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
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
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
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.
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)
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.
Men diagnosed with significant cancer confined to the prostate currently undergo radical therapy directed to the whole prostate (radiotherapy or prostatectomy). These provide good cancer control but can cause significant side effects. Focal Therapy involves targeting the cancer alone, whilst leaving healthy prostate gland alone. Case series have shown similar cancer control over 5 years with a much better side effect profile. However, there have been no randomised control trials (RCTs) comparing the success in cancer control and the quality of life in patients that undergo radical therapy vs those that undergo focal therapy. Further, there is a need to assess the use of additional therapies that may improve the cancer control outcomes following focal therapy. By having a trials platform with two RCTs (CHRONOS-A and CHRONOS-B) that reflect best patient and physician preferences/ equipoise, we aim to answer these questions. To improve acceptability, recruitment and compliance we have an embedded study aimed at reviewing clinician and patient perspectives and trial acceptability. CHRONOS-A will compare radical therapy to focal therapy, whilst CHRONOS-B will compare focal therapy alone to focal therapy with various therapies targeting the testosterone pathway that can shrink the cancer before it is treated. We think this might improve outcomes further for men that definitely want focal therapy.
1) Prostate cancer confirmed on biopsy of Gleason 6 or Gleason 7 overall 2) Serum PSA (prostate specific antigen) less than or equal to 20ng/ml 3) Stage < / = (radiological) T3aN0M0 or < / = (clinical rectal examination)T2N0M0 4) Minimum age of 18 years of age 5) Clinically fit enough to undergo all procedures listed in the trial that the patient has been been enrolled into
1) Previous prostate cancer treatment 2) Life expectancy less than 10 years 3) Unable to consent to participation in the trial 4) Previous or current use of current LHRH agonist or LHRH antagonist or anti-androgen use in CHRONOS-B 5) Less than 6 months of discontinuation of 5 alpha-reductase inhibitor use in CHRONOS-B
This study addresses the specific Health-related Quality of Life (HRQoL) concerns facing Adolescents and Young Adults (AYA) with cancer. Our previous research has found that there are issues specific to AYAs with cancer (aged 14-25) that are currently not covered by the European Organisation for Research and Treatment of Cancer core measure (EORTC QLQ C30). In our previous research, we defined AYAs as 14-25 years. Following the advice of international experts on AYA oncology, we have decided to extend our work to align it more closely to international definitions of AYAs which goes up to 39 years. This first phase of the research is largely exploratory, where we will extend our previous research and gain insight into the important issues for young adults with cancer aged 26-39 years. The second phase of the research will involve reviewing the 77 issues identified in our previous research with AYAs aged 14-25 and developing a list of questionnaire items. The third phase will involve pilot testing the AYA questionnaire with a larger group of patients aged 14-39 years recruited from the UK and across the world.
-Diagnosis of cancer -Treatment with curative intent or palliative / supportive care -Age 14-39 years -Comprehension of the language of the questionnaire -Willingness and ability to give informed consent
-Participation in the earlier phase of the study -Cancer survivors (i.e., participants who have completed treatment with curative intent and are now cancer free).
NuTide:121 compares NUC-1031 with gemcitabine, both in combination with cisplatin, in patients with previously untreated advanced biliary tract cancer.
The primary hypotheses are:
- The combination of NUC-1031 plus cisplatin prolongs overall survival compared to the gemcitabine plus cisplatin standard of care
- The combination of NUC-1031 plus cisplatin increases overall response rate compared to the gemcitabine plus cisplatin standard of care
1. Written informed consent and authorization to use and disclose health information.
2. Ability to comprehend and willingness to comply with the requirements of this protocol, including the QoL questionnaires.
3. Female or male patients aged ≥18 years.
4. Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers) that is locally advanced, unresectable or metastatic. Patients with measurable (as per RECIST v1.1 criteria) or non-measurable disease are permitted.
5. Life expectancy ≥16 weeks.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Adequate biliary drainage with no evidence of ongoing infection. If applicable, treatable and clinically-relevant biliary duct obstruction has been relieved by internal endoscopic drainage/stenting at least 2 weeks previously or by palliative bypass surgery or percutaneous drainage prior to study treatment, and the patient has no active or suspected uncontrolled infection. Patients fitted with a biliary stent should be clinically stable and free of signs of infection for ≥2 weeks prior to study treatment. Patients with improving biliary function who meet all other inclusion criteria may be re-tested during the screening window.
8. Adequate bone marrow, hepatic, and renal function, as evidenced by:
- Absolute neutrophil count (ANC) ≥1,500/μL without colony-stimulating factor support
- Platelet count ≥100,000/μL
- Haemoglobin ≥10 g/dL without need for haematopoietic growth factor or transfusion support in prior 2 weeks
- Total bilirubin < 2 × upper limit of normal (ULN); does not apply to patients with Gilbert's syndrome. Consistent with inclusion criterion 7, patients whose whole bilirubin and biliary function is recovering may be re-tested during the screening period.
- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < 5 × ULN
- Creatinine clearance ≥45 mL/min actual or calculated by the Cockcroft-Gault method
- International normalized ratio (INR) < 1.5 and partial thromboplastin time (PTT) < 1.5 × ULN; does not apply to patients on an anti-coagulant with stable dose 28 days prior to first dose.
9. QTc interval < 450 msec (males) or < 470 msec (females), in the absence of bundle branch block. In the presence of bundle branch block with consequent QTc prolongation, patients may be enrolled based on a careful risk-benefit assessment.
10. Human Immunodeficiency Virus-infected patients who are healthy and have a low risk of Acquired Immunodeficiency Syndrome-related outcomes may be included in this study.
11. Female patients of child-bearing potential (i.e., all women except those who are post-menopausal for ≥1 year or who have a history of hysterectomy or surgical sterilization) must have a negative pregnancy test within 3 days prior to the first study drug administration. All patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method of contraception, from the time of screening until 6 months after the last dose of study medication.
12. Male patients with a female partner must either have had a successful vasectomy or they and their female partner meet the criteria above (not of childbearing potential or practicing highly effective contraceptive methods).
1. Combined or mixed hepatocellular/cholangiocarcinoma.
2. Prior systemic therapy for advanced or metastatic biliary tract cancer. However, prior chemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunction with radiotherapy in the adjuvant setting and completed at least 6 months prior to enrolment is permitted. The following prior interventions are allowed provided the patient has fully recovered:
- Surgery: non-curative resection with macroscopic residual disease or palliative bypass surgery. Patients who have previously undergone curative surgery must now have evidence of non-resectable disease requiring systemic chemotherapy.
- Radiotherapy: prior radiotherapy (with or without radio-sensitizing low-dose chemotherapy) for localized disease and there is now clear evidence of disease progression requiring systemic chemotherapy.
- Photodynamic therapy: prior photodynamic therapy for localized disease with no evidence of metastatic disease or for localized disease to relieve biliary obstruction in the presence of metastatic disease provided there is now clear evidence of disease progression requiring systemic chemotherapy.
- Palliative radiotherapy: palliative radiotherapy provided that all adverse events have resolved and the patient has measurable disease outside the field of radiation.
3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin or other platinum-based agents or history of allergic reactions attributed to the excipients contained in NUC-1031 or diluent solution (dimethylacetamide [DMA], Kolliphor ELP, Tween 80).
4. Symptomatic central nervous system or leptomeningeal metastases.
5. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, low grade prostate cancer not requiring treatment or other solid tumours curatively treated with no evidence of disease for ≥3 years.
6. Concurrent serious (as deemed by the Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.
7. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV). As per inclusion criterion 10, patients with HIV who are healthy and have a low risk of AIDS related outcomes are eligible.
8. Other acute or chronic medical, neurological, or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
9. Prior exposure to another investigational agent within 28 days prior to randomization.
10. Major surgery within 28 days prior to randomization; patient must have completely recovered from any prior surgical or other procedures.
11. Pregnant or breastfeeding.
12. Residual toxicities from prior treatments or procedures which have not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia or ≤ Grade 2 peripheral neuropathy.
13. Concomitant use of drugs at doses known to cause clinically relevant prolongation of QT/QTc interval.
14. Administration of a live vaccination within 28 days prior to randomization.
15. Ongoing or recent (≤6 months) hepatorenal syndrome.
This is a non-interventional/observational cohort of NSCLC unresectable stage III patients treated with durvalumab.
The study will be carried out as a retrospective review of established medical records for a subset of unresectable stage III patients treated with durvalumab.
This is a non-interventional/observational study including NSCLC unresectable Stage III patients treated with durvalumab. Patient selection and retrospective data collection will be from participating countries: Australia, Belgium, Israel, Netherlands, Norway France, Germany, Italy, Switzerland, Spain
Chart abstractions will occur at specified intervals up to five years after the patient had the first dose of durvalumab. A target of four (maximum five) chart extractions is anticipated for each participant. Dates may be adjusted based on local market ethics processes or patient enrolment.
- First chart extraction will be used to determine which patients meet the inclusion/exclusion criteria for the study and will retrospectively collect all data from diagnosis of stage III unresectable NSCLC and the durvalumab start date (index date).
- The second chart extraction will be triggered at time of estimated maturity of PFS data to provide an accurate measure of the PFS outcome.
- The third chart extraction will be triggered at time of estimated maturity of OS data to provide an accurate measure of the OS outcome• The fourth and fifth chart extractions will occur approximately 3-years and 5-years after enrolment
- The dates for the second through fifth chart abstractions may be adjusted, pending data availability. The estimated PFS and OS maturity will be calculated from the actual patient index dates (date of first dose of durvalumab) and any available data on PFS and OS observed in the first extraction together with the distribution of PFS and OS observed in the PACIFIC trial.
- Written informed consent or any locally required authorisation obtained from the patient prior to performing any protocol-related procedures
- Age ≥ 18 years at time of study entry or adult according to each country regulations for age of majority
- Patients must have histologically or cytologically documented diagnosis of NSCLC with a locally advanced, or locally recurrent, unresectable (stage III) disease (according to American Joint Committee on Cancer [AJCC] lung cancer edition 7 or 8)
- Patients must have been enrolled in one of the durvalumab EAPs Patients must have been treated with at least one dose of durvalumab within the EAP prior to the study entry and between start of EAP in the country, from September 2017 or later up to end of EAP enrolment or MA + three months (estimated as maximum to 30 December 2018) (whichever occurs earlier).
Patients who die during the EAP are eligible to enter in the study when local laws allow for a consent waiver, if all other inclusion/exclusion criteria are met.
-Patients treated with durvalumab in clinical studies prior to the index date (first dose of durvalumab received within the EAP).
A Phase 1/2a study to assess the safety, tolerability, PK and biological activity of CCS1477 in patients with Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukaemia or High Risk Myelodysplastic syndrome.
- Provision of consent
- ECOG performance status 0-2
- Patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (NHL, MM and AML)
- Must have previously received standard therapy
- Adequate organ function
- Intervention with any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives of the first dose
- Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of 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
- Strong inducers of CYP3A4 within 4 weeks of the first dose of study treatment
- Patients should discontinue statins prior to starting study treatment
- CYP2C8 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment
- Any unresolved reversible toxicities from prior therapy >CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2 neuropathy)
- Any evidence of severe or uncontrolled systemic diseases
- Any known uncontrolled inter-current illness
- QTcF prolongation (> 480 msec)
The purpose of this study is to determine if treatment with androgen deprivation therapy (ADT) plus apalutamide before and after radical prostatectomy in participants with high-risk localized or locally advanced prostate cancer results in an improvement in pathological complete response (pCR) rate and metastasis-free survival (MFS), as compared to ADT plus placebo.
High-risk prostate cancer accounts for approximately 15 percent (%) of newly diagnosed prostate cancers. A systemic therapy that eradicates micrometastatic disease is needed to improve survival in high-risk participants undergoing radical prostatectomy. It is hypothesized that androgen blockade prior to and after radical prostatectomy may improve outcomes for participants at the highest risk for recurrence. This study is designed to evaluate if androgen blockade administered prior to and after radical prostatectomy will increase the rate of pathological complete response (pCR) and lead to better overall outcomes. ERLEADA (apalutamide, also known as JNJ-56021927 and ARN-509) is an orally available, non-steroidal small molecule, which acts as a potent and selective antagonist of the androgen receptor (AR), currently being developed for the treatment of prostate cancer. The study includes screening phase (approximately up to 35 days before randomization), treatment phase (up to 12 months) and follow-up phase. The end of study (study completion) is defined as last participant assessment at study site with approximate study duration of 8 years. Participants will undergo efficacy, pharmacokinetics and biomarker evaluations. The safety will be monitored throughout the study.
- Histologically confirmed adenocarcinoma of the prostate
- Candidate for radical prostatectomy with lymph node dissection as per the investigator
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
- Contraceptive (birth control) use by men (or female partners of men enrolled in the study who are of childbearing potential or are pregnant) should be consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies
- Able to receive androgen deprivation therapy (ADT) for up to 1 year, per the investigator's assessment
- Distant metastasis (clinical stage M1). Nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion. Diagnosis of distant metastasis (clinical M stage; M0 versus M1a, M1b, M1c) and pelvic nodal disease (clinical N stage; N1 versus N0) will be assessed by central radiological review. Participants are considered eligible only if the central radiological review confirms clinical stage M0
- Prior treatment with antiandrogen
- History of pelvic radiation for prostate cancer
- Use of any investigational agent less than or equals to (<=)4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
- Major surgery <= 4 weeks prior to randomization
The purpose of this study is to show that Nivolumab, or Nivolumab plus Ipilimumab, or Nivolumab plus Platinum-Doublet Chemotherapy improves progression free survival and/or overall survival compared with chemotherapy in patients with advanced lung cancer.
- Subjects with histologically confirmed Stage IV or recurrent NSCLC squamous or non-squamous histology, with no prior systemic anticancer therapy
- Subjects must have programmed death-ligand 1 (PD -L1) immunohistochemical (IHC) testing, with results, performed by the central lab during the Screening period
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
- Measurable disease by CT or MRI per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) criteria
- Subjects with untreated Central nervous system (CNS) metastases are excluded
- Subjects with an active, known or suspected autoimmune disease are excluded
- Any positive test for hepatitis B virus or hepatitis C virus or human immunodeficiency virus (HIV) indicating acute or chronic infection
This Phase 3 clinical study compares the efficacy and safety of elacestrant to the standard of care (SoC) options of fulvestrant or an aromatase inhibitor (AI) in women and men with breast cancer whose disease has advanced on at least one endocrine therapy including a CDK4/6 inhibitor in combination with fulvestrant or an aromatase inhibitor (AI) .
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, Phase 3 clinical study comparing the efficacy and safety of elacestrant to the SoC options of fulvestrant or an aromatase inhibitor (AI) in postmenopausal women and in men with advanced or metastatic ER+/HER2- breast cancer, either in subjects with tumors that harbor mutations in the ligand binding domain (LBD) of the estrogen receptor 1 (ESR1) gene (ESR1-mut subjects) or in all subjects regardless of ESR1 status (ESR1-mut and ESR1 wild type [ESR1-WT]) and whose disease has relapsed or progressed on at least one and no more than two prior lines of endocrine therapy (with documented progression), which must have included prior CDK4/6 inhibitor therapy in combination with fulvestrant or an aromatase inhibitor (AI) and for whom hormonal monotherapy with one of the SoC drugs (fulvestrant, anastrozole, letrozole, exemestane) is an appropriate treatment option.
1. Subjects with proven diagnosis of adenocarcinoma of the breast with evidence of either locally advanced disease not amenable to resection or radiation therapy with curative intent or metastatic disease not amenable to curative therapy.
2. Subjects must be appropriate candidates for endocrine monotherapy
3. Subjects must have measurable disease or, nonmeasurable (evaluable) bone-only disease
4. Female or male subjects age ≥ 18 years; female subjects must be postmenopausal women and male subjects must not allow pregnancy with their sperm (abstain, do not donate sperm, etc).
5. Subjects must have ER+/HER2-tumor status
6. Subjects must have previously received at least one and no more than two lines of endocrine therapy for advanced/metastatic breast cancer and meet additional previous treatment criteria.
7. Subjects must have received prior treatment with a CDK4/6 inhibitor in combination with either fulvestrant or an aromatase inhibitor (AI).
8. Subjects may have received no more than one line of chemotherapy in the advanced/metastatic setting.
9. Subjects must have ctDNA ESR1-mut or ESR1-WT status as determined by central testing before subject is randomized.
1. Prior treatment with elacestrant, GDC-0810, GDC-0927, GDC-9545, LSZ102, AZD9496, bazedoxifene, or other investigational SERD or investigational ER antagonist.
2. Prior anticancer or investigational drug treatment within the following windows:
1. Fulvestrant treatment < 28 days before first dose of study drug
2. Any endocrine therapy < 14 days before first dose of study drug (with the exception of GnRH agonist therapy in male subjects)
3. Chemotherapy < 21 days before first dose of study drug
4. Any investigational anti-cancer drug therapy < 28 days or five half-lives (whichever is shorter) before the first dose of study drug. Enrollment of subjects whose most recent therapy was an investigational agent should be discussed with the Sponsor
3. Presence of symptomatic visceral disease as defined in protocol.
The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.
This is an interventional active-controlled, open-label, randomized Phase 3 study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low or intermediate risk MDS in ESA naïve subjects who require RBC transfusions.
The study is divided into the Screening Period, a Treatment Period and a Post-Treatment Follow-up Period.
Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus epoetin alfa in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), are ESA naïve, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or epoetin alfa arm, followed by an open-label treatment period. In both treatment arms, best supportive care (BSC) may be used in combination with study treatment when clinically indicated per investigator. Best supportive care includes, but is not limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed. Best supportive care for this study excludes the use of ESAs outside of the study treatment. Patients should receive treatment up to a minimum of 24 weeks after which an MDS Disease assessment visit is scheduled to assess the response to treatment. Patients who are determined to be experiencing clinical benefit may continue treatment. Continued clinical benefit will be re-assessed every 24 weeks. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.
Subjects must satisfy the following criteria to be randomized in the study:
1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease, and:
• < 5% blasts in bone marrow.
5. Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L.
6. Subject requires RBC transfusions, as documented by the following criteria:
• Average transfusion requirement of 2 - 6 units/8 weeks of pRBCs confirmed for a minimum of 8 weeks immediately preceding randomization.
- Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 9.0 g/dL with symptoms of anemia (or ≤ 7 g/dL in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
- The hemoglobin level after the last RBC transfusion prior to randomization must be < 11.0 g/dL (centrally or locally analyzed).
7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
8. Females of childbearing potential (FCBP), defined as a sexually mature woman who:
- Has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must:
- Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
- If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must:
- Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.
The presence of any of the following will exclude a subject from randomization (with the randomization date defined as the date in which the subject is randomized in IRT):
1. Subject with the any of the following prior treatments:
- Erythropoiesis-stimulating agents (ESAs)
- Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for treatment of febrile neutropenia
- Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide]
- Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator's discretion.
- Hypomethylating agents
- Subjects may be randomized at the investigator's discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization.
- Luspatercept (ACE-536) or sotatercept (ACE-011)
- Immunosuppressive therapy for MDS
- Hematopoietic cell transplant
2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
3. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable.
4. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
5. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate).
• Iron deficiency to be determined by serum ferritin < 100 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
6. Subject with known history of diagnosis of AML.
7. Subject receiving any of the following treatment within 8 weeks prior to randomization:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
- Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
- Other RBC hematopoietic growth factors (eg, Interleukin-3)
- Androgens, unless to treat hypogonadism
- Oral retinoids (except for topical retinoids)
- Arsenic trioxide
- Interferon and interleukins
- Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)
8. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment.
9. Subject with any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)
- Platelet count < 50,000/μL (50 x 109/L)
- Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula)
- Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
- Total bilirubin ≥ 2.0 x ULN.
- Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
10. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
- Basal or squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
11. Subject with major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization.
12. Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to randomization Note: prior superficial thrombophlebitis is not an exclusion criterion.
13. New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization.
14. Subject with the following cardiac conditions within 6 months prior to randomization: myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator. Subjects with a known ejection fraction ˂ 35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan performed within 6 months prior to randomization.
15. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
16. Subject with known human immunodeficiency virus (HIV), known evidence of active infectious Hepatitis B, and/or known evidence of active Hepatitis C.
17. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in luspatercept (see Investigator's Brochure).
18. Subject with known hypersensitivity to the active substance or to any of the excipients in epoetin alfa.
19. Subjects with history of pure red cell aplasia (PRCA) and/or antibody against erythropoietin.
20. Pregnant or breastfeeding females.
21. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study.
22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
23. Subject has any condition or receives concomitant medication that confounds the ability to interpret data from the study.
The purpose of the study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug called NKTR-214, when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (adults 18 years or older)/Lansky Performance Score ≥ 80% (minors ages 12-17 only)
- Histologically confirmed stage III (unresectable) or stage IV melanoma
- Treatment-naive participants (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) with the exception of prior adjuvant treatment
- Active brain metastases or leptomeningeal metastases
- Uveal melanoma
- Participants with an active, known or suspected autoimmune disease
This is a Phase 3, randomized, multinational, double-blind, dual placebo-controlled, 4-arm study evaluating rucaparib and nivolumab as maintenance treatment following response to front-line treatment in newly diagnosed ovarian cancer patients. Response to treatment will be analyzed based on homologous recombination (HR) status of tumor samples.
- Newly diagnosed advanced (FIGO stage III-IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer.
- Completed cytoreductive surgery, including at least a bilateral salpingo-oophorectomy and partial omentectomy, either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking)
- Completed first-line platinum-based chemotherapy and surgery with a response, in the opinion of the Investigator
- Sufficient tumor tissue for planned analysis
- ECOG performance status of 0 or 1
- Pure sarcomas or borderline tumors or mucinous tumors
- Active second malignancy
- Known central nervous system brain metastases
- Any prior treatment for ovarian cancer, other than the first-line platinum regimen
- Evidence of interstitial lung disease or active pneumonitis
- Active, known or suspected autoimmune disease
- Condition requiring active systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications
This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
This is a global, Phase 3, randomized study of zanubrutinib versus ibrutinib in approximately 400 patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
The primary efficacy endpoint is overall response rate determined by independent central review. Patients will be randomized in a 1:1 manner to either zanubrutinib or ibrutinib. Treatment with zanubrutinib and ibrutinib will be open label.
1. Age 18 years or older
2. Confirmed diagnosis of CLL or SLL that meets the 2008 IWCLL criteria
3. CLL/SLL requiring treatment per 2008 IWCLL criteria
4. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL
5. Measurable disease by CT/magnetic resonance imaging (MRI)
6. ECOG performance status of 0, 1, or 2
7. Life expectancy ≥ 6 months
8. Adequate bone marrow function
9. Adequate renal and hepatic function
1. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
2. Clinically significant cardiovascular disease.
3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
4. History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention
5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
6. Severe or debilitating pulmonary disease
7. Active fungal, bacterial, and/or viral infection requiring systemic therapy
8. Known central nervous system involvement by leukemia or lymphoma
9. Known infection with HIV or active viral hepatitis B or C infection
10. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
11. Major surgery within 4 weeks of the first dose of study drug
12. Prior treatment with a BTK inhibitor
13. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1
14. Pregnant or lactating women
15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
16. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug
17. Concurrent participation in another therapeutic clinical trial
A global, randomized phase III study to evaluate perioperative pembrolizumab with radical cystectomy + pelvic lymph node dissection (RC+PLND) versus RC+PLND alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC)
- Histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology. Participants with mixed histology are eligible provided the urothelial component is ≥50%. Urothelial carcinomas not originating from the bladder are not eligible. Participants whose tumors contain any neuroendocrine component are not eligible.
- Clinically non-metastatic bladder cancer determined by imaging
- Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND ), and agreement to undergo curative intent standard RC + PLND (including prostatectomy if applicable)
- Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
- Impaired renal function with measured or calculated CrCl 30 to 59 mL/min
- Eastern Cooperative Oncology Group (ECOG) Performance Status 2
- Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
- CTCAE v.4 Grade ≥2 peripheral neuropathy
- New York Heart Association (NYHA) Class III heart failure
- Transurethral resection (TUR) of a bladder tumor that is submitted and adequate for evaluation of histology, muscle invasion and PD-L1 status
- ECOG performance status of 0, 1, or 2
- Adequate organ function
- Known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization, with certain exceptions
- Received any prior systemic anti-neoplastic treatment for muscle-invasive bladder cancer (MIBC)
- Received prior therapy with a anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2), or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
- Received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization
- Received any prior radiotherapy to the bladder
- Received a live vaccine within 30 days prior to the first dose of study drug
- Current participation in or participation in a study of an investigational agent or use of an investigational device within 4 weeks prior to the first dose of study intervention
- Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug
- Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
- Active autoimmune disease that has required systemic therapy in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is allowed.
- History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
- Active infection requiring systemic therapy
This open-label, single arm study will evaluate the safety of obinutuzumab administered as a short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards in combination with chemotherapy in participants with previously untreated advanced follicular lymphoma (FL). The study has two phases: in the first phase, participants will receive the first cycle of obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first three infusions of obinutuzumab (1000 mg) administered at the regular infusion rate on Day 1, 8, and 15 of cycle 1. Phase 2 starts when participants who do not experience any Grade ≥ 3 infusion related reactions during the first cycle receive their first obintuzumab infusion given at the faster infusion rate in Cycle 2. For Cycle 2, Day 1 and all other following infusions (including maintenance), obinutuzumab will be administered at a faster infusion of 90-minute SDI, as long as the participant does not experience any Grade ≥ 3 infusion related reactions. The investigator is free to choose the chemotherapy for each participant (bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone]). The total number of cycles of G-chemo induction therapy and the cycles length depends on the chemotherapy chosen for each participant.
- Patients with previously untreated Stage III or IV FL or Stage II bulky disease scheduled to receive obinutuzumab plus chemotherapy due to at least one of the following criteria: a.) Bulky disease, defined as a nodal or extranodal (except spleen) mass
≥ 7 cm in the greatest diameter b.) Local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass c.) Presence of B symptoms (fever [> 38ºC], drenching night sweats, or unintentional weight loss of > 10% of normal body weight over a period of 6 months or less) d.) Presence of symptomatic extranodal disease (e.g., pleural effusions, peritoneal ascites) e.) Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count < 1.0 × 109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L) f.) Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm g.) Symptomatic splenic enlargement
- Histologically documented CD-20-positive FL, as determined by the local laboratory
- Eastern Cooperative Oncology Group (ECOG) performance status 0−2
- Adequate hematologic function (unless abnormalities are related to FL)
- Life expectancy of ≥ 12 months
- For women who are not postmenopausal (≥ 12 consecutive months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 18 months after the last dose of obinutuzumab, for at least 3 months after the last dose of bendamustine or according to institutional guidelines for CHOP or CVP chemotherapy, whichever is longer
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
- Relapsed / refractory FL
- Prior treatment for FL with chemotherapy, radiotherapy, or immunotherapy
- Grade IIIb FL
- Histological evidence of transformation of FL into high-grade B-cell NHL
- Treatment with systemic immunosuppressive medications, including, but not limited to, prednisone/prednisolone/methylprednisolone (at a dose equivalent to > 30 mg/day prednisone), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1
- History of solid organ transplantation
- History of anti-CD20 antibody therapy
- History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies
- Known sensitivity or allergy to murine products
- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any of the study drugs
- Active bacterial, viral, fungal, or other infection or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
- Positive test results for chronic HBV infection (defined as positive HBsAg serology)
- Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
- Known history of HIV positive status
- History of progressive multifocal leukoencephalopathy (PML)
- Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study
- History of prior other malignancy with the exception of: a. Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-grade, early-stage localized prostate cancer b. Any previously treated malignancy that has been in remission without treatment for ≥ 2 years prior to enrollment
- Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)
- Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1, Day 1, or anticipation of a major surgical procedure during the course of the study
- Any of the following abnormal laboratory values:
1. Creatinine > 1.5 × the upper limit of normal (ULN) (unless creatinine clearance normal) or creatinine clearance < 40 mL/min
2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN
3. Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN.
4. International normalized ratio (INR) > 1.5 in the absence of therapeutic anticoagulation
5. Partial thromboplastin time or activated partial thromboplastin time > 1.5 × ULN in the absence of a lupus anticoagulant
- For patients who will be receiving CHOP: left ventricular ejection fraction (LVEF) < 50% by multigated acquisition (MUGA) scan or echocardiogram
- Pregnant or lactating, or intending to become pregnant during the study
- Any investigational therapy within 28 days prior to the start of Cycle 1
- Positive test results for human T-lymphotropic virus 1 (HTLV-1)
This Phase 1/2 study will evaluate the safety, efficacy, PK, and PD of FT-2102 (olutasidenib) as a single agent or in combination with azacitidine or cytarabine. The Phase 1 stage of the study is split into 2 distinct parts: a dose escalation part, which will utilize an open-label design of FT-2102 (olutasidenib) (single agent) and FT-2102 (olutasidenib) + azacitidine (combination agent) administered via one or more intermittent dosing schedules followed by a dose expansion part. The dose expansion part will enroll patients in up to 5 expansion cohorts, exploring single-agent FT-2102 (olutasidenib) activity as well as combination activity with azacitidine or cytarabine. Following the completion of the relevant Phase 1 cohorts, Phase 2 will begin enrollment. Patients will be enrolled across 8 different cohorts, examining the effect of FT-2102 (olutasidenib) (as a single agent) and FT-2102 (olutasidenib) + azacitidine (combination) on various AML/MDS disease states.
- Pathologically proven acute myeloid leukemia (AML) (except acute promyelocytic leukemia [APL] with the t(15;17) translocation) or intermediate, high-risk, or very high risk Myelodysplastic Syndrome (MDS) as defined by the World Health Organization (WHO) criteria or Revised International Prognostic Scoring System (IPSS-R) which is relapsed or refractory (R/R) to standard therapy and/or for which standard therapy is contraindicated or which has not adequately responded to standard therapy.
- Patients must have documented IDH1-R132 gene-mutated disease as evaluated by the site
- Good performance status
- Good kidney and liver function
- Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy
- Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within 1 year prior to study entry, uncontrolled hypertension or uncontrolled arrhythmias
- Pulmonary disease (e.g. COPD, asthma, etc) that is not controlled (moderate to severe symptoms) with current medication
- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
This is a single‑arm, open‑label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single‑agent monotherapy in adult and pediatric patients with relapsed or refractory CD33‑positive AML.
This is a single‑arm, open‑label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single‑agent monotherapy in adult and pediatric patients with relapsed or refractory CD33‑positive AML. Approximately 50 adult (age >= 18 years) and 6 pediatric (12 years =< age =< 17 years) patients who satisfy the study eligibility criteria will be enrolled. Enrolled patients will receive GO 3 mg/m2 up to 2 cycles on Days 1, 4, and 7 at each cycle. The impact of GO on VOD/SOS in the context of previous and subsequent HSCT will also be assessed. Patients enrolled in the study will receive three doses of GO 3 mg/m2 (up to one vial) as a 2‑hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the following criteria after Cycle 1: Bone marrow with a decrease of blast percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%; and Blood count with neutrophils >= 1,000/µL, and platelets >= 50,000/µL, except in patients with the bone marrow blasts >= 5%, the decrease in neutrophils and platelets thought to be due to the underlying leukemia. After GO treatment, subsequent anticancer therapy such as consolidation or conditioning regimen and/or HSCT could be considered at the investigator's discretion. A minimum interval of 2 months is recommended between the last dose of GO and HSCT.
- Refractory or relapsed (ie, bone marrow blasts > 5%) CD33‑positive AML.
- Age >= 12 years.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
- Initial peripheral white blood cells (WBC) counts >= 30,000/mL; patients with a higher WBC count should undergo cytoreduction.
- Adequate renal/hepatic functions
- Patients with prior treatment with gemtuzumab ozogamicin (GO).
- Patients with prior history of VOD/SOS.
- Prior HSCT is not allowed, if it was conducted within 2 months prior to study enrollment.
- Patients with known active central nervous system (CNS) leukemia.
- Uncontrolled or active infectious status.
- Uncontrolled cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial fibrillation of any grade.
- Sero‑positivity to human immunodeficieny virus (HIV).
- Active hepatitis B or hepatitis C infection
- Chemotherapy, radiotherapy, or other anti‑cancer therapy (except hydroxyurea as cytoreduction) within 2 weeks prior to enrollment in the study.
- Major surgery within 4 weeks prior to enrollment.
- QTc interval > 470 milliseconds (msec) using the Fridericia (QTcF), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
- The use of medications known to predispose to Torsades de Pointes within 2 weeks prior to enrollment
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemtuzumab ozogamicin (GO).
The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.
This is a randomized, open-label, parallel-group, multi-center trial in adult subjects with Relapsed or refractory (R/R) aggressive Non-Hodgkin lymphoma (NHL) to compare safety and efficacy between the standard of care (SOC) strategy versus JCAR017 (also known as lisocabtagene maraleucel or liso-cel). Subjects will be randomized to either receive SOC (Arm A) or to receive JCAR017 (Arm B).
All subjects randomized to Arm A will receive Standard of care (SOC) salvage therapy (R-DHAP, RICE or R-GDP) as per physician's choice before proceeding to High dose chemotherapy (HDCT) and Hematopoietic stem cell transplant (HSCT).
Subjects from Arm A may be allowed to cross over and receive JCAR017 upon confirmation of an EFS event.
Subjects randomized to Arm B will receive Lymphodepleting (LD) chemotherapy followed by JCAR017 infusion.
1. Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the informed consent form (ICF).
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
3. Histologically proven diffuse large B-cell lymphoma (DLBCL) NOS (de novo or transformed indolent NHL), high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]), primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich large B-cell lymphoma (THRBCL) or follicular lymphoma grade 3B. Enough tumor material must be available for confirmation by central pathology.
4. Refractory or relapsed within 12 months from CD20 antibody and anthracycline containing first line therapy.
5. [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) positive lesion at screening.
6. Adequate organ function
7. Participants must agree to use effective contraception
1. Subjects not eligible for hematopoietic stem cell transplantation (HSCT).
2. Subjects planned to undergo allogeneic stem cell transplantation.
3. Subjects with, primary cutaneous large B-cell lymphoma, EBV (Epstein-Barr virus) positive DLBCL of the elderly and Burkitt lymphoma.
4. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
- Other completely resected stage 1 solid tumor with low risk for recurrence
5. Treatment with any prior gene therapy product.
6. Subjects who have received previous CD19-targeted therapy.
7. History of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
8. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
9. Active autoimmune disease requiring immunosuppressive therapy.
10. History of any one of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
11. History or presence of clinically relevant central nervous system (CNS) pathology
12. Pregnant or nursing (lactating) women.
This is a global, multicenter, randomized, double-blind, controlled Phase 3 study in patients with newly diagnosed, Stage III or IV non mucinous epithelial ovarian, fallopian tube, or peritoneal cancer (collectively referred to as "ovarian cancer"). The currently recommended standard of care therapy for the first line treatment of Stage III or IV ovarian cancer is the combination of paclitaxel and carboplatin, with or without concurrent and maintenance bevacizumab.
- Patients with a histologically confirmed diagnosis of high-grade nonmucinous epithelial ovarian (serous, endometrial, clear cell, carcinosarcoma, an mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria.
- All patients with Stage IV disease are eligible. This includes those with inoperable disease, those who undergo primary debulking surgery (complete cytoreduction (CC0) or macroscopic disease), or those for whom neoadjuvant chemotherapy is planned.
- Patients with Stage III are eligible if they meet one or more of the following criteria:
1. High risk Stage IIIC disease.
2. Planning to receive neoadjuvant chemotherapy.
- Patients must provide a blood sample for research at Screening.
- Patient must provide sufficient tumor tissue sample (a minimum of 2 formalin-fixed paraffin embedded blocks) at Screening for research.
- Patients must have adequate organ function (Note: complete blood count test should be obtained without transfusion or receipt of stimulating factors within 2 weeks before obtaining Screening blood sample)
- Patients must have an ECOG score of 0 or 1.
- Patients must have normal blood pressure (BP) or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and/or diastolic BP ≤90 mmHg).
- Patients must agree to complete HRQoL questionnaires throughout the study.
- Patients must be able to take oral medication.
- Patient has mucinous, germ cell, transitional cell, or undifferentiated tumor.
- Patient has low-grade or Grade 1 epithelial ovarian cancer.
- Stage III patient with complete cytoreduction (CC0) resection after primary debulking surgery (ie, no macroscopic residual disease, unless the patient has aggregate 5 cm extra-pelvic disease during primary debulking surgery.
- Patient has not adequately recovered from prior major surgery.
- Patient has a known condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment in the opinion of the Investigator.
- Patient has been diagnosed and/or treated with any therapy for invasive cancer < 5 years from study enrollment, completed adjuvant chemotherapy and/or targeted therapy (eg, trastuzumab) less than 3 years from enrollment, or completed adjuvant hormonal therapy less than 4 weeks from enrollment. Patients with definitively treated non-invasive malignancies such as cervical carcinoma in situ, ductal carcinoma in situ, Grade 1 or 2, Stage IA endometrial cancer, or non-melanomatous skin cancer are allowed.
- Patient is at increased bleeding risk due to concurrent conditions (eg, major injuries or major surgery within the past 28 days prior to start of study treatment and/or history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
- Patient is immunocompromised. Patients with splenectomy are allowed. Patients with well-controlled known human immunodeficiency virus (HIV) are allowed.
- Patient has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
- Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection.
- Patient has had investigational therapy administered within 4 weeks or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study.
- Patient has received a live vaccine within 14 days of planned start of study therapy. Seasonal influenza vaccines that do not contain live viruses are allowed.
- Patient has a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, dostarlimab, or their excipients.
- Prior treatment for high-grade nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer (immunotherapy, anti-cancer therapy, radiation therapy).
- Patient has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (eg, thyroid hormone or insulin).
- Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment.
The Phase 1 part of the study is conducted to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory solid tumors (excluding central nervous system [CNS] tumors).
The Phase 2 part of the study is conducted to assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and ewing sarcoma (EWS).
Participants must be
- Greater than or equal to (≥)12 months to less than (<)18 years old at the time of consent.
- Greater than (>) 6 months and < 12 months at the time of consent (Phase 1 and Schedule A only) participants will be enrolled one dose level behind the dose level at which the ≥12 months to < 18 years old group are enrolled.
- Phase 1: Participants must be diagnosed with histologically confirmed solid tumors (excluding CNS tumors), which is relapsed or refractory, and for which there are no currently available therapies.
- Phase 2: Participants must be diagnosed with histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy, including primary treatment.
- Phase 1: Participants must have either measurable or evaluable disease as per RECIST 1.1.
- Phase 2: Participants must have measurable disease as per RECIST 1.1.
- Participant's current disease state must be one for which there is no known curative therapy.
- Participant's performance score must be ≥50% Karnofsky (for participants > 16 years of age) or Lansky (for participants less than or equal to (≤)16 years of age).Participants who are unable to walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- Participants must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:
- Must not have received myelosuppressive chemotherapy within 21 days prior to study drug administration (42 days if prior nitrosourea).
- Must not have received a long-acting growth factor (eg, Neulasta) within 14 days or a short-acting growth factor within 7 days.
- Must not have received an antineoplastic targeted therapy within 14 days.
- Must not have received immunotherapy, eg, tumor vaccines, within 42 days.
- Must not have received monoclonal antibodies within at least 3 half-lives of the antibody after its last dose.
- Must not have received radiotherapy (XRT) within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if ≥50% radiation of pelvis.
- At least 84 days must have elapsed after stem cell infusion prior to study drug administration
- No evidence of active graft-versus-host disease (GVHD) and at least 100 days must have elapsed after allogeneic bone marrow transplant or stem cell infusion prior to study drug administration
- Participants must have adequate bone marrow function, defined as:
- Peripheral absolute neutrophil count (ANC) ≥1.0 × 10^9/liter (L).
- Platelet count ≥100 × 10^9/L (not receiving platelet transfusions within a 7-day period prior to study drug administration).
- Hemoglobin (Hb) at least 8.0 grams per deciliter (g/dL) at baseline (blood transfusions are allowed during the screening period to correct Hb values less than 8.0 g/dL).
- Participants must have adequate renal function, defined as:
- A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR), per protocol-specified criteria.
- Serum creatinine clearance or GFR ≥50 milliliters/minute/1.73 m^2, based on a 12 or 24 hours (h) urine creatinine collection.
- Participants must have adequate liver function, defined as:
- Bilirubin (sum of conjugated + unconjugated) ≤1.5 times the upper limit of normal (ULN) for age.
- Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN), unless there are bone metastases, in which case liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
- Serum albumin ≥2 g/dL.
- All participants and/or their parents or guardians must sign a written informed consent.
- Participants must be willing to comply with all aspects of the protocol.
- Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h before the first dose of study drug.
- Females of childbearing potential who:
- Do not agree to use a highly effective method of contraception for the entire study period and for 6 months after study drug discontinuation, ie:
- Total abstinence (if it is their preferred and usual lifestyle)
- An intrauterine device (IUD) or intrauterine system (IUS)
- A contraceptive implant
- An oral contraceptive OR
- Do not have a vasectomized partner with confirmed azoospermia.
- Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.
Waldenström’s macroglobulinaemia (WM) is a rare type of slow growing lymphoma. It develops when a certain type or types of white blood cells, grow abnormally. There are a number of standard treatments that are currently used in treating WM. Though the cancer often responds to these current treatments, at some point the cancer usually returns. Therefore there is a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. The PembroWM study will investigate whether the drugs rituximab (already used to treat WM) in addition to pembrolizumab (a type of immunotherapy designed to ‘re-awaken’ the immune system) will improve response to treatment. In this study, 42 adult (aged > = 18 years) patients with WM, whose disease has either come back or not responded to treatment, will be given pembrolizumab with rituximab. Treatment lasts for a maximum of 1 year with pembrolizumab given once every 3 weeks and rituximab a total of 7 times. Patients will be seen regularly during treatment and then yearly until the last patient entering the study completes their 2 year follow-up. The study will be conducted at NHS hospitals and is expected to last 4 years and 6 months.
1. Patients > = 18 years old 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 3. Presence of measurable disease, (defined as a serum IgM level of > 0.5g/L) and fulfils other World Health Organisation (WHO) diagnostic criteria for WM 4. Relapsed or refractory WM who have received > = 1 prior lines of therapy 5. Adequate renal function: estimated creatinine clearance > = 30ml/min as calculated using the Cockroft-Gault equation 6. Adequate liver function, including: o Bilirubin < = 1.5x the upper limit of normal (ULN), unless documented Gilbert’s syndrome o Aspartate or alanine transferase (AST or ALT) < = 2.5 x ULN 7. Adequate organ and bone marrow function: o Neutrophils > = 0.75x109/L o Platelets > = 50x109/L 8. Willing to comply with the contraceptive requirements of the trial 9. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP) 10. Written informed consent
1. Refractory to rituximab as defined by progression on/within 6 months of finishing a rituximab based regimen 2. Women who are pregnant or breastfeeding, or males expecting to conceive or father children at any point from the start of treatment until 4 months after the last administration of pembrolizumab 3. Clinically significant cardiac disease within 6 months prior to registration including unstable angina or myocardial infarction, uncontrolled congestive heart failure (NYHA class III-IV), and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. 4. History of significant cerebrovascular disease in last 6 months 5. Known central nervous system involvement of WM 6. Clinically significant active infection requiring antibiotic or antiretroviral therapy (including Hepatitis B, C or human immunodeficiency virus (HIV)) 7. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease 8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy 9. Active autoimmune disease apart from: o Type I diabetes or thyroid disease, controlled on medication o Skin conditions such as psoriasis, vitiligo or alopecia not requiring systemic treatment o Auto-immune thrombocytopenia, thought to be secondary to WM, provided that platelet count meet the criteria specified above, on daily doses of corticosteroid < = 10mg prednisolone or equivalent 10. Prior history of haemolytic anaemia (either warm or cold) 11. History of colitis 12. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis 13. Systemic anti-cancer therapy within 4 weeks prior to trial registration (except for BTK inhibitors, which may continue until cycle 1, day 1 of trial treatment) 14. Received a T cell depleting antibody (e.g. Campath) within 3 months prior to starting treatment 15. Received a live vaccine within 30 days prior to starting treatment 16. Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis 17. Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to starting treatment (unless prior agreed with the TMG) 18. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder) 19. Positive serology for Hepatitis B defined as a positive test for HepB surface antigen (HBsAg). Note: patients who are HepB core antibody (HBcAb) positive will only be eligible for the study if the HepB virus deoxyribonucleic acid (HBV DNA) test is negative and patients are willing to undergo monthly monitoring for HBV reactivation 20. Major surgery within 4 weeks prior to trial registration 21. Prior therapy with an anti-PD-1,anti-PD-L1 or CTLA4 monoclonal antibody 22. Prior allogeneic bone marrow transplantation 23. Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy or known HIV or acquired immunodeficiency syndrome (AIDS)-related illness 24. Current or prior use of immunosuppressive therapy within 7 days prior to start of treatment except the following: intranasal, inhaled, topical steroids or local steroid injections (eg. Intra-articular injections); systemic corticosteroids at physiologic doses (< 10mg/ day of prednisolone or equivalent) 25. Known or suspected hypersensitivity to components of pembrolizumab and/or rituximab (or other CD20 monoclonal antibody) 26. Current participation in any other clinical trial of an investigational medicinal product (CTIMP)
This study will compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in participants with poor-prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control after 3 cycles of first-line platinum based induction chemotherapy.
- Histologically-confirmed unresectable cancer of unknown primary site (CUP) diagnosed according to criteria defined in the 2015 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for CUP
- Each patient must provide a blood sample for genomic profiling
- No prior lines of systemic therapy for the treatment of CUP
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Candidate for platinum-based chemotherapy (according to the reference information for the intended chemotherapy)
- At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
- Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue sample
- No brain metastasis (pretreated brain metastasis without residual disease or leptomeningeal disease is accepted)
- Squamous cell CUP
- Participants belonging to any of the following subsets of CUP with favorable prognoses: Poorly differentiated carcinoma with midline distribution; women with papillary adenocarcinoma of the peritoneal cavity; women with adenocarcinoma involving only the axillary lymph nodes; squamous cell carcinoma of the cervical lymph nodes; poorly differentiated neuroendocrine tumors; men with blastic bone metastases and elevated prostate-specific antigen (PSA); participants with a single, small, potentially resectable tumor; colon cancer-type CUP, including participants with a CK7 negative, CK20 positive, CDX-2 positive immunohistochemistry profile
- Known presence of brain or spinal cord metastasis (including metastases that have been irradiated only)
- Histology and immunohistology profiles (per 2015 ESMO guidelines) that are not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma
- Immunohistochemistry profile that provides a definitive clinical indication of a primary cancer with a specific treatment
- History or known presence of leptomeningeal disease
- Known human immunodeficiency virus (HIV) infection
- Significant cardiovascular disease
- Prior allogeneic stem cell or solid organ transplantation
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or for up to 24 months after the last dose of study treatment
This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10%.
- Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, unresectable, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
- No evidence of metastatic disease by whole body positron emission tomography/computed tomography (PET/ CT) scan, diagnostic quality CT scan, and brain imaging.
- Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
- Have provided tumor tissue sample (core, incisional, or excisional biopsy).
- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Have adequate pulmonary function test (PFT)
- Have adequate organ function
- A male participant must agree to use contraception through the end of treatment and refrain from donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation
- Has small cell lung cancer.
- Has had documented weight loss > 10% in the preceding 3 months.
- Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving > 20 Gy in total (V20) of more than 31% of lung volume.
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (programmed cell death protein 1 [PD-1] and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 [PD-L2]) or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
- Has received a live vaccine within 30 days prior to the first dose of study drug.
- Has had an allogenic tissue/solid organ transplant.
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
- Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
- Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients.
- Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
- 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).
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by local health authority.
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
- 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.
- Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through the end of treatment.
A study designed to evaluate the safety and efficacy of venetoclax plus dexamethasone (VenDex) compared with pomalidomide plus dexamethasone (PomDex) in participants with t(11;14)-positive Relapsed or Refractory Multiple Myeloma.
Subjects randomized to Arm 2 (PomDex) may elect, if eligible, to receive VenDex therapy after documented disease progression per International Myeloma Working Group (IMWG) criteria.
- Documented diagnosis of multiple myeloma (MM) based on standard IMWG criteria.
- Measurable disease at screening as defined per protocol.
- Has received at least 2 prior lines of therapy as described in the protocol.
- Has had documented disease progression on or within 60 days after completion of the last therapy.
- Has received at least 2 consecutive cycles of lenalidomide and be refractory to lenalidomide, as defined per protocol.
- Has received at least 2 consecutive cycles of a proteasome inhibitor (PI).
- Has MM positive for t(11;14).
- An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
- Laboratory values (liver, kidney and hematology laboratory values) that meet criteria as described per protocol.
- History of treatment with venetoclax or another B-Cell Lymphoma (BCL)-2 inhibitor or pomalidomide.
- History of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years (exceptions described in the protocol).
- Evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT).
- Prior treatment with any of the following: allogeneic or syngeneic SCT within 16 weeks prior to randomization; or autologous SCT within 12 weeks prior to randomization.
- Known meningeal involvement of MM.
- Concurrent conditions as listed in the protocol.
Children and adults diagnosed with high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow will be treated for up to 93 weeks with naxitamab and granulocyte-macrophage colony stimulating factor (GM-CSF). Patients will be followed for up to five years after first dose.
Naxitamab, also known as hu3F8 is a humanised monoclonal antibody targeting GD2
Each patient will receive treatment for up to 93 weeks following the first Naxitamab administration and remain in the trial for 101 weeks. After the end of trial visit, each patient will enter a long-term follow-up where they will be monitored for up to 5 years after first treatment cycle.
Each investigational cycle is started with 5 days, days -4 to 0, of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) administered at 250 µg/m2/day in advance of the start of Naxitamab administration. GM-CSF is thereafter administered at 500 µg/m2/day on days 1 to 5. As standard treatment, Naxitamab is administered at 3 mg/kg/day on days 1, 3, and 5, totalling 9 mg/kg per cycle.
Treatment cycles are repeated every 4 weeks (±1 week) until complete response or partial response followed by 5 additional cycles every 4 weeks (±1 week). Subsequent cycles are repeated every 8 weeks (±2 weeks) through 101 weeks from first infusion at the discretion of the investigator. End of treatment will take place around 8 weeks after the last cycle and thereafter long-term follow-up will continue.
- Diagnosis of neuroblastoma as defined per International Neuroblastoma Response Criteria
- High-risk neuroblastoma patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including stable disease, minor response and partial response) evaluable in bone and/or bone marrow.
- Life expectancy ≥ 6 months
- Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks before 1st dose of GM-CSF
- Evaluable neuroblastoma outside bone and bone marrow
- Existing major organ dysfunction > Grade 2, with the exception of hearing loss, hematological status, kidney and liver function
- Active life-threatening infection
The main goal of this study is to show how the results of the Oncotype DX® test changes the decisions of physicians in the UK for women with ER-positive (ER+), early breast cancer (EBC) with 1-3 positive lymph nodes who are potential candidates for chemotherapy, but for whom the benefits of chemotherapy may be uncertain. This study will also assess how the results of the Oncotype DX assay affect the treatment preferences of the patient.
1. Patients must have undergone surgical treatment for breast cancer with adequate evaluation of lymph node status with a sentinel lymph node procedure or full axillary dissection, with positive involvement of 1-3 axillary lymph nodes as confirmed by histologic examination. 2. Patient must have adequate performance status (PS ECOG 0, 1) 3. Patient must be a candidate for treatment of their cancer with systemic chemotherapy in addition to hormonal therapy. 4. Patients should, in the treating physician’s judgment, represent the population for which the benefit of adding systemic chemotherapy to hormonal therapy is either unclear or may not be large enough to warrant the risk of undergoing chemotherapy. 5. Eligible Staging Criteria: - T1-3 N1, M0 (inclusive of N1mic) 6. Patient’s tumour must undergo central pathology review at Genomic Health Inc. (GHI) and must be found adequate for the Oncotype DX assay. 7. Patient’s tumour must be oestrogen-receptor positive (ER+, Allred score > 2) as per institutional guidelines and not have HER2 positive tumours by immunohistochemistry (IHC) or in situ hybridisation (ISH). 8. Patient must be over 18 years of age.
1. Patients have ER negative tumours (ER-, Allred score ≥ 2) 2. Patients have HER2 positive tumours (HER2+) as defined by IHC 3+ or HER2 gene amplified if tested by ISH 3. Patients have not had evaluation of lymph node involvement, have been deemed not to have lymph node involvement, or have only immunohistochemical confirmation (N0(i+)) of node involvement 4. Patients have a prior history of breast cancer in the same breast 5. Patients have been newly diagnosed with more than one operable primary breast tumour 6. Patients have multi-centric tumours (note: patients with multi-focal tumours may be included) 7. Patients have known metastatic breast cancer 8. Patients have < 2mm invasive tumour as assessed by local pathologist 9. Patients have received any kind of neo-adjuvant treatment 10. Patients have poor performance status (ECOG 2, 3, 4) and/or other clinical factors that would render the patient a non-viable candidate for adjuvant chemotherapy 11. Patients with a current medical condition such as psychiatric illness that would interfere with their ability to consent and participate in this study 12. Male patients with breast cancer
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.
- Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components ( less than [<] 50 percent [%] overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable
- Metastatic or surgically unresectable urothelial cancer
- Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization
- Cohort 1: Prior treatment with an anti-PD-(L) 1 agent as monotherapy or as combination therapy; no more than 2 prior lines of systemic treatment. Cohort 2: No prior treatment with an anti-PD-(L) 1 agent; only 1 line of prior systemic treatment. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic therapy in the metastatic setting.
- A woman of childbearing potential who is sexually active must have a negative pregnancy test (beta human chorionic gonadotropin [beta hCG]) at Screening (urine or serum)
- Participants must meet appropriate molecular eligibility criteria
- Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
- Adequate bone marrow, liver, and renal function
- Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to randomization
- Active malignancies (that is, requiring treatment change in the last 24 months). The only allowed exceptions are: urothelial cancer, skin cancer treated within the last 24 months that is considered completely cured, localized prostate cancer with a gleason score of 6 (treated within the last 24 months or untreated and under surveillance) and localized prostate cancer with a gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence.
- Symptomatic central nervous system metastases
- Received prior fibroblast growth factor receptor (FGFR) inhibitor treatment
- Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
- Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade.
- History of uncontrolled cardiovascular disease
- Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
Ovarian cancer (OC) is the most lethal gynaecological cancer. 1 in 52 women will be diagnosed with the disease in their lifetime and survival from the disease is highly dependent on the stage at diagnosis. At stage 1, 90% of women will survive their cancer for 5 years or more after diagnosis. At stage 3 this figure drops to 20% and then to just 5% at stage 4. Due to the non-specific nature of symptoms (bloating, abdominal discomfort) most affected women (70%) are diagnosed at advanced stage 3 or 4. The current blood test CA-125 is poor and only identifies 50% of Stage 1 ovarian cancers. Therefore, novel diagnostic tools to detect ovarian cancer are urgently needed. This study is examining new biomarkers based on steroid hormones. Hypothesis: Steroid hormone metabolites are of diagnostic value in detecting ovarian cancer. Aim: to explore the steroid metabolome in ovarian cancer compared to benign tumours and normal ovary through the following research questions: Q1. Does the steroid pathway differ in OC subtypes and benign tumours? Q2. Is there a steroid profile in urine that can identify OC subtypes or benign tumours? Q3. Can we equate gene expression with activity in the steroid pathway? Hormones have been implicated in ovarian cancer progression but their true role remains unexplained. We plan to use new technology such as mass spectrometry to search for hormone metabolites that can spot the disease early. To do so we will recruit patients with ovarian tumours (benign and malignant), obtain samples from them (urine, tissue and blood) and analyse them for steroid and other novel markers. As research progresses, novel markers hitherto unknown may also be tested. We will also be studying the genes expressed in OC to understand how changes in steroid hormone production may take place.
Women over the age of 18 years with capacity to give informed consent and from the following patient groups: 1. Patients having elective surgery for their ovaries to be removed(oophorectomy)for malignancy or benign related conditions. 2. Patients diagnosed with ovarian cancer and having surgery after a period of neo-adjuvant chemotherapy. 3. Patients having elective surgery (oophorectomy) for benign unrelated conditions.
1.Age < 18 years. 2.Patients who do not understand verbal or written English 3.Patients lacking capacity to consent
This is an open-label, dose-escalation Phase 1/2 study to assess the safety of ASTX660, determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and recommended dosing regimen, and to obtain preliminary efficacy, pharmacokinetic (PK), and target engagement data, in subjects with advanced solid tumors or lymphoma for whom standard life-prolonging measures are not available.
ASTX660 is a synthetic small molecule dual antagonist of cellular inhibitor of apoptosis protein (cIAP) 1 and X-linked inhibitor of apoptosis protein (XIAP) that has been shown to have potent proapoptotic and tumor growth inhibitory activity in nonclinical models. ASTX660 has not been previously evaluated in human subjects. The Phase 1 portion of the study will determine the MTD, RP2D, and recommended dosing regimen. The Phase 2 portion will evaluate activity in selected tumor types.
Subjects will continue to receive their assigned treatment throughout the study until the occurrence of disease progression, death, or unacceptable treatment-related toxicity, or until the study is closed by the sponsor.
Tolerability and safety of study treatment will be evaluated throughout the study by collection of clinical and laboratory data. In Phase 2, antitumor response will be assessed using computed tomography (CT) or magnetic resonance imaging (MRI) scans or other appropriate disease evaluation methods. In subjects with solid tumors, response will be evaluated according to standard Response Evaluation Criteria in Solid Tumors (RECIST v1.1; Appendix 3). In subjects with DLBCL and PTCL, antitumor response will be evaluated according to the 2014 Lugano classification (Appendix 5). In subjects with CTCL, global overall response criteria will be used, based on skin, blood, node, and viscera assessments (Appendix 4).
1. Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
2. Men and women 18 years of age or older.
3. Subjects with histologically or cytologically confirmed advanced solid tumors or lymphoma that is metastatic or unresectable, and for whom standard life-prolonging measures are not available. Specific tumor types that will be selected for study in Phase 2 are detailed in the protocol.
4. In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate for their type of cancer (as explained in Section 9.1).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
6. Acceptable organ function, as evidenced by the following laboratory data:
1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.0 * upper limit of normal (ULN).
2. Total serum bilirubin <= 1.5 * ULN
3. Absolute neutrophil count (ANC):
- Phase 1 and 2 (except Phase 2 subjects with known lymphoma) >= 1500 cells/mm3
- Phase 2 subjects with known lymphoma: >= 1000 cells/mm3 (> 750 cell/mm3 for subjects with lymphoma in bone marrow)
4. Platelet count:
- Phase 1 and 2 (except Phase 2 subject with known lymphoma) >= 100,000 cells/mm3
- Phase 2 subjects with known lymphoma: >= 50,000 cells/mm3; >= 25,000 cells/mm3 for subjects with lymphoma in bone marrow
5. Serum creatinine levels <= 1.5 * ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measure creatinine clearance >= 50 mL/min.
6. Amylase and lipase <=ULN [Applies to Phase 2].
7. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment. Contraceptive measures which may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of birth control.
1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen.
2. Poor medical risk because of systemic diseases (e.g. active uncontrolled infections) in addition to the qualifying disease under study.
3. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of ASTX660.
4. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
1. Abnormal left ventricular ejection fraction (LVEF; < 50%) or echocardiogram ECHO or multiple gated acquisition scan (MUGA). [Applies to Phase 1 only; ECHO/MUGA scans are not performed in Phase 2.]
2. Congestive cardiac failure of >= Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest.
3. Unstable cardiac disease including angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
4. History or presence of complete left bundle branch block, heart block, cardiac pacemaker or significant arrhythmia.
5. Concurrent treatment with any medical that prolongs QT interval and may induce torsades de pointes, and which cannot be discontinued at least 2 weeks before treatment with ASTX660. [Applies to Phase 1 only].
6. Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
7. Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett's correction) of >= 470 msec).
5. Known history of human immunodeficiency virus (HIV) infection, or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
6. Grade 2 or greater neuropathy [Applies to Phase 1]. Grade 3 or greater neuropathy [Applies to Phase 2].
7. Known brain metastases, unless stable or previously treated.
8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
9. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX660), as follows:
- Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
- Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
- Investigational drugs (small molecules or biologics) within the longer of 2 weeks or 5 half-lives prior to study treatment and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
This is a prospective study for the long-term follow-up (LTFU) of safety and efficacy for all pediatric and adult subjects exposed to Gene-modified (GM) T cell therapy participating in a previous Celgene sponsored or Celgene alliance partner sponsored study.
Subjects who received at least one GM T cell infusion, will be asked to roll-over to this LTFU protocol upon either premature discontinuation from, or completion of the prior parent treatment protocol.
Subjects participating in this study will be followed from time of roll-over from the parent GM T protocol until 15 years after the last GMT infusion, withdrawal of consent, lost to follow-up, or death, whichever occurs first. Both local and central laboratory evaluations and safety assessments will be conducted during this trial. In addition, pediatric subjects will be monitored for growth, development and sexual maturity.
Stage 5 per Tanner Staging Criteria must be reached prior to study discontinuation.
Subjects who meet the following criteria will be eligible to participate in the Long-Term Follow-Up study:
1. All adult and pediatric subjects who received at least one GM T cells infusion in a previous Celgene sponsored or Celgene alliance partner sponsored study, and have discontinued, or completed the post-treatment follow-up period in the parent treatment protocol, as applicable.
2. Subject (and, parental/legal representative, when applicable) must understand and voluntarily sign an Informed Consent Form/Informed Assent Form prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
All UK patients who participated in the TARGIT-A Trial were initially treated for early breast cancer between 2000-2012. A total of 3451 patients from 33 hospitals in 11 countries participated in the trial and a comparison was made between traditional radiotherapy given over several weeks (external beam radiotherapy, EBRT) with TARGeted Intraoperative radioTherapy (TARGIT-IORT) as a single dose given during the operation to remove the breast cancer. The trial was funded by the Health Technology Assessment (HTA) programme of the Department of Health, UK and sponsored by University College London. The results from this trial have been published in major medical journals and have already started changing the way breast cancer in treated around the world; please see www.targit.org.uk for more details. We would like to continue to collect data about the health status of all patients to enable us to learn about longer term differences in the effects of these treatments on health. An analysis of this information could improve treatment for patients with breast cancer. For this, HTA have granted us further funding.
All patients who participated in the TARGIT-A trial.
1. Any patient who has withdrawn consent for further follow-up, or died. 2. Any patient who is unable to give formal written consent.
At present, there are no means of predicting if patients' symptoms are due to bowel cancer. When patients present to their GP with bowel symptoms that need investigating, they will be referred for a colonoscopy. We are conducting a study that aims to determine whether the Faecal Immunochemical Test (FIT) can be used in the future as an effective tool to identify patients at risk of bowel cancer. In 2005, NICE introduced guidelines where patients with certain symptoms that are associated with a high probability of bowel cancer are referred under the two week rule to secondary care for investigations. These patients must be seen within two weeks of referral and if a cancer is diagnosed, patients must be treated within 62 days of referral. The vast majority of patients referred undergo an endoscopic examination either a colonoscopy (to view the whole colon) or a flexible sigmoidoscopy (to view the left side of the colon) to confirm whether a patient has an underlying cancer or not. However, only 10-15% of these referrals have underlying bowel cancer or significant pathology such as precancerous polyps. The remaining patients do not have significant pathology. In 2015, NICE expanded the criteria significantly in order to increase the pick up rates of bowel cancer from these two week referrals. This means that a large number of patients unnecessarily undergo endoscopic examination with the associated risk of bowel perforation, sedation and the procedure itself. This also strains the cash-strapped resources of the NHS. The FIT test is a simple one-off stool test that patients can do at home and has shown promise in predicting bowel cancer in both the screening (Moss et al 2016) and symptomatic (MacDonald et al 2015, Auge et al 2015, Mowat et al 2015, Cubiella et al 2015) patient settings.
Referred for colonoscopy under 2 week rule for suspected colorectal cancer Informed consent
Unable to give informed consent Stool sample taken during bowel preparation Unable to take adequate stool sample Unable to complete bowel preparation Unable to tolerate complete colonoscopic examination
This is an open-label, Phase 1/2a dose escalation study with an expansion phase to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy of CORT125281 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) to identify a recommended dose (RD) for Phase 2 studies.
CORT125281 is a selective glucocorticoid receptor (GR) antagonist. In this study, CORT125281 will be administered orally in combination with enzalutamide to patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the regimen. The study consists of two phases: a dose-escalation phase and an expansion phase. The dose escalation phase is designed to determine DLTs, MTD/biologically active doses and the RD of CORT125281 plus enzalutamide in patients with mCRPC. Once the recommended dose has been determined, the following expansion cohorts will be enrolled and treated with CORT125281 plus enzalutamide at the recommended dose level.
1. Patients who have progressed during treatment with abiraterone, and have received no other androgen receptor (AR)-blocking therapies
2. Patients who have progressed during treatment with enzalutamide or other second-generation AR inhibitors.
The effect of food on CORT125281 PK will be assessed in a portion of the patients enrolled in the Expansion Phase. The expansion cohorts will be enrolled in parallel.
In each phase of the study, routine assessments of safety and tolerability will be performed using adverse event (AE) monitoring, measurement of vital signs, recording 12 lead electrocardiogram (ECG), physical examination and clinical laboratory safety tests, and samples will be collected to determine standard PK parameters for CORT125281, enzalutamide, and their major metabolites. PD, quality of life evaluations and preliminary evaluations of anti-tumor activity of CORT125281 with enzalutamide will be performed throughout the study.
- Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures, and provide written informed consent
- Males ≥18 years of age at the time of signing consent
- Histologically confirmed metastatic adenocarcinoma of the prostate without histological neuroendocrine differentiation or small cell features
- Prior surgical or chemical castration with serum testosterone < 1.7 nmol/L (50 ng/dL). If the method of castration is use of a luteinizing hormone releasing hormone (LHRH) analogue,there must be a plan to maintain effective LHRH analogue treatment for the duration of the trial
- Progressive disease by PSA or imaging after most recent prior therapy. PSA ≥1 ng/mL, if a confirmed rise in PSA is the only indication of progression. Progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥ 1 week apart. PSA measurements can be collected during or after most recent prior therapy.
- Consent to have all protocol required pharmacodynamic biomarker samples, including the pretreatment and on treatment paired tumor biopsies (mandatory for a subset of patients).
- Consent to provide mandatory pharmacogenomic blood sample.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate baseline organ function within 14 days prior to the first dose of enzalutamide and/or CORT125281
- Patients receiving systemic corticosteroids greater than 2-weeks in duration within 3 months of study entry or with clinical evidence of adrenal insufficiency must have evidence of adequate adrenal function based upon morning plasma cortisol concentration or ACTH (cosyntropin) stimulation test
- If a patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 100 days after completing treatment with CORT125281 or enzalutamide. A condom is required during and for 100 days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least 100 days after the final treatment administration.
- Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy, as follows:
- Cohort A: Patients must have progressed during treatment with abiraterone
- Cohort B: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide 160 mg once daily (QD). These patients will continue enzalutamide without interruption during the screening period (no wash-out period required).
- Received chemotherapy, non-palliative radiotherapy, immunotherapy, or any investigational cancer therapies within 21 days prior to the first dose of CORT125281, or treatment with such therapies is planned during protocol treatment. Concomitant anticancer therapy is not permitted during the enzalutamide Lead-in Period during dose escalation.
- More than two prior cytotoxic chemotherapy regimens for the treatment of mCRPC
Dose Escalation Phase and Expansion Phases will exclude patients for the following:
- Dose Escalation Phase
- Progressed during treatment with enzalutamide prior to Cycle 1 Day -28 (only applies to patients receiving enzalutamide Lead-in) or
- Received prior 2nd generation anti-androgen and require urgent disease response or stabilization
- Expansion Phase Cohort A:
- Received prior treatment with enzalutamide, or
- Received prior 2nd generation anti-androgen and require urgent disease response or stabilization
- Expansion Phase Cohort B: Require urgent disease response or stabilization
- Ongoing or anticipated therapy with hormone therapy (other than LHRH antagonist), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within 28 days prior to the first dose of CORT125281
- Contraindication or precaution for enzalutamide
- Parenchymal brain metastases
- Any clinically significant uncontrolled condition that may increase the risk to the study patient or that the Investigator considers places the patient at unacceptable risk
- Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity (e.g., saw palmetto, PC-SPES, PC- HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 28 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study
- Received systemic glucocorticoids within 21 days prior to the first dose of CORT125281, or requirement for chronic or frequently used systemic glucocorticoids for medical conditions (e.g., rheumatoid arthritis, immunosuppression after organ transplantation). Short courses (< 5 days) for non-cancer related reasons are allowed if clinically required (such as prophylaxis for CT).
- Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 or with sensitive substrates of CYP3A4, CYP2C9 or CYP2C19
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.
-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 -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
A study to evaluate Nivolumab or Nivolumab Plus Experimental Medication BMS-986205 with or without BCG in BCG-Unresponsive non-muscle invasive Bladder Cancer
- Pathologically demonstrated BCG-unresponsive, high-risk non-muscle-invasive bladder cancer (NMIBC) defined as CIS with or without papillary component, any T1, or Ta high-grade lesions
- Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Sign of locally advanced disease or metastatic bladder cancer
- Urothelial cancer (UC) in the upper genitourinary tract (kidneys, renal collecting systems, ureters) within 24 months of enrollment
- Prior immuno-oncology therapy
Other protocol defined inclusion/exclusion criteria could apply
The purpose of the study is to evaluate the efficacy, safety and tolerability and of BGB-3111plus obinutuzumab versus obinutuzumab alone in subjects with relapsed/refractory non-Hodgkin follicular lymphoma.
This is an open-label, randomized active control study of BGB-3111 plus obinutuzumab versus obinutuzumab alone in subjects with relapsed or refractory follicular lymphoma. Randomization is 2:1 and subjects will be stratified by the number of prior lines of therapy (2 - 3 vs > 3) and rituximab-refractory status. The study will evaluate the efficacy, as measured by overall response rate by independent review, safety and tolerability. Pharmacokinetic profile of BGB-3111 and obinutuzumab combination therapy will also be evaluated.
1. Histologically confirmed diagnosis of B-cell follicular lymphoma based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue.
2. ≥2 prior systemic treatments for follicular lymphoma.
3. Previously received an anti-CD20 antibody and an appropriate alkylator-based combination therapy.
4. Disease progression within 12 months after completion of most recent therapy or refractory disease.
5. Presence of measurable disease.
6. Availability of archival tissue confirming diagnosis.
7. ECOG performance status of 0,1 or 2.
8. Life expectancy ≥6 months.
9. Adequate bone marrow function.
10. Adequate renal and hepatic function.
11. Females of childbearing potential and non-sterile males must agree to use highly effective methods of birth control throughout the course of study and at least up to 90 days after last dosing, or 18 months after the last dose of obinutuzumab, whichever is longer.
12. Male subjects are eligible if vasectomized or if they agree to the use of barrier contraception in combination with other methods during the study treatment period and for ≥ 90 days after the last dose of BGB-3111.
13. Ability to provide the written informed consent and can understand and comply with the requirements of the study.
1. Prior exposure to a BTK inhibitor.
2. Known central nervous system involvement by leukemia or lymphoma.
3. No evidence of transformation from follicular lymphoma to other aggressive histology.
4. No allogeneic hematopoietic stem cell transplantation within 12 months of enrollment
5. Prior malignancy within the past 5 years, except for basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix of breast, or localized Gleason score 6 prostate
6. Clinically significant cardiovascular disease.
7. Major surgery or significant injury ≤ 4 weeks prior to start of study treatment.
8. Active fungal, bacterial or viral infection requiring systemic treatment.
9. History of severe bleeding disorder.
10. History of stroke or intracranial hemorrhage within 6 months before first study drug.
11. Severe or debilitating pulmonary disease.
12. Known human immunodeficiency virus (HIV) or active hepatitis B or C.
13. Unable to swallow capsules or significant gastrointestinal disease that would interfere with drug absorption.
14. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
15. Pregnant or nursing females.
16. Vaccination with live vaccine within 35 days prior to first dose.
17. Ongoing drug or alcohol addiction.
18. Hypersensitivity to BGB-3111, known ingredients of BGB-3111 or obinutuzumab.
19. Participation in another therapeutic trial.
This is a randomized, open-label, multi-center, global, phase III study to determine the efficacy and safety of Durvalumab + BCG combination therapy in the treatment of patients with non-muscle-invasive bladder cancer.
Patients will be randomized in a 1:1:1 ratio to receive treatment with Durvalumab + BCG combination therapies, or Standard of Care (SoC) therapy.
- Aged at least 18 years
- BCG-naïve (patients who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry are eligible)
- Local histological confirmation (based on pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa. A high risk tumor is defined as one of the following
- T1 tumor
- High grade/ G3 tumor
- Multiple and recurrent and large (with diameter of largest tumor ≥3 cm) tumors (all conditions must be met in this point)
- Complete resection of all Ta/T1 papillary disease prior to randomization, with the TURBT removing high-risk NMIBC performed not more than 4 months before randomization in the study. Patients with residual CIS after TURBT are eligible
- No prior radiotherapy for bladder cancer
- No prior exposure to immune-mediated therapy of cancer including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 antibodies. Patients who have been treated with anticancer vaccines will be excluded
- Evidence of muscle-invasive, locally advanced, metastatic, and/or extra vesical bladder cancer (ie, T2, T3, T4, and / or stage IV)
- Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium
- Previous investigational product (IP) assignment in the present study
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is acceptable. Chemotherapy for previous instances of NMIBC is acceptable.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
- Patients with celiac disease controlled by diet alone
- History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of IP and of low potential risk for recurrence during the study period
- Adequately treated nonmelanoma skin cancer or lentigo maligna withoutevidence of disease
- Adequately treated CIS without evidence of disease
- Prostate cancer (tumor/node/metastasis stage) of stage ≤ T2cN0M0 without biochemical recurrence or progression that in the opinion of the Investigator does not require active intervention
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
This study evaluates the safety of acalabrutinib and AZ6738 when taken in combination.
- Diagnosis of relapsed or refractory CLL that meets published diagnostic criteria (International Workshop on Chronic Lymphocytic Leukemia [IWCLL] Hallek 2008) and supported/documented by medical records
- Subjects must be Relapse/Refractory high risk CLL and have exhausted other therapeutic options according to local/regional standard of care
- Must have received ≥1 prior therapy for treatment of their disease.
- A diagnosis of ataxia telangiectasia
- Any prior exposure to an ATR inhibitor or known hypersensitivity to an excipient of the product.
- Known history of infection with human immunodeficiency virus (HIV).
This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib [AZD1775]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+AZD6738 and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.
This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib) in second or third line setting in patients with TNBC prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the HRR pathway.
Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous in a 28-day cycle, Arm 2: AZD6738 Days 1-7 with olaparib continuous in a 28-day cycle or Arm 3: adavosertib Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Following closure of this arm the randomisation ratio will be 1:1 to olaparib monotherapy or AZD6738+olaparib. Patients who were receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).
The study subject population will be divided into Stratum A (patients with mutations in BRCA1 or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of the HRR genes). Within each stratum A, B and C, there will be further stratification by whether the patient received prior platinum-based therapy.
In the olaparib monotherapy treatment arm as well as in the AZD6738+olaparib treatment arm, patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib tablets will be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL). In the adavosertib+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and adavosertib 150 mg bd from Day 1 to Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. AZD6738 will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered AZD6738 od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg of AZD6738 tablets will be taken at the same time on each day of dosing with approximately 250 mL of water. Adavosertib will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. Adavosertib will be taken with approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib, AZD6738 and adavosertib will be provided by AstraZeneca.
Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5 patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and Non HRRm patient populations. Tumour and germline mutation status will be analysed only in the all patient population. PK outcome measures will be analysed only in the all patient population. Blinded Independent Central Review (BICR) of radiological imaging data will be carried out using RECIST version 1.1 and Investigator assessments will also be analysed for sensitivity purposes.
Pertinent Inclusion criteria:
1. Informed consent prior to any study specific procedures.
2. Male or female ≥18 years of age.
3. Progressive cancer at the time of study entry.
4. Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013.
5. Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting.
6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.
7. At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).
9. ECOG PS 0-1 within 28 days of randomisation.
10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).
11. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks.
This is a Phase 1a/1b, open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, immune response, and pharmacokinetics of RO7198457 as a single agent and in combination with atezolizumab (MPDL3280A, an engineered anti-programmed death-ligand 1 [anti-PD-L1] antibody).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy greater than or equal to (>= 12 weeks)
- Adequate hematologic and end-organ function
- Measured or calculated creatinine clearance >= 50 milliliters per minute (mL/min) on the basis of the Cockcroft-Gault glomerular filtration rate estimation
Cancer-Specific Inclusion Criteria:
- Participants with histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care
- Participants with confirmed availability of representative tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks (preferred), or sectioned tissue
- Participants with measurable disease per RECIST v1.1
Additional Inclusion Criteria for Participants in Each Indication-Specific Exploration/Expansion Cohort of Phase 1b:
- NSCLC Cohorts (CIT-Naïve): Participants with histologically confirmed incurable, advanced NSCLC not previously treated with anti-PD−L1/PD-1 and/or with anti-CTLA−4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD−L1/PD-1 antibody is considered an acceptable treatment option (if CIT [including anti-PD−L1/PD-1 agents] is approved as treatment for NSCLC by local regulatory authorities).
- NSCLC Cohort (CIT-Treated): Participants with histologically confirmed incurable, advanced NSCLC previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)
- Triple negative breast cancer (TNBC) Cohort (CIT-Naïve): Participants with histologically confirmed incurable, advanced estrogen receptor (ER)-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast (triple-negative) not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
- Colorectal cancer (CRC) Cohort (CIT-Naïve): Participants with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
- Head and neck squamous cell carcinoma (HNSCC) Cohort (CIT-Naïve): Participants with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent HNSCC (oral cavity, oropharynx, hypopharnyx, or larynx) not amenable to curative therapy not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
- Urothelial carcinoma (UC) Cohort (CIT-Naïve): Participants with histologically confirmed incurable, advanced transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, and urethra, not previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD−L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD−L1/PD-1 agents) is approved as treatment for UC by local regulatory authorities
- UC Cohort (CIT-Treated): Participants with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)
- Renal cell carcinoma (RCC) Cohort (CIT-Naïve): Participants with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
- Melanoma Cohort (CIT-Naïve in metastatic setting): Participants with histologically confirmed incurable, advanced melanoma not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved) in the metastatic setting
- Melanoma Cohort (CIT-Treated): Participants with histologically confirmed incurable, advanced melanoma previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
Additional Inclusion Criteria for Participants in the Serial-Biopsy Expansion Cohort of Phase 1b
- Participants must have one of the locally advanced or metastatic solid tumor types specified in the protocol.
- Participants must have accessible lesion(s) that permit a total of two to three biopsies (pretreatment and on-treatment) or one biopsy (on-treatment, if archival tissue can be submitted in place of a pre-treatment biopsy) without unacceptable risk of a significant procedural complication. RECIST lesions should not be biopsied.
- Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse
- Major surgical procedure within 28 days prior to Cycle 1, Day 1, or anticipation of need for a major surgical procedure during the course of the study
- Any other diseases, metabolic dysfunction, physical examination finding, and/or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or may render the participant at high risk from treatment complications
- Previous splenectomy
- Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency)
- Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study Cancer-Specific Exclusion Criteria
- Any anti-cancer therapy, whether investigational or approved, including chemotherapy, hormonal therapy, and/or radiotherapy, within 3 weeks prior to initiation of study treatment, with the exceptions as mentioned in the protocol
- Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort for which the participant is being considered, as described below. In addition, all criteria pertaining to adverse events attributed to prior cancer therapies must be met
All Cohorts (Dose-Escalation in Phase 1a and Dose-Escalation, Backfill, and Expansion in Phase 1b):
- Prior neoantigen-specific or whole-tumor cancer vaccines are not allowed, with the exception as specified in protocol
- Prior treatment with cytokines is allowed provided that at least 6 weeks or 5 half-lives of the drug, whichever is shorter, have elapsed between the last dose and the proposed Cycle 1, Day 1
- Prior treatment with immune checkpoint inhibitors, immunomodulatory monoclonal antibody (mAbs), and/or mAb-derived therapies is allowed provided that at least 6 weeks (Phase 1a) or 3 weeks (Phase 1b) have elapsed between the last dose and the proposed Cycle 1, Day 1, with the exceptions as specified in protocol Phase Ib Dose-Exploration/Expansion Group Only Cohorts
- In the CIT-Naïve expansion cohort in Phase Ib, prior treatment with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved), is not allowed.
- In the melanoma CIT-naïve expansion cohort in Phase Ib, prior treatment with anti-PD- L1/PD-1 and/or anti-CTLA-4 (investigational or approved) in the metastatic, is not allowed.
- Prior treatment with immunomodulators, including toll-like receptor (TLR) agonists, inhibitors of indoleamine 2,3-dioxygenase (IDO)/ tryptophan-2,3-dioxygenase (TDO), or agonists of OX40, is allowed provided that at least 5 half-lives of the drug or a minimum of 3 weeks have elapsed between the last dose of the prior treatment and the proposed Cycle 1, Day 1, with the exception as specified in protocol
- Any history of an immune-related Grade 4 adverse event attributed to prior CIT (other than endocrinopathy managed with replacement therapy or asymptomatic elevation of serum amylase or lipase)
- Any history of an immune-related Grade 3 adverse event attributed to prior CIT (other than hypothyroidism managed with replacement therapy) that resulted in permanent discontinuation of the prior immunotherapeutic agent and/or occurred less than or equal to (<=) 6 months prior to Cycle 1 Day 1
- Adverse events from prior anti-cancer therapy that have not resolved to Grade <= 1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy
- All immune-related adverse events related to prior CIT (other than endocrinopathy managed with replacement therapy or stable vitiligo) must have resolved completely to baseline
- Primary central nervous system (CNS) malignancy, untreated CNS metastases, or active CNS metastases (progressing or requiring corticosteroids for symptomatic control)
- Leptomeningeal disease
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Malignancies other than disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death
- Uncontrolled hypercalcemia
- Participant has spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >= 2 weeks prior to screening
Treatment-Specific Exclusion Criteria:
- History of autoimmune disease with caveats as specified in protocol
- Treatment with monoamine oxidase inhibitors (MAOIs) within 3 weeks prior to Cycle 1, Day 1
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1
- History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- Positive test for human immunodeficiency virus (HIV) infection
- Active hepatitis B, hepatitis C
- Known active or latent tuberculosis infection
- Severe infections within 4 weeks prior to Cycle 1, Day 1
- Recent infections not meeting the criteria for severe infections within 2 weeks prior to Cycle 1, Day 1
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
- Known hypersensitivity to the active substance or to any of the excipients in the vaccine
- Phase 1b and crossover only: History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins; Known hypersensitivity to Chinese Hamster Ovary (CHO)-cell products; Allergy or hypersensitivity to components of the atezolizumab formulation
This is a modular, Phase I/II, multicentre study to investigate the optimal monotherapy dose of CT7001 in advanced solid malignancies (Module 1A) and to further investigate the monotherapy dose of CT7001 in specific participant groups (Module 1B). Further modules will be added as substantial protocol amendments. A food-effect study of CT7001 monotherapy in advanced solid malignancies (Module 4) is ongoing. A study of combination doses of CT7001 with fulvestrant in hormone receptor-positive (HR+ve) / human epidermal growth factor-2 negative (HER2-ve) breast cancer (Module 2) is planned to start in 2019.
Module 1 comprises two sequential parts:
- Part A: First-in-human (FiH) dose escalation investigating the safety and tolerability of CT7001 to identify the minimum biologically active dose (MBAD) and maximum tolerated dose (MTD). Part A also includes a cohort expansion for breast cancer participants only: this includes sequential tumour biopsies for evaluation of pharmacokinetic (PK), pharmacodynamic (PD) and tumour responses. Part A has now completed recruitment (39 participants dosed) and has identified the MBAD as 120mg once daily and the MTD as 360mg once daily. The recommended dose to take forward to Phase II is 360mg.
- Part B: To refine the safety, tolerability, and PK and PD profiles of CT7001 in participants with advanced solid malignancies from up to four tumour-specific cohorts, which may include, but is not limited to, triple-negative breast cancer, ovarian cancer, small-cell lung cancer and prostate cancer.
- Part B, Cohort 1, Triple-Negative Breast Cancer (M1B-1 TNBC) will recruit up to 50 participants treated with a 360mg daily dose of CT7001 as monotherapy. Recruitment is currently open.
- Part B, Cohort 2, Prostate Cancer (M1B-2 CRPC) will recruit up to 25 participants treated with a 360mg daily dose of CT7001 as monotherapy. Recruitment is not yet open.
- Additional Module 1B Cohorts of up to 25 participants each may be added in the future.
Module 4 is a study investigating the effect of food on the PK of CT7001 monotherapy in participants with advanced solid malignancies. Up to 24 participants will be recruited. Recruitment is currently open.
Module 2 is a Phase Ib/II, 3-part safety and efficacy study in participants with hormone-receptor positive (HR+ve) and human epidermal growth factor-2 negative (HER2-ve) breast cancer. This module will recruit up to 75 participants and will dose CT7001 in combination with fulvestrant. Part B will be single-blind, randomized and placebo-controlled.
1. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks
2. Estimated life expectancy of greater than 12 weeks
3. Ability to swallow and retain oral medication
4. Women either of non-childbearing potential or of childbearing potential willing to practice effective contraception for the duration of the study and for 6 months (Module 1, Module 4) and 12 months (Module 2) after the last dose of CT7001
5. Men, if sexually active, must be willing to use condoms for the duration of the study and for 3 months after the last dose of CT7001
6. Provision of signed and dated, written informed consent
1. Any other malignancy that has been active or treated within the past 3 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer
2. Any unresolved toxicity (except alopecia) from prior therapy of ≥ CTCAE Grade 2
3. Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the first dose of investigational product (IP)
4. Refractory nausea and vomiting, chronic gastrointestinal (GI) disease or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of CT7001
5. Uncontrolled seizures
6. Active infection requiring systemic antibiotic, antifungal, or antiviral medication
7. Severe or uncontrolled medical condition or psychiatric condition
8. Active bleeding diatheses
9. Renal transplant
[continue, please contact lead site for more details]
The purpose of this study is to compare the efficacy of maribavir to valganciclovir for the treatment of cytomegalovirus (CMV) infection in asymptomatic hematopoietic stem cell transplant (HSCT) recipients.
- Be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures. As applicable, a parent/both parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the participants before completing any study-related procedures.
- Be greater than or equal to (>=) 16 years of age at the time of consent.
- Be a recipient of hematopoietic stem cell transplant.
- Have a documented asymptomatic CMV infection, with a screening value of CMV DNA >= 1365 International Units per millilitre (IU/mL) to less than or equal to (<=) 273000 IU/mL in whole blood or >= 455 IU/mL to <= 91000 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to randomization with second sample obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator. Participants with CMV DNA less than (<) 910 and >= 455 IU/mL in plasma or < 2730 and >= 1365 IU/mL in whole blood will also need to meet at least 1 of the following criteria for high-risk CMV infection to be eligible:
1. Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 1 of the following 3 HLA-gene loci: HLA-A, -B or -DR,
2. Haploidentical donor
3. Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: HLA-A, -B, -C and -DRB1,
4. Use of umbilical cord blood as stem cell source,
5. Use of ex vivo T-cell-depleted grafts,
6. Grade 2 or greater graft-versus-host-disease (GVHD), requiring the use of systemic corticosteroids (defined as the use of >= 1 milligram per kilogram per day (mg/kg/day) of prednisone or equivalent dose of another corticosteroid).
- Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation, which in the investigator's opinion requires treatment.
- Per investigator's judgment, be eligible for treatment with valganciclovir.
- Have all of the following results as part of screening laboratory assessments (results from either the central laboratory or a local laboratory can be used for qualification):
1. Absolute neutrophil count to >= 1000 per cubic millimeter (/mm^3) [1.0 x 10^9/L].
2. Platelet count >= 25,000/mm^3 [25 x 10^9/L].
3. Hemoglobin >= 8 grams per deciliter (g/dL).
4. Estimated creatinine clearance >= 30 milliliters per minute (mL/min).
- Have a negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test at screening, if a female of child bearing potential. Urine pregnancy tests may be done per institutional requirements; however they are not sufficient for eligibility determination. Sexually active females of child bearing potential must agree to comply with any applicable contraceptive requirements of the protocol. If male, must agree to use an acceptable method of birth control, as defined in the protocol, during the study treatment administration period and for 90 days afterward the last dose of study treatment.
- Be able to swallow tablets.
- Have life expectancy of >= 8 weeks.
- Weigh >= 40 kilograms (kg).
- Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol.
- Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0.
- Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence.
- Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a participants who had at least one previously documented episode of CMV infection post-transplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes during active surveillance, based on same local laboratory and same sample type). The Participants must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection.
- Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] co-infection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection.
- Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated.
Note: Participants who may be receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Participants receiving letermovir must discontinue use 3 days prior to first dose of study treatment. Participants receiving artesunate must discontinue the use prior to the first dose of study treatment.
- Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or cidofovir) for the current CMV infection for longer than 72 hours.
- Have known hypersensitivity to the active substance or to an excipient of the study treatments.
- Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the first dose of study treatment that would preclude administration of oral medication.
- Require mechanical ventilation or vasopressors for hemodynamic support at the time of randomization.
- Be female and pregnant or nursing
- Have previously completed, discontinued, or have been withdrawn from this study.
- Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or CMV vaccine at any time.
- Have received any unapproved agent or device within 30 days before initiation of study treatment.
- Have any clinically significant medical or surgical condition that, in the investigator's opinion, could interfere with interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the participant.
- Have previously received maribavir.
- Have serum aspartate aminotransferase (AST) greater than (>) 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) > 5 times ULN at screening, or total bilirubin >= 3.0 x ULN at screening (except for documented Gilbert's syndrome), as analyzed by local or central lab.
- Have known (previously documented) positive results for human immunodeficiency virus (HIV). Participants must have a confirmed negative HIV test result within 3 months of study entry or, if unavailable, be tested by a local laboratory during the screening period.
- Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Participants who experience relapse or progression of their underlying malignancy (for which HSCT was performed), as determined by the investigator, are not to be enrolled.
- Be undergoing treatment for acute or chronic hepatitis C
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.
• 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
•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.
Metastatic melanoma has a poor prognosis if untreated. Recently, two types of drugs which activate the immune system have been shown to extend survival. The most active are those which target a molecule known as PD1. Two anti-PD1 drugs, pembrolizumab and nivolumab, are licensed to treat metastatic melanoma and are becoming the initial treatment of choice, in the UK and worldwide. Pembrolizumab and nivolumab are given as intravenous infusions every 2 or 3 weeks for as long as there is benefit. Anti-PD1 drugs are given continuously because that is how they were given in trials, but there is no biological evidence for this. Up to 40% of patients remain on treatment after 1-2 years. The drugs seem to make most difference within the first year of treatment. There is no evidence that continuing treatment beyond 1 year brings any benefit. It is possible that shorter durations may be equally effective, with fewer side-effects. Continuing treatment exposes patients to potentially severe immune-related side-effects. Also, the burden of continuous treatment is significant, as patients must attend clinic before each treatment for safety checks. There is evidence that some patients continue to respond even after treatment has stopped. This study will assess whether treatment with anti-PD1 drugs can be stopped after 1 year. Consenting patients will, after 12 months of treatment, be randomly allocated to stop treatment, or to continue for as long as there is benefit (the current standard). All patients will be closely monitored for response and to assess and manage side-effects. The main goal is to compare how long patients in the two groups live without melanoma re-growing. If the trial shows that anti-PD1 drugs can be given for a shorter time compared with standard recommendations, without compromising their effectiveness and safety, these findings will change clinical practice worldwide.
Eligibility for REGISTRATION • Histologically or cytologically confirmed unresectable stage III or stage IV (metastatic) melanoma, including cutaneous and non-cutaneous melanoma • Aged > = 18 years • Planned or currently receiving (< 12 months) treatment with first-line pembrolizumab or nivolumab • Written informed consent for registration Inclusion criteria for RANDOMISATION • Registered in DANTE • Progression-free by RECIST v1.1 criteria at 12 months (+/- 4 weeks) from the start of pembrolizumab or nivolumab • 12 months (+/- 4 weeks) from start of pembrolizumab or nivolumab • Eastern co-operative oncology group (ECOG) performance status 0-2 • Considered fit by the treating clinician to continue to receive ongoing treatment with pembrolizumab or nivolumab • Written informed consent for randomisation
Exclusion criteria for RANDOMISATION • Severe co-morbidities, including severe auto-immune disease or pneumonitis • Active infection requiring systemic therapy • Known history of HIV, hepatitis B or C • Other malignancy within past 5 years, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers • Pregnant, breast-feeding or patients with reproductive potential (female and male) unwilling to use adequate contraception while receiving anti-PD1 therapy and for 6 months after the last dose. Women of reproductive potential are defined as: following menarche and until becoming post-menopausal, unless permanently sterile. Men of reproductive potential are defined as: post-pubescent and not sterile by vasectomy or bilateral orchidectomy. • Prior systemic treatment for advanced melanoma, including ipilimumab and combination ipilimumab and nivolumab, other than BRAF and MEK inhibitors and the current treatment for advanced melanoma. Prior adjuvant or neo-adjuvant therapy is allowed as long as it was completed at least 12 months prior to starting anti-PD1 therapy. • Treated brain metastases with MRI evidence of progression and/or requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisolone equivalents) • Untreated brain metastases that are symptomatic and/or require local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed or refractory haematological malignancies
- Subjects with histologically confirmed, relapsed or refractory haematological malignancies Subjects will include but are not limited to the following:
Arm A : B-cell Non-Hodgkin lymphoma , T-cell Non-Hodgkin lymphoma , Small lymphocytic lymphoma (SLL) , Multiple myeloma (MM) Arm B: CLL (chronic lymphocytic leukaemia), Richter's syndrome , AML/secondary AML, ALL , High-risk myelodysplastic syndrome (MDS), CMML (chronic myelomonocytic leukemia)
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
- Must have received at least 2 prior lines of therapy
- Documented active disease requiring treatment per respective NCCN/ESMO guideline that is relapsed or refractory defined as: Recurrence of disease after response to prior line(s) of therapy Or progressive disease after completion of the treatment regimen preceding entry into the study
- Adequate hematologic, hepatic and renal function
- Women should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential
- Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm donation during and after the conduct of the trial.
The purpose of this study is to determine whether the combination of nivolumab and ipilimumab is safe and effective for delaying or preventing recurrence of cancer in patients who have experienced the partial or entire removal of a kidney
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com - Kidney tumor has been completely resected 4 to 12 weeks prior to randomization - Pathologic TNM staging meeting one of the following: pT2a, G3 or G4, N0 M0; pT2b, G any, N0 M0; pT3, G any, N0 M0; pT4, G any, N0 M0; pT any, G any, N1 M0 - Post-nephrectomy tumor shows RCC with a predominantly clear cell histology, including participants with sarcomatoid features
- Participants with an active known or suspected autoimmune disease
- Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Any severe or serious, acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation
- Participants with a condition requiring systemic treatment with corticosteroids
Background: Multiple myeloma (MM) is a blood cancer with approximately 4500 new cases in the UK each year. Treatment for MM has changed in the last decade with the arrival of new drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). These new drugs have been shown to improve response rate and duration of response in second-line treatment (second treatment for patients whose MM has deteriorated since their first treatment). The Myeloma X study showed that an autologous stem cell transplant (ASCT) (using the patient’s own stem cells) as part of second-line treatment prolongs progression free survival (PFS) following chemotherapy containing a proteasome inhibitor (known as re-induction therapy). Consequently, the number of second ASCTs performed in the UK has risen and is now recommended (for suitable patients) by the International Myeloma Working Group. However, the Myeloma X study showed that depth and duration of response in second-line ASCT, was less than that of first-line ASCT. Hence, this study will investigate whether depth and duration of response can be improved by the addition of a proteasome inhibitor called ixazomib to melphalan conditioning, consolidation and maintenance treatment. Aims: This trial aims to determine and compare: a) The depth of response between standard melphalan conditioning and augmented (adding ixazomib) melphalan conditioning at second ASCT. b) The impact of adding consolidation and maintenance treatment versus no further treatment, on progression free survival. Methods: This is a phase III, randomised, controlled, multi-centre, open-label trial with a single intervention registration stage and two randomisations. The first randomisation will be between augmented ASCT and standard ASCT. The primary end-point is to assess improvement in depth of response. The second randomisation will be between consolidation and maintenance treatment versus no further treatment. The primary end-point being to assess the duration of response as determined by PFS.
1.Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) previously treated with ASCT). 2.First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy. 3.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3). 4.Aged at least 18 years. 5.Participants must have the following blood results within 14 days before registration: a.Absolute neutrophil count (ANC) ≥1x109/L b.Platelet count ≥75x109/L. If the participant has ≥50% bone marrow infiltration a platelet count of ≥50x109/L is allowed. Platelet transfusions are not allowed within 3 days before registration in order to meet these values. 6.Adequate renal function within 14 days before registration: a.Creatinine clearance ≥30ml/min (calculated according to Cockcroft-Gault equation or other locally approved formula) 7.Adequate hepatobiliary function within 14 days before registration: a.Total bilirubin < 2 x upper limit of normal (ULN) b .ALT < 2 x ULN 8.Adequate pulmonary function within 14 days before registration: a.Adequate respiratory functional reserve (delineated by KCO/DLCO (carbon monoxide diffusion in the lung) of ≥50%). No evidence of a history of pulmonary disease. If a significant history, then a review by a respiratory medicine physician is required. 9.Adequate cardiac function within 12 weeks before registration: a.Left ventricular ejection fraction (LVEF) ≥40%. Note: repeat confirmation of cardiac function is needed if treatment is given between this assessment and registration. 10.Female participants who: a.Are not of childbearing potential (Appendix 8), OR b.If they are of childbearing potential (Appendix 8), agree to practice 2 effective methods of contraception (Appendix 8), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a.Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Contraception for female and male participants must be in accordance with (and consent to) the Celgene-approved Thalidomide Pregnancy Prevention Programme. 11.If female and of childbearing potential (see Appendix 8), must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Thalidomide Pregnancy Prevention Programme. 12.Patients agree not to receive other clinical trials treatment, including investigational medicinal products (IMPs) not included in this trial, within 30 days of trial registration and throughout the duration of the trial, until disease progression. 13.Able to provide written informed consent.
1.Received prior second line therapy for their relapsed disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone (up to a maximum of 200mg is allowed but not within 30 days prior to registration). Radiotherapy sufficient to alleviate or control pain of local invasion is permitted, but must not be within 14 days before registration. Patients who have received hemi-body radiation or similar since relapse will not be eligible. 2.≥Grade 2 peripheral neuropathy within 14 days before registration. 3.Known HIV or Hepatitis B/C seropositivity. 4.Known resistance, intolerance or sensitivity to any component of the planned therapies. 5.Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 6.Previous or concurrent malignancies at other sites (excluding completely resected non-melanoma skin cancer or carcinoma in situ of any type, such as cervical cancer). 7.Pregnant, lactating or breast feeding female participants. 8.Failure to have fully recovered (i.e. less than or equal to Grade 1 toxicity) from the reversible effects of prior chemotherapy. 9.Major surgery within 14 days before registration. 10.Central nervous system involvement with myeloma. 11.Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration. 12.Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 13.Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 14.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing. 15.Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.
Some breast cancers are considered low risk. Low risk means there is a small chance of the breast cancer returning after it has been removed during surgery. Currently, patients with low risk breast cancer have radiotherapy after surgery, followed by drug treatment (hormone therapy tablets) for 5 years. Radiotherapy reduces the risk of cancer returning in the breast (local recurrence). However for patients with a low risk breast cancer, the risk of radiotherapy side effects may start to outweigh its benefit. The PRIMETIME study aims to identify a group of women who can safely avoid radiotherapy because the risk of their cancer returning is so low. A research calculation called IHC4+C will be used to calculate a woman's risk of cancer returning 10 years after surgery. 'Very low' risk patients are those where the chance of their cancer returning 10 years after surgery is less than 5%. This means that out of 100 women with 'very low' risk breast cancer, cancer will return in less than five women. In the PRIMETIME study women with 'very low' risk breast cancer can avoid having radiotherapy. All other women will be recommended to have radiotherapy according to standard care. Patients who are eligible to take part are those with a small, slow growing breast cancer which has not spread beyond the breast. Patients will be 60 years or over, have had surgery to remove their cancer with a plan to receive at least 5 years of drug treatment (hormone therapy) for their cancer. The study will be conducted in NHS hospitals in the UK. Participating patients will be followed up by their treating hospital for 10 years following surgery.
1.Provision of written informed consent to participate in the PRIMETIME study 2.Provision of slides for research testing and availability of Ki67 result (contact ICR-CTSU to confirm Ki67 result is available) 3.Women aged ≥ 60 years (younger patients are eligible if they are post-menopausal and have co-morbidities that imply a high risk of radiotherapy toxicity (e.g. significant cardiovascular disease with left sided breast cancer); 4.Women having had breast conserving surgery with complete resection of tumour tissue (≥1 mm microscopic, circumferential margins of normal tissue from invasive cancer and DCIS); 5.AJCC staging of pT1/pN0/M0 (DCIS is allowed in combination with invasive breast cancer, providing whole tumour size (in-situ and invasive ≤2cm); isolated tumour cells in axillary nodes are allowed); 6.Histological confirmation of grade 1 or 2 invasive breast cancer; 7.Oestrogen receptor (ER) positive according to local practice. The H score must be available; 8.Progesterone receptor (PR) positive according to local practice. The percentage positivity must be available; 9.Human epidermal growth factor receptor (HER2) negative according to local practice; 10.Patients must be recommended for ≥5 years adjuvant endocrine therapy according to local policy, they must also be willing to start endocrine therapy and in the investigator’s opinion, deemed able to comply with the duration of treatment.
1.Patients known to have lymphovascular space invasion and/or axillary nodal micrometastases or macrometastases. 2.Patients with a past history of malignancy except (i)basal cell skin cancer and CIN cervix uteri or (ii)treated, localised squamous cell carcinoma of the skin or (iii)malignancies treated with curative intent and the patient has been disease free ≥5 years; 3.Patients who have had an ipsilateral mastectomy; 4.Patients who have received neoadjuvant therapy (endocrine or cytotoxic chemotherapy with therapeutic intent) or who are deemed by the MDT to require adjuvant cytotoxic chemotherapy. NB. In most instances treatment within a window of opportunity study is not considered of therapeutic intent and will therefore be allowed: please check with the PRIMETIME trial manager if a patient has participated in a window of opportunity study. 5.Patients with mammographically occult breast cancers, ie. present with lump, but not visible on mammogram
This study proposes to investigate a range of clinically significant co-morbidities which develop in female Hodgkin Lymphoma survivors treated in childhood and young adulthood. Hodgkin Lymphoma is one of the most common malignancies in young adults and has seen significant improvement in survival over recent decades resulting in an increasing number of long term Hodgkin Lymphoma survivors. However, the high dose chemotherapy and radiotherapy treatments used are known to be toxic to patients and can greatly increase long-term risks of side effects such as second primary cancers, cardiovascular disease, and other adverse events. Relatively little has been published about the full range of longterm treatmentrelated effects that impact on life quality and health status in Hodgkin Lymphoma patients. There is also a lack of information on the effects of more modern treatments, intended to reduce long-term toxicity, and a lack of consensus about how to tailor long-term follow-up to best diagnose and manage late-effects. This study will collect and analyse treatment and co-morbidity information on women treated for Hodgkin Lymphoma across England and Wales at ages ≤35 years during 1956-2010. We will expand an existing national cohort study of 5,000 women treated for Hodgkin Lymphoma, the largest of its kind in the world, which has undertaken research to inform the risks of developing breast cancer after Hodgkin Lymphoma treatments. The cohort would be doubled in size to include young female Hodgkin Lymphoma patients who have been treated with a much wider range of treatments and more recently diagnosed patients. We aim to improve understanding of late-effects of different types of treatment, of longer follow-up periods and to greatly expand the range of long-term effects which have been reported on. By doing so we aim to contribute to the development of risk profiles to help inform treatment choices and personalised follow-up and screening schedules for Hodgkin Lymphoma patients.
Women diagnosed with Hodgkin Lymphoma and treated before the age of 36 years. Treated for Hodgkin Lymphoma before 2010. Treated in England and Wales.
Male. Treated outside UK. Resident outside UK. Treated for Hodgkin Lymphoma (for the first time) over the age of 35 years.
A multicenter, prospective cohort study of the mutation status of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are being treated with first or subsequent tyrosine kinase inhibitor (TKI) therapy in the UK, Ireland, or France.
- Adult patients (age ≥ 18 years) with CML (in all phases of disease) or Ph+ ALL with detectable BCR-ABL levels who are being treated with a first or subsequent TKI.
- Patients with CML must meet the warning or failure criteria as per the ELN guidelines for first second and subsequent treatment line, including:
- BCR-ABL/ABL IS transcripts > 10% at 3 months
- BCR-ABL/ABL IS transcripts > 1% at 6 months
- BCR-ABL/ABL IS transcripts > 0.1% at 12 months or later
- Patients with CML must not currently be in MMR (ie, have disease with BCR-ABL1/ABL1 transcripts > 0.1% IS).
- Patients with Ph+ ALL with any level of BCR-ABL/ABL IS transcripts. Patients with Ph+ ALL should have BCR-ABL1/ABL1 transcript levels > 0.1% and should not be currently enrolled in UKALL14 but may have relapsed during or after participation in UKALL14.
- Patients with an intermediate or high Sokal score (> 0.8) can be recruited into the study from 3 months after diagnosis, irrespective of BCR-ABL1/ABL1 transcript levels at 3 months.
- Patients with additional chromosomal abnormalities at diagnosis and patients with AP-CML may be recruited into the study, irrespective of BCR-ABL1/ABL1 transcript levels at 3 months and beyond provided BCR-ABL1/ABL1 transcript levels are > 0.1% IS. It is recommended that these patients have mutational analysis performed every 3 months irrespective of BCR-ABL1/ABL1 transcript levels until they reach MR3/MMR (BCR-ABL1/ABL1 < 0.1% IS).
- Any patients who have previously undergone testing for KD mutations, irrespective of KD mutational analysis test results.
- Patients who have the ability to understand the requirements of the study and provide written informed consent.
Patients without detectable BCR-ABL and patients who have switched TKI due to intolerance but who have met the criteria for optimal response (CP-CML, ELN 2013 guidelines).
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.
• 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.
• 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
Prostate cancer PCa (PCa) is the most common male cancer and second most common cause of male cancer death. Currently most men are diagnosed with PCa as a result of a blood test called the PSA (Prostate Specific Antigen). Men, who present to their GPs with symptoms due to benign (non-cancerous) enlargement or simply requesting a PCa check, are offered a PSA test. However, the PSA test is not consistently accurate: the PSA level can be high and the man may not have PCa or likewise, to a lesser degree, the PSA can be normal and the man may harbour significant cancer. There is therefore an urgent need to identify a test which is more accurate than PSA, a test that can identify men with significant PCa who need an MRI and prostate biopsy, but can also exclude men who don't have significant PCa, ensuring these men do not undergo unnecessary testing or anxiety. We have completed a number of pilot studies and have shown that EN2 protein is expressed by cancer cells and actively secreted into the urine of men with PCa. We have shown urinary EN2 has high specificity and sensitivity as a diagnostic marker. A specific level of urinary EN2 was able to distinguish between PCa that was significant (needed immediate treatment) versus insignificant (could be monitored) on the basis of tumour volume. The aim of this study is to evaluate urinary EN2 as a diagnostic biomarker in the setting of conventional urological practice. In addition, we will determine whether specific levels of EN2 in this setting correlate with radiological and pathological findings and aid in defining patients suitable for active surveillance versus those requiring immediate treatment.
Men over 18 referred from the GP to a urology clinic, who have elevated PSA levels between 4-20ng/ml
An active urine infection as confirmed by urine dipstick testing or midstream urine microscopy Men with PSA 20, men already diagnosed with prostate cancer, men with a prior or concurrent malignancy (apart from basal cell carcinoma of the skin) and men who cannot give informed consent.
There are many different types of breast cancer defined by the genetic code present within cancer cells. The genetic code is stored in the form of DNA, and changes within DNA are called mutations. Mutations are usually identified by analysis of tumour samples obtained through surgery or biopsy. Treatments that target specific mutations (known as targeted therapies) have led to improvements in the treatment of breast cancer. DNA from cancer cells is found in the blood of over 90% of patients with advanced breast cancer (breast cancer that has either reappeared following treatment, known as recurrent or locally advanced breast cancer, or breast cancer that has spread to another part of the body, known as metastatic breast cancer). DNA from cancer cells found in the blood is called circulating tumour DNA (ctDNA). Patients with advanced breast cancer will be asked to provide a blood sample which will be analysed for several specific mutations in the ctDNA. Depending on the ctDNA screening results, the patient may be invited to enter a treatment cohort and receive a treatment targeted to their type of disease. Patients will receive treatment until their cancer gets worse (progresses). The main aims of plasmaMATCH are to assess whether ctDNA screening can be used to detect patient subgroups who will be sensitive to targeted therapies and then to assess the safety and activity of the targeted treatments. Treatment cohorts: Cohort A: Patients with an ESR1 mutation will receive extended-dose fulvestrant. Cohort B: Patients with a HER2 mutation will receive neratinib. Patients with estrogen receptor (ER) positive breast cancer in this cohort will also receive fulvestrant. Cohort C: Patients with ER positive breast cancer and an AKT1 mutation will receive AZD5363 and fulvestrant. Cohort D: Patients with one of several mutations that activate a process called the ‘AKT pathway’ will receive AZD5363. Cohort E: Patients with triple negative breast cancer on their most recent tumour biopsy who do not have a targetable mutation identified by ctDNA screening or tumour sequencing that would allow entry into Cohorts A to D, or who have an actionable mutation identified but are not otherwise eligible for Cohorts A to D, will be invited to enter Cohort E and receive AZD6738 and olaparib.
1. Female. 2. Aged ≥ 18 years old. 3. Histologically confirmed invasive breast carcinoma. 4. Metastatic or recurrent locally advanced breast cancer that is not suitable for treatment with radical or curative intent. 5. Demonstrated progression of disease by radiological assessment or by clinical assessment within the last 6 weeks. 6. Measurable disease by RECIST v1.1. 7. Patients must have completed at least one prior line of treatment for advanced breast cancer and/or relapse within 12 months of completing (neo)adjuvant chemotherapy. Patients with HER2 positive breast cancer must have been treated with at least two courses of HER2 targeted therapy in the advanced setting (or one course if no further courses of HER2 targeted therapy are available locally). 8. Patient must either be suitable for a baseline biopsy of recurrent disease or have an archival biopsy of recurrent disease available. Patients are requested to consent to a baseline biopsy but if deemed unsafe by the Investigator, an archival biopsy of recurrent disease can be used instead. If it is deemed unsafe to proceed with baseline biopsy, and no archival recurrent disease biopsy is available, the patient will not be eligible for entry into the treatment cohort. 9. ECOG performance status ≤ 2. 10. Life expectancy > 3 months. 11. Patients must be surgically sterile, be postmenopausal or must agree to use effective contraception during the period of trial treatment and be willing to do so for 6 months following the end of trial treatment. Effective contraception is defined as double barrier contraception (e.g. condom plus spermicide in combination with a diaphragm, cervical cap or intrauterine device). Ovarian suppression with an LHRH agonist is not a method of contraception. 12. Patients of childbearing potential should have a negative serum pregnancy test within 14 days prior to initiation of trial treatment. 13. At least 4 weeks washout period after the end of trial treatment on a different cohort within plasmaMATCH. 14. Adequate haematological, renal and hepatic function as defined by: • Haematology: - Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 x 109/L) - Platelet count ≥100,000/mm3 (≥100 x 109/L) - Haemoglobin ≥9g/dL (≥90g/L) • Renal function: - Serum creatinine ≤1.5 x upper limit of normal (ULN) and calculated creatinine clearance more than 30ml/min • Liver function tests: - Total bilirubin ≤1.5 ULN - Alanine aminotransferase (ALT) ≤3 ULN. In the presence of liver metastases ALT ≤5 ULN. For patients in Cohort B, C and D: aspartate aminotransferase (AST) ≤3 ULN. In the presence of liver metastases AST ≤5 ULN. 15. For patients with ER positive breast cancer in Cohorts A, B and C: EITHER postmenopausal, as defined by at least one of the following criteria: • Age > 60 years; • Age < 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females; • Documented bilateral oophorectomy; medically confirmed ovarian failure. OR Pre-/peri-menopausal (i.e. not meeting the criteria for being postmenopausal) if being treated with an LHRH agonist that was commenced at least 4 weeks prior to Cycle 1 Day 1, and continues on the LHRH agonist throughout the trial period. NB. Additional eligibility criteria apply for entry into each treatment cohort.
1. Prior treatment with radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy or IMPs during the previous 4 weeks (6 weeks for nitrosoureas, Mitomycin-C) before trial treatment, except for hormonal therapy with LHRH analogues, which are permitted, and bisphosphonates or RANK ligand antibodies that are permitted for the management of bone metastases. 2. Uncontrolled CNS disease (brain metastases or leptomeningeal disease). Patients with prior diagnosis of CNS metastases must be stable by clinical assessment having ceased steroids after prior treatment. 3. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction within the last 6 months or ventricular arrhythmia. Patients with a history of any of the above listed cardiac conditions judged not to be clinically significant by the local investigator must be notified to the trial team at the ICR-CTSU for approval by the CI and/or Cohort Lead. 4. Ongoing toxic manifestations of previous treatments Grade ≥1. Exceptions to this are alopecia or toxicities which in the opinion of the Investigator should not exclude the patient. Such cases should be clearly documented in the patient’s notes by the Investigator. 5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of trial treatment. 6. Pregnant or breastfeeding. 7. Any condition that according to the treating physician may compromise the patient’s safety or the conduct of the trial. 8. Current malignancies of other types, with the exception of adequately treated in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy and have no evidence of the disease for 3 years or more are eligible for the trial. NB. Additional eligibility criteria apply for entry into each treatment cohort.
This is a study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme versus placebo in patients with malignant pleural mesothelioma with low argininosuccinate synthetase 1 expression. Malignant pleural mesothelioma have been found to require arginine, an amino acid. Thus the hypothesis is that by restricting arginine with ADI-PEG 20, the malignant pleural mesothelioma cells will starve and die.
1. Histologically proven advanced MPM of biphasic or sarcomatoid histology. Biphasic MPM is defined using the World Health Organization's international histological classification of tumors as containing an epithelial and a sarcomatoid component with each component comprising at least 10% of the tumor
2. Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy study).
3. MPM tumor sample for determination of ASS1 status. ASS1-deficiency is not required for study entry at study start, but tumor sample for ASS1 status is required. This study will employ an adaptive biomarker-driven design with an interim analysis to be conducted at the end of the phase 2 portion. The interim analysis will evaluate the treatment effect of ADI PEG 20 in combination with pemetrexed and cisplatin on overall survival (OS) in the overall population (biphasic and sarcomatoid histology patients) and pre-defined subpopulation of biomarker-positive patients (ASS1-deficient subpopulation). Thus ASS1 deficiency may be required for the phase 3 portion of the study, pending the interim analysis. ASS1-deficiency, demonstrated on tissue specimen (cytospin samples are not acceptable), will be defined in the laboratory manual. If archived tissue is not sufficient or not available, then tissue must be obtained by biopsy.
4. Measurable disease as assessed by modified RECIST for MPM for thoracic disease (Appendix A) and RECIST 1.1 for extra-thoracic disease (Appendix B).
5. ECOG performance status of 0 - 1 (Appendix C).
6. Predicted life expectancy of at least 12 weeks.
1. Radiotherapy (except for palliative reasons) the previous two weeks before.
2. Ongoing toxic manifestations of previous treatments.
3. Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery).
4. Major thoracic or abdominal surgery from which the patient has not yet recovered.
5. Serious infection requiring treatment with intravenous antibiotics at the time of study entrance, or an infection requiring intravenous therapy within 7 days prior.
6. Known to be serologically positive for human immunodeficiency virus (HIV). Testing to determine possible infection status is not required.
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.
• 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
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
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.
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.
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.
This study will evaluate patients who have melanoma that has spread from the eye to the liver: Patients in the study will be treated with Melphalan/HDS up to 6 total treatment, and will be followed until death. This study will evaluate the safety and effects of the treatment on how long patients live and how long it takes for the cancer to advance or respond to the treatment.
The study will consist of 3 phases: a screening phase, treatment phase, and follow-up phase.
Screening Phase: Screening assessments will be conducted within 28 days prior to the eligibility date to determine each patient's overall eligibility and baseline characteristics. These assessments will include medical history, physical examination, Eastern Cooperative Oncology Group (ECOG) performance status (PS), 12 lead electrocardiogram (ECG), echocardiogram (ECHO), vital signs, full hematology and biochemistry, Quality of Life questionnaire, radiologic assessments of baseline disease status and concomitant medications.
For patients with a history of liver surgery or major vasculature surgery, an angiogram evaluation of their vasculature will be performed for compatibility for Percutaneous Hepatic Perfusion (PHP) prior to confirming eligibility.
Eligibility date: This is the date on which all screening assessments have been completed and the patient is determined to be eligible for the trial.
Treatment Phase: Eligible patients will be treated with Melphalan/HDS 3.0 mg/kg Ideal Body Weight (IBW) and must begin treatment within 14 days being eligible. Melphalan/HDS treatment, patients will receive up to 6 treatments. Each treatment cycle consists of 6 weeks with an acceptable delay for another 2 weeks before the next planned treatment to allow for recovery of melphalan-related toxicity, if needed. Tumor response will be assessed every 12 weeks (+ 2 weeks) until disease progression. If the patient receives only 1 treatment, the disease assessment scans will be conducted 12 weeks after the date of the first treatment. The assessment scans will be reviewed by an Independent Review Committee (IRC), also referred to as Independent Central Review. At any time when progressive disease (PD) is observed, the patient will be removed from further study treatment and followed until death. Melphalan/HDS treatment will also be discontinued in the event that recovery from treatment related toxicity requires more than 8 weeks from last treatment. An end-of-treatment visit will be conducted approximately 6 to 8 weeks following the final study treatment. Ongoing treatment related adverse events (AEs) at the end-of-treatment visit will be followed until the severity is within one of the following parameters (1) Symptoms are resolved or return to baseline; (2) CTCAE Grade < 1 or can be explained; (3) patient death. The maximum possible duration of the study treatment for any patient will be 12 months.
NOTE: Active Melphalan/HDS patients (currently in treatment) on PHP-OCM-301 will continue treatment on PHP-OCM-301A following the re-consenting process.
NOTE: Patients on PHP-OCM-301 that have completed treatment and are entering or are already in the follow-up phase will be followed-up for survival and disease progression (as applicable) on PHP-OCM-301A following the re-consenting process.
Follow-up Phase: Once the patient has completed the end-of-treatment (EOT) visit in accordance with the schedule of events they will enter the follow-up phase. If the disease has not progressed at the EOT (Section 6.2), the patient will need to continue with disease assessment visits every 12 weeks (+ 2 weeks) until disease progression is documented. If the disease has progressed before or at the EOT their follow-up is to be by phone every 3 months for survival status until death.
Patients will be monitored, following the completion of study treatment, for the development of myelodysplasia and secondary leukemia.
1. Male or female patients ≥ 18 years of age.
2. Patients must weigh ≥ 35 kg (due to possible size limitations with respect to percutaneous catheterization of the femoral artery and vein using the Delcath Hepatic Delivery System).
3. 50% or less histologically or cytologically-proven ocular melanoma metastases in the parenchyma of the liver.
4. Disease in the liver must be measurable by computed tomography (CT) and/or magnetic resonance imaging (MRI).
5. Evidence of limited extrahepatic disease on preoperative radiological studies is acceptable if the life threatening component of disease is in the liver. Limited extrahepatic disease is defined in this protocol as follows: metastasis in bone, subcutaneous, lung or lymph nodes that is amenable to resection or radiation and has a defined treatment plan. Patients with extra-hepatic tumor burden which does not have a defined treatment plan (i.e. monitor or is unable to be resected or radiated) must not be included in the trial.
6. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to randomization. An MRI of the liver is required at screening to validate that CT accurately reflects the extent of disease in the liver. For patients with MRI intolerance, a 3-phase liver CT is to be done in place of liver MRI.
7. Patients must not have chemotherapy, radiotherapy, chemoembolization, radioembolization, or immunoembolization for their malignancy within 30 days prior to treatment and must have recovered from all side effects of therapeutic and diagnostic interventions except those listed in Appendix B of the study protocol.
8. Patients receiving anti programmed cell death protein 1 (PD-1) immunotherapy such as pembrolizumab or nivolumab, or human cytotoxic T-lymphocyte antigen 4 blocking antibody such as ipilimumab should wait 8 weeks before Melphalan/HDS treatment.
9. Patients must have an ECOG PS of 0-1 at screening and on the day prior to treatment.
10. Patients must have adequate hepatic function as evidenced by total serum bilirubin ≤ 1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of the upper normal limit. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) must be ≤ 2.5 x ULN.
11. Patients must have a platelet count > 100,000/µL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, and a serum creatinine ≤ 1.5 mg/dL unless the measured creatinine clearance is > 40 mL/min/1.73 m2.
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (β-human chorionic gonadotropin) within 7 days prior to randomization.
13. Provided signed informed consent.
1. Patients with Child-Pugh Class B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies.
2. Those with New York Heart Association functional classification II, III or IV active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.
3. History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
4. Women of childbearing potential (WOCBP) i.e. fertile meaning not permanently sterilized and having had a menstrual period within the past 12 months) unable to undergo hormonal suppression to avoid menstruation during treatment.
5. WOCBP and fertile males (not permanently sterile by bilateral orchidectomy) unwilling or unable to use highly effective contraception method for consent to at least 6 months after the last administration of study treatment (e.g. combined hormonal contraception; progestogen-only hormonal contraception; Intrauterine device, intrauterine hormone-releasing system; bilateral tubal occlusion, vasectomized partner or sexual abstinence).
6. Females that are pregnant or breastfeeding patients
7. Patients taking immunosuppressive drugs; however, oral corticosteroids ≤ 10 mg/day are allowed.
8. Patients who are unable to be temporarily removed from chronic anti-coagulation therapy.
9. Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate therapy.
10. Patients with severe allergic reaction to iodine contrast, which cannot be controlled by premedication with antihistamines and steroids (because a hepatic angiogram is needed for the Delcath system procedure).
11. Patients with a history of or known hypersensitivity to melphalan or the components of the Melphalan/HDS system.
12. Patients with latex allergy.
13. Patients with a history of hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
14. Patients with a history of bleeding disorders or evidence of intracranial abnormalities which would put them at risk for bleeding with anti-coagulation (e.g., strokes, active metastases).
15. Patients with a history of gastrinoma, hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting.
16. Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer.
17. Patients with prior Whipple's procedure.
18. Patients with brain metastases or presence of other intracranial lesions at risk for bleeding by history or baseline radiologic imaging.
19. Patients with active liver infection, including Hepatitis B and Hepatitis C infection. Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are exception(s).
20. Uncontrolled endocrine disorders including diabetes mellitus, hypothyroidism, or hyperthyroidism.
21. Received any investigational agent for any indication within 30 days prior to first treatment.
22. Not recovered from side effects of prior therapy to ≤ Grade 1 (according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Certain side effects that are unlikely to develop into serious or life-threatening events (e.g. alopecia) are allowed at > Grade 1.
23. Cancers other than ocular melanoma for which the patient is currently under treatment or still deemed not to be cancer free.
The aim of this prospective non-interventional registry is to establish an accepted standard of care for melanoma patients with minimal sentinel node (SN) tumour burden. Currently, if a melanoma patient has a positive (or metastatic) SN, this patient will be offered a Completion Lymph Node Dissection (CLND). This is a surgery which aims to remove all lymph nodes from the same area as the SN. However, if the positive SN is only minimally involved, some centres do not normally offer a CLND. In fact, the CLND does not increase survival for patients with a minimal SN tumour burden, but it can give doctors some information that may help them to make treatment decisions. This surgical operation may have significant side effects for the patient. In addition, only approximately 20% of patients with a positive SN have further lymph node metastases in the same area. This means that about 4 patients out of 5 will not benefit from a CLND. As a result, there is an urgent need to identify which SN positive patients could be safely spared from a CLND. Evidence shows that breast cancer patients with minimal SN tumour burden can be safely managed with observation only, and without a CLND. There is some evidence that the same situation exists in melanoma as well. The purpose of this registry is to confirm this. The results of this registry will support the aim of discovering whether melanoma patients with minimal SN tumour burden should undergo a complete lymph node dissection (CLND) or not. In addition, translational research on the tumour tissue will be carried out if participants consent to use of their tissue for such purposes. This is optional; participants will be able to refuse permission to use their tumour tissue and still participate in the main study.
♦ Histological evidence of primary cutaneous melanoma ♦ Metastases solely confined within the SN: - in the sub-capsular space (with no parenchymal infiltration) and with a maximum diameter of the largest metastasis not greater than 0.4 mm or - regardless of the site, any sub-micrometastasis with a maximum diameter not greater than 0.1 mm If there is more than 1 metastatic SN, the patient will be still eligible provided that all involved SN have minimal tumor burden, regardless of the amount of positive SNs and the basin of interest ♦ Absence of clinically apparent metastatic disease at the time of or before undergoing a SN procedure ♦ No previous SN procedure for locally recurrent melanoma or uncertain malignant disease, such as atypical Spitz tumor/naevi ♦ Age ≥18 years ♦ No history of a previous melanoma (preceding the melanoma which prompted the SN biopsy) ♦ No history of any other malignancy within the past 5 years, except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and in situ cervical cancer ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial ♦ Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations
See Main Inclusion Criteria
This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll patients with RRMM following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients will receive either melflufen+dex or pomalidomide+dex.
This is a randomized, controlled, open-label, Phase 3 multicenter study which will enroll patients with RRMM following 2-4 lines of prior therapy and who are refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide.
Patients will be randomized to either one of two arms:
Arm A: Melflufen 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Patients ≥ 75 years of age will have a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B.
Patients may receive treatment until such time as there is documented disease progression, unacceptable toxicity or the patient/treating physician determines it is not in the patient's best interest to continue.
Dose modifications and delays in therapy may be implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it is recommended to continue dexamethasone weekly.
1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening
3. Measurable disease defined as any of the following:
- Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis.
- ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis
- Serum free light chain ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
4. Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization. Refractory to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle.
5. Life expectancy of ≥ 6 months
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
7. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to start of treatment. Participants must agree to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the pomalidomide Pregnancy Prevention Plan (PPP).
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec Fridericia Formula.
10. The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1:
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L)
- Platelet count ≥ 75,000 cells/mm3 (75 x 109/L)
- Hemoglobin ≥ 8.0 g/dl
- Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor.
- Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x ULN.
- Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min.
11. Must be able to take antithrombotic prophylaxis.
12. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC-line], or central venous catheter) (Insertion only required if randomized to Arm A).
1. Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy)
2. Evidence of mucosal or internal bleeding or platelet transfusion refractory
3. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
4. Prior exposure to pomalidomide
5. Known intolerance to IMiDs.
6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization.
7. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance.
8. Pregnant or breast-feeding females
9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
10. Known human immunodeficiency virus or active hepatitis C viral infection
11. Active hepatitis B viral infection (defined as HBsAg+).
- Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
- Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation.
12. Concurrent symptomatic amyloidosis or plasma cell leukemia
13. POEMS syndrome
14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, PIs and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization
15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted)
16. Prior peripheral stem cell transplant within 12 weeks of randomization
17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease.
18. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization
19. Known intolerance to steroid therapy
Mantle cell lymphoma is a rare but aggressive form of non hodgkins' lymphoma that typically affects older patients. For younger, fitter patients the most effective treatment is considered to be stem cell transplantation. For older patients, this is not an option and they are generally offered a combination of chemotherapy and rituximab. The purpose of this study is to compare the effect on progression-free survival of treatment with ibrutinib given in combination with rituximab (IR) against treatment with standard chemotherapy given in combination with rituximab. Participants will receive treatment for 24 weeks, followed by a 2 year maintenance period. They will then be followed up until disease progression or the end of the study, whichever comes first. We are also interested in the cost of delivering these two types of treatments, the quality of life they give patients and the side effects they cause. This is a multicentre, open label, integrated phase II/III randomised controlled study in untreated patients with mantle cell lymphoma who are over the age of 60 and are therefore considered unsuitable for stem cell transplant. There will be an interim analysis after 77 evaluable participants have completed 24 weeks of treatment with IR in order to establish that the overall response rate with IR is high enough to justify continuing to a phase III study. We will recruit 400 patients from as many hospitals and cancer centres in the United Kingdom as have the capacity to open the study. ENRICH is funded by Cancer Research UK and the ibrutinib is supplied and distributed free of charge by Janssen. Janssen have also provided funds for a sub study to explore the value of minimal residual disease flow cytometry in mantle cell lymphoma.
• Male/female patients 60 years and over • Pathologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t (11:14)(q13;q32) and/or overexpress cyclin D1 • Stage IIIV disease, measurable by imaging and requiring treatment in the opinion of the treating clinician • No previous treatment for MCL (other than localised radiotherapy or 7 day pulse of steroids for symptom control) • Performance status ECOG 02 • Absolute neutrophil count > 1.0x10*9/L or platelets > 100x10*9 /L independent of growth factor support or unless related to lymphoma • AST and/or ALT < 3xULN • Total bilirubin ≤1.5xULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin • Calculated creatinine clearance > 30mL/min • Able to give voluntary written informed consent
• Patients considered fit enough to undergo autologous or allogeneic stem cell transplant as treatment for MCL • Known serological positivity for HBV, HCV, HIV • Major surgery within two weeks prior to Day 1 of Cycle 1 • Diagnosed with or treated for any other malignancy than MCL within 2 years prior to Day 1 of Cycle 1 (except BCC, SCC or any in situ malignancy) • Active systemic infection requiring treatment • Male subjects with female partners of childbearing potential who are unwilling to use appropriate contraception methods whilst on study treatment • Women who are pregnant or breastfeeding • Serious medical or psychiatric illness likely to interfere with participation in this clinical study • Concurrent treatment with another investigational agent
The main purpose of this study is : To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.
Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation): • A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary) • Age < 18 years • No prior chemotherapy or biological therapy for AML other than that permitted in the protocol • Normal cardiac function (fractional shortening ≥28% or ejection fraction ≥55%) • Fit for protocol chemotherapy • Documented negative pregnancy test for female patients of childbearing potential • Patient agrees to use effective contraception (patients of childbearing potential) • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study: • Patients meets the inclusion criteria for trial entry • Age ≥12 months for the major dose finding study • Age ≥ 12 weeks and < 12 months for the minor dose finding study • Karnofsky or Lansky performance score of ≥50 • Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2 • Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert’s syndrome or similar disorder • ALT or AST ≤10 x ULN for age • Written informed consent from the patient or parent/legal guardian Inclusion criteria for participation in R3: • Patient meets the inclusion criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial • Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories, see national MyeChild 01 Laboratory Manual): 1) Patients with good risk cytogenetics/molecular genetics and a MRD level < 0.1% by flow after course 2, or a decrease in transcript levels of > 3 logs after course 2 for those with an informative molecular marker but without an informative marker of sufficient sensitivity for flow MRD monitoring Or 2)Patients with intermediate risk cytogenetics/molecular genetics with a MRD level < 0.1% by flow after course 1 and course 2, or a decrease in transcript levels of > 3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in R4: • Patient meets the eligibility criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial • Patient is in CR or CRi defined as < 5% blasts confirmed by flow cytometry//molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4. • Patient meets one of the following criteria and is a candidate for haemopoeitic stem cell transplant (HSCT) as per the protocol: 1) High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi) 2) Intermediate risk cytogenetics with MRD > 0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of > 0.1% may be used 3) Good risk cytogenetics with flow MRD > 0.1% confirmed by a decrease in molecular MRD of < 3 logs or rising transcript levels after course 3 despite treatment intensification (FLAIda) and after discussion with the Clinical Coordinators Availability of a 910/10 human leukocyte antigen (HLA) matched family or unrelated donor or 58/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1 • Written informed consent from the patient or parent/legal guardian
Exclusion criteria for all randomisations • Acute promyelocytic leukaemia (APL) • Myeloid leukaemia of Down Syndrome (ML DS) • Blast crisis of chronic myeloid leukaemia • Relapsed or refractory AML • Bone marrow failure syndromes • Prior anthracycline exposure which would inhibit the delivery of study anthracyclines • Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML • Pregnant or lactating females
The purpose of this study is to evaluate the efficacy and safety of imetelstat in transfusion dependent participants with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment.
This is a Phase 2/3, multicenter study of imetelstat that consists of 2 parts. Part 1 is an open-label, single-arm design to assess the efficacy and safety of imetelstat. Approximately 55 participants will be enrolled in Part 1, including the expansion cohort, and be followed-up for safety, hematologic improvement and reduction in transfusion requirement. Part 2 of the study will be initiated if data from Part 1 are supportive of a satisfactory benefit/risk profile. Part 2 is a double-blind, randomized design to compare the efficacy of imetelstat with placebo. Approximately 170 eligible participants will be randomized in a 2:1 ratio to receive either imetelstat or placebo, respectively. Each part of the study will consist of 3 phases: a Screening phase (up to 28 days); a treatment phase; and a post-treatment follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first). The End of the Study is defined as 2 years after the study entry of the last participant or anytime the sponsor terminates the study, whichever comes first.
- Man or woman greater than or equal to (>=) 18 years of age
- In Part 1, diagnosis of myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria
- International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS
- Red blood cell (RBC) transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period during the 16 weeks prior to Study Entry; pre-transfusion hemoglobin (Hb) should be less than or equal to 9.0 gram per deciliter (g/dL) to count towards the 4 units total
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
- Participant has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients
- Participant has received an investigational drug or used an invasive investigational medical device within 30 days prior to Study Entry or is currently enrolled in an investigational study
- Prior treatment with imetelstat
- Have received corticosteroids greater than (>) 30 milligram per day (mg/day) prednisone or equivalent, or growth factor treatment within 4 weeks prior to study entry
- a) Prior treatment with a hypomethylating agent (example [eg], azacitidine, decitabine); b) Prior treatment with lenalidomide; c) Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs)
The study's primary objective [in a population of patients with MDS after failure of treatment with azacitidine (AZA) or decitabine (DAC)], is to compare the overall survival (OS) of patients in the rigosertib group vs the Physician's Choice group, in all patients and in a subgroup of patients with IPSS-R very high risk.
This is a Phase III, open-label, randomized, controlled, international study. Approximately 360 patients < 82 years of age with MDS classified as RAEB-1, RAEB-2, or RAEB-t who received AZA or DAC for ≤ 9 months and/or ≤ 9 cycles over 12 months and had their last dose of AZA or DAC within 6 months prior to screening will be stratified by:
- Very high risk (VHR) vs non-VHR per IPSS-R, and
- Geographic region (North America vs Europe vs Asia; because approved products and standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of the following 2 treatment groups:
- Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a 2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle thereafter (N = approximately 240 patients);
- Physician's Choice of alternative treatment, which may include any approved or standard-of-care therapy that the patient has not shown to be hypersensitive to, based on frequently used treatment for MDS, as per institutional guidelines, after receipt of HMAs (N = approximately 120 patients). The drugs used in the Physician's Choice arm should be used according to the recommendations, if clinically appropriate, provided in the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information of these drugs. Experimental therapies are not allowed on the PC arm.
Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance. For all randomized patients who discontinue study treatment, subsequent therapies with their start and end dates, as well as survival time after treatment discontinuation, will be documented at least monthly until death. Patients in the PC group who progress will not be allowed to cross over to rigosertib. All patients in both treatment groups will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (granulocyte colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin).
MDS classified as follows:
- RAEB-1 per World Health Organization (WHO) MDS criteria (5% to < 10% BM blasts)
- RAEB-2 per WHO MDS criteria (10% to < 20% BM blasts)
- RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)
- At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin [Hgb] < 10 g/dL)
- Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment or Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
- Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months
- Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
- Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
- Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Willing to adhere to protocol prohibitions and restrictions
- Patient must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate. Should patient be incapable of giving consent, the patient's legally authorized representative (as defined by local regulation) must give consent. However, should patient, in any manner, choose not to participate this takes precedence and will be respected.
- Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated
- Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation
- Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3 days of an anthracycline, or high-dose cytarabine
- Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found
- Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years
- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
- Active infection not adequately responding to appropriate therapy
- Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease
- Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN)
- Serum creatinine ≥2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) < 40 mL/min.
- Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:
- HIV or hepatitis C - presence of viral load
- Hepatitis B - antigen positive
- Uncorrected hyponatremia (defined as serum sodium value of < 130 mEq/L)
- Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period. Examples of acceptable contraception methods include:
- estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal),
- gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
- intra-uterine devices (IUDs),
- intra-uterine hormone-releasing systems (IUSs),
- bilateral tubal occlusion
- vasectomized partner
- sexual abstinence in accordance with an individual's lifestyle
- Female patients of child-bearing potential (pre-menopausal and not surgically sterilized) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin pregnancy test at Screening
- Major surgery without full recovery or within 3 weeks before planned randomization;
- Uncontrolled hypertension
- New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
- Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
- Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
- Investigational therapy within 4 weeks of planned randomization
- Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
- Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage of > 30%).
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 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 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
The trial consists of a series of parallel multi-centre single arm Phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers. The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive design is adopted to achieve this objective. The trial is primarily an enrichment putative biomarker design, including patients who are positive for at least on of the actionable targets included in the trial. Patients who are positive for just one putative biomarker will receive the experimental targeted drug specific for that putative biomarker. Putative biomarkers within each drug cohort have been chosen such that in the majority of cases it is not expected that patients will be positive for two or more putative biomarkers within the same drug. In the rare situation that patients are positive for two or more putative biomarkers relevant across different drugs, treatment will be allocated in accordance with the following strategy: - All amplifications and rearrangements will be treated with targeted agent appropriate to them irrespective of concomitant mutations. This will yield crucial predictive biomarker information. - For concomitant mutations decisions will be made by the Chief Investigator on a case-by-case basis and based on close consideration of pathway preference and likely dominance of one signal pathway over another together with any pre-clinical efficacy studies that address the activity of the drugs in the presence of concomitant mutations.
• Patients must have completed all standard of care therapy that the treating oncologist thinks is appropriate. As a minimum patients must have failed one or more lines of treatment (either radiological documentation of disease progression or due to toxicity). • Patients who have progressed after surgical resection and adjuvant therapy will be eligible for entry without the need for the administration of first line metastatic therapy, if they have progressed within 6 months of completing their adjuvant treatment. • Patients will also be eligible without the necessity for first line regimen if they have relapsed within 6 months of completion of definitive chemoradiation. • Consented and provided an adequate specimen to adequately characterise the molecular genotype of the tumour in the molecular pre-screening according to the molecular exclusion rules (see section 6.4 for definition of an adequate sample). • Histological or cytologically confirmed NSCLC stage III (not suitable for radical radiotherapy or surgery) or stage IV. This includes patients who may have abnormal histology, but IHC strongly support either squamous cell carcinoma (p63 positivity) or adenocarcinoma (Thyroid transcription factor 1 [TTF1] positivity). If a physician and pathologist are convinced after multi-disciplinary review that the patient has stage III or IV NSCLC but where all the IHC is negative and the morphology does not distinguish a specific sub-type, these patients will be eligible for non-histology specific cohorts. • CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1 (see Appendix 1). • Adequate haematological function within 7 days of treatment. o Haemoglobin ≥ 90 g/L. o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. o Platelets ≥ 100 x 109/L. • Adequate hepatic function within 7 days of treatment in patients with no liver metastasis (see arm specific entry criteria for adequate hepatic function in patients with liver metastases). o Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN). o Alanine transferase (ALT) ≤ 2.5 x ULN. o Aspartate transferase (AST) ≤ 2.5 x ULN. • Adequate renal function within 7 days of treatment. o Creatinine clearance (CLcr) > 50 ml/min (measured or calculated by Cockcroft and Gault equation – see Appendix 4). • Age ≥ 18 years. • Females must agree to use adequate contraceptive measures (as defined in Section 6.3), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. o Women aged under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution. • Provision of signed and dated, written informed consent prior to any study specific
• Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment. • Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption. • Any psychological, familial, sociological or geographical condition hampering protocol compliance. • Concurrent malignancies or invasive cancers diagnosed within past 3 years except for adequately treated basal cell carcinoma of the skin and in situ carcinoma of the uterine cervix. • Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. • Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration (see CTCAE - Appendix 3). • Patients who have previous symptomatic brain metastases or spinal cord compression are excluded unless they have had adequate treatment, no evidence of progression or symptoms, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • Patients with asymptomatic brain metastases picked up at screening CT scan are not excluded providing that in the view of the investigator they do not require immediate radiotherapy or surgical intervention, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. • Pregnant or breast-feeding women.
Background: Cancer is a global problem. There is significant pre-clinical and epidemiological evidence demonstrating that aspirin has anti-cancer effects. Recently, individual patient data meta-analyses, from trials designed to assess cardiovascular benefits of aspirin, have shown reductions in cancer incidence and mortality associated with regular aspirin use. Additionally, the CAPP2 trial has demonstrated that daily aspirin prevents cancers associated with the Lynch syndrome. In the meta-analyses, short-term effects on cancer mortality and a decrease in risk of metastases suggest a role for aspirin in the treatment as well as prevention of cancer. This is supported by several large observational datasets. Concerns over toxicity, particularly serious haemorrhage, have limited the use of aspirin in the primary prevention of cancer. In the adjuvant setting the benefit:risk ratio will be different, with higher morbidity and mortality from recurrent cancer potentially outweighing risks associated with regular aspirin use. Aim: To assess whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in patients with early stage common solid tumours. International recruitment will allow assessment of the intervention in different communities. Methods: The question will be addressed in four tumour sites (colorectal, breast, gastrooesophageal, prostate) using parallel trials with a common infrastructure. Each trial will be a multicentre, phase III, double-blind, placebo-controlled randomised trial. Participants will be randomised to 100mg aspirin, 300mg aspirin or a matching placebo, to be taken daily for 5 years. Primary outcomes will depend on tumour site and trials will be separately powered, requiring 2000-3000 patients with each tumour type to demonstrate effects of aspirin on disease recurrence and survival. Secondary outcomes include overall survival, adherence, gastrointestinal complications and cardiovascular events.
COMMON INCLUSION CRITERIA 1. Written informed consent 2. WHO performance status 0, 1 or 2 3. Previous or current participants of other primary treatment trials if agreed in advance between trials 4. No clinical or radiological evidence of residual or distant disease BREAST COHORT INCLUSION CRITERIA 1. Men or women with histologically confirmed invasive breast cancer 2. Undergone complete primary invasive tumour excision with clear margins 3. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection 4. In those patients with a positive sentinel node biopsy: a. If 1, 2 or 3 nodes are positive, subsequent management of the axilla (with surgery, radiotherapy or no further intervention) should be completed prior to registration b. If 4 or more nodes are involved, patients must have undergone completion axillary node dissection 5. Radiotherapy (RT) a. Patients who have undergone breastconserving surgery should receive adjuvant RT b. Patients who have undergone mastectomy should receive RT if they have more than 3 axillary lymph nodes involved c. Patients who have undergone mastectomy and have T3 tumours and/or 1, 2 or 3 involved lymph nodes may (or not) receive radiation per institutional practice 6. Final histology must fall within at least one of these 3 groups: a. Node positive b. Node negative with highrisk features 2 or more of: i. ER negative ii. HER2 positive iii. Grade 3 iv. Lymphovascular invasion present v. Age < 35 vi. Oncotype Dx score of > 25 c. In patients who have received neoadjuvant chemotherapy, patients are eligible if they have both a hormone receptor negative/HER2 negative tumour, a HER2 positive tumour or a hormone receptor positive grade 3 tumour and did not achieve a pathological complete response with neoadjuvant systemic therapy 7. Patients who received standard neoadjuvant and/or adjuvant chemotherapy or RT are eligible. 8. Known HER2 and ER status 9. Participants may receive endocrine therapy and trastuzumab. All ER positive patients should be planned to undergo at least 5 yrs of adjuvant endocrine therapy COLORECTAL COHORT INCLUSION CRITERIA 1. Histologically confirmed stage II or III adenocarcinoma of the colon or rectum and patients who have undergone resection of liver metastases with clear margins and no residual metastatic disease 2. Patients with synchronous tumours if one of the tumours is at least stage II or III 3. Serum CEA ideally ≤1.5 x upper limit of normal 4. Have undergone curative (R0) resection with clear margins GASTROOESOPHAGEAL COHORT INCLUSION CRITERIA 1. Patients with histologically confirmed adenocarcinoma, adenosquamous carcinoma or squamous cell cancer of the oesophagus, gastrooesophageal junction or stomach 2. Have undergone curative (R0) resection with clear margins or primary chemoRT given with curative intent PROSTATE COHORT INCLUSION CRITERIA 1. Men with histologically confirmed node negative nonmetastatic adenocarcinoma of the prostate 2. Have undergone curative treatment, either: a. Radical prostatectomy b. Radical RT c. Salvage RT (following rise in PSA after prostatectomy) 3. Intermediate or high risk according to D’Amico classification Treatment pathway specific inclusion criteria: (a) Prostatectomy patients 4. Open, laparoscopic or robotic radical prostatectomy 5. Men treated with immediate adjuvant RT 6. Men receiving adjuvant hormone therapy planned for a maximum duration of 3 yrs 7. Men randomised to any of the 3 arms of RADICALS HD are eligible (b) Radical RT patients 9. Men receiving neoadjuvant and/or adjuvant hormone therapy planned for a maximum duration of 3yrs (c) Salvage RT patients following PSA rise after previous radical prostatectomy 13. Men treated with salvage RT following a rise in PSA are eligible 14. Men receiving neoand/ or adjuvant hormone therapy planned for a maximum of 3yrs 15. Men randomised to any of the 3 arms of RADICALS HD are eligible
Participants must not meet any of the common or their tumourspecific exclusion criteria. COMMON EXCLUSION CRITERIA 1. Current or previous regular use of aspirin (at any dose) or current use of another NSAID for any indication. 2. A past history of adverse reaction or hypersensitivity to NSAIDs, celecoxib, aspirin or other salicylates or sulphonamides, including asthma, that is exacerbated by use of NSAIDs. 3. Current use of anticoagulants. 4. Current or longterm use of oral corticosteroids. The treating physician should make the clinical decision whether a patient has been exposed to longterm therapy. 5. Active or previous peptic ulceration or gastrointestinal bleeding within the last year, except where the cause of bleeding has been surgically removed. 7. Active or previous history of inflammatory bowel disease. 8. History of moderate or severe renal impairment, with eGFR< 45ml/min/1.73m2. 9. Previous invasive or noninvasive malignancy except: DCIS where treatment consisted of resection alone. Prostate cancer initially treated with prostatectomy and now being treated with salvage radiotherapy following a rise in PSA. Cervical carcinoma in situ where treatment consisted of resection alone. Basal cell carcinoma where treatment consisted of resection alone or radiotherapy. Superficial bladder carcinoma where treatment consisted of resection alone. Other cancers where the patient has been diseasefree for ≥15 years. 10. Any other physical condition which is associated with increased risk of aspirinrelated morbidity or, in the opinion of the Investigator, makes the patient unsuitable for the trial, including but not limited to severe asthma, haemophilia and other bleeding diatheses, macular degeneration and patients with a highrisk of mortality from another cause within the trial treatment period. 11. Known glucose6phosphate dehydrogenase deficiency. 12. Known lactose intolerance 13. LFTs greater than 1.5x the upper limit of normal unless agreed with TMG. 14. Anticipated difficulties in complying with trial treatment or followup schedules. 15. < 16 years old. 16. Participants in other treatment trials where this has not been agreed in advance by both trial teams. 17. Pregnant or breast feeding, or intending to become pregnant or breast feed during the trial treatment period. BREAST COHORT EXCLUSION CRITERIA 1. Metastatic or bilateral breast cancer. COLORECTAL COHORT EXCLUSION CRITERIA 1. Proven (or clinically suspected) metastatic disease (patients who have undergone resection of liver metastases with clear margins and no residual metastatic disease are eligible). GASTROOESOPHAGEAL COHORT EXCLUSION CRITERIA 1. Proven (or clinically suspected) metastatic disease. PROSTATE COHORT PARTICIPANT CRITERIA 1. Biopsy proven or radiologically suspected nodal involvement, or distant metastases from prostate cancer. 2. Adjuvant hormone therapy planned for > 3 years. 3. Bilateral orchidectomy.
Patients with cancers of the blood often develop low blood cell counts either as a consequence of the disease or the treatment by chemotherapy or stem cell transplantation. Platelet transfusions are commonly given to raise any low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). But recent studies have indicated that many patients continue to experience bleeding, despite the use of platelet transfusions. Tranexamic acid is a type of drug that is called an antifibrinolytic. These drugs act to reduce the breakdown of clots formed in response to bleeding. These drugs have been used widely in both elective and emergency surgery and have been shown to decrease blood loss and the use of red cell transfusions. The purpose of this study is to test whether giving tranexamic acid to patients receiving treatment for blood cancers reduces the risk of bleeding or death, and the need for platelet transfusions. Patients will be randomised to receive tranexamic acid (given intravenously through a drip, or orally) or a placebo. We will measure the rates of bleeding daily using a short structured assessment of bleeding, and we will record the number of transfusions given to patients.
1. At least 18 years of age 2. Confirmed diagnosis of a haematological malignancy 3. Undergoing chemotherapy or haematopoietic stem cell transplantation 4. Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count of ≤10x10 to the power of 9/L for ≥ 5 days 5. Able to comply with treatment and monitoring
1. Diagnosis of acute promyelocytic leukaemia and undergoing induction chemotherapy 2. History of ITP, TTP or HUS 3. Patients receiving L-asparginase as part of their current cycle of treatment 4. Patients with a past history or current diagnosis of arterial or venous thromboembolic disease including myocardial infarction, peripheral vascular disease and retinal arterial or venous thrombosis 5. Patients with a diagnosis/previous history of veno-occlusive disease (also called sinusoidal obstruction syndrome) 6. Patients receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor VIIa or Prothrombin Complex Concentrates (PCC) within 48 hours of enrolment, or with known hypercoagulable state 7. Known inherited or acquired bleeding disorder. E.g. acquired storage pool deficiency; paraproteinaemia with platelet inhibition; known inherited or acquired prothrombotic disorders 9. Patients receiving anticoagulant therapy or anti-platelet therapy 10. Patients with overt disseminated intravascular coagulation 11. Patints with visible haematuria at time of randomisation 12. Patients requiring a platelet transfusion threshold > 10x10 to the power of 9/L at time of randomisation 13. Patients with anuria (defined as urine output < 10mls/hr over 24 hours) 14. Patients who are pregnant 15. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth factors or other pro-coagulant agents 16. Allergic to tranexamic acid or epsilon amino caproic acid 17. Previously randomised in this study at any stage of their treatment
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.
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
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
Each year more than 48,000 women are diagnosed with breast cancer in the UK. Currently women having surgery to treat their cancer undergo removal of the first one or two lymph glands (called sentinel nodes) from the armpit (axilla) to check if the cancer has spread to these. This procedure is called sentinel node biopsy. For about a quarter of women, this test shows that the breast cancer has spread to their sentinel nodes. These women then undergo treatment to their armpit (axillary treatment). This is either a second operation to remove all the lymph glands in the armpit (axillary node clearance) or radiotherapy to the armpit (axillary radiotherapy) depending on their hospital practice. After recovery from this treatment, they have chemotherapy and/or endocrine therapy. Some women may also have radiotherapy to their breast or chest wall. This chemotherapy, endocrine therapy, breast and chest wall radiotherapy is called adjuvant therapy. We now know that adjuvant therapy is very good at preventing the cancer from coming back. So, armpit treatment may no longer be needed. Armpit treatment damages the drainage channels of the lymphatic system. Fluid called lymph begins to collect in the arm and doesn't drain. The arm and hand swell and this swelling is called lymphoedema. One in 5 women will get lymphoedema in the arm after armpit treatment. Lymphoedema can be painful and make it difficult to move the arm. It cannot be completely cured, and without treatment it may get worse. Also, 1 in 3 people will have numbness or pain after armpit treatment and 1 in 5 may experience shoulder stiffness. These problems can be upsetting and difficult to cope with. If armpit treatment is no longer needed, it would be important to know this. We could then spare women unnecessary treatment, and avoid the long term problems it causes.
Women will be eligible for inclusion only if ALL of the following criteria apply: • 18 years or older • Unifocal or multi-focal invasive tumour with lesion ≤5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound (tumour size should be based only on the single largest tumour; do not add the sizes together from the multiple foci) • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit > 2.0mm in largest dimension or defined as macrometastasis on molecular assay) • Fit for axillary treatment and adjuvant therapy • Have given written informed consent
Women will be excluded if they have: • bilateral breast cancer • more than 2 nodes with macrometastases • neoadjuvant therapy for breast cancer • previous axillary surgery on the same body side as the scheduled sentinel node biopsy • not receiving adjuvant systemic therapy • previous cancer less than 5 years previously or concomitant malignancy except o adequately treated basal or squamous cell carcinoma of the skin o adequately treated in situ carcinoma of the cervix o adequately treated in situ melanoma o contra- or ipsilateral in situ breast cancer
This is a phase III, multicentre, randomised, controlled, open, parallel group trial in patients with previously untreated CLL.
At least 18 years old. • Maximum age of 75 years old. • B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma • Binet’s Stages C, B or Progressive Stage A • Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. 4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30x10^9/L 5. A minimum of any one of the following disease-related symptoms must be present: (a) Unintentional weight loss more than or equal to 10% within the previous 6 months. (b) Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities). (c) Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection. (d) Night sweats for more than 1 month without evidence of infection. • Considered fit for treatment with FCR as determined by the treating clinician. • World Health Organisation (WHO) performance status (PS) of 0, 1 or 2 • Able to provide written informed consent • Biochemical values must be within the following limits within 14 days prior to randomization and at baseline: - Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤3 x ULN. - Total bilirubin ≤1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non hepatic origin
• Prior therapy for CLL • History or current evidence of Richter’s transformation • Major surgery within 4 weeks prior to randomisation • Active infection. • > 20% P53 deletion, determined by FISH • Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies. • Concomitant warfarin or equivalent vitamin K inhibitor or other oral anticoagulant. • Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction. • Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile. • CNS involvement with CLL. • Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) • Respiratory impairment (bronchiectasis or moderate COPD) • Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study. • Inability to swallow oral medication • Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc) • Known HIV positive • Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded. • Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result. • History of prior malignancy, with the exception of the following: - Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician - Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. - Adequately treated cervical carcinoma in situ without current evidence of disease. • Persisting severe pancytopenia (neutrophils < 0.5 x 10^9/l or platelets < 50 x 10^9/l) unless due to direct marrow infiltration by CLL • Current treatment with prednisolone of > 10mg/day. • Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10mg or less per day can be entered into the trial) Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula). • History of stroke or intracranial hemorrhage within 6 months prior to enrollment. • Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer •Cardiac event (e.g. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment.
Lung cancer is the most common cancer worldwide and the second most common cancer in the United Kingdom. The majority of patients in the UK (69%) are diagnosed at a late stage where curative treatment is not possible. In addition to treatments for cancer like chemotherapy and radiotherapy, in recent years another type of treatment that targets the immune system (immunotherapy) has shown promising results in improving the outcome for patients with many different cancers including lung cancer. Currently less than 50% of people benefit from this approach. This is the result of large gaps in our knowledge of how immunotherapy works and how to choose the right treatment or treatment combination for a particular patient. We will be looking at tissue from patients in whom there is a possibility there might be lung cancer or lung fibrosis. Lung fibrosis is not a cancer but shares some basis characteristics with lung cancer and looking at these samples will help our understanding of these diseases. We will compare these to samples collected from patients with lung nodules, other lung diseases and healthy lungs. We hope to be able to see if there are any particular immune or genetic markers that are related to the development of lung cancer and lung fibrosis, and to see if there are any markers we can potentially target with the outcome that the cancer or fibrosis may not develop, or may be made less harmful so we might be able to improve treatment for people with these diseases.
For the prospective collection of sputum, bronchoscopic lavage, lung/tissue/lymph node biopsies, peripheral blood and where possible pulmonary vein blood and bone marrow: - Suspected diagnosis of lung cancer, lung fibrosis, lung nodules, other lung diseases or healthy lungs - Patient aged 18 or over - Patients with the ability to understand the study requirements and provide written informed consent. - Patient scheduled to undergo diagnostic procedure – Bronchoscopy/EBUS/CT or ultrasound guided biopsy/Thoracic surgery - Patients with pulmonary nodules who consent to a research bronchoscopy
- Patient deemed medically unfit for sample collection - Patient has contraindication for any study specific procedure - The absence/withdrawal of consent
Disease specific • Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition • Relapsed or refractory neuroblastoma o Relapsed: any relapsed or progressed high-risk neuroblastoma o Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g myeloablative chemotherapy) • Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study General • Age ≥1 to ≤21 years • Informed consent from patient, parent or guardian Performance and organ function • Performance Status: o Lansky ≥ 50%, Karnofsky ≥ 50% or ECOG ≤3 (Patients who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score) • Life expectancy of ≥12 weeks • Bone marrow function (within 72 hours of randomisation): o No bone marrow disease: Platelets ≥ 75 x 10e9/L (unsupported for 72 hours) ANC ≥ 0.75 x 10e9/L (no G-CSF support for 72 hours) Haemoglobin > 7.5 g/dL (transfusions allowed) o Bone marrow disease: Platelets ≥ 50 x109/L (unsupported for 72 hours) ANC ≥0.5 x 10e9/L (no G-CSF for 72 hours) Haemaglobin > 7.5 g/dL (transfusions allowed) • Renal function (within 7 days of randomisation): o Absence of clinically significant proteinuria (early morning urine dipstick ≤2+). When the dipstick urinalysis shows a proteinuria > 2+, a protein:creatinine (Pr/Cr) ration must be < 0.5 or a 24 hour protein excretion must be < 0.5g o Serum creatinine ≤1.5 ULN for age, if higher, a calculated GFR (radioisotope) must be ≥ 60 ml/min/1.73 m2 • Liver function (within 72 hours of randomisation): AST and ALT ≤2.5 ULN and total bilirubin ≤1.5 ULN. In case of liver metastases, AST and ALT ≤5 ULN and total bilirubin ≤2.5 ULN • Cardiac function, measured by echocardiogram within 4 weeks of randomisation or 12 weeks if the patient has not recieived anthracyclines or cardiotaxics. Shortening fraction ≥29% on echocardiogram • Coagulation, patients not on anticoagulation must have an INR ≤1.5 and APTT ≤1.5 ULN for age. Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment. Blood pressure below 95th centile for age and sex. Use of antihypertensive medication is permitted • Males or females of reproductive potential may not participate unless they agree to use an adequate method of contraception, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables combined oral contraceptives, intrauterine device (IUDs), sexula abstinence or vasectomised partner), for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche
• Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs • Known hypersensitivity to: o Any study drug or component of the formulation o Chinese hamster ovary products or other recombinant human or humanised antibodies o Dacarbazine • Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) • Any ongoing arterial thrombo-embolic events • Patient less than (at point of planned randomisation): o 48 hours post bone marrow aspirate/trephine o 48 hours post central line insertion o Four weeks post major surgery o One week post core biopsy o Two weeks from prior chemotherapy o Six weeks from prior craniospinal or MIBG therapy and two weeks from radiotherapy to the tumour bed o Eight weeks from prior myeloablative therapy with haempoietic stem cell rescue (autologous stem cell transplant) o Three months from prior allogeneic stem cell transplant o 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP trial o Six months from presentation of lung haemorrhage/haemoptysis • Bleeding metastases (Patients with CNS metastases can be enrolled as long as the metastases are not bleeding) • Invasion of major blood vessels • Use of enzyme inducing anticonvulsants within 72 hours of eligibility assessment • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation) • History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment •Current chronic intestinal inflammatory disease/bowel obstruction •Known intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose • Pregnant or lactating patient • Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer) • Low probability of treatment compliance • Planned immunisation with live vaccine
AML 18 is the replacement trial for AML16 intensive. The UK sees approximately 2000 new cases of AML being diagnosed each year in adults aged over 60 years. This 1600 patient trial is primarily designed for patients over the age of 60 who are considered fit enough for an intensive chemotherapy approach and will aim to test the effects of adding new treatment agents to commonly used chemotherapy combinations in order to improve patient survival and treatment regimes. The AML18 Trial is available to any patient who has primary or secondary AML as defined by the WHO Classification (excluding Acute Promyelocytic Leukaemia), or high risk Myelodysplastic Syndrome (i.e. > 10% marrow blasts) over the age of 60. It is a randomised controlled Phase II/III trial using a factorial design for maximum efficiency to evaluate two induction options followed by treatment with a small molecule post course 1 and dose intensification for suitable patients. There are four randomisation comparisons within the trial: The first randomisation will compare standard the chemotherapy schedule Daunorubicin/AraC (DA) combined with 1 or 2 doses of Mylotarg in course 1. Following recovery from course 1 patients who fail to achieve CR or are MRD positive by centralised flow cytometry will be randomised to one of three options, either DA chemotherapy, DA chemotherapy plus Cladribine or Flag Ida for up to 2 courses of therapy. Patients who achieve CR after course 1 will be randomised to 1 or 2 further courses of DA chemotherapy. Patients who have known adverse risk cytogenetics at diagnosis may enter a phase 2 evaluation of the combination of Vosaroxin plus Decitabine, for up to 5 courses. At course 2 all patients will also enter a randomisation to receive AC220 versus no AC220 with or without maintenance. Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable HLA matched donor is available The study has been set up by the Centre for Trials Research in Cardiff.
1)They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML – or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB2). 2)They should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the AML19 trial. 3)They have given written informed consent. 4)Serum creatinine ≤ 1.5 × ULN (upper limit of normal) 5)Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics 6)Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Similarly women must agree to adequate contraceptive measures. Contraceptive measures must be in place for 3 months following completion of Decitabine and 6 months after the last administration of Cladribine. 7)ECOG Performance Status of 0-2
Patients are not eligible for the AML18 trial if: They have previously received cytotoxic chemotherapy for AML [Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion] They are in blast transformation of chronic myeloid leukaemia (CML) They have a concurrent active malignancy excluding basal cell carcinoma They are pregnant or lactating They have Acute Promyelocytic Leukaemia Known infection with human immunodeficiency virus (HIV) Patients with AST or ALT more than 2.5 times the local upper limit of normal, or bilirubin more than 1.5 upper limit of normal, are not eligible for the Mylotarg randomisation or Vosaroxin/Decitabine registration. For the Vosaroxin/Decitabine Entry Left ventricular ejection fraction (LVEF) < 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)] History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry Hemodialysis or peritoneal dialysis required. In addition patients are not eligible for the AC220 randomisation if they have: Cardiovascular System Exclusion Criteria: Known serious cardiac illness or medical conditions, including but not limited to: I. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker II. Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted. III. Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix for the list of such medications) IV. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker V. Complete left bundle branch block (LBBB) VI. History of long QT Syndrome or a family member with this condition VII. Serum potassium, magnesium, and calcium levels not outside the laboratory’s reference range VIII. QTc > 450 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient’s QTc measurements. QTcF (Fridericia’s formula) is preferred. Please see the trial website for QTcF calculator.
Added as of 23/01/2013: Prostate cancers depend upon the male hormone testosterone for their growth. Lowering testosterone levels (either by removing all or part of both testes, or by giving anti-hormone treatment) slows the growth of prostate cancers. This type of treatment is called hormone treatment and is often used when prostate cancers have spread outside the prostate gland. Although hormone treatment is usually successful at stopping the cancer growing for a period of time, the cancer will begin to grow again in most men. There are increasing numbers of treatments available for advanced prostate cancer. These treatments are usually used in prostate cancer when hormone treatment is no longer effective and the cancer has started to grow again. The aim of this trial, which is called STAMPEDE, is to assess some of these treatments, given earlier in the course of the disease in combination with hormone treatment. The treatments currently assessed inthe trial are: - Radiotherapy to the prostate - Abiraterone and enzalutamide combination Treatments previously assessed but now closed to recruitment: Zoledronic acid, Docetaxel, Celecoxib and Abiraterone alone. The trial information can also be found at the following MRC CTU web page: http://http://stampedetrial.org/
PATIENT INCLUSION CRITERIA Patients must fulfil both of the criteria in Section 1 or one criterion in Section 2 or at least one criteria in Section 3. Additionally, all patients must fulfil the criteria in Section 4. 1. HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE Both: - At least two of: Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10 - Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU) OR 2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE At least one of: - Stage Tany N+ M0 - Stage Tany Nany M+ OR 3 PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING1 At least one of: - PSA ≥4ng/ml and rising with doubling time less than 6 months - PSA ≥20ng/ml - N+ - M+ AND 4. FOR ALL PATIENTS I. Histologically confirmed prostate adenocarcinoma II. Intention to treat with long-term androgen deprivation therapy III. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23 IV. Have completed the appropriate investigations prior to randomisation V. Adequate haematological function: neutrophil count > 1.5x109/l and platelets > 100x109/l VI. Estimated creatinine clearance > 30ml/min VII. Serum potassium ≥3.5mmol/L VIII. Written informed consent IX. Willing and expected to comply with follow-up schedule X. Using effective contraceptive method if applicable SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE All patients meeting criteria are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this “RT to the prostate” comparison are: - Newly diagnosed prostate cancer - Demonstrable M1 disease - No contraindication to radiotherapy e.g. no previous pelvic radiotherapy, - No previous radical prostatectomy
Patients must not fulfil any of the criteria, below. I. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3 II. Metastatic brain disease or leptomeningeal disease III. Abnormal liver functions consisting of any of the following: Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN IV. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment V. Patients with contra-indications to prednisolone, including active peptic ulceration or a history of gastrointestinal bleeding VI. Patients with active inflammatory bowel disease VII. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5 VIII. Any surgery (e.g. TURP) performed within the past 4 weeks IX. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include: Severe/unstable angina Myocardial infarction less than 6 months prior to randomisation Arterial thrombotic events less than 6 months prior to randomisation Clinically significant cardiac failure requiring treatment (NYHA II-IV)6 Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg X. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 XI. Prior exposure to abiraterone XII. Prior exposure to enzalutamide XIII. Prior chemotherapy for prostate cancer XIV. Prior therapy with zoledronic acid or other bisphosphonates other than treatment for hypercalcaemia or low bone density XV. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2) XVI. History of seizure including any febrile seizure, loss of consciousness, or transient ischaemic attack within 12 months of randomisation or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization) XVII. Unexplained history of loss of consciousness within 12 months of randomisation XVIII. Operation of heavy machinery during treatment
Patients with either Monoclonal B cell lymphocytosis, Chronic Lymphocytic Leukaemia or Splenic marginal Zone lymphoma. Samples should be taken at defined time points eg diagnosis, pre-therapy or refractory disease Clinical and outcome data should be available
Aim 1B. (precursor-B lineage) To determine if the addition of monoclonal antibody (or antibodies – arms B1 to B2) to standard induction chemotherapy results in improved EFS in patients with precursor B-cell lineage ALL. Aim 1T (T lineage) To determine if the addition of nelarabine following standard induction therapy (arms T 1 and T2) improves outcome for patients with T cell ALL. Aim 2 To determine the tolerability of pegylated asparaginase in induction (for all patients) and to compare anti-asparaginase antibody levels between patients in the 2 randomisation groups from aim 1B. Aim 3 To determine whether risk-adapted introduction of unrelated donor HSCT (myeloablative conditioning in patients aged up to and including 40 years at time of study entry and non-myeloablative conditioning in patients aged greater than 40 years, ie having reached their 41st birthday at time of study entry) result in greater EFS for patients at highest risk of relapse. Aim 4 To compare 2 schedules of administration (standard P1 vs., ‘collapsed’ P2) of keratinocyte growth factor (palifermin) for efficacy in preventing the severe mucosal toxicity of etoposide/TBI HSCT conditioning regimen.
a)Subjects must be aged ≥ 25 and ≤ 65 years old with acute lymphoblastic leukaemia OR ≥ 19 and ≤ 65 years old with Philadelphia Chromosome. b)Newly diagnosed, previously untreated ALL (a steroid pre-phase of 5-7 days is acceptable and can be started prior to registration) c)Written informed consent
a) Known HIV infection b) Hepatitis B infection (defined as positive HBsAg and/or HBcAb). Antibodies to Hep B surface antigen only is acceptable c) Hepatitis C infection (antibodies against hepatitis C or a PCR evaluation which is positive for hepatitis C DNA) d) Pregnant or lactating women e) Blast transformation of CML f) Mature B-cell leukemia i.e. Burkitt’s disease t(8,14)(q24 ;q32) and all disorders amplification of c-myc e.g. t(2;8)(p12’q24), t(8;22)(q24;q11)
The CRUK Stratified Medicine Programme has now progressed to Part 2 (SMP2) after demonstrating in the pilot, Part 1, that the study was feasible in the UK. SMP2 has a sole focus on advanced non small cell lung cancer and is designed to facilitate molecular profiling for enrolment in the National Lung Matrix trial of patients with locally advanced or late stage metastatic lung cancer (Stage IIIA, IIIB or IV primary carcinoma of the lung). The programme aims to profile patient’s tumour samples to identify aberrations that make them eligible for the Matrix trial. In order to recruit patients to the trial the programme aims to successfully profile 2000 tumour samples per year across several centres in the UK. We will seek patient consent for: 1. Referral of surplus diagnostic tumour biopsies to genetic testing laboratories (technology hubs) in the UK for analysis of patterns of genetic change in the tumours. 2. Collection of a sample of blood for the extraction of normal germline nucleic acid, for the purposes of comparison to the paired tumour. 3. Collection of routine clinical data on demographics, initial and subsequent diagnostics, treatment and outcomes 4. The linkage of this information in a pseudonymised database for further analyses by the partners in the programme and researchers. 5. The communication of the results of molecular testing to the oncology team at the referral site
•Adenocarcinoma (all subtypes, IASLC classification recommended) •Squamous cell carcinoma •Other non-squamous non-small cell primary lung carcinoma subtypes, including large cell carcinoma providing neuroendocrine differentiation has been excluded using immunohistochemistry Tumour samples may be from the following types: •Bronchoscopic, percutaneous or surgical biopsies from primary tumour, lymph node or other metastases including visceral, cerebral and bone (see below for decalcification requirements) •Paraffin-embedded cell blocks from endoscopic bronchial ultrasound fine needle aspiration/biopsy (EBUS FNA/B) samples from tumour/lymph nodes or malignant effusions •Late stage (IIIA and above) lung resections •DNA remaining after local molecular testing (e.g. for EGFR or ALK) may be acceptable for analysis. Any centre intending to submit extracted DNA should in the first instance discuss this with the lead scientist at the relevant SMP2 molecular genetics laboratory (i.e. Birmingham, Cardiff or Royal Marsden/ICR). Each patient must have a matching blood sample. Capable of giving informed consent, and such consent recorded. Over the age of 18
Under the age of 18. Incapable of giving informed consent. The following are not eligible for the CRUK Stratified Medicine programme: •Non-epithelial malignancies •Small cell carcinoma •Typical or atypical carcinoid and tumourlets •Large cell neuroendocrine carcinoma •Malignant mesothelioma •Malignant tumour of another primary site metastatic to the lung e.g. metastatic colorectal carcinoma •Samples should not be from a patient known to have bloodborne or transmissible infection such as HIV, viral hepatitis (with a detectable viral load) or tuberculosis.
It is normal clinical practice to offer several months of adjuvant chemotherapy to patients with early breast cancer who have involved axillary lymph nodes. A recommendation for chemotherapy is incorporated into a number of guidelines. Recently however it has been argued that chemotherapy may have little effect on the subtype of breast cancer that is broadly identified as being hormonally responsive without HER2 gene amplification/HER2 protein overexpression and with a low or intermediate grade. These patients already benefit substantially from hormonal therapies and for many, the addition of chemotherapy is thought to confer no significant additional survival advantage. Conventional clinico-pathological assessment however does not reliably identify those individuals with this breast cancer subtype who can safely avoid chemotherapy. Preliminary evidence however strongly suggests that multi-parameter genomic tests are superior to conventional assessment at identifying patients who will not significantly benefit from chemotherapy despite being at risk of relapse as a result of tumour size or lymph node involvement. The OPTIMA trial seeks to advance the development of personalised treatment of early breast cancer by the prospective evaluation of multi-parameter analysis as a means of identifying those patients who are likely to benefit from chemotherapy whilst sparing those who are unlikely to do so from an unnecessary and unpleasant treatment, and to establish the cost-effectiveness of this approach. The OPTIMA study population would ordinarily be treated with a combination of chemotherapy and endocrine therapy. The trial compares the management of patients using test-directed assignment to chemotherapy with standard management (chemotherapy) in a non-inferiority design. A preliminary phase of the study, OPTIMA prelim, was successfully completed. OPTIMA prelim demonstrated the feasibility of a large scale trial and selected the test technology to be used in the main trial.
• Female or male, age ≥ 40 • Excised invasive breast cancer with local treatment either completed or planned according to trial guidelines. • ER positive (Allred score ≥3 or H-score ≥10 or > 1% of tumour cells stained positive) as determined by the referring site (in a laboratory meeting NEQAS standards). • HER2 negative (IHC 0-1+, or ISH negative/non-amplified [ratio of HER2/chromosome 17 < 2.00 and copy number < 6]) as determined by the referring site (in a laboratory meeting NEQAS standards). • Axillary lymph node status: i. 1-9 lymph nodes involved and if 1-3 nodes, at least 1 node containing a macrometastasis (i.e. deposit > 2mm diameter) ii. 1-3 lymph nodes involved with micrometastases only (i.e. deposit > 0.2-2mm diameter) AND tumour size ≥ 20mm iii. node negative AND tumour size ≥ 30mm. • Considered appropriate for adjuvant chemotherapy by treating physician. • Patient must be fit to receive chemotherapy and other trial-specified treatments with no concomitant medical, psychiatric or social problems that might interfere with informed consent, treatment compliance or follow up. • Bilateral cancers are permitted provided at least one tumour fulfils the entry criteria and none meet any of the exclusion criteria. • Multiple ipsilateral cancers are permitted provided at least one tumour fulfils the entry criteria and none meet any of the exclusion criteria. • Written informed consent for the study.
• ≥10 involved axillary nodes (with either macrometastases and/ or micrometastases) or evidence for internal mammary node involvement. • ER negative OR HER2 positive/amplified (as determined by the referring site). • Metastatic disease. • Previous diagnosis of malignancy unless: i. managed by surgical treatment only and disease-free for 10 years ii. basal cell carcinoma of skin or cervical intraepithelial neoplasia iii. ductal carcinoma in situ (DCIS) of the breast treated with surgery only iv. lobular carcinoma in situ (LCIS) or lobular neoplasia of the breast. • The use of oestrogen replacement therapy (HRT) at the time of surgery. Patients who are taking HRT at the time of diagnosis are eligible provided the HRT is stopped before surgery. • Pre-surgical chemotherapy, endocrine therapy or radiotherapy for breast cancer. Treatment with endocrine agents known to be active in breast cancer treatment including ovarian suppression is permitted provided this was completed > 1 year prior to study entry. • Commencement of adjuvant treatment prior to trial entry. Short-term endocrine therapy initiated because of, for instance, prolonged recovery from surgery is permitted but must be discontinued at trial entry. • Trial entry more than 8 weeks after completion of breast cancer surgery. • Planned further surgery for breast cancer, including axillary surgery, to take place after randomisation, except either re-excision or completion mastectomy for close or positive/involved margins which may be undertaken following completion of chemotherapy.
All patients attending the Royal Marsden Hospital prostate clinics with a diagnosis of prostate cancer. Additionally, outside referrals of single cases of prostate cancer diagnosed at age 60 or under, first degree related pairs with at least one diagnosed at age 65 or under and any family with three or more cases of prostate cancer, at any age.
Men who do not have prostate cancer or who do not fall within the inclusion criteria.