -Patients who undergo surgery for NF-PNEN< 2cm within 12 months. In these cases, diagnosis has to be proven by histological confirmation of NF-PNEN -Able to consent.

    • Exclusion Criteria:

      Exclusion Criteria -NF-PNEN > 2 cm of maximum diameter -Presence of genetic syndrome (MEN1, VHL, NF) -Presence of symptoms (specific symptoms suspicious of a clinical syndrome related to hypersecretion of bioactive compounds) or unspecific symptoms

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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

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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

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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.

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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.

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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

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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.

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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 (> 5 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

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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

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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.

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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.

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  • A randomised placebo-controlled phase III trial of the effect of the omega-3 fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases

    • Research Summary

      A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to their liver (metastases) develop disease recurrence and die from their disease. A previous small study (the EMT study) suggested a possible survival benefit in patients who took naturally-occurring ‘omega-3’ EPA (a fish oil supplement) before their liver surgery. The EMT2 study is a larger study which will recruit 448 men and women with liver metastases from bowel cancer. Trial participants will receive either EPA-triglyceride (purified from fish oil) or placebo (dummy capsules). EMT2 will investigate whether patients who take this supplement before liver surgery and for up to four years after surgery, remain free of recurrence for longer than those who take placebo. Participants will receive five capsules per day of either EPA or placebo and the allocation will be generated at random by a computer. This is a double blinded trial which means that neither the participant nor the clinician will know which treatment the participant is receiving during the trial. Trial treatment will start at least two weeks prior to liver surgery and will continue for at least two, and up to four years, after surgery. The trial will be open for at least two years after the last participant enters the trial so the length of treatment will depend on when the participant joins the trial. The trial visit schedule closely mirrors the standard follow-up visits which are part of standard care. Participants are seen at least two weeks before liver surgery, at liver surgery and then at six-monthly intervals thereafter for a minimum of two years and a maximum of four years. Depending on when the participant last attended clinic at the time the trial closes, a trial-specific appointment at the end of the trial may be required.

    • Inclusion Criteria:

      • Aged ≥18 years • Able to provide written informed consent • Histological diagnosis of colorectal cancer with evidence of liver metastases • Planned liver resection surgery for colorectal cancer liver metastasis with curative intent, including repeat ‘re-do’ colorectal cancer liver metastasis liver surgery (a second independent resection for a separate colorectal cancer liver recurrence) • Intention to receive IMP treatment prior to colorectal cancer liver metastasis surgery

    • Exclusion Criteria:

      •Previous CRCLM surgery for the management of the current metastatic disease •Incurable extra-hepatic metastases • Current (in the last 2 months) or planned regular (> 3 doses per week) use of O3FA-containing supplements, including fish oil and cod-liver oil supplements • Fish/seafood allergy • Inability to comply with trial treatment and follow-up schedule • Known bleeding tendency/condition (e.g. von Willebrand disease) • A previous malignancy within the last 5 years other than: - colorectal cancer - 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 • A previous malignancy where the patient has been disease-free for ≤5 years • Pregnant or breastfeeding women or women of childbearing potential not willing to use effective contraceptive measures. Women of childbearing potential are defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. • Men defined as fertile (post-pubescent and not permanently sterile by bilateral orchidectomy) and not willing to use effective contraceptive measures if appropriate.

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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

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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

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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

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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

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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

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  • The Identification and characterisation of Inherited Predispositions to Colorectal Tumours (CORGI) 2

    • Research Summary

      Colorectal cancer (CRC) remains an important cause of morbidity and mortality. Identifying those at higher risk is important in targeting preventive measures, such as screening colonoscopy, to those most likely to benefit. Much of the risk of CRC and its precursor lesions (mostly polyps) is genetic, but a great deal of the heritability of CRC remains unexplained. Some of the remaining genetic risk probably results from rare genes with large effects, some from uncommon genetic variants with moderate effects and some from common differences with modest or very modest effects. The sub-division between these categories is extremely difficult to predict in advance of successful searches for these genes. The principal aim of this study is to identify additional susceptibility genes for CRC and cancers genetically related to CRC, such as endometrial cancer. This will involve studying CRC patients, their families, patients with other cancer types and controls. Secondary aims include determining the extent of that genetic risk, building risk models that incorporate multiple risk factors, and performing functional studies to work out how CRCs develop and how inherited risk factors act. Blood samples, tumour samples, non-cancer material and medical information from study participants is required to perform molecular and statistical analyses. Dysregulation of DNA repair pathways is known to be involved in the development of colorectal cancer and other cancers. Analysis of additional non-bowel samples from participants with and without germline mutations will aid in understanding why particular germline mutations lead to the development of tumours specifically in the bowel. Characterisation of inherited predispositions is further aided by analysis in the context of other cancers and conditions, which will be assessed by inclusion of other cancers and healthy controls, and by means of questionnaires focusing on cancer history, fertility and birth defects.

    • Inclusion Criteria:

      • Index patient o > 6 years, male or female; o with a colorectal tumour (malignant or benign) or with a cancer or disease strongly related to colorectal tumours (e.g. endometrial cancer). o Individual and/or parent/guardian willing and able to give informed consent for participation in the study. In practice, recruitment centres may be asked to focus on patients who are more likely to have a genetic basis to their disease (e.g. early onset, multiple tumours, syndromic features). • Blood relative of the index patient o Age > 18 years, male or female; o Willing and able to give informed consent for participation in the study. • Control o Non-blood relative or other individual who has never had a colorectal tumour/ cancer or cancer in any other site; o No first degree relatives with bowel cancer; o Age > 18 years, male or female; o Willing and able to give informed consent for participation in the study.

    • Exclusion Criteria:

      An individual may not enter the study if ANY of the following apply: • For adults/parents: unwilling to provide informed consent • For children: expressing dissent An individual may not supply additional research-only skin sample if they • Have a history of bleeding disorders • Are taking any medications that would preclude safe skin biopsy

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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)

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  • Clinical and Biological factors associated with relapse and length of survival following relapse in UK neuroblastomas

    • Research Summary

      Neuroblastoma is an embryonal childhood tumour derived from cells which go on to form the sympathetic nervous system. It most often develops in the adrenal medulla but can occur anywhere from the neck to the pelvis. It is one of the most difficult childhood cancers to cure with around 40% five-year survival in high risk cases (50% of all cases). Despite advances in neuroblastoma therapy relapse still occurs in 50% of high risk cases and in most high risk cases cure is no longer possible. Knowledge of factors which influence subsequent response and length of survival following relapse in neuroblastoma are important to determine which, if any, treatment at relapse is appropriate in individual cases, and may significantly affect the results obtained when evaluating new therapies for neuroblastoma in Phase I and II clinical trials. Recent studies report an increased frequency of recurrent, genetic abnormalities at relapse including segmental chromosomal abnormalities (SCA) and gene mutations for which a targeted treatment exists. The present study is a retrospective epidemiological and genetic study which aims to determine clinical and genetic factors associated with neuroblastoma relapse and length of survival following relapse. This will be done by linking epidemiological data, clinical and existing genetic data analysed by multiplex ligation PCR dependent amplification (MLPA) or array comparative genomic hybridisation on recurrent chromosomal losses and gains and treatment information. We will also compare existing genetic profiles on patients on the current high risk neuroblastoma trial who have relapsed with those who haven’t to determine whether particular types and number of segmental chromosomal abnormalities are associated with an increased risk of relapse. The study will also investigate whether the median survival time following relapse is associated with the time interval from diagnosis to relapse. The outcomes from this study will be used to inform future Phase I, II and III clinical trials for children with neuroblastoma.

    • Inclusion Criteria:

      All cases of relapsed/refractory neuroblastoma in the UK and Ireland diagnosed in children and young people aged 0-40 years from the year 2000 onwards. For the second aim of work package I of the study we will include all cases of high risk neuroblasoma who are registered on the high risk trial and who have had genetic studies in addition to MYCN undertaken at diagnosis. Based on numbers of patients registered on the current high risk neuroblastoma trial to date from the UK (around 500) and the numbers on which genetic analyses have been performed (around 250) it will be possible to identify at least 100 relapsed and non-relapsed patients (based on 50% relapse rate). Work package II - cases of neuroblastoma where the tumour cell content is > 30% (30 cases) from diagnosis and relapse (partly from a previous study from our group) and the remainder from the neuroblastoma genetic reference centre work undertaken in Dr Nick Bown's laboratory).

    • Exclusion Criteria:

      N/A

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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.

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  • A longitudinal observational study with phenotypic, functional and molecular analyses in real-world patients with mature lymphoid malignancies in the UK

    • 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

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  • The SCOTTY Study - whole genome sequencing study of young colon cancer patients and their parents

    • Research Summary

      Cancer of the large bowel (colorectal cancer) is common in the general population and the lifetime risk for someone living in the UK is 1 in 17. Whilst modern surgery, radiotherapy and chemotherapy treatments have impacted beneficially on survival outcome, many patients still die from their disease. Hence, there is a pressing need to understand the causes of colorectal cancer and to intervene early. Colorectal cancer under the age of 40 years of age is particularly rare, with less than 1.2% of all cases aged < 40 years. We have published extensively that patients within this age group are highly enriched for underlying major genetic effects. A number of genes have been identified over the past 20 years, but much of the genetic aetiology remains to be discovered. We now plan a major initiative to conduct “next-generation” sequencing of the whole genome of young patients and both parents where there is no evidence of cancer “running in the family”. Our aim in this study is to look at samples (blood and tissue removed from tumours) from individuals who have developed bowel cancer at a young age and also blood samples from each of their parents. These samples will be analysed using a technique called “Next-Generation Sequencing” (NGS). NGS is a scientific technique that gives us a “read-out” of all the genetic information that is stored in our DNA within each of our cells within the body. It is this information that makes every person unique. We aim to identify changes in patients DNA (mutations) that may not be present in parents. We aim to collect this information to help us identify mutations that are causing bowel cancer. This will in the long term help us to develop new treatments and predict who will be susceptible to cancer and so be able to prevent disease progression.

    • Inclusion Criteria:

      PATIENT INCLUSION CRITERIA •Patients who have developed colorectal cancer at aged 40 years of age or younger at the time of diagnosis. (Individuals OVER the age of 40 years ARE eligible if they were previously diagnosed with colorectal cancer when aged 40 years or younger). •Patients will not have a known molecular genetic predisposition to the development of colorectal cancer or a strong family history of cancer consistent with known dominant disorders. •Patients are able to provide written informed consent for whole genome sequencing and blood/saliva biomarkers. •Documentary evidence of a pathologically confirmed adenocarcinoma of colon or rectum along with consent to access archived tumour material from the time of operation. •Demographic and drug history are available or can be ascertained from patient. •If the patient is under the age of 16 years, both parents are available to sign/countersign a consent form. Whilst cases under the age of 16 years are extremely rare, these cases greatly enhance the value of their contribution to the study. •Inclusion can be from any part of mainland GB and Northern Ireland and of any ancestry. •Patients will be asked if they agree to being re-contacted if further confirmatory samples are required and/or results are of clinically significant relevance. PARENTS INLCUSION CRITERIA •Neither parent will have had a past or present diagnosis of colorectal cancer or other cancer relevant to CRC predisposition such as endometrial cancer. •Both parents will be alive and are contactable within the United Kingdom and Northern Ireland. •Both parents will not have a known genetic predisposition to the development of colon cancer. •Both parents will be able to provide written informed consent for sampling. •Both parents will provide a simple blood sample for whole genome sequencing & blood or saliva biomarkers. •Demographic and drug history are available or can be ascertained from parents. •Both parents will be asked to agree to being re-contacted if further confirmatory samples are required and/or results have clinical implications.

    • Exclusion Criteria:

      Exclusion criteria – PATIENTS - BOTH parents unable to provide samples. - The inability to provide informed consent. - Patients who have developed CRC aged over 40 years at diagnosis. - Tumour that has shown loss of DNA mismatch repair gene protein expression or tumour that has exhibited MSI (micro satellite instability). - Familial CRC (a strong family history) Exclusion criteria – PARENTS - Both parents are unable to provide samples. - The inability to provide informed consent. - Known mutations in colorectal susceptibility genes within the family (eg APC,MLH1, MSH2, MSH6, PMS2, MUTYH, POLE1, POLD1, SMAD4/BRCA/STK11).

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  • Phenotypic and Genotypic Characteristics of Paediatric Myelodysplastic Syndromes

    • Research Summary

      This research project will study a group of rare blood disorders in children, called Paediatric Myelodysplastic Syndromes (MDS).Paediatric MDS is characterised by failure of normal blood cells production. Without treatment these syndromes are usually fatal and can lead to leukaemia.The aim of this project is to improve our current understanding of the molecular pathways that lead to the disease development;identify all the disease related genetic abnormalities;document the natural history of the disease;create correlations between the clinical presentations and genetic defects and create targets for future therapies .Children with a diagnosis of Paediatric MDS from across all specialist paediatric haematology centres in the UK will be invited to participate in this project. From the study of these cases we aim to built a comprehensive picture of paediatric MDS,which is something that has not been achieved so far. We will record how these disorders present, all their clinical characteristics; laboratory tests results, how the disorders progress with time and the response of the different subgroups of patients to the current treatments.The samples collected will be in the form of blood,bone marrow,nail clippings,skin biopsies, saliva and hair follicles.These samples will be tested for all genetic abnormalities that have been previously described in different types of MDS. In cases that no known genetic abnormality is detected, further genetic testing(called whole genome sequencing) will be performed, after appropriate consent, in order to identify new genetic defects linked with MDS.This will enable us to provide an accurate diagnosis for each family, but also to select the most appropriate treatment for each case.We will study the behaviour of blood cells from children with MDS,using state­of­-the-­art technology,with the objective to identify the molecular pathways that lead to the disease development.

    • Inclusion Criteria:

      1. Age from birth to 21 years 2. Probable diagnosis of MDS ie a. Sustained (> 3 months) unexplained cytopenia b. Bi/trilineage morphological myelodysplasia c. Acquired clonal cytogenetic abnormality in haematopoietic cells d. Bone marrow blasts > 5% 3. Children with syndromic MDS or suspected syndromic MDS 4. Children with secondary MDS: chemotherapy, radiotherapy, toxic agents 5. Children with IBMFS and features of myelodysplasia 6. Children with suspected familial MDS 7. Denovo MDS (hypocellular or hypercellular ) 8. Juvenile Myelomonocytic Leukaemia 9. MDS/MPS 10. MDS with systemic disease 11. Children with Downs MDS

    • Exclusion Criteria:

      1. Patients who do not fulfil inclusion criteria 2. Patients who have not consented for the study 3. Children with known CBF AML translocations

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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

    • 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)

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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

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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

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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.

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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

    • 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.

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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

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  • Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA­-1 trial) A randomized, multidisciplinary, multinational AIO/DGAV/DGVS phase III trial.

    • Research Summary

      Biliary tract tumours are relatively rare, accounting for 0.7% of malignant tumours in adults, with approximately 1200 new cases registered each year in England and Wales. The 1-year and 5-year survival is poor at 22% and 9% respectively (Cancer Survival Trends in England and Wales 1971 – 1995). Approximately 15-20% of cases are suitable for surgical resection but the outlook remains poor with survival at 5 years approximately 15% (Cancer Survival Trends in England and Wales 1971 – 1995. Most tumours are advanced at presentation and are unsuitable for surgical resection. The ACTICCA-1 trial will investigate the role of adjuvant chemotherapy with Cisplatin and Gemcitabine compared to surveillance. This study will determine whether the Cisplatin and Gemcitabine regimen which is effective in advanced disease will show a benefit in the adjuvant setting. This is an international, multicentre, prospective, randomised controlled trial comparing adjuvant treatment with Cisplatin and Gemcitabine with no adjuvant treatment in patients who have undergone a complete macroscopic resection of biliary tract cancer. Patients will be followed up for a period of 5 years, primarily assessing disease free survival and overall survival at 2 and 5 years respectively. Quality of Life sub studies are planned to be investigated within the trial also. The results of this study will be used to further define the optimum management for patients who undergo a complete resection of their biliary tract cancer. This result could have the potential to change the current practice for treating these patients.

    • Inclusion Criteria:

      Eligibility criteria for enrolment phase 1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic biliary tract cancer, or muscle invasive gallbladder cancer) scheduled for radical surgical therapy 2. Written informed consent 3. No prior chemotherapy for biliary tract cancer 4. No previous malignancy within 3 years or concomitant malignancy, except: non­melanomatous skin cancer or adequately treated in situ cervical cancer 5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 9. No pregnancy or lactation Eligibility criteria for treatment phase (before randomisation) 1. Histologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic biliary tract cancer or muscle invasive gallbladder cancer) after radical surgical therapy with macroscopically complete resection (mixed hepatocellular tumours are excluded) 2. Macroscopically complete resection (R0/1) within 6 (­16) weeks before scheduled start of chemotherapy 3. ECOG 0­1 4. Age > 18 years 5. Adequate haematologic function: ANC ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin ≥9 g/dl or ≥5.59 mmol/L 6. Adequate liver function as measured by serum transaminases (AST and ALT) ≤5 x ULN and bilirubin ≤3 x ULN 7. Adequate renal function, i.e. serum creatinine ≤1.5 x ULN, glomerular filtration rate ≥ 60 mL/min (MDRD) 8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy 9. No concurrent treatment with other experimental drugs or other anti­cancer therapy, treatment in a clinical trial within 30 days prior to randomisation 10. Negative serum pregnancy test within 7 days of starting study treatment in pre­menopausal women and women < 1 year after the onset of menopause (Note: a negative test has to be reconfirmed by a urine test, should the 7­day window be exceeded) 11. Written informed consent 12. No prior chemotherapy for biliary tract cancer 13. No previous malignancy within 3 years or concomitant malignancy, except: non­melanomatous skin cancer or adequately treated in situ cervical cancer 14. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 15. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informedconsent 16. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 17. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 18. No pregnancy or lactation

    • Exclusion Criteria:

      Mixed hepatocellular tumours are excluded

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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).

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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 SACT can improve overall survival in non-­small cell lung cancer (NSCLC) patients with 1- ­5 metastases (max. up to 3 organs). 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 SACT. • After two cycles of SACT, 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 (SACT only) will receive 2 more cycles of chemotherapy. • Patients randomised to the investigational group (SACT 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

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  • Short-course radiotherapy plus olaparib for newly diagnosed glioblastoma in patients unsuitable for radical chemoradiation: a randomised phase II clinical trial preceded by a lead-in phase I dose escalation study.

    • Research Summary

      The primary objective of Phase I is to identify a recommended dose of olaparib to be administered in combination with radiotherapy. The primary objective of Phase II is to determine the effect of olaparib administered in combination with radiotherapy compared with placebo administered in combination with radiotherapy on life expectancy (overall survival) in patients with newly diagnosed glioblastoma who are not fit enough to receive aggressive treatment with both chemotherapy and radiotherapy.

    • Inclusion Criteria:

      1. Age 18 – 69: WHO performance status 2 at initial oncology consultation or performance status 0-1 but otherwise unsuitable for radical radiotherapy with concomitant and adjuvant temozolomide 2. Age ≥70: WHO performance status 0 or 1 at initial oncology consultation 3. Histologically confirmed diagnosis of glioblastoma 4. Life expectancy greater than 12 weeks 5. No previous radiotherapy or chemotherapy for primary or secondary CNS malignancy 6. Adequate haematological, hepatic and renal function defined as below: •Haemoglobin ≥ 10 g/dL (no blood transfusions in the 28 days prior to trial entry) •Absolute neutrophil count ≥ 1.5 x 109/L •White Blood Cells > 3x109/L •Platelet count ≥ 100 x 109/L •Bilirubin ≤ 1.5 x upper limit of normal (ULN) •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN •Adequate renal function with creatinine clearance / glomerular filtration rate > 50 ml/min. If the creatinine clearance / glomerular filtration rate is less than 50 ml/min as calculated by the Cockroft-Gault/ Wright formula, then the creatinine clearance / glomerular filtration rate should be measured by either a radioisotope technique or by 24-hour urine collection 7. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed 8. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures 9. Ability to swallow oral tablets/capsules 10. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of trial treatment, confirmed prior to treatment on day 1 Posmenopausal is defined as: •Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments •LH and FSH levels in the postmenopausal range for women under 50 •Or surgical sterilisation (bilateral oophorectomy or hysterectomy)

    • Exclusion Criteria:

      1. WHO performance status > 2 2. Life expectancy less than 12 weeks 3. Active concurrent malignancy (except non-melanoma skin cancer or in situ carcinoma of the cervix). If history of prior malignancy, must be disease-free for > 5 years 4. Prior treatment for primary or secondary CNS malignancy 5. Confusion or altered mental state that would prohibit understanding and giving of informed consent 6. Concomitant treatment with medicines detailed in section 5.10 of protocol 7. Female patients who are able to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intrauterine device and condom, diaphragm with spermicidal gel and condom) effective at the first administration of either IMP, throughout the trial, and for six months afterwards, are considered eligible 8. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] effective at the first administration of IMP, throughout the trial, and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate 9. Administration of any investigational drug within 28 days prior to receiving the first dose of trial treatment 10. Any previous treatment with a PARP inhibitor, including olaparib 11. Blood transfusions within 1 month prior to trial start 12. Patients with myelodysplastic syndrome/acute myeloid leukaemia 13. Major surgery within 14 days of starting trial treatment and patients must have recovered from any effects of major surgery 14. Patients with a known hypersensitivity to olaparib or any of the excipients of the product 15. Patients with uncontrolled seizures 16. Patients who are known to be HIV positive, or who are known to have positive Hepatitis B or C serology

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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.

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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 dif