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- Signed Informed Consent Form - Women or men ≥ 18 years of age at time of signing Informed Consent Form - If female, patients must meet at least one of the following definitions: – Postmenopausal, as defined by at least one of the following criteria: • Age ≥ 60 years • Age < 60 years and ≥ 12 months of amenorrhea plus follicle-stimulating hormone and plasma or serum estradiol levels within postmenopausal range by local laboratory assessment in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone analogue • Documented bilateral oophorectomy (Documented bilateral oophorectomy (≥14 days prior to first treatment on Day 1 of Cycle 1 and recovery to baseline) – Premenopausal or perimenopausal (i.e., not meeting the criteria for postmenopausal) and meeting the following criterion: Treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment - If male, recommendation of treatment with LHRH agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment - Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent. Documented HR tumor, according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, defined as - 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally (Wolff et al. 2007) - Documented HER2 + tumor according to ASCO/CAP guidelines, defined as: a HER2 immunohistochemistry (IHC) score of 0 or 1 +, or HER2 IHC score of 2 + accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of ERBB2 gene amplification, or a HER2/CEP17 ratio of < 2.0 based on the most recent tumor biopsy (or archived tumor sample) - Confirmation of biomarker eligibility: valid results from either central testing of blood or prior local testing of blood or tumor tissue documenting PIK3CA-mutated tumor status. Eligible PIK3CA mutations are defined as follows: H1047D/I/L/N/P/Q/R/T/Y G1049A/C/D/R/S E545A/D/G/K/L/Q/R/V E453A/D/G/K/Q/V E542A/D/G/K/Q/R/V K111N/R/E Q546E/H/K/L/P/R G106A/D/R/S/V N345D/H/I/K/S/T/Y G118D C420R R88Q M1043I/T/V The central test for identification of eligible PIK3CA mutations is the FoundationOne Liquid CDx (F1LCDx) assay performed at Foundation Medicine, Inc. (FMI). In localities where F1LCDx is not available, samples will be submitted to an alternative, Sponsor-designated central testing laboratory. All patients are required to submit a freshly collected pre-treatment blood sample, regardless of whether patients are enrolled by local or central test results, unless previously collected as part of the pre-screening process. Local tests must have been ordered by the health care provider (HCP) for the patient as part of clinical and regional standard-of-care for patients with HR+/HER2- breast cancer. Local tests must be an appropriately validated PCR- or NGS-based assay performed at a CLIA- or equivalently-certified laboratory. In the European Union, local tests must comply with the In Vitro Diagnostic Regulation (IVDR) requirements applicable to the region. The full laboratory report documenting the study-eligible PIK3CA mutation result must be available and submitted for confirmation upon enrollment. Local test results reported from blood should be from a blood specimen representative of the patient’s locally advanced or metastatic disease state, collected after conclusion of the patient’s most recent anti-cancer therapy. Local test results reported from tumor tissue should be from the patient’s locally advanced or metastatic disease state whenever possible. Consent to provide a fresh (preferred) or archival tumor tissue specimen. It is preferred that the specimen be from the most recently collected and available tumor tissue, and whenever possible, from a metastatic site of disease. If neither of these options is available, the Medical Monitor is available to advise as needed. Please refer to the laboratory manual for specimen requirements. Disease progression after or during treatment with a combination of CDK4/6i and ET: – Patients must have received no more than two prior lines of systemic therapy in the locally advanced (recurrent or progressed) or metastatic setting – The CDK4/6i therapy does not need to be the latest treatment regimen received prior to study entry. – Each “line” (i.e., unique regimen) is defined as a single or combination of agents given for a new relapse/progression. Maintenance therapies, where applicable, must be regarded as part of the main line of therapy. – One of the prior lines of systemic therapy in the LA/mBC setting may have included chemotherapy. Measurable disease per RECIST v1.1. Moreover, patients with no measurable disease may be eligible provided they have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). – Any tumor lesions previously irradiated or subjected to other locoregional therapy will be deemed measurable only if disease progression at the treated site after completion of therapy is clearly documented. Patients for whom endocrine-based therapy is recommended and treatment with cytotoxic chemotherapy is not indicated (e.g., patients with visceral crisis) at time of entry into the study, as per national or local treatment guidelines - For women participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below: Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 60 days after the final dose of inavolisib. Based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the final dose of fulvestrant and 1 week after the last dose of alpelisib. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: - With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 98 days after final dose of inavolisib. Based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the final dose of f
- Metaplastic breast cancer - Prior treatment in locally advanced or metastatic setting with any PI3K, AKT, or mTOR inhibitor or any agent whose mechanism of action is to inhibit the PI3K/-AKT/-mTOR pathway. Participant who relapsed with documented evidence of progression > 12 months from completion of adjuvant CDK4/6i based therapy with no treatment for metastatic disease Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of study treatment (based on local prescribing information for fulvestrant, patients may be advised to use an effective means of contraception for up to 2 years after the last dose of fulvestrant and 1 week after the last dose of alpelisib Women of childbearing potential (including those who have had a tubal ligation) must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes - Inability or unwillingness to swallow pills - Malabsorption syndrome or other condition that would interfere with enteral absorption - Any history of leptomeningeal disease or carcinomatous meningitis - Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Measurable disease outside the CNS – No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for ³ 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases – Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic assessments – Screening CNS radiographic assessments ³ 4 weeks since completion of radiotherapy – No history of intracranial haemorrhage or spinal cord haemorrhage Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures every 2 weeks or more frequently Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved prior to enrollment. Known active, systemic bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 7 days prior to Day 1 of Cycle 1 - Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition - Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye - Requirement for daily supplemental oxygen - Symptomatic active lung disease, including pneumonitis - History of or active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazines) are considered to have active disease and are therefore ineligible. - Any active bowel inflammation (including diverticulitis) - Clinically significant and active liver disease, including severe liver impairment (Child-Pugh Class B/C), viral or other hepatitis (e.g., hepatitis B or hepatitis C), current alcohol abuse, or cirrhosis Patients with known HIV infection (screening HIV test should be performed as allowed by local regulations), who have: – CD4 + T-cell (CD4 +) counts< 350 cells/μL AND/OR – A history of AIDS-defining opportunistic infection within the past 12 months Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, or infectious disease) or any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that renders the patient at high risk from treatment complications - Chemotherapy, radiotherapy, or any other anti-cancer therapy within 2 weeks before randomization - Investigational drug(s) within 4 weeks before randomization or within 5 half-lives of the investigational drug(s), whichever is longer Prior radiotherapy to > 25% of bone marrow, or hematopoietic stem cell or bone marrow transplantation - Unresolved toxicity from prior therapy, except for hot flashes, alopecia, and Grade ≤ 2 peripheral neuropathy - History of other malignancy within 5 years prior to screening, except for cancers with very low risk of recurrence including, but not limited to, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer History of or active clinically significant cardiovascular dysfunction, including the following: – History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment – History of angina pectoris or myocardial infarction within 6 months prior to first dose of study treatment – History of documented congestive heart failure (New York Heart Association Class II-IV) or cardiomyopathy – Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication – Coronary heart disease that is symptomatic or unstable angina – Congenital long QT syndrome or QT interval corrected through use of Fridericia’s formula > 470 ms demonstrated by at least two ECGs > 30 minutes apart, or family history of sudden unexplained death or long QT syndrome Chronic therapy of ≥ 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant, or alpelisib formulations - Treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors within 1 week or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment - History of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) - Active ongoing osteonecrosis of the jaw Major surgical procedure, or significant traumatic injury, within 28 days prior to Day 1 of Cycle 1 or anticipation of the need for major surgery during the course of study treatment Patients must have sufficiently recovered from surgery, including adequate wound healing. Minor surgical procedures < 7 days prior to first dose of study treatment Patients must have sufficiently recovered from surgery, including adequate wound healing.
This study investigates venetoclax use in the treatment of acute myeloid leukaemia (AML) in Great Britain (GB). Venetoclax is a treatment for AML that was recently approved in GB. Venetoclax is given as a combination with other medications, with different combinations available, for AML patients who have never received a previous treatment and who cannot receive intensive chemotherapy. Clinical trials have shown venetoclax works well compared to other medications, but currently there is limited information on how it works in everyday clinics. This study will help provide information on how this treatment is used in the real world. The study aims to describe how well this treatment works, including survival, time the treatment continues to work for the patient, how often patients have to visit their doctor or hospital when taking the treatment, and how different treatment combinations are used in GB overall. This multi-centre study will be run across eight to nine sites. Doctors will review medical records for AML patients treated with different venetoclax combinations and enter patient information into an online form. Patients themselves are not directly involved, and there will be no changes to their care. The study aims to include data for 150-200 adult patients with AML (aged 18 years or older at AML diagnosis) who are taking a venetoclax combination treatment (for at least 28 days) because they cannot receive chemotherapy. Patient demographics (e.g. age, sex), clinical characteristics (e.g. other diseases or medical conditions a patient has at the time), treatment patterns (e.g. when the treatment was taken and how much was taken), effectiveness (how well the medicine works including survival), and how often patients visit their doctor or hospital whilst taking the treatment will be collected. Information that cannot reveal the patient’s identity will be collected, and this will be anonymised in the final database.
▪The patient received a diagnosis for AML, if available, suggested diagnosis codes: ICD-9 205.0x or ICD-10 C92.0x, C92.4x, C92.5x ▪ The patient was at least 18 years old at AML diagnosis date ▪ The patient was initiated on the studied line of therapy (first line venetoclax regimen per the indicated label in GB) for previously untreated AML: ▪ Venetoclax in combination with an HMA (on or after 28th May 2021) or LDAC (on or after 25th February 2022), the date of MHRA approvals of venetoclax (for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy) ▪ The patient was treated with the studied line of therapy at least 28 days prior to date of data collection ▪ Information on the patient's treatments, selected (or important) clinical characteristics, and outcomes is available from the start of the studied line of therapy onwards
▪ The patient received the studied line of therapy as part of a clinical trial ▪ Patient received prior lines of therapy for AML ▪ The patient has a history of malignancies within 2 years prior to the studied line of therapy, other than AML, and with the exception of: o Myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN) or chronic myelomonocytic leukemia (CMML) o Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast o Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin o Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
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1) Histologically-confirmed FL (grade 1, 2, or 3a) per local diagnosis. If clinically permissible, a new biopsy is strongly recommended at screening to exclude subjects with transformed disease or those who were initially misdiagnosed. Tumor tissue must be provided for retrospective central pathology review. If an archival specimen is not available, a new biopsy is required prior to randomization. 2) R/r disease as defined as one of the following options: a) At least 1 prior line and high-risk disease, defined as relapse or progression within 24 months of initiation (Cycle 1 Day 1) of the first course of chemoimmunotherapy consisting of an anti-CD20 monoclonal antibody plus either B, CHOP, or CVP (ie, POD24). Progression is measured from the first day of the first cycle of the initial chemoimmunotherapy. The first line of chemoimmunotherapy must have consisted of at least 3 cycles of an anti-CD20 monoclonal antibody plus either B, CHOP, or CVP. The CHOP regimen may have included a prednisone-equivalent dose of another corticosteroid. Frontline anti-CD20 monoclonal antibody monotherapy before an initial line of chemoimmunotherapy is permissible and not considered a line of therapy for purposes of eligibility. For those who received consolidation or maintenance therapy, the timing of progression from chemoimmunotherapy will be counted from the initiation of initial chemoimmunotherapy. OR b) R/r disease after ≥ 2 prior lines of therapy. Involved field/site radiation, maintenance, and consolidation therapies are not considered separate lines of therapy for purposes of eligibility. Single-agent anti-CD20 will not be considered a separate line of therapy for purposes of eligibility. Subjects with stable disease for < 1 year following their last line of therapy are eligible. 3) Clinical indication for treatment, including but not limited to local symptoms due to progressive or bulky disease, systemic B symptoms, compromised organ function due to disease progression, cytopenias due to marrow involvement, or symptomatic extranodal disease. 4) At least 1 measurable lesion per the Lugano Classification {Cheson 2014} on anatomical imaging such as computed tomography (CT) imaging (functional imaging such as positron emission tomography [PET] may not be used to identify a measurable lesion). Previously irradiated lesions are considered measurable only if progression was documented following completion of radiation therapy. 5) No known history or suspicion of central nervous system (CNS) lymphoma involvement. 6) Elapsed time of at least 2 weeks or 5 half-lives, whichever was shorter, since any prior systemic therapy and randomization, except for systemic inhibitory/stimulatory immune checkpoint therapy. Elapsed time of at least 3 half-lives since any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy and randomization (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, and 4-1BB agonists). 7) Toxicities due to prior therapy must have been stable and recovered to Grade 1 or lower (except for clinically nonsignificant toxicities, such as alopecia). 8) Age 18 or older. 9) Eastern Cooperative Performance Status of 0 or 1. 10) Absolute neutrophil count ≥ 1000/μL. 11) Platelet count ≥ 75,000/μL. 12) Absolute lymphocyte count ≥ 100/μL. 13) Adequate renal, hepatic, pulmonary, and cardiac function defined as the following: a) Creatinine clearance (Cockcroft Gault) ≥ 60 mL/min b) Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 upper limit of normal c) Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s Syndrome d) Cardiac ejection fraction ≥ 50% with no evidence of clinically significant pericardial effusion as determined by echocardiogram (ECHO). Multiple-gated acquisition (MUGA) scan may be used if an ECHO is not available at the site. e) No clinically significant pleural effusion or ascites f) Baseline oxygen saturation > 92% on room air. 14) Females of childbearing potential must have a medically supervised negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). Additional information is in Section 4.5.
1) History of transformed FL or clinical evidence of transformed FL at the time of screening. 2) FL grade 3b. 3) History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) unless disease-free and without anticancer therapy for at least 3 years. Subjects with asymptomatic localized low-grade prostate cancer, for which a watch-and-wait approach is SOC, are eligible. 4) Intention for subject to proceed to auto-SCT or allogeneic SCT. 5) History of allogenic SCT. 6) Auto-SCT within 6 weeks of the planned axicabtagene ciloleucel infusion. 7) Prior CD19-targeted therapy. 8) Prior CAR therapy or other genetically modified T-cell therapy. 9) History of severe, immediate hypersensitivity reaction attributed to aminoglycosides. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if the subject is responding to active treatment and after consultation with the Kite medical monitor. 10) Infection with human immunodeficiency virus, hepatitis B virus (HBV; ie, hepatitis B surface antigen [HBsAg] positive), or hepatitis C virus (anti-hepatitis C virus-positive). If there is a positive history of HBV or hepatitis C virus, the viral load must be undetectable per quantitative polymerase chain reaction and/or nucleic acid testing. a) Note: Subjects who are seropositive for HBV (ie, hepatitis B surface [HBs] antibody-positive HBs and/or hepatitis B core antibody-positive) are eligible if they are HBsAgnegative and negative for viral DNA. Subjects who are seropositive because of HBV vaccination are eligible (ie, HBs antibody-positive, hepatitis core antibody-negative, and HBsAg-negative). 11) History or presence of a CNS disorder, such as haemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome, or cerebral edema with confirmed structural defects by appropriate imaging. History of stroke or transient ischemic attack within 12 months before randomization, or seizure disorders requiring active anticonvulsive medication. 12) Detectable cerebral spinal fluid (CSF) malignant cells or brain metastases or a history of CNS lymphoma, primary CNS lymphoma, or spinal epidural involvement. 13) Cardiac atrial or cardiac ventricular lymphoma involvement. 14) History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of randomization. 15) Possible requirement for urgent therapy within 6 weeks of randomization due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome [TLS]). 16) History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome. 17) History of non-line associated, clinically significant deep-vein thrombosis (ie, proximal DVT) or pulmonary embolism requiring therapeutic anticoagulation within the 6 months before randomization. 18) Any medical condition likely to interfere with assessment of safety or efficacy study treatment. 19) History of severe hypersensitivity reaction to any of the agents used in this study. 20) Live vaccine ≤ 6 weeks of randomization. 21) Neuropathy greater than Grade 1 (subjects with neuropathy with Grade 1 neuropathy are eligible). 22) Females who are pregnant or breastfeeding (due to potentially dangerous effects of the preparative chemotherapy or SOC on the foetus or infant). 23) Subjects of both genders who are not willing to practice birth control from the time of consent through 12 months following conditioning chemotherapy administration or 12 months after the completion of axicabtagene ciloleucel or SOC, whichever is longer. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. Subjects of both genders must also comply with any relevant REMS or aRMMs as part of an RMP. Additional information is in Section 4.5. 24) As per the investigator’s judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation (eg, subjects who are at a risk for a thromboembolic event and are not willing to take venous thromboembolism prophylaxis if R2 is prescribed should be excluded).
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1. Participants age ≥18 years (or the minimum country-specific age of consent if > 18). 2. Prior diagnosis of MM as defined according to IMWG criteria.1 3. Measurable disease based on IMWG criteria as defined by at least 1 of the following: a. Serum M-protein ≥0.5 g/dL by SPEP; b. Urinary M-protein excretion ≥200 mg/24 hours by UPEP; c. Serum immunoglobulin FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (< 0.26 or > 1.65). 4. Prior anti-MM therapy: a. Part 1: At least 3 prior lines of anti-MM therapy including treatment with lenalidomide and a PI. b. Part 2: At least 2 prior lines of anti-MM therapy including treatment with lenalidomide and a PI. (NOTE - The protocol will be amended prior to start of Part 2. The inclusion criteria for prior therapy will be changed to ‘At least 1 prior line of anti-MM therapy including treatment with lenalidomide and a PI.') 5. ECOG performance status < 1. 6. LVEF ≥40% as determined by a MUGA scan or ECHO. 7. Adequate hepatic function characterised by the following: a. Total bilirubin ≤1.5 x ULN; b. AST ≤2.5 x ULN and ALT ≤2.5 x ULN.8. Estimated creatinine clearance ≥30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or per the local institutional standard method). 9. Adequate BM function characterised by the following: a. ANC ≥1.0 × 109^9/L (use of granulocyte-colony stimulating factors is permitted if completed at least 28 days prior to planned start of dosing); b. Platelet count ≥75,000/µL if < 50% of BM nucleated cells are plasma cells, or ≥ 50,000/µL if ≥50% of BM nucleated cells are plasma cells (transfusion support is permitted if completed at least 28 days prior to planned start of dosing); and c. Hemoglobin ≥8 g/dL (transfusion support is permitted if completed at least 28 days prior to planned start of dosing) 10. Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L). 11. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1
1. Smoldering MM. 2. Plasma cell leukemia 3. Systemic amyloid light chain amyloidosis. 4. POEMS Syndrome 5. Stem cell transplant within 12 weeks prior to enrollment, or active GVHD. 6. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrolment: a. Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion); b. Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); c. Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism); d. Prolonged QT syndrome (or QTcF > 470 msec at screening). 7. Ongoing Grade 2 or higher peripheral sensory or motor neuropathy. 8. History of Guillain-Barre syndrome or GBS variants, or history of any Grade > 3 peripheral motor polyneuropathy.9. Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 14 days prior to enrollment. a. COVID-19/SARS-CoV2: While SARS-CoV2 testing is not mandated for entry into this study, testing should follow local clinical practice standards. If a participant has a positive test result for SARS-CoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, he/she is excluded. 10. Any other active malignancy within 3 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. 11. Participants with known or suspected hypersensitivity to the study interventions or any of their excipients. 12. Other surgical (including major surgery within 14 days prior to enrolment), medical or psychiatric conditions including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 13. Previous treatment with a BCMA-directed therapy. 14. Anti-CD38-directed therapy within 6 months preceding the first dose of treatment in this study. 15. Part 2 only: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the end of the last dose). 16. Part 2 only: Previous pomalidomide therapy. 17. Concurrent or anticipated use of a non-topical medication known to be a strong CYP1A2 inhibitor within 7 days prior to first dose of study intervention and throughout study duration. Refer to Section 6.8 Concomitant Therapy. 18. Live attenuated vaccine must not be administered within 4 weeks of the first dose of study intervention.19. Administration with an investigational product (e.g. drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criteria for time elapsed from previous administration of investigational product. Cases must be discussed with sponsor’s medical monitor to judge eligibility. 20. For females of childbearing potential: Serum pregnancy test positive at screening. 21. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).
This study is a multi-centre, non-interventional cohort study involving the collection of retrospective data from the medical records of patients who were initiated on acalabrutinib as part of the UK Early Access Program (EAP). The study is expected to include approximately 350 patients who received acalabrutinib as first-line treatment for Chronic lymphocytic leukaemia (CLL), from approximately 40 National Health Service (NHS) centres participating in the EAP in the United Kingdom (UK). Patients included in the study are expected to be followed for up to 60 months (5 years) from the date of the first acalabrutinib dose. At all centres, data collection will be performed by members of the direct care team, and de-identified data will be collected for all patients (living or deceased) to preserve patient confidentiality. The data collected will provide real world information on the characteristics, treatment patterns and clinical outcomes of UK patients with CLL who are treated with acalabrutnib in the first-line setting. There will be no changes to patient management for the purposes of any part of the study and no additional tests, investigations or visits will be required.
- Treatment-naïve patients who were initiated on acalabrutinib as part of the UK EAP (Early Access Program). - Received their first dose of acalabrutinib between 1 April 2020 and 1 April 2021. - Patients aged ≥ 18 years old.
MK3475-U03
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Patients may be entered in the study only if they meet all of the following criteria: 1. Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma according to AJCC staging system (8th edition). 2. Known BRAF V600 mutation status or consent to BRAF V600 mutation testing before randomization. 3. Tumor tissue available for PD-L1 testing at central lab. PD-L1 expression level is required for randomization. In order to be randomized, a patient must be classified as PD-L1 positive or PD-L1 negative according to the following criteria: • PD-L1 positive (≥ 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells) vs. • PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells). Note: If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the Screening Phase, patients must consent to allow the acquisition of additional tumor tissue for assessment of the biomarker. 4. Males or females 12 years of age or older. 5. ECOG performance status ≤ 1 for age ≥ 18 years, Lansky performance score ≥ 80% for age 12 to 17 years. 6. At least one measurable lesion defined by RECIST 1.1 criteria, (separate from the lesion to be used for tumor tissue collection for PD-L1 testing) not counting brain metastasis with: • Longest diameter ≥ 10 mm by CT (when slice thickness is ≤ 5 mm); or ≥ 2 × slice thickness (when slice thickness is > 5 mm) • Pathologically enlarged lymph node: ≥ 15 mm in short axis by CT (when slice thickness is ≤ 5 mm) • Clinical: ≥ 10 mm (that can be accurately measured with callipers). 7. Have not received anti-PD-1, anti-PD-L1 or other systemic therapy for unresectable or metastatic melanoma, except for the following, provided that the patient has recovered from all treatment-related toxicities: a. BRAF mutation targeting therapy > 4 weeks before administration of Study Treatment. b. Adjuvant or neoadjuvant therapy with PD-1 or PD-L1 inhibitors or anti-CTLA-4) is allowed if disease progression/or recurrence occurred at least 6 months after the last dose and no clinically significant immune related toxicities leading to treatment discontinuation were observed. c. Adjuvant interferon therapy must have been completed > 6 weeks before administration of Study Treatment. 8. Any prior radiotherapy or minor surgery must be completed at least 2 weeks and 1 week respectively before Day 1 dosing and recovered from all treatment related toxicities. 9. Screening laboratory results within 14 days prior to randomization: a. Haematology: WBC ≥ 3000/μL, neutrophils ≥ 1500/μL, platelets ≥ 100 × 103/μL, hemoglobin ≥ 10.0 g/dL independent of transfusion. The use of erythropoietic growth factor to achieve hemoglobin (Hgb) ≥ 10 g/dl is acceptable. b. The CrCL ≥ 30 mL/min using Cockcroft-Gault formula (Cockcroft et al. 1976). c. AST and ALT ≤ 3 × ULN, alkaline phosphatase ≤ 2.5 × ULN unless bone metastases present (patients with documented bone metastases: alkaline phosphatase < 5 x ULN), bilirubin ≤ 1.5 × ULN (unless known Gilbert’s disease where it must be ≤ 3 × ULN), serum albumin ≥ 3.0 g/dL). 10. Negative serum pregnancy test at baseline for women of childbearing potential. 11. Females of childbearing potential (non-surgically sterile or premenopausal female capable of becoming pregnant) and all males (due to potential risk of drug exposure through the ejaculate) must agree to use adequate birth control measures from study start, during the study and for 5 months after the last dose of Study Drug. Acceptable methods of birth control in this trial include two highly effective methods of birth control (as determined by the Investigator; one of the methods must be a barrier technique) or abstinence. 12. Have the ability to understand and the willingness to sign a written informed consent document, comply with study scheduled treatment, visits and assessments.
1. History of ≥ Grade 3 hypersensitivity reactions to monoclonal antibodies. 2. Previous treatment with a PD-1, PD-L1, PD-L2, CTLA-4 inhibitor, or any other agents targeting T-cell co-stimulation or immune checkpoint pathways for unresectable or metastatic melanoma. 3. History of a cardiovascular illness including: congestive heart failure (New York Heart Association Grade III or IV) unstable angina or myocardial infarction within the previous 6 months; or symptomatic cardiac arrhythmia despite medical management. QT interval corrected by heart rate using QTcF > 450 ms in males or > 470 ms in females, or congenital long QT syndrome. 4. Uncontrolled hypertension, systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg. 5. Patients with new, active, or progressive brain metastases or eptomeningeal disease with except when considered for a separate special open-label cohort. 6. History of haemorrhagic diarrhoea, inflammatory bowel disease, active uncontrolled peptic ulcer, or bowel resection that affects absorption of orally administered drugs. 7. Active, known, or suspected autoimmune disease, except for Type I diabetes mellitus, hypothyroidism requiring only hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic therapy. 8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy. 9. Known history of testing positive for HIV, known AIDS. 10. Hepatitis B surface antigen positive or hepatitis C antibody positive. Further investigation per institutional practices may be performed to exclude active infection. 11. Patients with a condition requiring chronic systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalents) or other immunosuppressive medications within 14 days before administration of Study Treatment. Inhaled or topical steroids, or adrenal replacement dose of corticosteroids at dose ≤ 10 mg/day prednisone equivalent are permitted. 12. Use of another investigational agent (drug or vaccine not marketed for any indication) 28 days or before administration of Study Treatment. If the investigational agent is a monoclonal antibody then within 3 months before administration of Study Treatment. 13. Pregnant or breast-feeding women. 14. Second malignancy unless in remission for 2 years or locally curable cancers that have been treated with curative intent with no evidence of recurrence, such as: • Basal or squamous cell skin cancer • Superficial bladder cancer • Carcinoma in situ of cervix or breast • Incidental prostate cancer • Non melanomatous skin cancer • Carcinoma in situ of the cervix treated with curative intent • Prostate cancer treated with curative intent with serum prostate specific antigen (PSA) < 2.0 ng/mL 15. Patients with medical conditions requiring administration of strong cytochrome P450 (CYP), CYP3A4 Inducers and Inhibitors. 16. Uncontrolled adrenal insufficiency or active chronic liver disease. 17. Has received approved live vaccine/live attenuated vaccines within 30 days of planned Cycle 1 Day 1. Inactivated viral vaccines or vaccines based upon subviral component are allowed. however intranasal influenza vaccines (e.g. Flu-Mist) are not allowed. COVID-19 vaccination should be administered at least 7 days before Cycle 1 Day 1. 18. Underlying medical conditions that, in the Investigator’s opinion, will make the administration of Study Treatment hazardous or obscure the interpretation of toxicity determination or AEs. 19. Unwilling or unable to comply with procedures required in this protocol.
Head and neck squamous cell carcinoma (HNSCC) is the sixth commonest cancer worldwide. For the past 20 years, head and neck cancer has been associated with 5-year survival rate of 50%. Traditional risk-factors for HNSCC patients have included alcohol consumption and tobacco use. More recently, however, the incidence of HPV-related HNSCC is increasing, in line with the overall rise in the incidence of malignancies associated with HPV infection. In recent years, numerous approaches have shown that the immune system can be ‘trained’ and strengthened to both engage and destroy cancer cells. BioNTech SE, the sponsor of this study, are developing BNT113, a novel treatment designed to instruct immune cells to recognise HPV16+ HNSCC cells and potentially destroy them. BNT113 will be given in combination with Pembrolizumab, a cancer medicine that works by activating immune cells to fight cancers cells and blocks the growth and spread of the cancer cells in the body. By giving BNT113 and pembrolizumab together, the goal is to increase the immune system response against cancer cells. This is an open-label, controlled, Phase II trial of BNT113 in combination with pembrolizumab vs pembrolizumab monotherapy as first line treatment in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing PD-L1 with CPS > = 1. This trial has two parts. Part A, a Safety Run-In Phase to confirm the safety and tolerability at the selected dose range level of BNT113 in combination with pembrolizumab. Part B, the Randomised Phase of BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy to assess if the combination of the study drug with pembrolizumab works better to treat people with HNSCC than pembrolizumab alone. This study will take place in approximately 160 centres in 20 countries. Approximately 12 to 18 people with HNSCC will be participating in Part A and 267 people in Part B.
1. Patients must sign the written informed consent form before any screening procedure. Informed consent must be documented before any trial-specific screening procedure is performed. 2. Patients must be aged ≥ 18 years on the date of signing the informed consent. 3. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial. 4. Patients who present histologically confirmed recurrent or metastatic HPV16+ HNSCC that is considered incurable by local therapies. • Note 1: HPV16 positivity in the Safety Run-In Phase (Part A) will be determined using an investigational real time PCR-based (qPCR) test detecting HPV16 E7 DNA derived from FFPE tumor tissue (therascreen HPV RGQ PCR Kit). • Note 2: For the randomized phase (Part B), HPV16 positivity will be determined using an investigational real time PCR-based qPCR test (therascreen HPV Panel RGQ PCR Kit) detecting HPV16 E7 DNA derived from FFPE tumor tissue. 5. Patients who have a tumor expressing PD-L1 [CPS ≥ 1] as determined by the FDA-approved test PD L1 22C3 pharmDx kit performed and evaluated according to the manufacturer’s specifications. 6. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Patients may not have a primary tumor site of nasopharynx (any histology). 7. Patients must not have had prior systemic anticancer therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization, if given as part of multimodal treatment for locally advanced disease is allowed. 8. Patients who have measurable disease based on RECIST 1.1 as determined by the site and confirmed by BICR. Tumor lesions situated in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesions disease by RECIST 1.1. 9. Patients have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. 10. Patients have adequate bone marrow function as defined by hematological parameters as described in protocol points a/b/c. 11. Patients have adequate hepatic function, as defined in protocol points a/b. 12. Patients should have adequate kidney function, assessed by the estimated glomerular filtration rate ≥ 45 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CPK-EPI) equation Kidney Disease Improving Global Outcomes [KDIGO] 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease; Levey et al. 2009). 13. Patients should be stable with adequate coagulation, as defined in the protocol points a/b. 14. All patients must provide a tumor tissue sample (FFPE blocks/slides) from archival tissue, or fresh biopsy if collected as part of patient’s standard clinical practice before the first dose of trial treatment. The sample should preferably be derived from the primary tumor and from the last tumor sample taken. FFPE block is preferred. If not possible, at least 16 (preferably 20) consecutive slides should be provided. More information about sample quality, requirements, and handling will be provided in a Laboratory Manual. 15. Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin) at screening. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential. 16. WOCBP must agree to practice at least one highly effective method of contraception during trial, i.e., starting at screening, during the trial and for at least 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab. 17. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial starting at screening, during the trial and for 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab. 18. A man who is sexually active with a WOCBP and has not had a vasectomy must agree to practice at least one highly effective contraception method during the trial and for at least 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab.
1. Patients are pregnant or breastfeeding. 2. Patients present primary tumor site of nasopharynx (any histology). 3. Patients with uncontrolled intercurrent illness as defined in the protocol points a/b/c/d/e/f/ g/h/I/j/k/l/m. 4. Patients with a known allergy, hypersensitivity, or intolerance to BNT113 or its excipients, or to pembrolizumab or its excipients. 5. Patients who have had a splenectomy. 6. Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or have not fully recovered from surgery, or have a surgery planned during the time of trial participation. 7. Patients who have a known history (testing not required) or has a positive test at screening of any of the following: a. Human immunodeficiency virus (HIV) 1 or 2. b. Hepatitis B (carrier or active infection). c. Hepatitis C (unless considered cured 5 years post curative anti-viral therapy). 8. Patients with another primary malignancy that has not been in complete remission for at least 2 years, with the exception of those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, non-invasive basal or non-invasive squamous cell skin cancer, localized prostate cancer, non-invasive superficial bladder cancer or breast ductal carcinoma in situ). Note: Any uncertainties should be discussed with the Medical Monitor. 9. Patients with any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. 10. Patients who have received or currently receive the therapy/medication as defined in the protocol points a/b/c/d/e/f. 11. Prior anti-cancer therapy in the metastatic or in the unresectable recurrent HNSCC setting. 12. Prior treatment with anti-cancer immunomodulating agents, such as blockers of PD 1, PD-L1, tumor necrosis factor receptor superfamily member 9 (TNRSF9, 4 1BB, CD137), OX 40, therapeutic vaccines, cytokine treatments, or any investigational agent within 4 weeks before the first dose of BNT113. 13. Treatment with other anti-cancer therapy including chemotherapy, radiotherapy with curative intent, major surgery with curative intent or biological cancer therapy within 6 months prior to randomization. Adjuvant hormone therapy used for breast cancer in long term remission (refer to Exclusion criterion#8) is allowed. Note 1: Palliative radiotherapy and palliative surgery are allowed. Note 2: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is allowed assuming that the patients have been on stable doses for ≥ 4 weeks prior to first dose of trial treatment. 14. Current evidence of Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) Grade > 1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria. Patients with Grade 2 neuropathy may be eligible at Investigator’s discretion. 15. Current evidence of new or growing brain or spinal metastases during screening. Patients with known brain or spinal metastases may be eligible if they: a. had radiotherapy or another appropriate therapy for the brain or spinal metastases, b. have no neurological symptoms (excluding Grade ≤ 2 neuropathy), c. have stable brain or spinal disease on the computer tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent, d. do not require steroid therapy within 7 d before randomization, e. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated. 16. Patients who have previously been enrolled in this trial. 17. Patients with substance abuse or known medical, psychological, or social conditions that may interfere with the patient’s participation in the trial or evaluation of the trial results. 18. Patients affiliated with the investigational site (e.g., a close relative of the investigator or dependent person, such as an employee or student of the trial site).
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All patients: • Voluntary agreement to provide written informed consent prior to any study procedures and the willingness and ability to comply with all aspects of the protocol. • Male or female ≥ 18 years of age at the time of informed consent. • At least one measurable and injectable (including use of image-guided injection) tumor of ≥ 1 cm in longest diameter. • Females of childbearing potential must have negative beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG. • Female subjects of childbearing potential must be willing to use a highly effective method of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study and 3 months after last dose of study medication (see Section 6.3.7). • Male subjects of reproductive potential must agree to use a highly effective method of contraception during sexual contact with females of childbearing potential starting with the first dose of study medication and 3 months after the last dose of study therapy (see Section 6.3.7). • Adequate hematologic function including: - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L - Platelet count ≥ 100 x 109/L - Hemoglobin ≥ 9 g/dL (without requiring transfusion or hematologic growth factor) • Adequate hepatic function including: - Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) - Aspartate amino transferase (AST) ≤ 2.5 x ULN - Alanine amino transferase (ALT) ≤ 2.5 x ULN • Adequate renal function including: - Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50cc/min • Prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio [INR] ≤ 1.3) and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN Phase 1 patients only: • Patients with advanced/metastatic solid tumors, who have progressed on standard therapy or cannot tolerate standard therapy, or for which there is no standard therapy preferred to enrollment in a clinical trial. • ECOG performance status ≤ 2 Phase 2 patients only: • ECOG performance status 0 - 1 • Measurable disease based upon RECIST v1.1 • Life expectancy of at least 3 months • Patients with STS: Diagnosis of primary soft tissue sarcoma (T2a or T2b disease), superficial or deep tumor, Grade 1, 2, 3 or 4, tumor located on the upper/lower extremity or trunk, or locally recurrent disease for which local radiation therapy followed by surgery are the standard of care, tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI for which radiation is feasible • Patients with TNBC: Initial diagnosis of TNBC by central laboratory and according to ASCO/CAP current guidelines, metastatic or locally recurrent inoperable disease; newly obtained tumor biopsy from metastatic site; received either one or two prior systemic treatments for metastatic breast cancer; documented disease progression on the most recent therapy; previously treated with an anthracycline and/or taxane in the neoadjuvant/adjuvant or metastatic setting. • Patients with melanoma: Diagnosis of stage IIIb-IV melanoma, LDH < 1.5 ULN, for whom pembrolizumab therapy is indicated according to a current approved label, and who have not received prior systemic therapy • Patients with NSCLC: Diagnosis of metastatic NSCLC for whom pembrolizumab therapy is indicated according to a current approved label • Patients with NMSC: Histologic or cytologic diagnosis of basal cell carcinoma, squamous cell carcinoma of the skin (vulvar squamous carcinoma, basosquamous carcinoma, and squamous cell carcinoma of unknown primary), basosquamous cell carcinoma of the skin, Merkel cell carcinoma (MCC) or cutaneous T cell lymphoma (CTCL), that is advanced (tumors considered unresectable) or refractory (persistent or recurrent disease with prior therapy including either: surgery, radiation, intralesional/topical therapy or systemic therapy) • Patients with Melanoma, NSCLC, TNBC and NMSC: Willingness to comply with the pembrolizumab risk minimization plan (e.g., be educated about the associated risks and carry and use the Patient Alert Card).
All patients: • Prior treatment with an oncolytic therapy, • Known to have acute or chronic active hepatitis B/C or human immunodeficiency virus (HIV) infection, • Had systemic infection requiring intravenous (IV) antibiotics or other serious infection within 14 days prior to dosing • Immunocompromised patients including those with history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS, or other clinical manifestations of infection with human immunodeficiency viruses. • Evidence of active, known or suspected autoimmune disease or non-infectious pneumonitis, glomerulonephritis, vasculitis or evidence of immune suppression for any reason o Vitiligo, Type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, non-autoimmune hypothyroidism and resolved childhood asthma/atopy are permitted • With active significant herpetic infections or prior complications of HSV-1 infection (e.g. herpetic keratitis or encephalitis), • Requires intermittent or chronic use of systemic (oral or intravenous) anti-virals with known anti-herpetic activity (e.g. acyclovir), • Systemic anti-cancer therapies within 2 weeks of first dose and not recovered (or reached non-clinically significant stability) from all toxicities associated with prior treatments. • Requiring chronic systemic steroid treatment, or any other form of immunosuppressive medication; patients using physiologic replacement doses of hydrocortisone (or equivalent) will be eligible provided it does not exceed 20 mg hydrocortisone (5 mg prednisone) morning dosing and 10 mg hydrocortisone (2.5 mg prednisone) evening dosing; inhaled or local steroid injections are not excluded, • Known active CNS metastases (previously treated brain metastases will be permitted provided they are stable for 4 weeks), • Major surgery ≤ 2 weeks prior to starting study drug • Prior other malignancy that progressed or required active treatment within the last 2 years; exceptions include basal and squamous cell carcinoma of the skin that has had likely curative treatment or in situ cervical cancer • Female who is pregnant or breast-feeding or planning to become pregnant during study treatment and 3 months after the last dose of study treatment Phase 2 patients only: • Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1) or anti-PD-L1, agent • Patients with STS: wide field radiotherapy ≤ 4 weeks or limited field radiation ≤ 2 weeks prior to starting study drug • Patients with melanoma: no ocular or mucosal melanoma • Patients with melanoma, NSCLC, TNBC and NMSC: history of interstitial lung disease • Patients with melanoma, NSCLC, TNBC and NMSC: severe hypersensitivity to another monoclonal antibody.
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1. Patient must be ≥ 18 years of age (≥ 20 years of age in Japan), at the time of signing the informed consent. 2. Histologically-confirmed prostate adenocarcinoma. Note: adenocarcinoma must be the predominant histological pattern in previous biopsies and patients with neuroendocrine or small cell cancers in any previous prostate biopsies are not eligible. 3. Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable). Note: Local lymph node involvement is not considered metastatic disease. 4. Patient must have been previously treated with a next generation hormonal agent (NHA), ie, abiraterone, enzalutamide, apalutamide or darolutamide, for prostate cancer for at least 3 months and shown evidence of disease progression (radiological or via PSA assessment) while receiving the NHA. 5. Evidence of mCRPC with progression of disease despite androgen deprivation therapy (ADT) and after anti-androgen withdrawal, if applicable, as documented by one or more of the following: a. Progression of measurable soft tissue disease b. Bone scan progression (appearance of ≥ 2 new lesions on bone scan, attributable to prostate cancer) c. Rising PSA, as defined by increasing levels on at least two consecutive assessments, following a prior assessment taken as a reference value, where all of the following are met: • The assessments are at least 1 week apart, with the first assessment at least 1 week later than the reference value • Progressive increase of at least 50% in each of the 2 assessments after the reference value, without an intervening decrease between assessments. The last value prior to study entry is ≥ 2 ng/mL 6. Serum testosterone level ≤ 50 ng/dL. 7. Candidate for docetaxel and steroid therapy. 8. Ongoing ADT with LHRH agonist, LHRH antagonist, or bilateral orchiectomy. 9. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1 and anticipated minimum life expectancy of 12 weeks. 10. Able and willing to swallow and retain oral medication. 11. Confirmation that archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample which meets the minimum pathology and sample requirements is available to send to the central laboratory (see Section 8.7.2). (Patient consents to provision of this tissue sample; this inclusion criterion does not apply to patients in China). 12. Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm: • Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). • Patients should use barrier contraception (ie, condoms) during sexual intercourse from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the pre clinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if patients wish to father children, they should be advised to arrange for collection of sperm samples prior to the start of study treatment; refer to Section 5.3.4. Female partners of childbearing potential should be advised to use a highly effective form of contraception during their partner’s participation on the trial and for 16 weeks after discontinuation of study treatment. 13. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and CSP. 14. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
1. Radiotherapy with a wide field of radiation (affecting ≥ 30% of the bone marrow) within 4 weeks before the start of study treatment. • Samarium must have been completed 4 weeks prior to the first dose of therapy. • Strontium and lutetium Lu 177 therapy must have been completed at least 12 weeks prior to the first dose of therapy. • Radium-233 must have been completed at least 6 weeks prior to the first dose of therapy. 2. Major surgery (excluding placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, or internal stents) within 4 weeks of the start of study treatment. 3. Brain metastases, or spinal cord compression (unless spinal cord compression is asymptomatic, treated, and stable and not requiring steroids for at least 4 weeks prior to start of study treatment). 4. Investigator judgment of 1 or more of the following cardiac criteria: • Mean resting corrected QT corrected by Fridericia’s formula (QTcF) interval > 470 ms, obtained from triplicate electrocardiograms (ECGs) performed at screening. • Medical history significant for arrhythmia (eg, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study. • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia of Grade ≥1, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first-degree relative, history of QTc prolongation associated with other medications that required discontinuation of the medication. See Appendix D for guidance on patients receiving any concomitant medication known to prolong the QTc interval and with the potential to interact with capivasertib. • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥ 2. • Uncontrolled hypotension: systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg. • Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) as measured by echocardiogram (ECHO) (or multiple-gated acquisition [MUGA] scan if an ECHO cannot be performed or is inconclusive). 5. Clinically significant abnormalities of glucose metabolism as defined by any of the following: • Diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment. • HbA1c ≥ 8.0% (63.9 mmol/mol). 6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: • Absolute neutrophil count < 1.5 x 109/L (If sites only collected % differential of neutrophils, the absolute neutrophil count will need to be calculated for eligibility, based on leukocytes [white blood cell] (WBC) and % of neutrophils). • Platelet count < 100 x 109/L. • Haemoglobin < 9 g/dL (< 5.59 mmol/L). [Note: any blood transfusion must be > 14 days prior to the determination of a haemoglobin ≥ 9 g/dL (≥ 5.59 mmol/L)] (If anaemia is present, it must be able to be managed by standard supportive care). • Alterations in hepatic function tests defined as any one of the following: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases - Total bilirubin > 1.5 x ULN (> 3 x ULN in the presence of documented Gilbert's syndrome) - Serum alkaline phosphatase (ALP) levels > 6 x ULN, plus either bilirubin > ULN or AST and/or ALT > 3.5 × ULN. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastases and liver function is otherwise considered adequate in the investigator’s judgement. • Creatinine clearance (CrCL) < 50 mL/min per the Cockcroft-Gault formula (using actual body weight) without the need for chronic dialysis therapy. 7. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant and active bleeding diseases), which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol. Screening for chronic conditions is not required. 8. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib. 9. Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contra indicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. Evidence of dementia, altered mental status, or any psychiatric condition that would prohibit understanding or rendering of informed consent. 10. Previous allogeneic bone marrow transplant or solid organ transplant. 11. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥5 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy. 12. Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the medical monitor. 13. Known to have active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody at screening. Known to have human immunodeficiency virus (HIV) with a CD4+ T-cell count < 350 cells/uL or a history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). Known history of drug or alcohol abuse within 1 month of screening. Note, please see Appendix D for restricted concomitant medications with capivasertib, including select antiretroviral therapy. 14. Treatment with any of the following: • Prior chemotherapy for CRPC. Chemotherapy for metastatic or localized HSPC (including docetaxel) is allowed provided that chemotherapy was completed ≥ 6 months before randomisation and progression of the prostate cancer occurred ≥ 6 months after the completion of therapy. • Prior exposure to AKT inhibitors or PI3K inhibitors • Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment. • Any other immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents (except ADT) within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologics) as agreed by the sponsor. • Strong inhibitors or inducers of cytochrome P450 (CYP)3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort), or drugs that are sensitive to inhibition of CYP3A4 within 1 week prior to the first dose of study treatment (See Appendix D for details). • Due to the important potential risk of QT prolongation derived from the capivasertib non-clinical development programme, it is recommended that administration of any drugs, other than ADT (at screening or during study conduct), considered essential for patient management which are known to prolong the QT interval is discussed with the medical monitor and that consideration should be given for close monitoring of QT interval prolongation through frequent ECG and electrolyte monitoring. See Appendix D for additional guidance regarding drugs known to prolong the QT interval and that are at risk for a potential PK interaction with capivasertib. 15. Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer. 16. History of hypersensitivity to active or inactive excipients of capivasertib, docetaxel, or drugs with a similar chemical structure or class. 17. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 18. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. 19. Any restriction or contraindication based on the local prescribing information that would prohibit the use of docetaxel.
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Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study. 1. Histologically confirmed diagnosis of colorectal carcinoma with KRAS G12C mutation in tumor tissue. 2. Prior receipt of first-line treatment in the advanced disease setting with a fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan, and radiographically documented progression of disease on or after treatment. Notes: - Maintenance therapy given in the metastatic setting will not be considered a separate regimen. - Patients experiencing disease relapse during adjuvant treatment or within 6 months following completion of adjuvant therapy are eligible. Patients with relapse more than 6 months after completion of adjuvant therapy are not eligible. - Source documents for historical disease evaluations to allow Investigator certification of disease progression on or after first-line treatment must be available. 3. Candidacy to receive treatment with cetuximab in accordance with the local product label, with the exception that patients must have documented KRAS G12C mutation and may or may not have demonstrated tumor positivity for EGFR-expression. 4. Presence of evaluable or measurable disease per RECIST 1.1. 5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory testing of KRAS G12C mutation status (minimum of 5 slides, preferably 15 slides). 6. Age ≥ 18 years. 7. Life expectancy of at least 3 months. 8. Recovery from the adverse effects of prior therapy to baseline or Grade 1 (any grade alopecia and Grade ≤ 2 peripheral neuropathy are eligible). 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Laboratory values within the screening period: a. Absolute neutrophil count ³1,500/mm3 (³1.5 × 109/L) b. Platelet count ³100,000/mm3 (³100 × 109/L) c. Hemoglobin ≥ 9.0 g/dL. Note: Transfusions will be allowed to achieve this provided the patient has not received more than 2 units of red blood cells in the prior 4 weeks d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); if associated with liver metastases, ≤ 3 × ULN. e. Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase ≤ 2.5 × ULN; if associated with liver metastases, ≤ 5 × ULN. f. Creatinine clearance ≥ 60 mL/min or glomerular filtration rate ≥60 mL/min/1.73 m2 calculated using a validated prediction equation (e.g., Cockcroft-Gault, MDRD, or 24-hour urine CrCl). g. Electrolyte levels within the screening period: corrected serum calcium ≥ 8.0 mg/dL or ionized calcium ≥ 1.0 mmol/L; magnesium ≥ 1.2 mg/dL; phosphorus ≥ 1.8 mg/dL. 11. Able to take oral medications. 12. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment. 13. Completed informed consent process, including signing IRB/EC-approved informed consent form. 14. Willing to comply with clinical trial instructions and requirements.
Patients presenting with any of the following will not be included in the study: 1. Prior treatment with both an oxaliplatin- and irinotecan-based regimen for CRC in the adjuvant and/or later treatment settings. 2. Prior treatment with a therapy targeting KRAS G12C mutation (e.g., AMG 510). 3. Prior treatment with an anti-EGFR antibody (e.g., cetuximab or panitumumab). 4. Most recent prior anticancer therapy (e.g., chemotherapy, antiangiogenic therapy or radiation therapy) discontinued within 2 weeks before the date of randomization. 5. Known contraindication to receive cetuximab, 5-FU or folinic acid at the planned doses. 6. Active brain metastases or carcinomatous meningitis. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable for at least 2 weeks prior to randomization without the use of corticosteroids or are on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). 7. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Note that the following are permitted: • Patients treated for hepatitis C (HCV) with no detectable viral load; • Patients treated for HIV with no detectable viral load for at least 1 month prior to randomization while on a stable regimen of agents that are not strong inhibitors of CYP3A4; and • Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of hepatitis B (either [HBsAg-positive with normal ALT and HBV DNA < 2,000 IU/mL or < 10,000 copies/mL] or [HBsAg-negative and anti-HBcpositive]). 8. Major surgery within 4 weeks prior to randomization. 9. History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications. 10. Any of the following cardiac abnormalities: a. Unstable angina pectoris or myocardial infarction within 6 months prior to randomization. b. Symptomatic or uncontrolled atrial fibrillation within 6 months prior to randomization. c. Congestive heart failure ≥NYHA Class 3 within 6 months prior to randomization. d. Prolonged QTc interval > 480 milliseconds or family or medical history of congenital Long QT Syndrome. 11. History of stroke or transient ischemic attack within 6 months prior to randomization. 12. Ongoing need for treatment with concomitant medication known to cause prolonged QTc interval or known as strong inhibitor or inducer of CYP3A enzyme and that cannot be switched to alternative treatment prior to study entry. 13. Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments. 14. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented prior to randomization. 15. Breast-feeding or planning to breast-feed during the study or within 6 months after the last dose of study treatment. 16. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical condition or history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s capacity to provide informed consent, with the patient’s participation in the study, or with the interpretation of the results.
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1. Each patient must sign an ICF indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient’s disease. 2. Patients must be ≥ 18 years of age. 3. Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, DLBCL, FL, MCL, MZL, or WM. 4. Patients in Phase 1a must meet the following: a. Received at least 2 prior systemic therapies (or 1 prior therapy for WM) and have no other therapies known to provide clinical benefit. 5. Patients in Phase 1b (Cohort Expansion) must have one of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment, and must have failed 2 prior lines of therapy (or 1 prior line of therapy for patients with WM, PCNSL, or secondary CNS involvement): a. Cohort A: CLL or SLL without a BTK C481 mutation with disease progression on a BTKi. Patients who stopped BTKi due to side effects must have subsequent progression. b. Cohort B: CLL or SLL with a BTK C481 mutation with disease progression on a BTKi. c. Cohort C: i. DLBCL with disease progression on an anthracycline and an anti-CD20 mAbbased regimen, including transformed indolent lymphoma, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphomas NOS, or ii. MCL with disease progression on a BTKi and an anti-CD20 mAb-based regimen. d. Cohort D: i. FL with disease progression on an anti-CD20 mAb-based regimen, or ii. MZL with disease progression on an anti-CD20 mAb-based regimen, or iii. WM with disease progression on a BTKi. e. Cohort E: i. PCNSL with disease progression on 1 prior therapy, or ii. Any of the indications listed above with CNS involvement, with disease progression on 1 prior therapy (see Section 5.1.3 for rationale). 6. Patients must have radiographically measurable disease per response criteria specific to the malignancy (i.e., iwCLL, Lugano Classification of Lymphoma response criteria, WM response criteria, or International PCNSL Collaboration Group criteria) by CT, CT/PET scan, or MRI. Target lymph nodes must be > 1.5 cm and extranodal lesions must be ≥1.0 cm in longest diameter. Evaluable disease in bone marrow or compartment (pleural effusion) is also allowed. 7. ECOG performance status of 0 or 1. 8. Adequate organ and bone marrow function, in the absence of growth factors and without platelet transfusions, as defined by the following laboratory parameters (see table in attachment section) 9. WOCBP must agree to use highly effective contraception (failure rate of < 1% per year) during the study from Screening through 6 months after the last dose of study drug. WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe. WOCBP and contraception methods are defined as per the 2020 CTFG recommendations (CTFG 2020). 10. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception (condom) (defined as per CTFG 2020) during the study from Screening through 3 months after the last dose of study drug. Men must agree to not donate sperm during the same timeframe. 11. Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
1. Prior treatment for the indication under study that includes: a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation). b. Prior chemotherapy within 4 weeks of planned start of study drug. c. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug. d. Prior small molecule therapy within 4 weeks or 5 half-lives (whichever is shorter) of planned start of study drug. e. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug. f. CAR-T therapy within 100 days prior to start of study drug (30 days for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR-T therapy. g. Use of systemic corticosteroids outside of dosing limits described below and within the 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with CNSL: no greater than 40 mg/day prednisone, or equivalent, CNSL patients using greater than 20 mg/day prednisone, or equivalent must be clinically stable at that dose for 14 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent. h. Use of immunosuppressive drugs other than systemic corticosteroids within 30 days, prior to first dose of study drug. 2. Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. 3. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study drug. 4. Patients with active GVHD or on anti-GVHD treatment or prophylaxis. 5. History of known or suspected uncontrolled seizure disorder not related to CNSL involvement. 6. Patient has any of the following: a. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study drug. b. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or NYHA class III or IV heart failure within 6 months of planned start of study drug. c. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug. d. Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease, or persistent uncontrolled hypertension defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management) within 6 months of planned start of study drug. 7. Bleeding diathesis, or other known risk for acute blood loss. 8. History of Grade ≥2 hemorrhage within 28 days. 9. Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 7 days prior to first dose of study drug or patients treated with dual anti-platelet therapy and vitamin K antagonists. 10. Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy, or hematologic parameters meeting inclusion criteria). 11. Active known second malignancy with the exception of any of the following: a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer. b. Adequately treated Stage I cancer from which the patient has been disease-free for ≥2 years. c. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL. 12. Patient has known allergies, hypersensitivity, or intolerance to components of study drug. 13. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug; for WOCBP, negative pregnancy status must be confirmed by pregnancy test at Screening and within 24 hours of first dose of study drug. 14. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug. 15. Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of study drug, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 4 weeks after the last dose of study drug. Note: patients with minor planned surgical procedures to be conducted under local anesthesia may participate. 16. Active, significant bacterial, fungal, parasitic, viral, or COVID infection including: a. Current active liver disease from any infectious cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), and hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by detectable HCV ribonucleic acid). Exceptions: Patients with hepatitis B virus (HBV) who are negative for HBV deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) are eligible irrespective of serology findings; as are, patients with a history of Hepatitis C with undetectable viral levels following treatment. b. Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible. c. Active viral reactivation (e.g., CMV or EBV) 17. Any other medical or psychiatric condition or social situation that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives or the protocol or completion of treatment per protocol. 18. Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or completion of COVID-19 vaccinations within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period. 19. Administration of any strong or moderate CYP3A inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (See Section 6.8.2.2). 20. Administration of any sensitive substrates or inhibitors of P-glycoprotein, BCRP, or OATP1B1/1B3 transporters within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (see Section 6.8.2.3). 21. Administration of a proton pump inhibitor within 14 days for 5 half-lives, whichever is longer, prior to first dose of study drug. See Section 6.8.2.4 for allowed use of alternative agents. 22. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg within 3 days prior to Screening and during study treatment (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry).
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1. Male or female patients aged ≥ 18 years, inclusive, at the time of informed consent. 2. Willing and able to give informed consent and to comply with the requirements of the study. 3. Histologically-or cytologically-confirmed diagnosis of SCCHN(ie, primary tumour arising from the oral cavity [including tongue], nasal cavity, paranasal sinuses, oropharynx, hypopharynx, or larynx) that is recurrent or metastatic(including both HPV+ve and HPV-ve SCCHN), with or without nodal involvement, and with or without metastatic spread. 4. Candidates for first-line treatment for pembrolizumab for recurrent or metastatic SCCHN, at the discretion of the investigator. 5. A positive CAFs level (defined as CAFs level in tumours ≥ 5%), performed at a central laboratory, with fresh tumour biopsy taken during the Screening Period. Suitable archival tissue, if available, can be used to assess tumour CAFs level and determine patient eligibility. 6. Measurable disease, in accordance with RECIST v1.1, and with tumour accessible and of sufficient volume for pre-treatment and on-treatment biopsy. 7. Combined positive score (CPS) ≥ 1, as determined on the archival or fresh tumour biopsy taken at Screening. 8. HPV status known at Randomisation. 9. Life expectancy of at least 6 months in the judgment of the investigator. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 11. Adequate organ and bone marrow function within 28 days of starting study treatment. Criteria “a” to “c” cannot be met in patients with ongoing or recent (within 14 days of screening test) transfusions or who require ongoing growth factor support: a. Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 × 109/L). b. Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L). c. Haemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks. Patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9g/dL are not eligible. d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤ 3 × ULN). e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN. f. Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min (measured or calculated according to the method of Cockcroft and Gault). 12. Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥ 4 weeks before randomisation and must agree to continue strict contraception up to 120days after the last dose of IMP or pembrolizumab, whichever is the later. a. For the purposes of this study, women of childbearing potential are defined as “All female patients after menarche unless they are postmenopausal for at least 2 years or are surgically sterile.” b. For female patients ≤ 55 years of age who are considered postmenopausal and who are not on concomitant oestrogen replacement therapy, confirmation of postmenopausal status will be required with follicle-stimulating hormone (FSH) test results in the postmenopausal range for age at Screening. c. Highly effective contraception is defined as use of 2 barrier methods (eg, female diaphragm and male condoms) or use of at least 1 barrier method in combination with spermicide, an intrauterine device or hormonal contraceptives (eg, implant or oral). 13. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomisation before dosing. 14. Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the investigator, such as an established form of hormonal contraceptive, a diaphragm or cervical/vault cap, or intrauterine device. This requirement begins at the time of informed consent and ends 120 days after receiving the last dose of IMP or pembrolizumab, whichever is the later. 15. Male patients must be willing to not donate sperm, and female patients must be willing to not donate eggs, from Baseline until 120days after the last dose of IMP or pembrolizumab, whichever is the later.
1. Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at doses not to exceed 10 mg/day of prednisone or equivalent. Steroids as premedication for hypersensitivity reactions due to radiographic contrast agents are allowed. 2. Anti-cancer monoclonal antibody treatment within 4 weeks prior to study Day 1. 3. Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 (radiation therapy can be allowed for palliative therapy of bone metastasis only). 4. Not recovered from AEs Grade 2 or greater (except for alopecia) due to previously administered agents. 5. Treatment with any investigational agent within 12 weeks of Screening Visit or 5 half-lives of the IMP (if known), whichever is longer, or current enrolment in an interventional clinical study. 6. Prior treatment with setanaxib or participation in a previous setanaxib clinical study. 7. Prior treatment with pembrolizumab. 8. Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, or malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of IMP and of low potential risk for recurrence. 9. Known active central nervous system metastases and/or carcinomatous meningitis. 10. Active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents. The following are exceptions to this criterion: a. Patients with vitiligo or alopecia. b. Any chronic skin condition that does not require systemic therapy. c. Patients with coeliac disease controlled by diet alone. 11. Any evidence of current interstitial lung disease or pneumonitis, or a prior history of interstitial lung disease or non-infectious pneumonitis requiring high-dose glucocorticoids. 12. Active infection requiring systemic therapy. 13. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Patients with a past or resolved hepatitis B virus infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]) are eligible provided the hepatitis virus DNA test is negative. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction (PCR) is negative for hepatitis C virus RNA. Patients with ongoing anti-viral therapy with potent inhibitors of cytochrome P450 (CYP) 3A4 are not eligible. Testing for HIV is only required if clinically indicated and is not mandatory for this study. 14. Serious chronic gastrointestinal conditions associated with diarrhoea. 15. History of significant haematological problems, such as blood dyscrasias requiring treatment, aplastic anaemia, myelodysplastic syndrome, or leukaemia. 16. Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the investigator). 17. A positive pregnancy test or breastfeeding for female patients. 18. Evidence of any of the following cardiac conduction abnormalities: a QTc Fredericia interval > 450milliseconds for male patients or > 470milliseconds for female patients. Patients with a second- or third-degree atrioventricular block are to be excluded. 19. TSH > ULN at Screening. 20. Unstable cardiovascular disease as defined by any of the following: a. Unstable angina within 6months prior to Screening. b. Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6months prior to Screening. c. Cerebrovascular accident within 6months prior to Screening. d. New York Heart Association Class III or IV heart failure. 21. Presence of any laboratory abnormality or condition that, in the opinion of the investigator, could interfere with or compromise a patient’s treatment, assessment, or compliance with the protocol and/or study procedures. 22. Any other condition that, in the opinion of the investigator, constitutes a risk or contraindication for the participation of the patient in the study, or that could interfere with the study objectives, conduct, or evaluation. 23. Use of medications known to be potent CYP3A4 inhibitors or inducers, or uridine diphosphate (UDP)-glucuronosyltransferase (UGT) inhibitors or inducers, within 21 days prior to IMP administration. 24. Legal incapacity or limited legal capacity. 25. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. 26. Patients who are unable to provide informed consent, are incarcerated or unable to follow protocol requirements. 27. Previous randomisation in this study.
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These criteria are to be checked to confirm eligibility of an ESR1m positive patient prior to randomisation for entry into the Study Treatment Phase of the study. Informed Consent 2.1 Evidence of a personally signed and dated informed consent document (ICF2) indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed. ICF2 must be signed and dated prior to initiation of the interventional study screening activities and randomisation outlined in Table 4. For those patients that wish to participate, provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative. This consent should be signed at Treatment Phase screening. If for any reason these samples are not collected at Treatment Phase screening, they may be taken at any time until the post treatment/disease relapse follow-up visit. For those patients that wish to participate, provision of signed and dated written Optional Pre-treatment and/or At Progression Tumour Sample Collection informed consent prior to collection of sample for optional translational research. This consent should be signed at the second screening for the Treatment Phase. Consent for tumour samples at disease progression could occur during the Treatment Phase. Weight 2.2 Minimum body weight of 35 kg. Type of Patient and Disease Characteristics 2.3 Patients who have ESR1m positive disease irrespective of concurrent mutation(s) detected by ctDNA during screening or surveillance. Qualifying ESR1m status (see Section 8.7.1.1) will be assessed by a prespecified Sponsor-selected assay at a central laboratory (see Section 8.7.1.1). 2.4 Confirmation that the patients are currently on treatment and have received ≥ 6 months (ie, 24 weeks) of AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib or abemaciclib) ± LHRH agonist treatment as their initial endocrine based treatment for their advanced disease in accordance with local palbociclib and abemaciclib label or treatment guidelines (a) Confirmation the patient has had no change in therapy since the start of STEP 1. Please note: (b) Dose modifications of the ongoing therapy are acceptable. 2.5 Documented absence of disease progression (by investigator assessment) prior to randomisation. (a) Clinical progression defined as unequivocal evidence of disease progression on clinical grounds in the absence of radiological progression, including development of new sites of disease or significant increase in tumour burden. (b) Radiological progression defined as unequivocal progression compared to previous imaging obtained during or prior to initiation of CDK4/6 inhibitor + AI. 2.6 Patients must be willing to provide archival radiological images (CT, MRI or bone scan, if not available, then available PET-CT scan is acceptable) used for tumour assessment at the initiation and/or during CDK4/6 inhibitor + AI for their metastatic disease treatment that support the non-PD assessment. 2.7 Eastern Cooperative Oncology Group performance status of 0 to 1. 2.8 Patients must have at least one evaluable lesion (defined as one lesion non previously irradiated, measurable and/or non-measurable, that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment). Patients with bone disease only must have at least one non previously irradiated lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. Bone scan at baseline is required. 2.9 Adequate organ and marrow function as follows: (a) Haemoglobin ≥ 9 g/dL (90 g/L). (b) Absolute neutrophil count ≥ 1000/mm3 (1.0 × 109/L) or documented institutional normal range for restarting palbociclib. (c) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia). (d) Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN; for patients on abemaciclib treatment, ALT and AST ≤ 5 × ULN. (e) Alkaline phosphatase ≤ 2.5 × ULN (≤ 5.0 × ULN if bone or liver metastases present) (f) Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight). (i) Males: CrCL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL) (i) Females: CrCL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL) Reproduction 2.10 For those female or male patients who are not abstinent (in line with their preferred and usual lifestyle choice), and intend to be heterosexually active with a partner: Female patients must be using 2 highly effective non-hormonal contraceptive measures from the time of screening until 4 weeks after discontinuation of study treatment, and must have a negative serum pregnancy test (with a test sensitivity of at least 25 mIU/mL) before first dose of any study treatment if they are of childbearing potential; or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: (a) Post-menopausal, defined as women with (i) Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (ii) Cessation of regular menses for at least 6 consecutive months with no alternative pathological or physiological cause AND with serum oestradiol and follicle stimulating hormone level within the laboratory's reference range for post-menopausal females (iii) Previous bilateral surgical oophorectomy Non sterilised male partners of a patient who is a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period (see Appendix G for complete list of highly effective birth control methods). Male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and the drug washout period (6 months after the last dose of study treatment) to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period. Concurrent Treatment 2.11 Pre-menopausal females and males who are currently receiving concurrent LHRH agonist (goserelin or leuprorelin) treatment while on CDK4/6 inhibitor + AI must be willing to continue to be treated with monthly LHRH agonists during the entire STEP2 treatment phase of the study. If the patients are currently receiving inhibition of LHRH treatment with alternative drugs or schedule other than monthly goserelin or leuprorelin, they must be willing to switch at the earliest practical time within STEP 2. 2.12 Male patients not currently receiving concurrent LHRH agonist treatment whilst on CDK4/6 inhibitor + AI must be willing to be treated with monthly LHRH agonists (goserelin or leuprorelin) unless the patients have clear orchiectomy medical history. Tumour Sample Requirements 2.13 Willingness and ability to provide an archived tissue tumour sample (Blocks or 12 unstained slides) to assess the correlation between genes, proteins, and RNAs relevant to the ER pathways and sensitivity/resistance to the investigational agents’ status/expression prior to enrolment as described in Section 8.7. Tissue from the most recent biopsy in the metastatic setting is preferred. If not available (for example bone only disease patients), then archival samples from the primary breast cancer will be required for patient participation. 2.14 Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Patients are excluded from the study if any of the following criteria apply: Type of Patient and Disease Characteristics 2.1 No evidence of disease, or bone only disease with sclerotic/osteoblastic bone lesions only at the screening for STEP 2. Medical Conditions 2.2 Have advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal]), pulmonary lymphangitis. 2.3 Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of brain or other CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before the screening phase of the study. 2.4 Any evidence of severe or uncontrolled systemic diseases which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol. 2.5 Chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of CDK4/6 inhibitor and/or study (AI or AZD9833) treatment. 2.6 History of another primary malignancy except for the following: (a) Malignancy treated with curative intent with no known active disease ≥ 3 years before the first dose of study treatment, and of very low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease (c) Other exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has undergone potentially curative therapy. 2.7 Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss) after consultation with the AstraZeneca study physician. 2.8 Patients with CDK4/6 inhibitor treatment-induced symptomatic interstitial lung disease (Grade ≥ 2). 2.9 Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV (known positive HBsAg result), and HCV. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required. 2.10 Known to have tested positive for HIV. Patients with HIV may be enrolled if they fulfil the criteria recommended by FDA and ASCO guidelines (FDA Guidance, Uldrick et al 2017): (a) CD4+ T-cell (CD4+) counts ≥ 350 cells/uL, AND (b) No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND (c) On established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment. Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load. 2.11 Unexplained syncope, symptomatic hypotension or asymptomatic hypotension with systolic blood pressure < 90 mmHg. 2.12 Second- and third-degree heart block, or clinically significant sinus pause or sinoatrial block. Patients with pacemakers or medically controlled atrial fibrillation are not excluded. 2.13 Left ventricular ejection fraction < 50% with heart failure NYHA Grade ≥ 2. 2.14 Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions (eg, cardiac valve repair or replacement surgery or transcatheter valve intervention), severe aortic regurgitation (Grade 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischaemic attack. 2.15 Untreated electrolyte abnormalities with potential QT-prolonging effect including serum/plasma potassium*, magnesium* and calcium* below the LLN. *Correction of electrolyte abnormalities to within normal ranges can be performed during screening. 2.16 Mean resting QTcF interval > 480 ms, obtained from triplicate ECGs performed at screening. 2.17 Resting heart rate < 60 beats per minute. 2.18 Uncontrolled hypertension. Blood pressure systolic > 160 and diastolic > 90 mmHg. Hypertensive patients may be eligible, but blood pressure must be adequately controlled at baseline. Patients may be rescreened regarding blood pressure requirement. Prior/Concomitant Therapy 2.19 Any concurrent anticancer treatment not specified in the protocol. Concurrent use of non-topical hormonal therapy for non cancer-related conditions (eg, hormone replacement therapy) is not allowed. 2.20 Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study treatment. 2.21 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days of the first dose of study treatment or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study. 2.22 Patients treated: (a) Within the last 2 weeks before randomisation: medications or herbal supplements known to be strong inhibitors/inducers of CYP3A4/5, sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin. (b) Within the timeframe indicated in Table I29 with drugs that are known to prolong the QT interval and have a known risk of TdP, as indicated in Appendix I 1. 2.23 Previous treatment with AZD9833, investigational SERDs/endocrine agents or fulvestrant. Prior/Concurrent Clinical Study Experience 2.24 Previous randomisation in the present study. 2.25 Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to randomisation or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 2.26 Patients with known hypersensitivity to anastrozole, or any of its excipients, or history of hypersensitivity to active or inactive excipients of AZD9833/placebo or drugs with a similar chemical structure or class to AZD9833 or known hypersensitivity to palbociclib and its excipients. In pre/perimenopausal female and male patients, known hypersensitivity to LHRH agonists or any of its excipients, that would preclude the patient from receiving any LHRH agonist. Note for patients who are receiving LHRH agonists. - Female patients with undiagnosed vaginal bleeding will be excluded. - Patients who are anticoagulated (INR > 2) and at higher risk of vascular injury and subsequent bleeding will be excluded. Other Exclusions 2.30 Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding. 2.31 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site or relative of those site staff members). 2.32 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
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1. Patient must be at least 18 years old at the Screening Visit. 2. Patient has given informed consent to participate in the study. 3. Suspected or confirmed diagnosis of Non-Small Cell Lung Cancer, melanoma or renal cancer with either primary, recurrent or metastatic disease scheduled for surgical excision and/or collection of multiple tissue samples via image or device guided biopsy. 4. Haemoglobin ‚â• 10g/dL. 5. White cell count ‚â• 3 x 109/L. 6. Negative laboratory test for blood borne pathogens (see exclusion criterion 5).
1. The patient is an employee of Achilles Therapeutics. 2. Clinical status precludes surgical removal of, or collection of multiple biopsies from, accessible tumour tissue. 3. Inadequate peripheral venous access precluding collection of blood. 4. Known pregnancy. 5. Known/laboratory confirmed diagnosis of an infectious disease preventing inclusion of tissue into cell manufacturing suite. As a minimum, the patient will undergo specific screening for the following infections: HIV 1 and 2, HTLV I/II, Hepatitis B, Hepatitis C, Syphilis (Appendix 1). 6. Patients who are currently participating in a clinical trial involving an unlicensed medical product. 7. Any medical reason why, in the opinion of the investigator, the patient should not participate in this study.
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1. Has previously untreated, unresectable, histologically or cytologically confirmed stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8 that is considered candidate for definitive concurrent chemoradiation. Note: Sites are encouraged to obtain tissue confirmation of mediastinal nodal involvement if this is safely accessible by endobronchial ultrasound (EBUS)/endoscopic ultrasound (EUS) or mediastinoscopy. However, mediastinal nodal involvement can be declared by imaging when the nodes have distinct margins and the size of the shortest axis of at least 1 node is ≥2.0 cm (positron emission tomography [PET]/magnetic resonance imaging [MRI]/computed tomography [CT] scan). Cases in which the distinct nodes all have short axis of < 2.0 cm must have pathologic confirmation of disease presence for participants to be declared eligible. 2. Participants with cervical nodal involvement are not permitted. Participants with supraclavicular nodal involvement may be entered into the study. The upper border of supraclavicular nodes must not extend above the upper border of the lateral end of the clavicle, extended medially. 3. Has no evidence of metastatic disease by protocol-approved imaging studies. The process for image collection and transmission to the central imaging vendor can be found in the Site Imaging Manual. NOTE: The presence of pleural/pericardial fluid is presumed indicative of metastatic disease unless proven otherwise. A pleural effusion fluid that is present on both a CT chest scan and routine chest x-ray requires a pleuracentesis to confirm the effusion is cytologically negative. Participants with effusions that are exudates are excluded even if the effusions are cytologically negative. Participants with effusions that are not visible on routine chest x-ray or are too small to be tapped safely may be entered on this study, provided the remaining inclusion/exclusion criteria are met. 4. Has at least 1 lesion that meets the criteria for being measurable as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review. Lesions that appear measurable, but have undergone palliative irradiation, cannot be target lesions. 5. Has not received prior systemic treatment for their Stage III NSCLC. Participants who received systemic therapy for earlier stages are eligible if the therapies were completed at least 12 months prior to the development of stage III NSCLC. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 6. Has provided tumor sample (tissue biopsy [core, incisional, or excisional]). Formalin-fixed, paraffin embedded (FFPE) blocks are preferred to slides. Newly obtained tumor sample is highly preferred over archival tissue. Note: If submitting unstained cut slides, newly cut slides must be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual). 7. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status assessed within 7 days prior to the first administration of study intervention. 8. Has a life expectancy of at least 6 months. 9. Has adequate pulmonary function test (PFT) defined as a forced expiratory volume in 1 second (FEV1) > 50% of predicted normal volume and the carbon monoxide lung diffusing capacity (DLCO) > 40% of predicted normal value. Participants for whom DLCO measurements are not available will be deemed to have adequate oxygen transfer if their resting capillary/arterial blood gas on room air reveals an oxygen pressure (PO2) > 60 mmHg. 10. Has adequate organ function as defined in Table 1; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment. Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological ANC ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La Renal Estimated creatinine clearance using the Cockcroft-Gault equation testb or a 24-hour urine test ≥51 mL/min Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin within normal limits for participants with total bilirubin levels > 1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN Endocrine TSH Within normal limits. Note: If TSH is not within normal limits at baseline, the participant may still be eligible if T3 and free T4 are within the normal limits Coagulation INR OR PT aPTT OR PTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulant Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. Demographics 11. Is male or female of at least18 years of age inclusive, at the time of signing the informed consent. Male Participants Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 12. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days following the last dose of study treatment. Note: Male participants should refrain from donating sperm during the treatment period and for at least 180 days following the last dose of study treatment. Female Participants Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 13. A female participant is eligible to participate if she is not pregnant (Appendix 5), not breastfeeding, and at least 1 of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5. OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 180 days following the last dose of pembrolizumab, olaparib, placebo or durvalumab or at least 180 days following the last dose of cytotoxic chemotherapy. Informed Consent 14. Has (or legally acceptable representative if applicable) provided written informed consent/assent for the study. The participant may also provide consent/assent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.
Medical Conditions 1. Has small cell lung cancer or a mixed tumor with presence of small cell elements. Note: Participants with squamous NSCLC are not eligible to receive pemetrexed based chemotherapy. 2. Has history, current diagnosis, or features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). 3. Has had documented weight loss > 10% in the preceding 3 months. Prior/Concomitant Therapy 4. Has a radiation treatment plan that is likely to encompass a volume of whole lung receiving > 20 Gy in total (V20) of more than 35% of lung volume. 5. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer. 6. Completed palliative radiotherapy within 7 days of the first dose of trial treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids for at least 7 days prior to the first dose of study intervention, and not have had radiation pneumonitis. The radiated lesion must not be included as a target lesion for RECIST 1.1 measurements. 7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 8. Has received prior therapy with olaparib or with any other PARP inhibitor 9. Had major surgery < 4 weeks prior to the first dose of study drug (except for placement of vascular access). Note: If participants received major surgery, or underwent placement of vascular access, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention. 10. Is expected to require any other form of antineoplastic therapy, including radiation therapy, while on study. 11. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 12. Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention. 13. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for pentobarbital and 3 weeks for other agents. Note: a current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 14. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm Pemetrexed-specific 15. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents [for example, piroxicam]) before, during, and for at least 2 days after administration of pemetrexed. 16. Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone. Prior/Concurrent Clinical Study Experience 17. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Diagnostic Assessments 18. Has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or participant has congenital long QT syndrome. 19. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Note: ocular, intranasal, or topical steroids or inhaled corticosteroids for management of asthma or chronic obstructive pulmonary disease are permitted. 20. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 21. Has severe hypersensitivity (≥ Grade 3) to study treatment and/or any of its excipients. 22. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 23. Has a known history of, or active, neurologic paraneoplastic syndrome. 24. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 25. Has an active infection requiring systemic therapy. 26. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 27. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority 28. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis). 29. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary. 30. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 31. In the opinion of the treating Investigator, is considered a poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome. 32. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. Other Exclusions 33. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g. gastrectomy, partial bowel, obstruction, malabsorption). 34. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study intervention.
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1. Be male or female and at least 18 years of age on the day of signing informed consent. 2. Have histologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies. 3. Have experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab. 4. Have disease progression on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Anti-PD-1/PD-L1 treatment progression is defined by meeting all the following criteria: • Most recent treatment with an anti-PD-1/PD-L1 mAb. • Has received at least 2 doses of an anti-PD-1/PD-L1 mAb. • Has demonstrated disease progression after an anti-PD-1/PD-L1 mAb as defined by RECIST 1.1. • Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb. Note: Eligible participants may have received anti-PD-1/PD-L1 mAb and platinum-containing therapy concomitantly. 5. Have submitted pre-study imaging that confirmed evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor. • Note: These pre-study images must be submitted to the iCRO for confirmation that they are of acceptable diagnostic quality. The iCRO must have received these images and confirmed that they are of acceptable diagnostic quality before randomization. • Note: The pre-study imaging submitted to the iCRO will be from disease progression on treatment with an anti-PD-1/PD-L1 mAb; NOT from images associated with disease progression on platinum-containing chemotherapy given sequentially. 6. Have documentation of results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using the CINtec® p16 Histology assay and a 70% cutoff point. Refer to Section 8.8.2 for details. If HPV status has previously been tested using this procedure, no retesting is required. 7. Have provided tissue for biomarker analysis from a core or excisional biopsy (fine needle aspirate is not adequate). Repeat samples may be required if adequate tissue is not provided. A newly obtained biopsy (within 90 days prior to start of study treatment) is strongly preferred, but an archival sample is acceptable. 8. Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) based on RECIST 1.1 as confirmed by BICR. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 9. Have an ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention. 10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least: • 30 days after the last dose of pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3). • 180 days after the last dose of SOC chemotherapy (Arm 2), and agree to the following: • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5]) as detailed below: - Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration. • Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex. Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed. 11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a WOCBP. OR - Is a WOCBP randomized to pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with lower user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. - A WOCBP randomized to SOC chemotherapy is eligible to participate if she is using a contraceptive method that is highly effective with low user dependency or abstinent from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate or freeze/store eggs during the intervention period and for at least 180 days after the last dose of SOC chemotherapy. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum; as required by local regulations) within 24 hours before the first dose of study intervention. - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 5. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 12. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. 13. Have adequately controlled BP with or without antihypertensive medications, defined as BP ≤ 150/90 mm Hg with no change in antihypertensive medications for at least 1 week prior to randomization. 14. Have adequate organ function as defined in Table 1. • Note: Specimens must be collected within ≤ 10 days prior to the start of study intervention.
1. Has carcinoma of the nasopharynx, salivary gland, unknown primary origin, or nonsquamous histologies as primary tumors. 2. Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer. 3. Has disease that is suitable for local therapy administered with curative intent. 4. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain), in the opinion of the treating investigator. 5. Has any evidence of symptoms or signs of active tumor bleeding within 6 months prior to randomization. 6. Has ulceration and/or fungation of disease onto the skin surface. 7. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates > 90 degree abutment or encasement of a major blood vessel. • Note: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy. 8. Has a history of (noninfectious) pneumonitis that required systemic steroids, or current pneumonitis/interstitial lung disease. 9. Has an active infection requiring systemic therapy. 10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated metastases may participate provided they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting study intervention. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study intervention. 12. Has a known additional malignancy that is progressing or has required active systemic treatment within the past 3 years. • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study enrollment. Other exceptions may be considered after consultation with the Sponsor. 13. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). • Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 14. Has had an allogeneic tissue/solid organ transplant. 15. Has a known history of human immunodeficiency virus (HIV) infection. • Note: No HIV testing is required unless mandated by local health authority. 16. Has a known history of hepatitis B (defined as hepatitis B surface antigen (HbsAg) reactive or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection. • Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority. 17. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥ Grade 3), lenvatinib or SOC chemotherapy. 18. Has pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula. 19. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption. 20. Has had major surgery within 3 weeks prior to first dose of study interventions. • Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. • Note: Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy. 21. Has clinically significant cardiovascular impairment within 12 months of the first dose of study drug, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident /transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability. • Note: Medically controlled arrhythmia that is stable with medication is permitted. 22. Has active tuberculosis. 23. Has difficulty swallowing capsules or ingesting a suspension either orally, by a nasogastric (NG) tube, or by a gastrostomy tube. Note: Gastrostomy tube (PVC, greater than or equal to 6 Fr) can be used to administer lenvatinib. 24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 3) or 180 days after the last dose of SOC chemotherapy. 25. Patients previously treated to one of the 5 SOC agents in this trial (ie, docetaxel, paclitaxel, capecitabine, methotrexate, or cetuximab) may not receive the same agent if randomized to the SOC chemotherapy arm. 26. Has had prior treatment with lenvatinib as monotherapy or in combination with an PD 1/PD-L1 inhibitor or other therapies. 27. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered (ie, ≤ Grade 1 or baseline) from AEs due to a previously administered agent. Note: Events of ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or laboratory values listed in Table 1 are allowed. Note: Participants must have recovered from all radiation-related toxicities and not have had radiation pneumonitis. 28. Has received a live vaccine within 30 days of planned start of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 29. Was previously treated with 4 or more systemic regimens given for recurrent and/or metastatic disease. 30. Is currently participating in or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device. 31. Has urine protein ≥ 1 g/24 hours Note: Participants with proteinuria > 1+ on urine dipstick testing/urinalysis will undergo 24 hour urine collection for quantitative assessment of proteinuria. 32. Has prolongation of QTc interval (calculated using Fridericia’s formula) to > 480 msec. 33. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO). 34. Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: In the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study treatment. 35. Has a history or current evidence of any condition, therapy, or laboratory abnormality that may confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant, in the opinion of the treating investigator. 36. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
This research study is being done to learn more about multiple myeloma (MM). The study will test if the investigational study treatment, called belantamab mafodotin (also referred to as GSK2857916), can help patients who have already received at least one other treatment and whose MM has worsened. This type of MM is called relapsed/refractory MM or RRMM. In this study, belantamab mafodotin will be given in combination with two other drugs that are currently approved to treat MM, pomalidomide and dexamethasone (abbreviated to pom/dex). Adult patients with Relapsed/Refractory Multiple Myeloma will be eligible to participate in this study if they meet all of the inclusion criteria and none of the exclusion criteria as listed in the study Protocol. The study will include about 450 study participants and will last for approximately 5 years. The study will include a screening period, study treatment period, and follow-up. During screening participants will be evaluated for study eligibility per protocol as defined in the Inclusion and Exclusion criteria. Following screening, eligible participants will be divided into 2 treatment arms (referred to as Arm A and Arm B). Arm A participants will receive the investigational study treatment, belantamab mafodotin. Arm B participants will receive the comparator study treatment bortezomib plus pom/dex. The effects of the drugs will be compared between the two treatment arms. The study assessments will be performed during Screening, prior to the first dose of Cycle 1, and during each cycle of treatment. Upon completion of study treatment, participants will enter the follow-up phase.
Please refer to Protocol for full Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria are met: • Capable of giving signed informed consent • Male or female, 18 years or older • Have a confirmed diagnosis of multiple myeloma • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 • Have been previously treated with at least 1 prior line of MM therapy including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles) and must have documented disease progression during or after their most recent therapy. • Note Participants intolerant or refractory to bortezomib at 1.3 mg/m2 dose twice weekly dosing schedule are not eligible. • Must have at least ONE aspect of measurable disease, as defined in the protocol inclusion criteria • Have undergone autologous stem cell transplant (SCT) or are considered transplant ineligible. Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met: a. Autologous SCT was > 100 days prior to the first dose of study medication. b. No active bacterial, viral, or fungal infection(s) present • All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0) must be < = Grade 1 at the time of enrolment, except for alopecia. • Adequate organ system functions as defined by the laboratory assessments listed in Table 2 in the inclusion criteria in Protocol. • Meet the contraception requirements of the inclusion criteria in the Protocol
Please refer to Protocol for full Exclusion criteria A participant will not be eligible for inclusion in this study if any of the following criteria are met: Prior or Concomitant Therapies • Active plasma cell leukemia at the time of screening. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes). • Participants after prior allogeneic SCT. NOTE: Participants who have undergone syngeneic transplant will be allowed only if no history of or no currently active graft versus host disease (GvHD). • Systemic anti-myeloma therapy (including chemotherapy and systemic steroids) or use of an investigational drug within 14 days or five half-lives (whichever is shorter) preceding the first dose of study drug; Prior treatment with a monoclonal antibody drug within 30 days of receiving the first dose of study drugs. • Plasmapheresis within 7 days prior to the first dose of study drug. • Received prior treatment with or intolerant to pomalidomide. • Received prior BCMA targeted therapy. • Intolerant to bortezomib or refractory to bortezomib (i.e., participant experienced progressive disease during treatment, or within 60 days of completing treatment, with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly). Prior- or Concomitant Diseases or Conditions • Evidence of cardiovascular risk including any of the detailed criteria listed in the exclusion criteria in the protocol. • Any major surgery within the last 4 weeks. • Previous or concurrent invasive malignancy other than multiple myeloma, except; The disease must be considered medically stable for at least 2 years; or The participant must not be receiving active therapy, other than hormonal therapy for this disease. • Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment. • Evidence of active mucosal or internal bleeding. • Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria). • Active infection requiring treatment. • Known human immunodeficiency virus (HIV) infection. • Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb) at Screening or within 3 months prior to first dose of study treatment). • Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. • Intolerance or contraindications to anti-viral prophylaxis. • Presence of active renal conditions (e.g. infection, severe renal impairment • requiring dialysis or any other condition that could affect participant’s safety). • Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in Table 4 of the Protocol. • Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain • Active or history of venous thromboembolism within the past 3 months. • Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis • Current corneal disease except for mild punctate keratopathy (as per Section 10.9 Protocol). • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures. • Pregnant or lactating female.
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1. Participants must have histologically- or cytologically-documented NSCLC who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]). Initial staging procedures performed prior to initiation of any component of definitive treatment should include: - Whole-body Positron Emission Tomography – Computed Tomography (PET-CT) scan performed up to 42 days prior to the first dose of concurrent chemoradiotherapy (CRT). Brain imaging must be obtained to allow for appropriate staging. o - Except for overt cT4 disease, biopsy strongly preferred to prove nodal status N2 or N3 via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. 2. Tumour sample requirements as follows: Provision of a tumour tissue sample (≤ 3 months old is preferred; ≤ 6 months old is acceptable). An FFPE block sufficient for sectioning 20 slides (5 micron thickness) is the preferred sample type. 3. Tumour PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a central laboratory, must be known prior to randomization. Patients with unknown PD-L1 status are not eligible for the study. “Unknown” refers to (1) insufficient sample which is not able to be analysed, or (2) sample could be analyzed but results not interpretable. 4. Documented EGFR and ALK status (locally or centrally). If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used. If performed locally, negative EGFR and ALK tests will be confirmed by central laboratory. EGFR and ALK status must be available prior to randomisation. Participants with sensitizing EGFR (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 insertion or S768I mutation) or ALK rearrangements are excluded from the study. 5. Tumours harbouring mutations in any of the following genes, as determined by existing local test results: ROS1, RET, MET, BRAF, NTRK1, NTRK2, ERBB2 and KEAP1/NRF2 are excluded. 6. Patients must have not progressed following definitive, platinum-based, concurrent chemoradiation therapy as demonstrated by the following imaging studies performed after completion of CRT: - Screening baseline RECIST imaging of chest and abdomen by CT (preferred) or MRI (see schedule of assessments Table 1) - Brain magnetic resonance imaging (MRI, preferred) or high-quality brain CT with IV contrast (See schedule of assessments Table 1). 7. Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 28 days prior to first dose of investigational product in the study (one cycle is defined as 21 or 28 days). . Sites are strongly encouraged to complete screening within the first 14 days of the 28 day screening period. 8. The platinum-based chemotherapy regimen must contain one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. Gemcitabine is not permitted. 9. The last dose of chemotherapy must be administered prior to, or concurrently with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted. Up to 2 cycles of induction chemotherapy prior to cCRT is permitted. 10. Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique. Sites are encouraged to adhere to the following organ dosimetric specifications: - Mean lung dose must be < 20 Gy and/or V20 must be < 35% - Mean oesophagus dose must be < 34 Gy - Heart V45 < 35% or V30 < 50%. 11. WHO/ECOG PS of 0 or 1 at randomization. 12. Adequate organ and marrow function. 13. Minimum life expectancy of 12 weeks at randomization.
1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active interstitial lung disease/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol. 2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy, adequately treated carcinoma in situ or Ta tumors treated with curative intent and without evidence of disease. 3. Mixed small cell and non-small cell lung cancer histology. 4. Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced, unresectable NSCLC. 5. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy (excluding alopecia). Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead. 6. Participants with ≥ grade 2 pneumonitis from prior chemoradiation therapy. 7. Any prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1. 8. Investigator judgment of 1 or more of the following: a. Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening. b. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP). c. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives. 9. History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead. 10. Subjects with a history of MI, TIA, stroke, or pulmonary embolism diagnosed in the past 6 months or venous thrombosis diagnosed in the past 3 months. 11. Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies, anti-CD73 antibodies, and anti NKG2A antibodies, excluding therapeutic anticancer vaccines.
Patients will be invited to take part in this study if they have neuroblastoma which has either not responded adequately to treatment or has relapsed in the bones and/or bone marrow. Neuroblastoma is one of the most common childhood cancers and accounts for a high proportion of childhood cancer deaths. The majority of patients have 'high risk' disease, with metastatic bone/bone marrow disease. Outcome in patients who don't respond well to frontline treatment, or who relapse after treatment, is extremely poor. The purpose of this research is to find out about the treatment effects of an antibody called humanized 3F8 (hu3F8/Naxitamab). In the last decade, antibody therapy has become part of the standard care for children with high risk neuroblastoma. Antibodies are proteins produced by the immune system to fight infections, but can also potentially be used to attack tumour cells. In order to enhance the positive effect of Naxitamab, the treatment will be combined with granulocyte-macrophage colony stimulating factor (GM-CSF). Granulocytes are white blood cells that are able to destroy cancer cells and GM-CSF increases the ability of granulocytes to more effectively kill cancer cells. The only treatment that is being tested in this trial is Naxitamab (hu3F8) in combination with GM-CSF, and all enrolled patients will receive both. Patients can receive treatment for up to 101 weeks following first administration via infusion of Naxitamab- hu3F8 and injections of GM-CSF. Depending on how the participant responds it is up to the treating investigator to decide how many cycles of treatment is required. After treatment has completed, patients will undergo long term follow up of 3 years during which patients will attend visits twice a year to monitor post treatment effects. This study will take place across 6 countries (UK, Spain, Denmark, United States Canada and Hong Kong.
1. Documented diagnosis of NB as defined per INRC as a. histopathology of tumor biopsy, or b. BM aspirate or biopsy indicative of NB by histology, plus high blood or urine catecholamine metabolite levels or Myelocytomatosis Viral-Related Oncogene, Neuroblastoma derived (MYCN) amplification, or c. MIBG-avid lesion(s) 2. High-risk NB patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including SD, MR and PR) evaluable in bone and/or BM as defined in section 6.7 in the protocol. 3. Life expectancy > = 6 months 4. Age > = 12 months 5. Acceptable hematological status, (hematological support is allowed if administered > = 1 week before first infusion of naxitamab), defined as: a. Hemoglobin > = 8 g/dL (5.0 mmol/L) b. White blood cell count > = 1000/μL c. Absolute neutrophil count (ANC) > = 500/μL d. Platelet count > = 25,000/μL 6. Acceptable liver function defined as: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < = 5 times upper limit of normal (ULN) b. Bilirubin < = 1.5 x ULN 7. Acceptable kidney function defined as: a. Estimated Glomerular Filtration Rate (eGFR) > 60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation 8. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations.
1. Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks before 1st dose of GM-CSF 2. Evaluable NB outside bone and BM 3. Actively progressing disease at trial entry 4. Existing major organ dysfunction > Grade 2, with the exception of hearing loss, hematological status, kidney and liver function. 5. Active life-threatening infection 6. Prior treatment with naxitamab 7. Karnofsky/Lansky score < 50% 8. Pregnancy or a woman who is breast-feeding (women of child-bearing potential must have a negative pregnancy test at screening). A woman of child-bearing potential is excluded if she does not agree to use adequate contraception for a period of 40 days after the last naxitamab infusion: intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections). In certain cases, it is accepted to use double barrier methods (a condom combined with a diaphragm). A sterilized or infertile woman is exempt from the requirement to use contraception after naxitamab treatment: she must have undergone surgical sterilization (hysterectomy, or bilateral ovariectomy) 9. Inability to comply with protocol requirements, including PK studies, as determined by the investigator 10. History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of the product.
The purpose of this study is to collect the long-term safety and survival information in participants with different tumour types who will be provided nivolumab or have finished treatment and are now in or have completed follow-up on a Bristol-Myers Squibb (BMS) clinical research study (parent study). The Sponsor for this clinical research study is Bristol-Myers Squibb (BMS) There is not a specific number of patients participating. Enrolment in the study is on a rolling basis and is dependent on the patient’s status in the BMS clinical trial (parent study). Their participation may be either: • as a participant who is being treated with nivolumab from a previous BMS clinical trial. The study doctor will continue to assess long-term safety and survival information. • as a participant who is being followed for survival or has completed follow-up from a previous BMS clinical study, having completed, discontinued, or progressed on treatment, and/or on another therapy. The study doctor will continue to assess long-term safety and survival. This study is being conducted at multiple clinical sites in the United Kingdom and Europe.
Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal participant care. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. Participants who have completed treatment with nivolumab, progressed on prior nivolumab treatment or discontinued nivolumab due to toxicity, in the Parent Study are not eligible to receive nivolumab in this study. These participants may be enrolled for safety and survival follow-up only. Participant is eligible for nivolumab treatment as per the Parent Study, and/or Investigator assessed clinical benefit, or Participant is in or has completed the follow-up phase of the Parent Study i) Participant has completed or discontinued treatment, or ii) Participant has progressed on treatment, and/or iii) Participant is on subsequent therapy. Male and female participants ages 18 and older.
Participant is not eligible for nivolumab treatment as per the Parent Study. Participants not receiving clinical benefit as assessed by the Investigator (participant is still eligible for study if entering survival follow-up only). Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the opinion of the Investigator, indicates that participation in the study is not in the best interest of the participant. History of allergy or hypersensitivity to study drug components. Prisoners or participants who are involuntarily incarcerated (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.) Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. Dementia or serious psychiatric condition that may compromise the informed consent process and increase the risks associated with study participation. Participants with any condition which, in the judgment of the Investigator, may pose a significant risk to the subject. Participants in survival follow-up have no exclusion criteria. Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.
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Patients who received at least one dose of JCAR017 in a previous treatment protocol, and have discontinued, or completed the post-treatment follow-up period in a previous JCAR017 protocol, as applicable.
There are no exclusion criteria.
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Target population 1. Patients with newly diagnosed stage IV NSCLC treated with Immunotherapy or Immunotherapy + Chemotherapy. 2. Patients with NSCLC stage IV treated with Immunotherapy at 2nd line or consecutive lines. 3. Patients with stage IV malignant melanoma treated with Immunotherapy with or without targeted therapy. 4. Patients with stage IIIb-d malignant melanoma treated with Immunotherapy as adjuvant therapy. 5. Patients with stage IV SCLC treated with Immunotherapy or Immunotherapy + Chemotherapy. Inclusion criteria 1. Provision of informed consent prior to any study-specific procedures. 2. Male or female aged at least 18 years. 3. ECOG PS – 0/1-2. 4. Normal hematologic, renal and liver function: • Absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, haemoglobin > 9 g/dL; • Creatinine concentration ≤ 1.4 mg/dL, or creatinine clearance > 40 mL/min; • Total bilirubin < 1.5 mg/dL, ALT+ AST levels ≤ 3 times above the upper normal limit. 5. The patient must have at least one measurable lesion and the relevant images in order to enable the assessment of the response.
1. Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of study drug. 2. Generalized impairment or mental incompetence that would render the patient unable to understand his/her participation in the study.
Published literature indicates that tumours arise as a consequence of a series of mutations in normal tissue, and that most tumour growth stems from the original clonal mutations within the tumour. This is a clinical study evaluating the safety and clinical response of a novel personalised therapy (termed ATL001) designed to attack patient specific clonal mutations that are hypothesised to occur solely within all cancer cells. This clinical study will treat adult patients (aged 18 and over) with metastatic or recurrent melanoma in selected hospitals who have experience handling this type of product and treating this stage of disease. The study will begin with the collection of patient material used to manufacture the therapeutic product. This will involve a surgical procedure and collection of blood samples. Whilst the product is being made patient will undergo standard treatment. Following successful manufacture of the product and as per protocol criteria, patients will be eligible to receive their personalised treatment. This will involve approximately 2 weeks of treatment which includes chemotherapy followed by administration of ATL001, and a product to help ATL001 kill the cancer cells. After this period of treatment, patients will be asked to visit the hospital a number of times over the next 2 year period to give blood samples and to have a scan to see if ATL001 has killed the cancer cells. Each patient will continue to be followed up for a further 5 years, as part of a separate protocol. If this clinical trial shows that ATL001 is safe and shows a level of effectiveness in treating melanoma, it will likely enable further development of ATL001 for more patients with melanoma and also patients with different cancers all based on the ability to target individual specific clonal mutations within the cancer cells.
Inclusion criteria will apply at multiple timepoints. Inclusion criteria 1. Patient must be at least 18 years old at the screening visit. 2. Patient must have given written informed consent to participate in the study. 3. Histologically confirmed diagnosis of melanoma. 4. Patients must have received a PD-1 inhibitor prior to treatment with ATL001. 5. Patients whose tumour is known to have a BRAF V600 mutation must have received BRAF targeted therapy (as well as a PD-1 inhibitor) prior to treatment with ATL001. 6. Patient is considered medically fit enough to undergo all study procedures and interventions: procedures to procure blood and tumour tissue, including a general anaesthetic if required, and to receive fludarabine, cyclophosphamide and IL-2 at protocol doses and schedules. 7. Patient is considered, in the opinion of the investigator, capable of adhering to the protocol. 8. ECOG Performance Status 0-1. 9. Adequate organ function, indicated by the following laboratory parameters: a. Haemoglobin > = 10.0 g/dL. b. White Blood Cell Count (WBC) > = 3.0 x10⁹/L. c. Absolute Neutrophil count (ANC) > = 1.5 x 10⁹/L. d. Platelets > = 100 x 10⁹/L. e. PT and APTT < 1.5 x ULN (unless receiving therapeutic anticoagulation). f. AST or ALT < = 2.5 x ULN. g. Bilirubin < 1.5 x ULN (or < 3 x ULN in Gilbert’s Syndrome). h. Creatinine clearance/estimated GFR > = 50 ml/min. 10. Female patients who are of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 12 months after the ATL001 infusion. Patients with female partners of childbearing potential must agree to use adequate contraception for at least 6 months after the ATL001 infusion. See Section 4.3 of the protocol for details of acceptable methods of contraception. In addition to 1-10, the following inclusion criteria must be met prior to tissue procurement: 11.To be eligible for this study a patient must fall into one of the following groups: a) Patients with unresectable metastatic disease (newly diagnosed or recurrent) who have had no prior systemic therapy for advanced disease and who have accessible sites of disease suitable collection of adequate tissue for ATL001 manufacture. b) Patients with high risk locally advanced resectable disease (i.e. palpable Stage III) who are scheduled to undergo surgery. These patients are not candidates for immediate treatment with ATL001 but may be treated in this protocol if the disease recurs. In these patients the tumour samples will be stored in compliance with the appropriate regulations to enable future manufacture and treatment with ATL001. c) Patients with unresectable metastatic disease who are on or have completed first line systemic therapy and have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. d) Other patients with unresectable advanced stage disease for whom no other alternative approved treatments are available, may be considered on a case-by-case basis and should be discussed with the Sponsor prior to enrolment. 12. Anticipated life expectancy > = 6 months at the time of tissue procurement. In addition to 1-10, the following inclusion criteria must be met prior to lymphodepletion and treatment with ATL001: 13. Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. (If patients have no measurable disease following standard therapy, lymphodepletion and ATL001 treatment may be delayed until there is evidence of measurable disease). 14. Patient is considered well enough to receive ATL001 treatment.
Exclusion criteria will apply at multiple timepoints. Exclusion criteria: 1. Patients with known leptomeningeal disease or CNS metastases. 2. Patients with ocular melanoma. 3. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection. 4. Patients with active autoimmune disease requiring immunosuppressive therapy. 5. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day (or equivalent). 6. Patients with a current or recent history, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease. 7. Patients who are pregnant or breastfeeding. 8. Patients who have undergone major surgery in the previous 3 weeks. 9. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except for in situ carcinomas, early prostate cancer with normal PSA or non-melanomatous skin cancers). 10. Patients with a history of organ transplantation. 11. Patients who have previously received any investigational cell or gene therapies. 12. Patients with contraindications for cyclophosphamide, fludarabine and IL-2 at per protocol doses (see Investigator Brochure for details). In addition to 1-12, the following exclusion criteria apply to patients who completed first line therapy prior to study entry: 13. Patients who have received any anti-cancer therapy within the 3 weeks prior to blood and tumour tissue procurement. In addition to 1-12, the following exclusion criteria apply to all patients prior to lymphodepletion and treatment with ATL001: 14. Patients who have received a live vaccination within the 28 days prior to lymphodepletion. 15. Patients with an active infection requiring antibiotics. 16. Patients who have received any anti-cancer therapy within the 3 weeks prior to lymphodepletion.
This study is a multi-national,observational, prospective registry of patients with high-risk neuroblastoma treated with dinutuximab beta. The study is non-interventional. All investigations and treatment decisions are made according to normal clinical practice and are not mandated by the protocol. Data collection will occur at baseline, during treatment and during the 10 year follow-up period.During the treatment phase, data will be collected on dose, total cumulative amount of dinutuximab beta per course, dose interruptions, dose discontinuations, prophylactic treatment, use of all concomitant analgesia, assessments of pain, and occurrence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions and other AEs. The study will have a 10 year follow-up period and the data will be collected from the subject approximately 14 times during this 10 year period. The doctor will collect information from the subject four times in the first year (approximately every three months in Year 1), two times in the second year (six monthly in Year 2) and once a year after that up until Year 10. Countries participating in this study may include (but is not restricted to) Austria, France, Spain, Italy, Germany, Poland and the United, Kingdom.
Patients meeting the following criteria will be considered for inclusion into the registry: 1. Patients diagnosed with high-risk neuroblastoma and starting treatment with commercially available dinutuximab beta OR 2. Patients diagnosed with high-risk neuroblastoma and starting treatment with dinutuximab beta in a clinical trial where dinutuximab beta is provided according to the country/regional marketing authorisation AND 3. Appropriate consent/assent has been obtained for participation in the registry with a willingness to be followed up for up to 10 years.
Patient will not be eligible for inclusion if the following criterion applies: 1. Patients commencing dinutuximab beta within a clinical trial where the product is being provided outside of the country/regional marketing authorisation OR 2. Appropriate consent/assent has not been obtained for participation in the registry or patient/legal representative is not willing for the patient be followed up for up to 10 years.
CCS1477 is a new experimental medication (sponsored by CellCentric Ltd) for a group of cancers that effect the blood and/or bone marrow. These include Acute Myeloid Leukaemia (AML), high-risk Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL). It is aimed at tumours that are not responsive to, or have become resistant to, existing medications used in late stage disease. The purpose of this study is to examine the safety, tolerability, pharmacokinetics (PK) and efficacy of CCS1477 when treating patients with the above disorders. It is expected that approximately 90 patients will be recruited from up to 10 hospitals in the UK. The study has 5 parts consisting of dose escalation and expansion cohorts. Patients will have regular clinic visits for various safety and clinical benefit assessments, to monitor any side effects and to find out how CCS1477 is handled by the body and affects this group of cancers. The information gained in this study will help the sponsor to determine whether CCS1477 is suitable for further studies in humans.
1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses. 2. Willing and able to participate in all required evaluations and procedures in this study protocol. 3. Men and women ≥ 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (NHL, MM and AML). Patients will include but are not limited to the following: • B-cell non-Hodgkin lymphoma (including Richter’s Syndrome) • T-cell non-Hodgkin lymphoma • Multiple myeloma • AML/secondary AML (patients with acute promyelocytic leukemia (APL) (FAB subtype M3) will be excluded). • High-risk MDS; according to revised International Prognostic Scoring System (IPSS-R). 6. Must have received standard therapy (for the majority of therapeutic indications - at least 2 prior lines of therapy) - refer to relevant disease guidelines, such as European Society for Medical Oncology (ESMO), International Myeloma Working Group (IMWG) or National Comprehensive Cancer Network (NCCN) guidelines. In circumstances where there may be no standard of care, or intensive treatment would not be tolerable or is refused, patients may be considered eligible for the study upon consultation and agreement between the medical monitor and the treating Investigator. 7. Adequate haematologic function defined as: • Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 10^9/L). • Platelet count without requiring ongoing blood product support ≥ 75,000 cells/mm3 (75 x 10^9/L). Platelet transfusions are not permitted within 3 days of screening. • Haemoglobin level ≥ 80 g/L. This criterion does not apply to AML/MDS patients. Patients with other malignancies involving bone marrow with parameters below the threshold may be considered eligible following discussion with the medical monitor. • For AML, WBC must be < 10,000/µl. 8. Adequate organ function at screening defined as: • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), or AST/ALT ≤ 5 x ULN (with underlying liver involvement following discussion with the medical monitor). • Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, patients with borderline elevation due to underlying liver involvement may be eligible following discussion with the medical monitor). • Serum creatinine < 1.5 x ULN, OR creatinine clearance ≥ 50 mL/min as measured or calculated by Cockcroft and Gault equation, or ≥ 30 mL/min in patients with kidney function affected by the underlying malignancy • Serum albumin > 2.5 g/dL.
Patients must not enter the study if any of the following exclusion criteria are fulfilled 1. Treatment with any of the following: • Any investigational agent, chemotherapy, immunotherapy or anticancer agents from a previous clinical study within 14 days or 5 half-lives of first dose of study treatment. Shorter wash-out may be considered for immunotherapies after discussion with medical monitor. • Strong inducers of CYP3A4 taken within 4 weeks of the first dose of study treatment or whilst on study treatment. • Strong inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment or while on study treatment. • CYP2C8 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment or while on study treatment. • Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment; palliative radiotherapy to ≤ 30% of the bone marrow within 2 weeks of the first dose of study treatment. • Herbal medications taken within 7 days of the first dose of study treatment (4 weeks for St John’s wort) or while on study treatment. • Statins; patients should discontinue statins prior to starting study treatment. • Steroids use > 10mg daily prednisolone or equivalent within 2 weeks of the first dose of study treatment. • Major surgery within 4 weeks of the first dose of study treatment. 2. With the exception of alopecia, and CTCAE Grade 2 neuropathy, any unresolved toxicities from prior therapy > Grade 1 at the time of starting study treatment. 3. Presence of, or history of, CNS lymphoma, symptomatic leptomeningeal disease, or spinal cord compression. 4. History of prior non-haematologic malignancy except for the following: • Adequately treated carcinoma in situ or non-melanomatous skin cancer • Malignancy treated with curative intent or in remission for > 6 months after the last therapy may be eligible after discussion with medical monitor. Maintenance treatment (eg. hormonal therapy) is allowed. 5. Any evidence of severe or uncontrolled systemic disease (e.g. current unstable or uncompensated respiratory or cardiac conditions; history of, or active, bleeding diatheses; uncontrolled active systemic infection, including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)*), which in the investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol. *Active viral infection is defined as requiring antiviral therapy. Screening for chronic conditions is not required. 6. Repeatable QTcF prolongation (> 480 msec). 7. History of severe allergic or anaphylactic reactions or history of hypersensitivity to active or inactive excipients of CCS1477. 8. Female patients who are pregnant or breast-feeding at study entry. 9. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
CCS1477 is a new experimental medication (sponsored by CellCentric Ltd) for a type of prostate cancer called metastatic castration resistant prostate cancer (mCRPC). It is aimed at tumours that are not responsive to, or have become resistant to, existing medications used in late stage disease. CCS1477 may also be used for other cancers with specific gene mutations, again where existing treatments are no longer working. The purpose of this study is to examine the safety, tolerability, pharmacokinetics (PK) and efficacy of CCS1477 when treating patients with mCRPC, when given alone or in combination with other standard mCRPC therapies, and in treating patients with other solid tumour cancers which have a gene mutation in p300 or CBP. It is expected that approximately 150 patients will be recruited from up to 20 hospitals in the UK and US. The study has 5 parts consisting of dose escalation and expansion cohorts. Patients will have regular clinic visits for various safety and clinical benefit assessments, to monitor any side effects and to find out how CCS1477 is handled by the body and affects the tumour. The information gained in this study will help the sponsor to determine whether CCS1477 is suitable for further studies in humans.
All Patients: o Provision of consent. o ECOG performance status 0-1. o Assessable disease (by CT, MRI, bone scan or X-ray). o Adequate organ functions defined as: AST/ALT < = 3 X ULN (upper limit of normal) or AST/ALT < = 5 X ULN [with underlying liver metastasis] Total bilirubin < = 1.5 X ULN Serum creatinine < = 1.5 X ULN ANC > = 1.5 x 109/L Platelets > = 100 x 109/L Haemoglobin > = 9g/dL o Highly effective contraception measures for duration of study. Additional inclusion criteria for mCRPC patients only: o Previously received abiraterone and/or enzalutamide (or equivalent anti-androgen), and docetaxel (unless ineligible or refused). o Progressive disease documented by one or more of the following: Biochemical progression defined as at least 2 stepwise increases in a series of any 3 PSA values. Progression as defined by RECIST v1.1 guideline for assessment of malignant soft tissue disease. Progression defined as two or more new metastatic bone lesions confirmed on bone scan from a previous assessment. o PSA at screening > = 2 μg/L. o Serum testosterone concentration < = 50 ng/dL. o Serum albumin > 2.5 g/dL. Additional inclusion criteria for patients in CCS1477 plus abiraterone combination arm: o Patients must have previously progressed on abiraterone treatment. o Patients whose last dose of abiraterone is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with abiraterone to confirm refractoriness to abiraterone treatment. Additional inclusion criteria for patients in CCS1477 plus enzalutamide combination arm: o Patients must have previously progressed on enzalutamide treatment. o Patients whose last dose of enzalutamide is greater than 6 months prior to start of study treatment will receive a 4-week run-in treatment with enzalutamide to confirm refractoriness to enzalutamide treatment. Additional inclusion criteria for p300/CBP mutation expansion only: o Patients must have histological or cytological confirmation of malignancy that is advanced and not considered to be appropriate for further approved/standard of care treatment. o Confirmation that the tumour harbours one or more p300 or CBP mutations (identified locally or by a central laboratory in tumour or blood circulating free DNA).
All Patients: o Intervention with any of the following: o Any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives (whichever is longer of these two) of the first dose of study treatment. o Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment. o Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study treatment. o Strong inducers or inhibitors of CYP3A4, or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment. Herbal medications cannot be taken within 7 days of the first dose of study treatment (3 weeks for St John’s wort) or while on study treatment. o Statins; patients should discontinue statins prior to starting study treatment. o Any unresolved reversible toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia. o Patients who are pregnant or breast-feeding at study entry. o Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). o Patients with any known uncontrolled inter-current illness including ongoing or active clinically significant infections, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. o QTcF prolongation (> 500 msec). o Prior malignancy that could affect compliance with the protocol or interpretation of results. o Primary brain tumours or known or suspected brain metastases. Additional exclusion criteria for patients in CCS1477 plus abiraterone combination arm: o Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not limited to) recent myocardial infarction (< = 6 months) or unstable angina (< = 3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is > = 50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension. Additional exclusion criteria for patients in CCS1477 plus enzalutamide combination arm: o History of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases and leptomeningeal disease, or alcoholism. o Use of substrates with a narrow therapeutic index metabolised by CYP2C9 or CYP2C19 within 2 weeks of the first dose of study treatment. o Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not limited to) recent myocardial infarction (< = 6 months) or unstable angina (< = 3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is > = 50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension.
Published literature indicates that tumours arise as a consequence of a series of mutations in normal tissue, and that most tumour growth stems from the original clonal mutations within the tumour. This is a clinical study evaluating the safety and clinical response of a novel personalised therapy (termed ATL001) designed to attack patient specific clonal mutations that are hypothesised to occur solely within all cancer cells. This clinical study will treat adult patients (aged 18 and over) with a type of lung cancer called advanced non-small cell lung cancer in selected hospitals who have experience handling this type of product and treating this stage of disease. The study will begin with the collection of patient material used to manufacture the therapeutic product. This will involve a surgical procedure and collection of blood samples. Whilst the product is being made patient will undergo standard treatment. Following successful manufacture of the product and as per protocol criteria, patients will be eligible to receive their personalised treatment. This will involve approximately 2 weeks of treatment with chemotherapy followed by administration of ATL001, and a product to help ATL001 kill the cancer cells. After this period of treatment, patients will be asked to visit the hospital a number of times over the next 2 year period to give blood samples and to have a scan to see if ATL001 has killed the cancer cells. If this clinical trial shows that ATL001 is safe and shows a level of effectiveness in treating non-small cell lung cancer, it will likely enable further development of ATL001 for more lung cancer patients and also patients with different cancers all based on the ability to target individual specific clonal mutations within the cancer cells.
Inclusion criteria will apply at three timepoints. Inclusion criteria: 1. Patient must be at least 18 years old at the screening visit. 2. Patient must have given written informed consent to participate in the study. 3. Histologically or cytologically confirmed diagnosis of non-small cell lung cancer. 4. Patient is considered medically fit enough to undergo all study procedures and interventions: procedures to procure blood and tumour tissue, including a general anaesthetic if required, and to receive fludarabine, cyclophosphamide and IL-2 at protocol doses and schedules. 5. Patient is considered, in the opinion of the investigator, capable of adhering to the protocol. 6. ECOG Performance status 0-1 7. Adequate organ function, indicated by the following laboratory parameters: a. Haemoglobin > = 10.0 g/dL b. White Blood Cell Count (WBC) > = 3.0x10⁹/L c. Absolute Neutrophil count (ANC) > = 1.5x10⁹/L d. Platelets > = 100x10⁹/L e. PT and APTT < 1.5x ULN (unless receiving therapeutic anticoagulation) f. AST, ALT < = 2.5 x ULN g. Bilirubin < 1.5 x ULN h. Creatinine clearance / estimated GFR > = 50ml/min 8. Patients who are of childbearing potential or have partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 6 months after the last dose of IL-2. See Section 4.3 of the protocol for details of acceptable methods of contraception. In addition to 1-8, the following inclusion criteria must be met prior to tissue procurement: 9. To be eligible for the study the patient must fall into one of the following groups: a. Operable locally advanced disease (stage IIIA) who are scheduled to undergo surgery. These patients are not candidates for immediate treatment with ATL001 but may be treated in this protocol at relapse. In these patients the tumour samples will be stored in compliance with regulations to enable future manufacture and treatment with ATL001. b. Relapsed disease following previous primary surgery +/- adjuvant therapy and either sufficient stored tissue for manufacturing of ATL001 or accessible site s of disease suitable for collection of adequate tissue for ATL001 manufacture. c. Late stage (IIIB/IV) newly diagnosed disease who have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. d. Late stage (IIIB/IV) disease who have completed first line chemotherapy, have achieved disease control, and have accessible sites of disease suitable for collection of adequate tissue for ATL001 manufacture. e. Late stage (IIIB/IV) disease who are undergoing or have completed treatment with PD-1/PD-L1 inhibitor, have achieved disease control and have accessible sites of disease suitable collection of adequate tissue for ATL001 manufacture. 10. Anticipated life expectancy > = 6 months at the time of tissue procurement In addition to 1-8, the following inclusion criteria must be met prior to lymphodepletion and treatment with ATL001: 11. Patients must have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. (If patients have no measurable disease following standard therapy, lymphodepletion and ATL001 treatment may be delayed until there is evidence of measurable disease). 12. Patient is considered will enough to receive ATL001 treatment.
Exclusion criteria will apply at two timepoints. Exclusion criteria: 1. Patients with known CNS metastases. 2. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection. 3. Patients who are non-smokers (have smoked < 100 cigarettes in their lifetime). 4. Patients with active autoimmune disease requiring immunosuppressive treatments. 5. Patients requiring regular treatment with steroids at a dose higher than prednisolone 10 mg/day (or equivalent). 6. Patients with superior vena cava syndrome. 7. Patients with a current or recent history, as determined by the Investigator, of clinically significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease. 8. Patients who are pregnant or breastfeeding. 9. Patients who have undergone major surgery in the previous 3 weeks. 10. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except for in situ carcinomas or non-melanomatous skin cancers). 11. Patients with a history of organ transplantation. 12. Patients who have previously received any investigational cell or gene therapies. 13. Patients with contraindications for cyclophosphamide, fludarabine or IL-2 at protocol doses. In addition to 1-13, the following exclusion criteria apply to patients who completed first line therapy prior to study entry: 14. Patients who have received any anti-cancer therapy within the 3 weeks prior to blood procurement. 15. Patients with evidence of disease progression at the first scan after commencing standard first line therapy. In addition to 1-13, the following exclusion criteria apply to all patients prior to lymphodepletion and treatment with ATL001: 16. Patients who have received a live vaccination within the 28 days prior to lymphodepletion. 17. Patients with an active infection requiring antibiotics. 18. Patients who have received any anti-cancer therapy within the past 3 weeks prior to lymphodepletion.
The principal objective of the study is to continue to follow up the original AspECT participants to see if the effectiveness of aspirin and Proton Pump Inhibitor (PPI) continues or increases long-term in the prevention of deaths and cancer. This will be done using a one-time snapshot data collection form.
1. Participants recruited to the original AspECT trial. 2. AspECT participants who have signed an AspECT-EXceL consent form or have the use of personal data covered by another access agreement. 3. Participants who have given consent to allow access to AspECT data or have access covered by another access agreement.
1. Participants who are alive and unable or unwilling to give consent to participate in AspECT ExceL and whose personal data is not covered by any other data access agreement. 2. Participants unwilling to give consent to allow access to AspECT data and are not covered by any other data access agreement. 3. Participants not included in the original AspECT trial.
Every year over 15,800 people are diagnosed with gullet (oesophageal) or stomach cancer and over 12,300 deaths are reported from both cancers in the UK. Currently, most gullet or stomach cancer patients are treated with surgery with or without additional chemo- or radio-therapy. Recently, there have been improvements in survival from these cancers, due to better therapies. However, around two-thirds of patients treated with surgery, the cancer will return within three years and they will ultimately die from this. There is little evidence as to how gullet and stomach cancer patients should be followed up after surgery and whether different methods of follow-up could improve survival. Currently, national and international guidelines do not provide consistency in their recommendations for follow-up after surgery. The SARONG study will investigate if earlier detection of cancer through more intensive surveillance results in improved survival and better quality of life for patients with gullet and stomach cancer. Participants who agree to take part will be allocated by chance to either more intensive surveillance or the current standard of care. The trial aims to recruit at least 952 participants in the UK from at least 24 NHS hospitals. Patients undergoing surgery for gullet and stomach cancer will be approached prior to hospital discharge and invited to participate in the trial around 4 to 8 weeks after their cancer treatment. (i) The intensive surveillance group will receive a clinic review, and a radiological scan, at 6, 12, 18, 24, 30 and 36 months after randomisation and a camera test (endoscopy) at 12 months after randomisation. (ii) The standard care group will receive a clinic review at 6 and 12 months post-randomisation. After this they will be either discharged to their local doctor or receive a review in clinic with a member of the surgical team every year.
1. Patients who have undergone surgical resection for curatively intended treatment of oesophageal or gastric cancer (adenocarcinoma and squamous cell carcinoma) with or without neoadjuvant/adjuvant chemotherapy or radiotherapy or immunotherapy (or in combination). 2. Aged 16 years or over 3. Patients willing and able to give informed consent
A patient with not be eligible for the trial if ANY of the following apply: 1. Patients with other cancers undergoing treatment or surveillance for this cancer
Acute myeloid leukaemia (AML), is an ‘aggressive’ blood cancer with only around 20% of affected adults surviving at 5 years. AML often presents as a medical emergency and treatment is intensive. After the initial course of urgent anticancer therapy, people with AML receive repeated intensive courses of chemotherapy aimed at cure, that may include ‘haemopoietic’ (blood) stem cell transplantation. They need to remain in hospital during courses of treatment, often in isolation, due to risk of infection, with short periods at home to recover. This treatment often has huge detrimental effects on physical, nutritional and mental health. Fatigue is the most debilitating problem for people with AML, and often continues into recovery. ‘Prehabilitation’ aims to improve physical and psychological wellbeing after diagnosis, to help people with AML get through treatment and stem cell transplants which are often critical for cure. The study will test whether a package of enhanced personalised prehabilitation can help people with AML cope better with treatment, with less fatigue, compared to the current best practice of prehabilitation care (best practice usual care). ‘PROPEL’, will involve 600 people treated for AML, who will be randomised to either: 1. Best practice usual care: a 30-minute appointment with a member of the central team, given once, before the first chemotherapy course to signpost to relevant resources on psychological health, nutrition and physical activity. 2. A ‘prehabilitation’ care package: A 60minute appointment with a central team of specialists to tailor a personalised care plan for psychological wellbeing, nutrition and physical activity before each chemotherapy and stem cell transplant. Participants will also have access to range of remote sessions with specialists.
• Age > = 16 years, treated on adult AML pathway And either: o Diagnosis of either AML or MDS-EB2 (MDS with 10% blasts in the bone marrow) o In complete remission at completion of induction chemotherapy (defined < 5% blasts) o Intention to undertake consolidation treatment (chemotherapy +/- HSCT), * Patients undergoing Venetoclax based treatment are only eligible if a HSCT is planned. OR o Relapsed AML who have achieved a further complete remission, with an intent to deliver further intensive consolidation treatment +/- HSCT. • Access to the internet and an email address • Willing to use videoconferencing to undertake the appointments and sessions.
• Diagnosis of Acute Promyelocytic Leukaemia • Undergoing non-intensive treatment (e.g. single agent azacitidine, low dose cytarabine).
Around 2000 patients each year in the UK need a bone marrow transplant as part of their treatment for blood cancers such as Leukaemia. Before a bone marrow transplant, patients must have their unhealthy bone marrow eliminated from the body by a treatment programme so that they can receive healthy donor bone marrow. The treatment programme uses medicines and radiation using high energy x-rays. If a patient receives x-ray treatment, they receive a known radiation dose to the bone marrow. However, many other organs also receive a radiation dose and this causes significant side effects for the patient, which may last for the rest of their life. Radioimmunotherapy is a new technique which could replace high energy x-rays. It uses a radioactive medicine which can be injected into the patient and goes to the bone marrow. Currently, it is possible to check that other organs in the body will not receive too much radiation but it is not possible to accurately calculate the radiation dose to the bone marrow. Developing a method to accurately calculate the radiation dose to bone marrow would allow clinicians to treat patients with a personalised dose to give patients the best outcome possible and reduce side effects, improving their quality of life. My research aims to develop a method to accurately calculate the radiation dose to the bone marrow. I will develop my method using existing patient bone marrow samples and test it against patient outcome results. I will publish a protocol to allow other hospitals to use the method. I will use bone marrow samples from patients on previous clinical trials and routine clinical practice. This means patient outcome data has already been collected and no patients will need to undergo any additional procedures.
Any patient who has undergone anti-cd66 radioimmunotherapy on a previous clinical trial prior to bone marrow transplant at University Hospital Southampton will be eligible for inclusion into the study. Patients who have undergone bone marrow biopsy for other reasons and have given permission for their sample to be used for future research may be included in the first part of the study and sample level dosimetry.
Any patient who does not fit the inclusion criteria above. For part 2 of the study only, any patient with an incomplete data set.
In the UK 42,000 people each year are diagnosed with bowel cancer. Surgery to remove the cancer is the best treatment. However, it has a risk of complications, which is doubled for people with overweight/besity. Patients experiencing complications recover more slowly, stay in hospital longer, and need more care. This isn’t good for patients or the NHS. Physical fitness and well-controlled blood sugar are linked with fewer complications from surgery. For people with overweight, weight loss improves both of these factors, so it may reduce complications. One reliable way to lose a meaningful amount of weight in the short period before surgery (3-4 weeks) is through a low-calorie diet programme: eating only special nutritious soups and shakes. With weekly support from a dietitian, most people succeed. Typically, people lose 5% of their weight within 20 days. The NHS uses a version of this programme to treat type 2 diabetes. To start to find out if this treatment is in the best interests of patients physical and mental health, we will recruit 72 patients with overweight awaiting bowel cancer surgery. Half will be randomly allocated to continue with their usual care and half will be offered the weight loss programme. We will see whether enough patients are willing to take part, lose weight, and return for follow-up visits. We will monitor complications for 30 days after surgery and any reduction in muscle mass as a result of the weight loss. We will interview patients about their experience. This information will tell us if a full trial is worthwhile to test whether this programme can reduce complications from surgery, improve outcomes for people with bowel cancer, and if the financial costs are likely to be worth the benefits. It will also help us refine the treatment plans according to patient feedback.
• Participant is willing and able to give informed consent for participation in the study. • Able to communicate in English or has a relative/friend/carer acting as interpreter. • Aged 18 years or above. • BMI > = 28 kg/m2 (or BMI > = 25 kg/m2 for people of Black, Asian, or minority ethnic origin). • Listed for curative elective colorectal resection for cancer. • If neoadjuvant treatment is indicated, it must have been completed. • Performance status 0-2.
• > = 10% self-reported weight loss in the 6 months before the screening visit • < 20 days from the screening visit until surgery. • Follows an exclusively vegan diet, having lactose intolerance, or having allergy to soy. • Documented stage 4-5 kidney disease. • Documented severe heart failure (defined as New York Heart Association grade 3 or 4). • Previous bariatric surgery. • Type 1 diabetes. • Currently on warfarin. • Pregnancy, breastfeeding, or planning pregnancy during the course of the trial. • Any other significant disease or disorder which, in the opinion of the Investigator or healthcare professional, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. • Currently taking part in other interventional clinical trials unless agreed in advance by all trial teams (participation in observational studies is allowed).
GUSTO is a multicentre,prospective,open-label,individually randomised,controlled,parallel-group,multi-stage phase II trial of patients with T2-4a N0 M0 MIBC or T(any) N1 M0 MIBC who are suitable for NAC with cisplatin and gemcitabine prior to radical cystectomy. The trial will assess whether the use of gene expression subtype stratified care using the GUSTO Classifier (Decipher Bladder platform and TCGA 2 classification system),to assign patients to whether they receive NAC and/or immunotherapy (durvalumab / tremelimumab),demonstrates sufficiently improved treatment activity to warrant a phase III trial. Stage 1 will assess the feasibility of both recruitment and the embedding of gene expression subtype stratification into the clinical pathway; stage 2 will confirm feasibility of recruitment and assess the assumptions for the sample size calculation and stage 3 will involve an assessment of treatment outcomes using this stratified approach. Movement between trial stages will be dependent upon the meeting of pre-defined progression criteria. The trial plans to recruit 320 participants over a 3-year period and the total sample size will be confirmed or re-estimated at the end of stage 2. The final sample size will depend on whether the frequencies of gene expression subtype and pathological complete response (pCR) rate in the standard care arm are as assumed based on available evidence,and whether the trial continues to stage 3. The sample size proposed (320) is based on a single-arm assessment within the gene expression subtype-guided arm,where the randomisation to the standard care arm will enable the correct design parameters to be estimated and a secondary unpowered randomised comparison to be carried out. Conducting a larger phase II study with powered randomised comparisons is considered infeasible in a reasonable timeframe. Eligible participants will be randomised via minimisation in a 1:1 ratio to receive either neoadjuvant chemotherapy (cisplatin and gemcitabine) prior to radical cystectomy (standard treatment) or to have radical cystectomy with neoadjuvant and adjuvant chemo/immunotherapy treatment (cisplatin,gemcitabine,durvalumab and tremelimumab) determined based on the gene expression subtype assigned by the GUSTO Classifier. Participants in the standard care arm (and local investigators) will remain blinded to gene expression subtype category. Outcomes will be collected at cystectomy and at 3,6,and 12 months post-cystectomy.
Inclusion criteria for registration: 1. Age ≥ 18 2. Eastern Co-operative Oncology Group (ECOG) performance status 0 or 1 3. Currently considered for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in this protocol) 4. Histological confirmation of MIBC with pure or mixed urothelial (transitional) cell carcinoma (full report not required) 5. Written informed consent for registration (PIS-1 and Participant Supplementary Document) Inclusion criteria for randomisation: 1. Diagnosed with MIBC staged as either T2-4a N0 M0 or T(any) N1 M0 2. Planned for neoadjuvant chemotherapy and radical cystectomy with curative intent and suitable for all protocol defined treatment (chemotherapy and immunotherapy as defined for all treatment groups in this protocol) 3. Confirmation of a pure or mixed urothelial (transitional cell) carcinoma (UC) tumour histology based on local institutional pathology reporting 4. ECOG performance status 0 or 1 5. Estimated glomerular filtration rate of ≥ 60 ml/min according to local institutional standard methods for estimation (For patients with impaired GFR (40-60 ml/min) a split dose cisplatin 35 mg/m2 on days 1 and 8 is permitted.) 6. Adequate haematological parameters a. Haemoglobin ≥ 90 g/L b. Neutrophil count ≥ 1.0 x109 /L c. Platelets ≥ 100 x109 /L 7. Adequate biochemical parameters a. Bilirubin ≤ 1.5 x ULN unless due to Gilbert’s syndrome b. ALT and/or AST ≤ 1.5 x ULN (both ALT and AST are recommended) 8. Body weight > 30 kg 9. Life expectancy of at least 12 weeks 10. For women of childbearing potential,negative blood serum pregnancy test and adequate contraceptive precautions 11. For men of reproductive potential,effective contraception if the risk of conception exists 12. Written informed consent for randomisation (PIS-2 and Participant Supplementary Document) 13. Patients must be able and willing to comply with the terms of the protocol
Exclusion criteria for randomisation 1. A bladder tumour where a gene expression subtype classification cannot be made 2. A delay in TURBT sample processing such that it is > 4 weeks from receipt of TURBT sample at central laboratory to receipt of gene expression subtype result at site 3. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients for any of the treatment groups in this protocol 4. Active infection likely to impact safety of treatment delivery for any of the treatment groups in this protocol or radical cystectomy. This includes known active tuberculosis,hepatitis B (known positive HBsAg result),hepatitis C,or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA) 5. Active documented autoimmune or inflammatory disorders,including but not limited to,inflammatory bowel disease (e.g.,colitis or Crohn’s disease),systemic lupus erythematosus,sarcoidosis,Wegener syndrome (granulomatosis with polyangiitis),Graves’ disease,rheumatoid arthritis and uveitis. The following are exceptions to this criterion: vitiligo,alopecia,hypothyroidism that is stable on hormone replacement and any chronic skin condition that does not require systemic therapy 6. Major surgical procedure (as defined by the treating clinician) within 28 days prior to randomisation 7. Coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,unstable angina pectoris or congestive cardiac failure (New York Heart Association > grade 2) within the last 6 months 8. Mean QT interval corrected for heart rate ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 9. Uncontrolled concurrent illness,including but not limited to,ongoing or active infection,symptomatic congestive heart failure,uncontrolled hypertension,unstable angina pectoris,cardiac arrhythmia,interstitial lung disease,serious chronic gastrointestinal conditions associated with diarrhoea,or psychiatric illness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia,vitiligo,and the laboratory values defined in the inclusion criteria a. Patients with Grade ≥2 neuropathy must be evaluated on a case-by-case basis after consultation with the Chief Investigator (or delegate). b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab,tremelimumab,cisplatin or gemcitabine may be included only after consultation with the Chief Investigator (or delegate). 11. Current or prior use of immunosuppressive medications within 14 days prior to randomisation including,but not limited to,systemic corticosteroids at doses exceeding 10 mg/day of prednisolone or equivalent,methotrexate,azathioprine,and tumour necrosis factor-α blockers. Permitted exceptions include: use prior to imaging procedures in patients with contrast allergies,use of inhaled,topical,and intranasal corticosteroids 12. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug 13. A current separate other malignancy. Current non-melanoma skin cancer,cervical carcinoma in situ or incidental localised prostate cancer is permissible. Other prior malignancy is acceptable if treatment within the GUSTO trial would be given with curative intent in the view of the principal investigator and the local multi-disciplinary team 14. Any concurrent chemotherapy,biologic,or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,hormone replacement therapy) is acceptable 15. Women who are breastfeeding 16. History of allogenic organ transplantation 17. History of leptomeningeal carcinomatosis 18. History of primary immunodeficiency 19. Receipt of live attenuated vaccine within 30 days prior to randomisation. 20. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. 21. Patients who have received prior anti–PD-1 (including durvalumab),anti PD-L1 or anti CTLA-4 (including tremelimumab): a. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. b. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. c. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are eligible if they are stably maintained on appropriate replacement therapy and are asymptomatic. d. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE,not have experienced recurrence of an AE if re-challenged,and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
Early diagnosis of cancer is a priority for the NHS, with a target of 75% of new cancers diagnosed at an early stage by 2028. Diagnosing cancer early is key to allow a wider range of treatment options which increase the chances of survival. Cancer affecting the mouth, throat, neck, and the gut have some of the lowest levels of early diagnosis amongst all cancer types in the UK. These cancers very often have vague symptoms and are common amongst people with lifestyle habits such as smoking tobacco and drinking too much alcohol, making them very difficult to find early. Certain markers in the body are linked to cancers - this project aims to find a new way to assist the early diagnosis of cancer in primary care and identify people with a high risk of cancer who might need an urgent referral from their GP for more tests. We will do this by developing special sensors that can fit on a toothbrush and find changes in these markers in saliva during teeth brushing done at home or in the GP surgery. We hope these new sensors can detect these markers related to cancers in the mouth, throat, neck and gut quickly, easily and cheaply. This particular part of the project will involve collecting and analysing saliva samples from patients recently diagnosed with a cancer in the mouth, throat or upper airways (often called head & neck cancer) for the selected markers. We will also collect and analyse saliva samples from healthy individuals to compare to the patients with cancer to confirm which markers should be picked up by the special sensors. The findings will then be passed to the members of the research team who are building the sensors to inform their work.
Head & Neck 5,000 cohort participants - Consented for sharing and further analysis of data collected as part of the cohort study - Early stage cancer (stage I/II) at diagnosis - Saliva sample collected and available for extraction and proteomic analysis Royal Devon University Healthcare NHS Foundation Trust patients - New diagnosis of early stage (stage I/II) head & neck cancer within the last 3 months - Not yet commenced treatment for head & neck cancer - Able to communicate in English language - Capacity to give consent for participation in study Exeter 10,000 cohort - No history of head & neck cancer - Able to communicate in English language - Capacity to give consent for participation in study
Head & Neck 5,000 cohort participants - Has not consented for sharing and further analysis of data collected as part of the cohort study - Late stage cancer (stage III/IV) at diagnosis - No saliva sample collected and/or available for extraction and proteomic analysis Royal Devon University Healthcare NHS Foundation Trust patients - Diagnosis of head & neck cancer more than 3 months ago or late stage (stage III/IV) at diagnosis - Already commenced treatment for head & neck cancer - Not able to communicate in English language - Lacks capacity to give consent for participation in study Exeter 10,000 cohort - History of head & neck cancer - Not able to communicate in English language - Lack capacity to give consent for participation in study
Pseudomyoma peritonei is a rare abdominal cancer that arises from the appendix. The current treatment is major surgery and heated chemotherapy which is administered directly into the abdomen. After surgery some patients develop reactive thrombocytosis (high platelet counts) which may cause abnormal blood clots. For this reason patients are given 75mg of aspirin prophylactically to inhibit platelets for a period of approximately 6 weeks. Although these patients are given aspirin we do not know currently how effective the aspirin is in blocking platelets as some patients do not respond to aspirin, a phenomenon known as 'aspirin resistance' or 'aspirin treatment failure'. This study aims to identity patients who are aspirin resistant using VerifyNow, a point of care test that measures how effectively aspirin is blocking platelets.
Patients > 18 years of age Diagnosis of Pseudomyxoma Peritonei Patients undergoing CRS and HIPEC
Patients < 18 years of age Having CRS and HIPEC for other conditions apart from Pseudomyxoma Peritonei Allergic to aspirin On other antiplatelet or drugs that affect platelet function e.g. NSAIDs Ischaemic vascular events, percutaneous coronary intervention, or coronary artery bypass within the last 12 months
Follicular lymphoma is a common mature B cell malignancy with a UK incidence of 3.3/100,000 people per year1. Most patients have advanced stage disease that follows a protracted and incurable disease course leading to a high overall disease prevalence. Despite advances in front line management, treatment of relapsed and refractory (r/r) FL has not been standardised and data on treatment patterns and clinical outcomes are lacking, presenting significant challenges for therapy selection and novel drug development to optimise clinical outcomes. FOUNDATION UK is a NCRI-led, multi-centre, non-interventional, retrospective, observational study aimed at collecting clinical outcome data for patients with r/r FL receiving real world contemporary therapies at participating NHS hospitals. The study will collect pseudonymised data for patients with r/r FL following initial diagnosis and treatment for FL between January 2003-December 2018, and will report on current treatment patterns and clinical outcomes by treatment line, regimen and sequence. Results of this unique study will inform clinical treatment decisions, FL management guidelines, prospective trial design, and regulatory approval of novel FL drugs. The study will be conducted at NHS sites in the UK that routinely treat patients with FL. The study will last for two years.
1. Age ≥18 years at initial diagnosis 2. FL lymphoma grade 1-3a at initial diagnosis 3. First systemic treatment started between Jan 2003-Dec 2018 using a contemporary therapy (anti-CD20 monoclonal antibody in combination with chemotherapy (CVP, CHOP, Bendamustine). Patients treated with initial rituximab monotherapy or radiotherapy are eligible, but this does not count as a line of therapy, as long as these patients subsequently started treatment with an anti-CD20 monoclonal antibody in combination with chemotherapy (CVP, CHOP, bendamustine) between Jan 2003 and Dec 2018. 4. At least 3 cycles of first line systemic therapy delivered. 5. Patient received the majority of their FL treatment at the participating centre (for data quality) . If not, the investigator must be able to collect complete/near complete consecutive treatment data for the full patient course. 6. Patients with r/r FL or high grade transformation: a. Relapsed or refractory FL (r/r FL) or high grade transformation (HGT) occurring at any time after initiating first line FL therapy as described above. Wherever possible, the diagnosis should be histologically confirmed. b. Patients treated for HGT who subsequently relapse with histologically confirmed FL are eligible for ongoing collection of treatment details for r/r FL. 7. Patients without FL relapse or high grade transformation: a. FL patients treated with one line of therapy as above with no subsequent relapse of FL or high grade transformation. Minimal data will be collected for these patients including treatment details and date of last follow-up or death
1. High grade transformation (HGT) concurrent with initial diagnosis of FL, or occurring prior to commencing any therapy for FL, or occurring within the first 2 cycles of first line systemic therapy 2. CNS involvement at any time 3. First line systemic treatment for FL using any regimen not listed above. Patients enrolled on a clinical trial are eligible if treated with an anti-CD20 monoclonal antibody in combination with bendamustine, CHOP or CVP 4. A significant proportion of FL treatment data is unavailable for collection .
AURORA is a single arm,open label,multicentre,phase II clinical trial of atezolizumab immunotherapy,in immunotherapy naive patients with urinary tract squamous cell carcinoma (UTSCC). Recruitment is intended to occur over approximately 2 years and will follow a two-stage statistical design (see section 7). However,the intention is to allow continuous recruitment between Stage 1 and Stage 2. Following a Screening Phase of up to 28 days,eligible patients will be registered and will then commence atezolizumab immunotherapy,every 28 days,within a Treatment Phase of up to 1 year. On treatment discontinuation,patients will be reviewed in an End of Treatment Visit,and then 12 weekly (timed such as to continue with the 12 weekly schedule of CT scans from the Treatment Phase) until disease progression. Following disease progression,patients will revert to routine local follow up processes. Consent will be obtained for long term collection of overall survival status.
Histologically confirmed cancer of the urinary tract with squamous cell carcinoma histology and without any TCC component. Mixed non-TCC histology is allowed if squamous cell carcinoma is the predominant histology. Newly diagnosed or progressive measurable disease as defined by RECIST version 1.1. To be considered measurable (and to be designated as a target lesion),a lesion must not have been treated with prior radiotherapy or focal ablation techniques. Suitable,in the judgment of the local investigator,for treatment with atezolizumab,with palliative intent. Adequate haematologic and end-organ function within 28 days prior to the first study treatment including: a. Absolute neutrophil count ≥ 1.5 x109/L,b. Platelet count ≥ 100 x109/L,c. Haemoglobin ≥ 90 g/L,d. Aspartate transaminase (AST),alanine transaminase (ALT),and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN),e. Total bilirubin ≤ 1.5 times ULN (or ≤ 3 ULN in patients with Gilbert’s syndrome),f. Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula). Up to one prior line of systemic chemotherapy for UTSCC. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 7. Life expectancy ≥ 12 weeks. 8. Representative formalin-fixed paraffin embedded (FFPE) tumour sample with an associated linkedanonymised pathology report that is available for central use in translational studies. 9. Able to comply with all trial procedures and processes. 10. Age ≥ 18 at time of signed inform consent form. 11. Provision of written informed consent.
Any component of TCC histology. Planned for treatment with curative intent. Prior systemic immunotherapy (prior intra-vesical treatments are allowed) AURORA Protocol Version 2 03-MAY-2022 Page 21 of 51. Major surgery within 30 days prior to enrolment. History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation. Use of oral or IV steroids for 14 days prior to enrolment. Use of inhaled corticosteroids,physiologic replacement doses of glucocorticoids (i.e.,for adrenal insufficiency),and mineralocorticoids (e.g.,fludrocortisone) is allowed. Administration of a live or attenuated vaccine within 4 weeks prior to enrolment (COVID-19 vaccination is allowed). Treatment with any other investigational agent within 4 weeks prior to enrolment. Coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,unstable arrhythmias,unstable angina or congestive cardiac failure (New York Heart Association ≥ grade 2) within 6 months prior to enrolment. Patients with known HIV infection or with active tuberculosis. Patients with known active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody and the absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Autoimmune disease including myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone or with controlled Type I diabetes mellitus on a stable dose of an insulin regimen are eligible for this study. History of idiopathic pulmonary fibrosis,organizing pneumonia (e.g.,bronchiolitis obliterans),drug-induced pneumonitis,idiopathic pneumonitis,or evidence of active pneumonitis on screening chest CT scan. A history of radiation pneumonitis in the radiation field (fibrosis) is permitted. Prior allogeneic stem cell or solid organ transplant. Patients who are pregnant or breast feeding. Patients of child-bearing potential who are not able to use a highly effective method of contraception (as detailed in section 3.7). A recent or current other cancer. Current non-melanoma skin cancer,cervical carcinoma in situ or localized prostate cancer not requiring current treatment are permissible,as is a history of a separate other malignancy having completed all active treatment ≥2 years previously.
Clinically assisted hydration at the end of life is much debated by healthcare professionals (HCP), it is also a debate that has moved into the public domain, which has caused much contention and anxiety for the dying patient, relatives and Health Care Professionals. The reason for the debate, contention and anxiety, is there is a lack of good quality research, which provides the evidence that guides end of life practice. The CHELsea II trial aims to provide robust data to enable new guidance on the use of assisted hydration in this patient group. The CHELsea II trial is a cluster randomised trial (sites randomised rather than participants) comparing the standard mouthcare with Clinically Assisted Hydration (CAH) versus the standard of mouthcare only in patients who are in the last days of life. Delirium can be one of the most distressing aspects of end of life and the CHELsea II trial will uniquely address the specific issue of the use of CAH at the end-of-life and to use an evidence based approach to create a pathway for the majority of end of life patients and to asses the reduction of delirium utilising CAH in this group of patients.
Estimated prognosis of death < = 1 week. [Clinical opinion - MDT]. Patient unable (or clinical opinion that they will soon be unable to) to maintain sufficient oral fluid intake (i.e., < 1L/day).
a) patient is dehydrated (patient eligible for inclusion after correction of dehydration) b) patient has a relevant Advance Directive to Refuse Treatment (ADRT) c) clinical indication for CAH d) clinical contraindication to CAH e) contraindication to cannulation f) total parenteral nutrition/enteral feeding in situ g) patient has had delirium in last 24 hours h) patient has had audible upper airway secretions in last 24 hours i) patient likely to be transferred elsewhere for end-of-life care j) patient has clinically significant cardiac failure as deemed by clinical team (see criteria “d”) k) patient has clinically significant renal failure as deemed by clinical team (see criteria “d”) l) patient has clinically significant dementia as deemed by clinical team (potential false positives on delirium screening)
The European Organisation of Research and Treatment of Cancer’s Quality of Life Group (EORTC QLG) has developed a four-phase framework that can be used to develop and validate quality of life questionnaires for individuals with cancer. These are developed as modules to supplement their existing EORTC core quality of life questionnaire, the ‘QLQ-C30’. For example, modules have previously been developed for endometrial cancer (QLQEN24), bone metastases (QLQ-BM22), and cancer-related fatigue (QLQ-FA12). The four-phase approach comprises a literature review followed by interviews with patients and clinicians (Phase 1), construction of a questionnaire (Phase 2), refinement of the questionnaire (Phase 3), and finally administration of the questionnaire to an international sample in a full validation study (Phase 4). The present study aims to contribute to the development of a module designed to measure quality of life in cancer survivors (i.e. those that are > 1 year post-diagnosis and have a good prognosis). The study aims to undertake Phase 4 of the above module development process.
• Aged 18 years and older at diagnosis. • A confirmed cancer diagnosis of: breast, colorectal, prostate, bladder, gynecological (ovarian, cervix and endometrial), head and neck, lung, and testicular cancer, lymphoma (Hodgkin and Non-Hodgkin), melanoma, or glioma. • Between one and ten years post-primary treatment or treatment for recurrence with curative intent (exception glioma –not treated with curative intent- and maintenance therapies e.g. tamoxifen). • No evidence of active disease (exception glioma). • Before patients complete the questionnaire, written informed consent must be given according to ICH/GCP, and national/local regulations including commitment to complete questionnaires during the course of the study.
• Unable to speak English. • Participated in Phase 3b of the module development. • Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol. • Lack of mental capacity to complete the questionnaires. • More than one primary cancer diagnosis.
OptiMATe is a randomised phase 3 superiority design with a primary endpoint of 2-year event-free survival. Patients will be randomised between the control arm (4 cycles of MATRix followed by HDT-ASCT) and the experimental arm. Patients in the experimental arm will receive one cycle of rituximab and high-dose methotrexate only; this less intensive initial treatment cycle aims to improve the patient's performance status and neurocognitive function and reduce early treatment-related morbidity and mortality. The second optimisation step involves abbreviation of MATRix induction to 2 cycles only. Responding patients in both arms will proceed to HDT-ASCT.
1. Immunocompetent patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). 2. Male or female patients aged 18-65 years irrespective of ECOG or 66-70 years with ECOG Performance Status ≤2. 3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy,CSF cytology examination or vitrectomy. 4. Disease exclusively located in the CNS. 5. At least one measurable lesion. 6. Previously untreated patients (previous or ongoing steroid treatment admitted). 7. Negative pregnancy test 8. Written informed consent obtained according to international guidelines and local laws by patient or authorized legal representative in case patient is temporarily legally not competent due to his or her disease. 9. Ability to understand the nature of the trial and the trial related procedures and to comply with them.
1. Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation. 2. Systemic lymphoma manifestation (outside the CNS). 3. Primary vitreoretinal lymphoma or primary leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord 4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ or other kinds of cancer without evidence of disease for at least 5 years. 5. Previous Non-Hodgkin lymphoma at any time. 6. Inadequate renal function (clearance < 60 ml/min). 7. Inadequate bone marrow,cardiac,pulmonary or hepatic function according to investigator´s decision 8. Active hepatitis B or C disease. 9. Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with study medication being administered within the last 30 days before the start of this study. 10. Clinically relevant third space fluid accumulation according to the investigator’s discretion. 11. Hypersensitivity to study treatment or any component of the formulation. 12. Taking any medications that are likely to cause interactions with the study medication 13. Known or persistent abuse of medication,drugs or alcohol. 14. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic 15. Patients without legal capacity who are unable to understand the nature,significance and consequences of the trial and without designated legal representative. 16. Previous participation in this trial. 17. Persons who are in a relationship of dependency/ employment with the sponsor and/ or the investigator. 18. Any familial,sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 19. Current or planned pregnancy,nursing period 20. For fertile patients: Failure to use one of the following safe methods of contraception: intra-uterine device or hormonal contraception in combination with a mechanical method of contraception.
This research aims to determine the quality-of-life (healthcare-related utility scores) following surgery to remove the womb (hysterectomy) to prevent endometrial cancer. We will use this information to build a model to determine the level of lifetime risk of endometrial cancer at which this preventive surgery is cost-effective. Finally, we will assess the acceptability of offering preventive hysterectomy to general population women at or around these risk thresholds determined. Part 1 is a cross-sectional cohort survey study of women with Lynch Syndrome, who are at increased cancer risk. This consists of a questionnaire and quality-of-life survey. This will determine the quality-of-life of women who have/ have not had preventive hysterectomy. It is expected that almost all women with Lynch Syndrome who had preventive hysterectomy will also have had their ovaries removed. Part 2 is a vignette-based study. This is designed to generate one or more vignettes which represent a woman who has not yet gone through the menopause, who is at increased risk of endometrial cancer. The woman described has preventive hysterectomy without removal of the ovaries. The quality-of-life of those described in vignettes will then be valued by participants. The development process follows methodological recommendations from NICE. Once utility scores for hysterectomy are known, a health-economic model will be developed, to determine the lifetime risk threshold of endometrial cancer at which preventive hysterectomy should be offered. Part 3 is an experimental survey study, designed to evaluate the prospective acceptability of hysterectomy and other prevention strategies. Acceptability will be tested at varying levels of lifetime endometrial cancer risk, as determined by modelling. All participants will only complete one survey at one time point only. This study has the potential to influence clinical practice for women at increased risk of endometrial cancer.
Part 1: a) Female b) Age > = 18 years old c) Lynch Syndrome diagnosis - confirmed germline mutation in MLH1, MSH2, MSH6, PSM2, or ECPAM d) UK Resident e) Able to provide informed consent Parts 2 and 3: a) Female b) Age 35 – 70 years old c) UK Resident d) Able to provide informed consent
a) Patient unable to read or write in English b) Personal history of endometrial, ovarian or cervical cancer c) Unable to provide informed consent
Lung cancer is the most common cause of cancer death. Things have improved with the use of drugs like pembrolizumab,which is often used following diagnosis of advanced non-small cell lung cancer (NSCLC). Pembrolizumab uses the immune system,the body’s natural defence. The immune system sends cells called T cells to fight infections and diseases. Cancer cells hide in the ‘PD-1/PD-L1 pathway’,allowing them to grow and spread. Pembrolizumab blocks the pathway. This prevents cancer cells from hiding,meaning they can be killed by T cells. The cancer may shrink or disappear as a result. Treatment is usually every 6 weeks,sometimes with chemotherapy. Treatment can last 2 years,and this may be too much. Research has not shown that length increases benefit,and many people who stop before 2 years continue to benefit from pembrolizumab after it has finished. There is a possibility that researchers can reduce treatment frequency without effectiveness being reduced. This is the main aim of REFINE-Lung,and has the potential to bring a number of positive consequences: • Similar effectiveness but less side effects • Improved quality of life • Less visits to and savings by hospitals Eligible participants will be about to or already receiving pembrolizumab as first treatment for NSCLC. After 6 months,they will be randomly allocated to one of the following with or without chemotherapy until the cancer grows significantly: • Pembrolizumab 6 weekly – the ‘control’ group,or standard treatment; • Pembrolizumab 12 weekly. After 150 participants are recruited,the researchers will see if 12 weekly is similar to 6 weekly,and if so 3 further groups will be opened: • Pembrolizumab 9 weekly; • Pembrolizumab 15 weekly; • Pembrolizumab 18 weekly. Up to 350 participants will be recruited into each group from 27-35 participating UK hospitals,1750 in total. Each participant will be followed up for 18 months.
• Written informed consent prior to initiation of any study procedures and willingness and ability to comply with the study schedule • Any patient ≥18yrs who has received 6 months of pembrolizumab treatment,with or without chemotherapy,for advanced NSCLC who is planned to continue / move to immunotherapy every 6 weeks because of continued benefit.
• Disease progression or not tolerating treatment at 6 months into therapy • Clinician does not intend to continue immunotherapy • Any patient currently receiving an investigational agent and/or using an investigational device or has participated in a study of an investigational agent and/or used an investigational device within 28 days of randomisation.
RESEARCH QUESTION: In post-menopausal women who will not require chemotherapy for >T1,strongly ER+,HER2- invasive breast cancer,does NET improve global HRQoL over 15 months and increase breast BCS rates? Patients will be randomised 1:1 to either the intervention (NET) arm (6 +/- 1 months of NET followed by surgery and adjuvant ET) or the control arm (2-4 weeks of presurgical NET and surgery within 2-4 weeks [up to 8 weeks permitted for trial purposes] followed by adjuvant ET). Both arms will receive the same treatments (surgery,ET,and radiotherapy where indicated),but the sequencing of surgery will differ; both arms starting ET at randomisation,with 6 months +/- 1 month of the course of ET delivered prior to surgery in the NET arm.
• Female,• Clinically post-menopausal; including one of: o amenorrhoea > 12 months and an intact uterus. o bilateral oophorectomy o for those with a history of hysterectomy,or HRT within 12 months,venous FSH levels classified as post-menopausal by the testing laboratory if any doubt. • Unifocal,newly diagnosed breast cancer visible on USS; • Strongly ER+; defined as Allred scores of 7 or 8 or equivalent • HER2- by immunohistochemistry,or 2+ and not amplified by in situ hybridisation • T-stage 2 or 3 (> 2cm); • Axillary N0-1 on diagnostic USS +/- negative FNA or core biopsy; • Suitable for surgery and radiotherapy; • Chemotherapy unlikely to be indicated; • Participant is able and willing to give informed consent for participation in the trial; • In the Investigator’s opinion,is able to comply with all trial requirements.
• Bilateral breast cancer; • ER- or HER2+; • Stage IV disease (distant metastasis); • Previous neoadjuvant treatment for breast cancer; • Previous invasive malignancy within 5 years other than basal cell carcinoma; • Concurrent use (at the time of randomisation) of HRT or any other oestrogen-containing medication (including vaginal oestrogens); • Ovarian suppression/ablation for the purposes of trial entry not permitted.
A multicentre,phase II,randomised (2:1) clinical trial of ASTX727 compared to best supportive care (BSC) +/- hydroxycarbamide in adult patients with MDS/Overlap syndromes including CMML. A total of 75 patients will be recruited over a 2 year period from across the network of UK TAP sites. Randomisation will be stratified by (i) presence or absence of proliferative disease (defined by WHO criteria as a white cell count ≥ or < 13 x109/L); and (ii) time from diagnosis,to extend eligibility to both newly diagnosed and longer established patients. At screening treating physicians will declare in advance a proposed BSC approach for that patient,to be employed in the event of randomisation to the BSC arm. The main aim of the study is to compare the overall response rate of ASTX727 vs best supportive care +/- hydroxycarbamide.
• ≥18 years of age at the time of trial entry • Morphologically confirmed diagnosis of MDS/MPN (excluding JMML),in accordance with WHO 2016 diagnostic criteria (Appendix 4),with any of the following characteristics: CMML-2 disease stage [CMML only] CPSS [Such et al Blood 2013] or CPSS-Mol [Elena et al Blood 2016] score of intermediate-2 or high risk [CMML only] Other patients with one or more of the following: o Bone Marrow blasts > 10% (including promonocytes) o Adverse risk cytogenetics (as defined by CPSS or MDS R-IPSS) o WCC ≥50 (or ≥30 with symptoms attributable to myeloproliferation) o RBC transfusion dependence with pre-transfusion Hb < 90 g/L o Symptomatic anaemia (with Hb ≤100 g/L) o Thrombocytopenia (Plt ≤50 x 109/L) o Symptomatic splenomegaly o Systemic symptoms with no alternative explanation (including weight loss ≥10% of baseline over previous 6 months) o Symptomatic extramedullary involvement (e.g. skin infiltration,serous effusions) • Treatment-naïve for prior hypomethylating agent,intensive chemotherapy or other disease-modifying anti-neoplastic therapy (e.g. lenalidomide); patients may have received prior hydroxycarbamide,recombinant erythropoietin,danazol,interferon or anagrelide. • ECOG performance status of 0,1 or 2 at trial entry (Appendix 3). • Life expectancy of ≥3 months at trial entry,as assessed by the treating physician. • Must have adequate hepatic,renal and endocrine function during screening as demonstrated by the following: ALT and/or AST ≤3x upper limit of normal (ULN); Total bilirubin ≤1.5x ULN or ≤2x ULN if upon judgement of the treating investigator the hyperbilirubinaemia is due to extramedullary haematopoiesis related to the underlying MDS/MPN or to Gilbert’s disease; Serum creatinine ≤1.5x ULN or estimated creatinine clearance >/= 30ml/min/1.73m2. • Patient willing and able to comply with scheduled visits,treatment plan and other study procedures. • Patient able to provide written informed consent for the trial
• Patients eligible for intensive chemotherapy and/or allogeneic haematopoietic stem cell transplantation (HSCT). • CMML with eosinophilia and 5q33 abnormality. • Previous cytotoxic chemotherapy for MDS/MPN,except hydroxycarbamide. • Prior hypomethylating agent exposure. • Transformation to AML (≥20% myeloid blasts in bone marrow or peripheral blood at screening). • Prior organ transplantation,including allogeneic haematopoietic stem cell transplant (HSCT). • Known or suspected central nervous system disease involvement. • Known history of clinically significant or uncontrolled cardiac disease,including recent history (within 6 months) of unstable angina,acute myocardial infarction,NYHA class III or IV congestive cardiac failure,or clinically significant arrhythmia. • Other active malignancy,not including localized non-melanoma skin cancer,cervical carcinoma in situ,breast ductal carcinoma in situ of the breast,or localized prostate cancer controlled with hormone therapy. Patients with history of other cancers should be free of disease without ongoing anti-neoplastic therapy for at least 2 years. • Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤28 days or limited field radiation for palliation ≤14 days prior to starting any study medications (or has not recovered from side effects of such therapy). • Active,uncontrolled infection. Patients with infection under control with active treatment are eligible. • Pregnant and lactating patients (patients of childbearing potential (see Section 7.7) must have a negative pregnancy test prior to study entry). • Females of childbearing potential,and their partners,not willing to use adequate contraception during and for up to 6 months after treatment (see Section 7.7). • Any other concurrent serious or unstable medical,psychiatric,familial,geographic or sociological condition that in the investigator’s opinion would jeopardise the patient’s ability to comply with the protocol.
Every year, 150,000 patients at risk of prostate cancer (PCa) are referred to hospital. Guidelines have recently recommended patients have a multi-parametric MRI (mMRI) before biopsy so those with a negative mpMRI can avoid an invasive biopsy. This is because a negative mpMRI means there is a low chance of there being important prostate cancer. In patients with a suspicious mpMRI, targeted biopsies improve detection of important PCa. We want to further improve this new pathway. First, mpMRI takes 40-minutes due to injection of a dye called gadolinium. This requires medical supervision due to risk of allergic reactions. Many hospitals do not have enough scanner time or expert radiologists to look at all the images. A 15-minute biparametric MRI (bpMRI), without gadolinium, which is less costly might be as accurate as mpMRI. Second, once a patient needs a biopsy the doctor has to estimate where to target the biopsy needle using live ultrasound. This so-called visual-registration targeting requires expertise which is not readily available everywhere. New image-fusion technology overlays MR images onto ultrasound images to guide the biopsy needle better. We want to test if a bpMRI, compared to mpMRI, is as accurate in diagnosing important PCa. We also want to test whether image-fusion is better than visual-registration biopsies. We want to answer both questions in one trial. Patients who need a prostate MRI and agree to participate will first be randomised to mpMRI or bpMRI. If the mpMRI or bpMRI is suspicious, patients will then be randomised to visual-registration or image-fusion targeted biopsy. We will look at the number of patients biopsied, and the numbers diagnosed with important and unimportant PCa. We also want to assess value for money in the NHS.
Summary: Patients with a prostate (either cis-male gender or trans-female gender with no prior androgen deprivation hormone use at all) referred to hospital urology departments by their GP due to a clinical suspicion of prostate cancer (elevated serum prostate specific antigen [PSA], abnormal feeling prostate on rectal examination). These patients are normally recommended to undergo a prostate MRI as part of standard care. Randomisation-1: bpMRI versus mpMRI Patients with elevated age-specific PSA or abnormal digital rectal examination of the prostate with PSA levels as determined by NICE guidance and local NHS Cancer Alliance or regional guidance. Recent UK consensus guidance [Prostate Cancer UK, 2016] from over 300 UK healthcare professionals and men affected by prostate cancer and endorsed by the British Association of Urological Nurses (BAUN), the British Association of Urological Surgeons (BAUS) and the Primary Care Urology Society (PCUS) also stipulates that patients with a family history (1 or more first degree male relatives) or ethnic risk group (those identifying as of Black-African/Black-Caribbean) should be further investigated with PSA >/= 2.5 when aged 45-49 years. We will also approach these patients as well. Randomisation-2: Visual registration targeting versus image fusion targeting Suspicious finding on mpMRI or bpMRI from randomisation-1 requiring targeted biopsy (MRI categories 3, 4 or 5)
Randomisation-1: bpMRI versus mpMRI - PSA > 50ng/ml. The rationale being that above this PSA level, rates of clinically important PCa are quite high and a pre-biopsy MRI is likely to be of less utility. - Prostate MRI or prostate biopsy within the previous 24 months from the date of screening. A prior prostate MRI which is negative will add selection bias and a prior biopsy can cause artefact changes which affect the quality of the images. These artefact changes can take a number of months to dissipate and in some patients up to 9-12 months after the biopsy. - Prior prostate cancer diagnosis at any time-point. Patients on active surveillance will have differing prior probabilities of clinically important cancer to those referred with a clinical suspicion and are therefore excluded. - Any absolute contraindication to MRI, gadolinium contrast or biopsy. Patients with one or two hip prostheses are excluded. These prostheses often cast a large imaging artefact over the prostate area on MRI and radiologists prefer a mpMRI scan because the diffusion images can be particularly affected. - Unable to give informed consent to the study Randomisation-2: Visual registration targeting versus image fusion targeting - As above for randomisation 1 - Patient refusal for biopsy
STATIC is designed with multiple pathways, the ‘Randomisation Pathway’ and the ‘Clinical Need Cohort’, which route a participant enters will be determined by their eligibility. Randomisation Trial: A prospective, national, multicentre, open-label, randomised, controlled, 2-arm, parallel-group, non-inferiority ,phase III trial to assess whether patients with CLL on long-term treatment with a BTK inhibitor, (including ibrutinib) have similar disease control with an intermittent treatment strategy (experimental arm) compared with standard continuous treatment (control arm). Patients who have received ibrutinib in the NHS after receiving at least one previous treatment and patients who have received ibrutinib as their first treatment as part of the FLAIR trial can enter the randomisation trial. Clinical Need Cohort: A prospective, national, multicentre, open-label, single-arm, non-randomised cohort to assess the safety and overall survival of patients with CLL receiving long-term continuous treatment with ibrutinib. Patients who have received ibrutinib as their first treatment as part of the FLAIR trial may be able to join the clinical need cohort. The primary aim is to assess whether patients with CLL on long-term treatment with BTK inhibitor (including ibrutinib) have similar disease control with an intermittent treatment strategy, known as the ‘Pausing Ibrutinib’ arm compared with standard continuous treatment, the ‘Continuous Ibrutinib’ arm. The primary objective is to assess non-inferiority (NI) of the intermittent treatment strategy in terms of time to treatment strategy failure, defined as the first documented instance of active disease (as defined by the 2018 iwCLL criteria) that does not respond to treatment or death.
Trial Registration Inclusion Criteria: 1.At least 18 years old 2.A diagnosis of chronic lymphocytic leukaemia (CLL) or small lymphocyticlymphoma (SLL) (by 2018 iwCLL criteria) 3.World Health Organisation (WHO) performance status (PS) of 0,1 or 2 4.Biochemical values must be within the following limits within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort and at baseline: -Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) OR 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 5.Agree to follow the pregnancy prevention guidelines 6.Able to provide informed consent Additional inclusion criteria for participants in the Clinical Need Cohort: 1.Meet all of the Registration Inclusion criteria 2.Currently receiving ibrutinib and nearing the end or having completed 6 years of ibrutinib treatment on FLAIR 3.Have signs of progressive or returning CLL after completing 6 years of ibrutinib treatment within FLAIR,but prior to entry into STATIC Additional inclusion criteria for Front Line participants entering the randomisation trial: 1.Meet all of the Registration Inclusion criteria 2.Currently receiving ibrutinib in FLAIR or having completed 6 years of ibrutinib of ibrutinib in FLAIR* 3. In clinical remission all of the following: a. no palpable lymph nodes; b. no palpable spleen; and 4.lymphocyte count below 5x109/L continuously for at least the 12 months before randomisation Additional inclusion criteria for Front-Line participants entering the randomisation trial: 1.Meet all of the registration inclusion criteria 2.Currently receiving ibrutinib for at least the previous 36 months. There is no restriction on maximum duration of treatment prior to enrolment. 3.In clinical remission fulfilling all of the following: a. no palpable lymph nodes; b. no palpable spleen; and 4.Lymphocyte count below 5x109/L continuously for at least the 12 months before randomisation
Trial Registration Exclusion Criteria: 1.Pregnant females 2.Known intolerance or hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption. 3.Receipt of live vaccination within 4 weeks prior to registration and for the duration of the study. 4.History or current evidence of Richter’s transformation 5.Major surgery within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort 6.Active infection 7.Concomitant warfarin (or equivalent vitamin K inhibitor) 8.Central nervous system involvement with CLL 9.Cardiac failure; including 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) 10.Respiratory impairment (e.g. bronchiectasis or severe COPD) 11.Other severe,concurrent diseases or mental disorders that could interfere with their ability to participate in the study 12.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),aHB DNA test will be performed and if positive the patients will be excluded.During treatment,these participants should be monitored and managed to prevent HBV reactivation. 13.Positive serology for Hepatitis C (HC) defined as a positive test for HCAb,in which case reflexively perform a test for hepatitis C RNA (for example HCV RNA PCR). If positive the patients will be excluded. 14.Persisting severe pancytopenia (neutrophils < 0.5 x 109/L or platelets < 50 x 109/L)unless due to direct marrow infiltration by CLL 15.Current treatment with prednisolone of > 20mg/day 16.Uncontrolled Active haemolysis 17.History of stroke or intracranial haemorrhage within 6 months prior to enrolment. 18.Requirement for treatment with a strong CYP3A inhibitor or inducer 19.New treatment with two or more antiplatelet drugs,treatment that has been administered at a stable dose for at least 3 months prior to registration is permissible 20.Current treatment with any concomitant ACE inhibitors Additional exclusion criteria for participants in the Clinical Need Cohort: 1.Meet none of the registration exclusion criteria 2.Active Disease,as per the 2018 iwCLL criteria requiring an alternative therapy. 3.Received treatment other than ibrutinib for CLL since completing FLAIR 4.Be eligible for front-line randomisation Additional exclusion criteria for Front-Line participants entering the randomisation trial: 1.Meet none of the registration exclusion criteria 2.Disease progression (according to 2018 iwCLL criteria) 3.Ibrutinib treatment break for toxicity/patient choice for more than 28 days in last12 months Additional exclusion criteria for Previously Treated participants entering the randomisation trial: 1.Meet none of the registration exclusion criteria 2.Disease progression (according to 2018 iwCLL criteria) 3.Ibrutinib treatment break for toxicity/patient choice for more than 28 days in last12 months 4.Any illness,disease or condition,such as active cancer or secondary primary malignancy (SPM),with a prognosis of less than 5 years 5.Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula).
FEDORA is a prospective, multicentre, open label, phase II clinical trial for patients with myelofibrosis (MF). MF is a rare blood disorder that causes scarring of the bone marrow. More than 55% of people with MF have a change in a gene called JAK2. JAK2 inhibitors are drugs that slow or stop the growth of cancer cells. Although JAK2 inhibitors have shown promising results for some patients with MF, treatment with a JAK2 inhibitor does not usually cure the patient’s disease. Previous studies have shown that combining a JAK2 inhibitor with a pegylated interferon is safe to administer and may be more effective because the interferon makes the cells that give rise to new blood cells more sensitive to the JAK2 inhibitor. The FEDORA study will use a selective JAK2 inhibitor (fedratanib), and a next generation pegylated interferon (ropeginterferon alfa-2b). The aims of the study are to gather information about whether this combination is tolerated, and whether it provides a therapeutic benefit to MF patients. Patients will begin with fedratinib monotherapy to establish a stable tolerated dose. After a month of monotherapy, a low starting dose of ropeginterferon alfa-2b will be added to the treatment regimen. The dose of ropeginterferon alfa-2b will be increased every month until a dose combination is achieved that is tolerated by the patient (combination doses will be patient-specific); these doses are then maintained for the duration of the study. 30 patients will be recruited to the study through the Cure Leukaemia-funded Trials Acceleration Programme (TAP); a network of haemato-oncology centres across the UK. Trial treatment will continue for 2 years, and patients will be followed-up every month during treatment, and then 3-monthly for survival, progression and subsequent treatments until the end of the trial.
• Age 18 or over at trial entry • Confirmed diagnosis of JAK2 V617F positive primary or secondary MF, according to WHO 2016 diagnostic criteria • Require treatment, as clinically determined by local investigator • Intermediate-2 or high risk according to DIPSS, or intermediate-1 according to DIPSS with palpable splenomegaly > 5cm • Peripheral blood or bone marrow blasts < 10% • Adequate blood counts: platelets ≥75 x10-9/L, neutrophils ≥1.0 x10-9/L • Adequate organ function • ECOG performance score ≤2
• Previous treatment with a JAK2 inhibitor or interferon alpha • Chemotherapy or biologic therapy within 2 weeks of commencing the trial treatment, or ongoing toxicity relating to prior therapy • Blood thiamine concentration below lower limit of normal • Active malignancy treated in the last 2 years • Pre-existing and uncontrolled thyroid disease, diabetes or autoimmune disease • History of severe psychiatric disorder, including severe depression, suicidal ideation and suicide attempt • Current severe or uncontrolled cardiovascular disease • Previous organ transplantation receiving ongoing immunosuppression • Evidence of active HIV, HBV or HCV infection • Pregnant and breast feeding patients and those unwilling to use effective contraception
The study will look at the effect of the combination of polatuzumab vedotin and R-ICE vs R-ICE alone in patient with relapsed or refractory DLBCL who are eligible for stem cell transplant following salvage therapy. The study is a Phase III,randomised controlled trial with 2 arms. Patients will be randomised at a 1:1 ratio to receive either polatuzumab vedotin + R-ICE or R-ICE alone. For all patients,the visit schedule consist of a screening visit up to 3 weeks before first treatment,cycle 1 at week 1,cycle 2 and week 4-5,interim re-staging at week 6-7,cycle 3 at week 7-8,final restaging at week 1—12 and quarterly follow-up visits for at least 12 months,or until the last patient on the trial has their last follow-up.
(1) The informed consent form (ICF) must be signed before any study specific tests or procedures are done (2) Adult male and female patients ≥ 18 years (≥16 years in the UK*) at the time of inclusion in the study * In the UK an “adult” means a person who has attained the age of 16 years,according to The Medicines for Human Use (Clinical Trials) Regulations 2004,Part 1 Point 2. (3) Ability to understand and follow study-related instructions,in the investigator’s judgement (4) Risk group: All patients with one of the following histologically defined entities: Histological diagnosis of primary refractory or relapsed aggressive B-NHL,confirmed by a biopsy of involved nodal or extranodal site. Patients with any of the following histologies can be included: • DLBCL not otherwise specified (NOS) • T-cell/histiocyte-rich large B-cell lymphoma • Primary cutaneous DLBCL,leg type • EBV-positive DLBCL,NOS • DLBCL associated with chronic inflammation • Primary mediastinal (thymic) large B-cell lymphoma • High-grade B-cell lymphoma,with MYC and BCL2 and/or BCL6 rearrangements • High-grade B-cell lymphoma,NOS Refractory disease is defined as no complete remission to first line therapy; subjects who are intolerant to first line therapy are excluded. Three groups of patients are eligible: • PD as best response to first line therapy (biopsy not mandatory if diagnostic sample available). • SD as best response after at least 4 cycles of first line therapy (e.g.,4 cycles of R-CHOP) (biopsy not mandatory if diagnostic sample available). • PR as best response after at least 6 cycles,and biopsy-proven residual disease or disease progression after the partial response. Relapsed disease is defined as complete remission to first line therapy followed by biopsy proven disease relapse. (5) Performance Status ECOG 0-2 at time of randomization or ECOG 3 at screening if this is DLBCL-related and has improved to ECOG 2 or less with a 7-day steroid treatment during the screening phase (e.g. 1 mg/kg prednisone). (6) Information on all 5 IPI factors (7) Staging (PET-CT based-staging according to Lugano criteria 2014 [36]). Patients must have PET-positive lesions. (8) Subjects must have received adequate first line therapy including at a minimum: i) anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative,and ii) an anthracycline containing chemotherapy regimen (9) Intent to proceed to HDT and SCT if response to second line therapy (10) Adequate hematological function,as defined by: hemoglobin ≥ 8 g/dL,ANC ≥ 1.0 x 109/L OR ≥ 0.5 x 109/L if neutropenia is attributable to underlying disease and before the administration of steroids,and platelet count ≥ 75 x 109/L OR ≥ 50 x 109/L if thrombocytopenia is attributable to underlying disease (11) Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first study drug administration (12) For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures,and agreement to refrain from donating eggs,as defined below: • Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 12 months after the final dose of study medication. Women must refrain from donating eggs during this same period. • A woman is considered to be of childbearing potential if she is post-menarcheal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause),and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation,male sterilization,hormonal contraceptives that inhibit ovulation,hormone-releasing intrauterine devices and copper intrauterine devices • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar,ovulation,symptothermal,or postovulation methods) and withdrawal are not acceptable methods of contraception (13) For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures,and agreement to refrain from donating sperm,as defined below (the patient should receive advice on the possibility of opting for cryoconservation of sperm prior to start of study treatment due to the possibility of irreversible infertility following therapy with study medication): • With a female partner of childbearing potential who is not pregnant,men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of study medication. Men must refrain from donating sperm during this same period • With a pregnant female partner,men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of study medication to avoid exposing the embryo • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar,ovulation,symptothermal,or postovulation methods) and withdrawal are not acceptable methods of contraception.
(1) Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. In particular,patients with the following organ dysfunction caused by accompanying disorders are to be excluded: • Heart failure with LVEF < 45% • Impaired pulmonary function with VC or FEV1 < 50% of normal (only in case of history of significant pulmonary disease) • Impaired renal function with GFR < 50 ml/min (calculated) • Impaired liver function with ALAT,ASAT,bilirubin > 1.5 x ULN. If elevation is caused by the disease,threshold of 2.5 x ULN is accepted • Peripheral neuropathy > Grade II (2) HIV-positivity with detectable viral load and/or a CD4+ count below 0.3/nL (3) Hepatitis B and C as defined by seropositivity (HBsAG and anti HBe / anti HBc; anti-Hc); in case of false positive serology (transfused antibodies) negative PCR-results will allow patient inclusion. Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable,provided that they are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment (4) Known active bacterial,viral,fungal,mycobacterial,parasitic,or other infection (excluding fungal infections of nail beds) at study inclusion or any unresolved major episode of infection (as evaluated by the investigator) within 1 week prior to Cycle 1 Day 1 (5) Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release assay (6) Primary or secondary CNS lymphoma at the time of recruitment (7) Richter’s transformation or prior CLL (8) Vaccination with a live vaccine within 4 weeks prior to treatment (9) Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis (10) Treatment with radiotherapy,chemotherapy,immunotherapy,immunosuppressive therapy,or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1 (11) Received more than one line of therapy for DLBCL (12) Received polatuzumab vedotin as part of the first line therapy (13) Any other diseases,metabolic dysfunction,physical examination finding,or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications (14) Ongoing treatment or study procedures within any other IMP clinical trial with the exception of follow-up. In case of a preceding clinical trial,last application of the respective IMP(s) must have been done more than five elimination half-lives before start of study medication in this trial. (15) History of severe allergic or anaphylactic reactions to human,humanized,chimeric,or murine monoclonal antibodies (16) History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure (17) Contraindications according to the IB of polatuzumab vedotin or the local SmPCs of the used rituximab,ifosfamide,carboplatin or etoposide products (18) Criteria which in the opinion of the investigator preclude participation for scientific reasons,for reasons of compliance,or for reasons of the subject’s safety (19) Pregnancy or breastfeeding,or intending to become pregnant during the study or within 12 months after the last dose of study drug (20) Close affiliation with the investigator (e.g. a close relative) or persons working at the study site (21) Subject is an employee of the sponsor or involved Contract Research Organization.
This study of Pembrolizumab in combination with rituximab,ifosfamide,carboplatin and etoposide aims to address the unmet need of patients with relapsed and refractory DLBCL. It is based upon a rational approach,investigating the activity of a novel agent in addition to the current best available treatment,recording response duration and toxicity profile. The primary objective will be to document the event free survival at one year from registration in patients with relapsed or refractory DLBCL and to determine the safety and toxicity profile of the combination. A maintenance phase of Pembrolizumab has been added as this may induce an on-going T-cell response to neo-antigens released as a result of chemotherapy.
• Histologically proven CD20 +ve diffuse large B-cell lymphoma,preferably with sufficient diagnostic material,obtained either at diagnosis or relapse (the latter is preferable) that is available to forward to the Haematological Malignancies Diagnostic Service (HMDS). • Refractory to,or relapsed following,first-line or second-line treatments with rituximab concurrently with anthracycline or anthracenedione-based chemotherapy or similar (etoposide allowed if comorbid). Refractory disease must fulfil one of the following: o Continuing partial response (PR) from termination of first-line treatment. It is strongly recommended the lymphoma be reconfirmed by biopsy however,if these procedures are deemed to be inappropriate,the CI may determine eligibility following review of the imaging results and disease history. o Continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) is recommended but not mandatory. o Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommended but not mandatory. • Potentially eligible for high-dose therapy and peripheral blood progenitor cell rescue in the event of response • Positive lesions shown on baseline PET-CT must be compatible with CT defined anatomical tumour sites. • At least 2 demarcated lesions/nodes with a long axis > 1.5 cm and a short axis equal to 1.0cm or 1 clearly demarcated lesion/node with a long axis > 2.0cm and short axis of 1.0cm • Previous therapy related toxicity should have resolved to a grade that the investigator deems appropriate to commence further treatment • ECOG Performance Status 0 – 1 • Has provided written informed consent • Willing to use acceptable contraception (see Section 4.6) • Aged 18 or over
• Previous lymphoma cancer treatment beyond third line • Radiotherapy or cytotoxic drugs within two weeks of trial treatment • Major surgery within 4 weeks of trial registration. If a subject had major surgery,more than 4 weeks ago,they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. • Treatment with any unlicensed drug within 4 weeks of trial treatment • History of stroke or intracranial haemorrhage within 6 months prior to registration • Pre-existing peripheral neuropathy grade > 2 • Clinically significant cardiac disease (inc. unstable angina,acute myocardial infarction,congestive heart failure,a current LVEF of < 40%) within 6 months of registration • Any significant uncontrolled medical condition or known hypersensitivity to the study drugs • Chronic or current infectious disease requiring systemic antibiotics,antifungal,or antiviral treatment such as,but not limited to,chronic renal infection,chronic chest infection with bronchiectasis and tuberculosis. • Other past or current malignancy within 2 years prior to registration unless in the opinion of the investigator it does not contraindicate participation in the study. Subjects who have a history of completely resected non-melanoma skin cancer,or successfully treated in situ carcinoma,are eligible • Known CNS involvement • Serological positivity for Hepatitis B,C,or known HIV infection. As per standard of care,prior to initiation of immunochemotherapy,the results of hepatitis serology should be known prior to commencement of therapy. Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Screening laboratory values : o platelets < 75x109/L (unless due to lymphoma involvement of the bone marrow) o neutrophils < 1.0x109/L (unless due to lymphoma involvement of the bone marrow) o creatinine > 2.0 times upper normal limit (unless due to lymphoma or unless creatinine clearance > 50mL/min) o total bilirubin > 1.5 times upper normal limit (unless due to lymphoma or a known history of Gilbert’s disease) o ALT/AST > 2.5 times upper normal limit (unless due to lymphoma) o Alkaline phosphatase > 2.5 times upper normal limit (unless due to lymphoma) • History of autoimmune disease,including but not limited to myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis (Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone will be eligible as will be patients with controlled Type I diabetes mellitus on a stable dose of insulin). • Patients who have previously undergone allogeneic transplantation. • Live vaccination within 28 days of study treatment. • Pregnant or lactating females. Women of child-bearing potential should have negative pregnancy test. • History of severe allergic anaphylactic reactions to chimeric,human or humanised antibodies,or fusion proteins. • History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. • Known hypersensitivity to CHO cell products or any component of the pembrolizumab formulation. • Previous treatment with an anti-PD-1,anti-PD-L1 or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,CTLA-4,OX 40,CD137). • Corticosteroid use > 10 mg/day of prednisolone or equivalent,for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with < 10 mg/day of prednisolone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment,prednisolone 100 mg or equivalent could be given for a maximum of 14 days as a pre-phase. A dose of up to 10mg or prednisolone or equivalent may be used during the screening phase to control symptoms.
The primary objective of this phase 1b trial is to establish the maximum tolerated safe dose of tolinapant (ASTX660) in combination with Cisplatin and Radiotherapy (CRT) to aid dose selection for a phase II trial in women with histologically proven adenocarcinoma or squamous cell carcinoma of the cervix stage IB2/IIB/IIIB suitable for radical treatment with CRT. In addition to standard of care chemoradiotherapy participants will receive tolinapant for 7 consecutive days on weeks 1,3 and 5 of CRT treatment.
1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the cervix stage IB2/IIB/IIIB. 2. Suitable for radical treatment with radiotherapy and cisplatin (using a standard dose of 45Gy in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2 ). 3. Adequate haematological parameters: • Haemoglobin ≥ 90 g/L • Neutrophil count ≥ 1.5 x 109/L • Platelets ≥ 100 x 109/L 4. Adequate biochemical parameters: • Bilirubin ≤ 1.5 x ULN • AST and ALT ≤2.0 x ULN • ALP ≤ 2.5 x ULN • Lipase and Amylase ≤1.2 x ULN • GFR Calculated (by Cockcroft-Gault formula or other accepted formula) or measured directly as ≥50 mL/min 5. Age 16 years or over. 6. ECOG Performance Status of 0-1. 7. Willing and able to give written informed consent.
1. Previous pelvic radiotherapy 2. Liver cirrhosis,or chronic liver disease Child-Pugh Class B or C 3. Women who are pregnant or breast feeding (WOCBP must have a negative serum pregnancy test at screening) 4. Patients of child-bearing potential who are not able to use a highly effective method of contraception (as detailed in section 4.6) 5. Any investigational medicinal product within 30 days prior to consent 6. Major surgery within 30 days prior to enrolment 7. Hypersensitivity to tolinapant,excipients of the drug product,or other components of the study treatment regimen 8. Patients with known HIV infection 9. Patients with known active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody and the absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA 10. Coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,unstable arrhythmias,unstable angina,left bundle branch block,third degree heart block,pacemakers or congestive cardiac failure (New York Heart Association ≥ grade 2) within 6 months prior to enrolment 11. Any patient who has received a live vaccine within 4 weeks of initiation of their treatment (COVID-19 vaccination is allowed). 12. Conditions requiring systemic treatment with either corticosteroids (≥ 20 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration 13. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (tolinapant),as follows: a. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less. b. Skin directed treatments,including topicals and radiation within 2 weeks prior. c. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less. d. Small molecules or biologics (investigational or approved) 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. e. At least 6 weeks must have elapsed since CAR-T infusion and subjects must have experienced disease progression,and not have residual circulating CAR-T cells in peripheral blood (based on local assessment). Any encountered treatment-related toxicities must have resolved to Grade ≤1. 14. Patients taking a QT prolonging agent (see appendix for example list). 15. Use of a concomitant medication which is a strong CYP3A4 inhibitor. 16. Abnormal left ventricular ejection fraction (LVEF) of < 50% on echocardiogram (ECHO). 17. History of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. 18. Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470 msec (according to either Fridericia’s or Bazett’s correction). 19. Any other active malignancy.
The measure for Health-Related Quality of Life (HRQoL) in pancreatic cancer (EORTC QLQ-PAN26), was developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group in 1996. As new treatments are now available for pancreatic cancer new symptoms and side-effects are being reported. A review is needed to see if the EORTC QLQ-PAN26 needs to be updated. We will invite people diagnosed with Pancreatic Duct Adenocarcinoma (PDAC; n= 95), and senior Health Care Professionals (HCP) with PDAC expertise (n= 20) for interviews in an international study. Patients will be purposely recruited by a member of the local research or clinical team while visiting the hospital as an inpatient or outpatient or they will be contacted by their clinician. Interviews will be carried out at the hospital, over the telephone, video conference or at home. In phase I, patients will be asked to talk about how PDAC has affected their HRQoL. Patients will be asked about their experience of PDAC, treatments, symptoms, side effects, their functioning and well-being. HCPs will be asked to share their experience of treating patients with PDAC and HRQoL issues. Both patients and HCPs will be asked to rate the content of the EORTC QLQ PAN26 for importance and relevance, and comment on issues on the more general cancer HRQoL questionnaire EORTC QLQ-C30. In phase II, any new content that has been proposed from phase I will be written in a style and format that fits with the EORTC QLG assessment system. This new content will then be presented in form of a list that will be reviewed by the project team and a patient panel, who decide in agreement what content will be included and how it they will be put together to form an updated questionnaire.
Patient participants inclusion criteria a.Adults aged > = 18 years b.Histologically proven as adenocarcinoma of the pancreas (head, body, tail) with disease stages I-IV. c.Patients receiving treatment (either currently or within the last 12 months) including a systemic treatment (chemotherapy, radiotherapy or chemoradiotherapy), biological and immunotherapy), surgical resection, and radiotherapy or receiving supportive or palliative care. d.Patients who are willing and able to give fully informed consent to participate. e.Patients who are currently enrolled in a clinical trial of a therapeutic agent (phase I-II) whose enrolment in this study is permitted under the trial eligibility criteria AND where any concurrent quality of life assessment (e.g., as part of the trial endpoint) will not affect the results of the current study. For example, inclusion would include a trial where the EORTC QLQ-C30 and QLQ-PAN26 are being formally used for the assessment of quality of life. Health Care Professional inclusion criteria a.Adults aged > = 18 years b.Clinician, nurse, or other HCP (e.g., advanced practitioner) with specific senior expertise and experience (> 2 years) in the treatment and care of patients with PDAC (e.g., oncology, surgery, radiotherapy, specialist nurse, palliative care). c.Willingness to undertake an interview or written questionnaire in English.
Patient participants exclusion criteria a.Patients under 18 years of age. b.Patients with a concurrent malignancy. c.Patients enrolled in other quality of life studies which will affect the results of the current study. Health Care Professional exclusion criteria a.HCPs under 18 years of age. b.HCPs with limited experience (< 2 years).
Cancer of the stomach and oesophagus (gullet) is among the world's top five cancers. Survival rates are very poor as the disease presents late and early symptoms are non-specific. We have developed a non-invasive test for cancers of the stomach and oesophagus based on the detection of small molecules in exhaled breath that we believe are produced by the cancer as well as gut bacteria that are associated with the cancer. Our proposed innovation is to improve the accuracy of this test by investigating whether the ingredients of simple foods can increase the production of these small molecules. It is expected that cancer and bacteria cells will break down these ingredients to produce larger amounts of the small molecules we have previously measured in the breath, therefore making it easier to detect the cancer. The study will be a prospective multi-centre study, recruiting patients to augment the production of organic compounds in the breath by the consumption of a stimulant drink. Serial breath tests will be performed following this and the collected breath samples will be analysed for organic compounds (associated with cancer and the gut microbiome). In addition to this we aim to establish a comprehensive bioresource of matched samples from patients with oesophageal and gastric cancer as well as controls. Biosamples including breath, urine, saliva, blood, tissue and gastric contents will be collected and analysed to further investigate the metabolic pathways involved in cancer development and organic compound production.
1.Male and females aged 18-90 years 2. Patients with biopsy proven oesophageal or gastric adenocarcinoma who have not yet undergone treatment with chemoradiotherapy or surgery 3. Control subjects with symptoms of upper gastrointestinal disease and either a normal upper gastrointestinal tract or benign upper gastrointestinal disease (e.g. gastritis or Barrett’s) as determined at the time of oesophago-gastro-duodenoscopy (± histopathology).
1. Oesophageal squamous cell carcinoma 2. Antibiotic therapy within the last 4 weeks 3. Previous oesophageal and gastric resection 4. Allergy to any of the constituents of the nutrient drink 5. Antibiotic allergy 6. Unable or unwilling to provide informed written consent 7. Pregnant women
Currently, the medical team collects information on patients’ symptoms before and after cancer treatment in response to direct questioning in outpatient clinics. It’s recognised that patient-reported symptoms often differ from doctor-documented symptoms. Over time, this leads to inaccuracies in doctors’ descriptions of the effects of cancer or its treatment to patients. Patients told us accurate description of expected symptoms is important when they are choosing which treatment to have. This study will use an electronic platform to allow colorectal cancer patients to document their symptoms. Patients will answer questions at study entry and at set intervals during treatment and follow-up. The questions are related to health and well-being. The questionnaires are patient reported outcome measures (PROMs) which have been used in paper format in trials with many patients internationally. The information the patients give us will help doctors describe treatment effects more accurately to future patients and to identify patients who may need extra support during or after their treatment. Electronic data collection allows patterns to be identified that may not be seen by doctors until a later stage. The symptoms identified in this study will be used to develop treatments that may benefit future patients. The electronic platform will be used identify the need for intervention then to deliver the recommended treatments to patients automatically when they are identified. For example, if questionnaire responses show a patient has an unplanned loss of 3% of their body weight an information sheet on increasing calorie intake and eating well with a small appetite would be emailed to them and a dietician alerted so a follow up call could be made two weeks later.
- Patients diagnosed with colorectal adenocarcinoma with no evidence of distant metastases - Patients due to undergo surgery or radiotherapy as a definitive treatment - > 18 years of age - The ability to complete an internet based English written questionnaire from their home or on a portable electronic device. - Patients to have read the patient information sheet and have electronically signed the informed consent
- Patient choice - < 18 years of age - History of other cancer within 5 years, excluding non-melanoma skin cancer - Evidence of metastatic disease - patients not undergoing surgery or radiotherapy as a definitive treatment - The inability to complete an internet based English written questionnaire from their home or on a portable electronic device. - Patient with history of poor compliance or current or past psychiatric conditions that would interfere with compliance to the study protocol or cause further psychological distress.
The study is designed to assess the safety and effectiveness of a new molecule,DTP3,in the treatment of patients with relapsed/refractory Multiple Myeloma (MM) and Diffuse Large B Cell Lymphoma (DLBCL). Multiple Myeloma is a cancer of plasma cells,which has a current median survival of approximately 5 years. There is no cure for MM and the vast majority of patients eventually relapse or become resistant to therapy. The prognosis for patients with relapsed MM which is no longer responsive to standard treatment remains poor. DLBCL is a cancer of the B cells. Whilst the majority of patients with DLBCL can effectively be cured with immuno-chemotherapy treatment,over a third will either be refractory to therapy or relapse after an initial response. The prognosis in this population remains poor. In both MM and DLBCL,the NF-κB signalling pathway has been shown to be involved in cancer cell survival. NF-κB is involved in many normal cellular functions,which is why targeting this pathway has proved to be difficult and results in unintended toxicity. DTP3 has been shown in laboratory studies to target the NF-κB to cause cancer cell death,while not being toxic to normal cells. A previous proof of concept study in 3 patients with MM showed DTP3 has no serious adverse effects. In this study,patients will be treated with DTP3 three times per week (4 weeks is one cycle) until disease progression or unacceptable toxicity. The study has a dose escalation and dose expansion stage. Up to 24 patients with MM and DLBCL will be enrolled into the dose escalation phase. The escalation stage will determine the maximum tolerated dose (MTD). The MTD will be used in the expansion stage which will recruit 24 MM and 24 DLBCL patients each. The study is expected to last approximately 40 months and is being funded by the Medical Research Council
Disease specific inclusion criteria [MM] 1. Documented diagnosis of multiple myeloma (IMWG 2014 criteria) 2. Any R-ISS stage 3. Measurable disease as determined by at least one of: • Serum M-protein ≥ 500 mg/dL • Urine M-protein ≥ 200 mg/24 hour • Involved serum free light chain (sFLC) level ≥10 mg/dL,provided that serum sFLC ratio is abnormal 4. Has previously been treated with an ImiD,a proteasome inhibitor and an anti-CD38 antibody 5. Previous treatment with at least 2 prior regimens 6. Relapsed (after most recent regimen) or refractory disease [refractory defined as either best response of progression on previous regimen or progression within 6 months of achieving PR (or better) on previous regimen] 7. Requires active therapeutic intervention (in the judgement of the investigator) 8. Not currently a candidate for stem cell transplantation or CAR T-cell therapy Disease specific inclusion criteria [DLBCL] 9. Documented diagnosis of DLBCL [WHO 2016 criteria] • Diffuse large B-cell lymphoma – de novo or transformed (from follicular lymphoma only) • High-grade B-cell lymphoma (MYC with BCL2 and/or BCL6); High-grade B-cell lymphoma (NOS) • Primary mediastinal B-cell lymphoma 10. Non-GCB by local IHC [Dose Expansion Only] 11. Measurable disease as determined by: • CT (or MRI) documentation of 2 or more clearly demarcated lesions/nodes with a long axis > 1.5 cm and short axis > 1.0 cm or 1 clearly demarcated lesion/node with a long axis > 2.0 cm and short axis ≥ 1.0 cm AND baseline FDG-PET scans must demonstrate positive lesion compatibility with CT (or MRI) defined anatomical tumour sites. 12. No available standard of care therapeutic regimens in the opinion of the investigator 13. Relapsed (after most recent regimen) or refractory disease [refractory defined as either best response of progression on previous regimen or progression within 6 months of achieving PR (or better) on previous regimen] 14. Requires active therapeutic intervention (in the judgement of the investigator) 15. Not currently a candidate for stem cell transplantation or CAR T-cell therapy General inclusion criteria: 16. Adequate hematologic function: • ANC ≥ 1 x 109/L (no restriction on prior growth factor support) • Platelet count ≥50 x 109/L (no platelet transfusions permitted in 7 last days prior to assessment). Platelet counts of < 50 x 109/L may be considered,on a case by case basis,for patients with significant malignant bone marrow involvement,after discussion with the medical monitor • Hb ≥8 gm/dL (no RBC transfusions permitted in 7 last days prior to assessment) • aPTT and PT within institutional normal range (unless patient is on full-dose warfarin,in which case INR within normal institutional therapeutic range is acceptable) 17. No evidence of bleeding diathesis or coagulopathy 18. Adequate laboratory biochemical function: • Serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 30 mL/min (Cockcroft-Gault calculation) • Bilirubin level < 1.5 X ULN. • AST and ALT < 2.5 X ULN 19. ECOG performance status 0-2 20. Age > 16 years 21. Written informed consent prior to admission into the study
1. Primary or secondary CNS lymphoma 2. T-cell rich B-cell lymphoma 3. Plasma cell leukaemia 4. POEMS syndrome (polyneuropathy,organomegaly,endocrinopathy,monoclonal protein,and skin changes) 5. Primary amyloidosis 6. Clinically significant (in the opinion of the investigator) cardiovascular disease,such as: • History of myocardial infarction,acute coronary syndromes (including unstable angina),coronary angioplasty/stenting/bypass grafting within the past 6 months prior to the date of consent • Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system • Severe cardiac arrhythmia requiring medication or severe conduction abnormalities • Poorly controlled hypertension (resting diastolic blood pressure > 100 mmHg) • Clinically significant valvular disease,cardiomegaly,ventricular hypertrophy,or cardiomyopathy,QTc prolongation [defined as a QTc interval > 450 msec (males) or > 470 msec (females)] or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate < 50 beats/min) 7. Clinically significant (in the opinion of the investigator) cerebrovascular disorders or vascular dementia 8. Clinically significant (in the opinion of the investigator) intercurrent medical or psychiatric illness,including serious active infection 9. Significant neuropathy (Grade 3,Grade 4,or Grade 2 with pain) 10. Concurrent treatment with other experimental drugs 11. A daily requirement for prednisone at a dose of > 10 mg/day (or steroid equivalent) at time of starting the first dose of study drug. Higher doses are permitted for primary disease symptomatic control during the screening period,after discussion with the medical monitor,but this must have been tapered to a dose of ≤10mg/day by the time treatment with DTP3 starts 12. Sem cell transplant (autologous/allogeneic) or CAR T-cell regimen within 12 weeks of the date of consent 13. Participation in another clinical trial with any investigational drug within 28 days prior to the date of consent 14. Prior (non-experimental) MM or DLBCL therapy within 28 days of the date of consent. Concomitant bisphosphonate therapy is permitted 15. Prior radiotherapy within 28 days of the date of consent. Localised palliative radiation therapy to a single site for symptomatic control is acceptable within this period 16. Anticipated need for concurrent radiotherapy during the study 17. Past or current history of other neoplasms,except for • Curatively treated non-melanoma skin cancer • Adequately treated in situ carcinoma of the cervix • Prostate adenocarcinoma with documented PSA value of < 0.1 ng/mL within six weeks of the date of consent • Other cancer curatively treated and with no evidence of disease for at least 3 years before the date of consent. 18. Known HIV infection 19. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody,hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result 20. Ability to become pregnant (or already pregnant or lactating). However,those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception: i) oral,injected or implanted hormonal contraception and condom,ii) have an intra-uterine device and condom,iii) vasectomised partner or iv) sexual abstinence during the trial and for 6 months after the last dose of DTP3 are considered eligible. Where age appropriate,female patients must be given advice on potential germ cell donation and cryopreservation 21. Male patients with partners of child-bearing potential [unless they agree to take measures not to father children by using one form of highly effective contraception (condom plus spermicide) during the trial and for 90 days after the last date of DTP3]. Where age appropriate,male patients must be given advice on potential germ cell donation and cryopreservation,Men with pregnant or lactating partners should be advised to use barrier method contraception (for example,condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
It is unknown whether the results of clinical trials evaluating state-of-the-art advanced radiotherapy technologies are generalisable to the target patient population as there may be additional barriers to recruitment. In addition to the usual considerations around study participation, advanced technologies such as proton beam therapy and MR Linac therapy are only available at a small number of specialist sites meaning that travel and a stay away from home may be necessary for treatment at a distant hospital and hence participation in the study. Such factors could influence a patient’s decision to participate in such a trial and could mean that certain demographics are inadvertently excluded from the research. In order to inform future studies using advanced radiotherapy techniques such as proton beam therapy, we need to understand more about the patients that decline participation. Patients who were eligible but decline participation in a UK proton beam therapy study will be asked to complete an optional one off optional questionnaire. Patients who accept participation in a UK proton beam therapy study will be asked to (optionally) consent to sharing of basic demographic data to allow comparison of decliners and acceptors. Up to 100 patients will be recruited.
a) Aged at least 16 years. b) Declined participation in a partner UK clinical trial where at least one of the arms is proton beam therapy.
none
This is a phase II,multicentre,single arm,open label pilot study to assess the safety and efficacy of acalabrutinib in combination with rituximab for previously untreated elderly frail mantle cell lymphoma patients. Patients will receive acalabrutinib and rituximab for up to six cycles. The cycle length is 28 days. Specifically,patients will receive acalabrutinib,orally,at a dose of 100 mg twice daily for 28 days and rituximab 375 mg/m2 intravenously on day 1 (+/-3) of each cycle.* Patients with any degree of response at the Week 12 (end of cycle 3) and Week 24 assessments (end of cycle 6) will continue with acalabrutinib monotherapy at a dose of 100 mg twice daily until disease progression,the development of unacceptable toxicity or any other reason (whichever occurs sooner). * Note: Acalabrutinib may be administered at a dose of 100 mg od po for cycle 1 day 1-7 at the local investigator’s discretion. The dose should be escalated to full dose (100 mg bd) by day 8 cycle 1 if no toxicity is seen. If a patient experiences toxicity during 100 mg od po for cycle 1 day 1-7,the case will be discussed with the Trial Management Group to decide if acalabrutinib should be continued. Rituximab may be administered subcutaneously at a flat dose of 1400 mg from cycle 2 onwards following an intravenous dose of 375 mg/m2 in cycle 1. Consideration to split the first dose of rituximab at cycle 1 in the minority of MCL patients presenting with a white cell count of > 25 x 109/L and splitting 25 mg/m2 on D1 and 350 mg/m2 on D2 of cycle 1. Primary objective: To determine the efficacy of acalabrutinib in combination with rituximab,in terms of disease response (overall response rate),at 6 months Secondary objectives: To determine the effect of acalabrutinib in combination with rituximab on progression free survival (PFS),overall survival (OS) and quality of life (QoL) To determine the best response rate and duration of response To assess the safety and toxicity of acalabrutinib in combination with rituximab Exploratory biological study objectives: Molecular features associated with clinical response To explore non-invasive molecular tumour profiling using cell-free DNA samples collected at screening To track dynamic changes in the circulating tumour DNA profile during therapy using a combination of deep targeted sequencing,shallow whole genome sequencing and epigenetic approaches To correlate the dynamic circulating tumour DNA profile with clinical outcomes
1. Men and women ≥ 60 years of age. 2. Pathologically confirmed MCL,with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 3. Stage II-IV MCL and requiring treatment in the opinion of the treating clinician. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 5. One or more of the following: - Age 80 years or more - Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score 6 or greater - Left ventricular ejection fraction (LVEF) less than or equal to 50% as assessed by echocardiogram - Significant co-morbidities or cardiac risk factors making anthracycline-containing chemotherapy inadvisable - Heart failure clinically determined by the presence of New York Heart Association (NYHA) failure grade II due to a cause other than MCL - Impaired respiratory function with DLCO and/or FVC/FEV1 ratio less than 75% of predicted due to a cause other than MCL - Significant respiratory illness e.g. moderate chronic obstructive pulmonary disease (COPD) bronchiectasis - Other co-morbidities that in the Investigator’s opinion which would preclude the use of standard full dose immuno-chemotherapy (to be discussed on a case-by-case basis with the TMG,via UCL CTC) 6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 7. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP). 8. Willing to comply with the contraceptive requirements of the trial 9. Written informed consent.
1. Any prior therapy (including targeted inhibitors) for MCL (other than prior localised radiotherapy,a 10-day pulse of high dose steroids or continuous prednisolone above 20mg od or equivalent for symptom control). 2. Patients considered by the investigator fit enough to receive standard,full dose cytotoxic immunochemotherapy as treatment for non-transplant eligible MCL e.g.,full dose R-CHOP,VR-CAP,R-Bendamustine,R-FC. 3. Prior malignancy (or any other malignancy requiring active treatment),except for adequately treated basal cell or squamous cell skin cancer,in situ cervical cancer,localised prostate cancer or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 5 years. 4. Clinically significant cardiovascular disease such as uncontrolled arrhythmias,or myocardial infarction within 6 months of screening,or any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification (33),or corrected QT interval (QTc) > 480 msec at screening. 5. Malabsorption syndrome,disease significantly affecting gastrointestinal function,or resection of the stomach or small bowel that is likely to affect absorption,symptomatic inflammatory bowel disease,partial or complete bowel obstruction,or gastric restrictions and bariatric surgery,such as gastric bypass. 6. Known history of infection with HIV or any uncontrolled active systemic infection (e.g.,bacterial,viral or fungal). 7. Known history of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand disease). 9. Uncontrolled AIHA (autoimmune haemolytic anaemia) or ITP (idiopathic thrombocytopenic purpura). 10. Known presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 11. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon) within 7 days prior to the first dose of study drug. 13. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) > 2 x upper limit of normal (ULN). 14. Requires treatment with proton pump inhibitors (e.g. omeprazole,esomeprazole,lansoprazole,rabeprazole,or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study. 15. History of significant cerebrovascular disease/event,including stroke or intracranial haemorrhage,within 6 months before the first dose of study drug. 16. Major surgical procedure within 28 days prior to the first dose of study drug. Note: If a subject had major surgery,they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 17. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB core) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) test. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Those who are hepatitis C antibody or PCR positive will be excluded (those who are hepatitis C antibody positive but PCR negative will not be excluded). Note,if a patient with known HBV or HCV infection who is on current antiviral treatment meets serology criteria for trial eligibility then the case must be discussed with the TMG prior to registering the patient. 18. Absolute neutrophil count < 1.0 x 109/L (or requires growth factor support to maintain absolute neutrophil count > 1.0 x 109/L) and/or platelets < 75 x109/L unless related to bone marrow infiltration or splenomegaly due to underlying MCL (where platelets between 50-75 x109/L are acceptable) 19. Total bilirubin > 1.5 x ULN,unless due to Gilbert's syndrome or of non-hepatic origin. 20. AST and/or ALT > 3 x ULN. 21. Calculated creatinine clearance < 30 mL/min. 22. Active central nervous system (CNS) involvement 23. Breastfeeding or pregnant. 24. Concurrent participation in another therapeutic clinical trial. 25. Live vaccine within 28 days prior to the first study drug dose
DISCUS is an open-label,randomised,international,multicentre phase II trial that aims to evaluate the impact of 3 vs 6 cycles of first-line platinum-based chemotherapy followed by maintenance avelumab in the quality of life of patients with locally advanced or metastatic urothelial carcinoma. Eligible patients will be randomised to receive either 3 cycles of Q3W gemcitabine (1000mg/m2) + carboplatin (AUC 4.5 or 5,as per local practice) / cisplatin (70mg/m2) followed by maintenance avelumab (800mg Q2W) – Arm A,or 6 cycles of Q3W gemcitabine (1000mg/m2) + carboplatin (AUC 4.5 or 5) / cisplatin (70mg/m2) followed by maintenance avelumab (800mg Q2W) – Arm B. Maintenance avelumab treatment will be given up to a maximum of 2 years from the end of chemotherapy in both arms. Following the end of study treatment,patients will attend safety follow up visits at 30 and 90 days post the last dose of IMP. Patients will then enter a follow up phase during which they will be contacted 12 weekly to collect survival and disease status data. Follow up duration will be until the end of avelumab treatment or for 2 years from completion of chemotherapy,whichever is longer. Quality of life will be assessed using patient reported outcomes from the EORTC-QLQ-C30 questionnaire collected at various timepoints throughout the study.
1. Willing and able to provide written informed consent. 2. Ability to comply with the protocol,including but not limited to,the repeated completion of the EORTC QLQ-C30 questionnaires. 3. Age ≥ 18 years. 4. Histologically confirmed,unresectable locally advanced or metastatic urothelial carcinoma (i.e.,cancer of the bladder,renal pelvis,ureter,or urethra). Patients with squamous or sarcomatoid differentiation or mixed cell types are eligible but a component of urothelial cancer is required. 5. Measurable disease by RECIST v1.1. 6. Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. The following criteria are established for the use of carboplatin (patients not fulfilling the following carboplatin criteria should be considered for gemcitabine/ cisplatin): a. GFR < 60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula. Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement. b. ECOG or WHO performance status of 2. c. NCI CTCAE Grade ≥2 audiometric hearing loss. d. NYHA Class III heart failure. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0,1 or 2. 8. Adequate haematologic and organ function as defined below: a. Haemoglobin ≥ 9.0g/dL b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/µL) without growth factor support c. Platelet count ≥ 100 x 109 /L (≥100,000/µL) d. Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology],who will be allowed only in consultation with their physician. e. Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN with the following exception in patients with documented liver metastases: AST and/or ALT ≤5 × ULN f. GFR ≥30mL/min measured by Cockroft-Gault. 9. Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only. Non-childbearing potential is defined as either: a. Postmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR b. Documented irreversible surgical sterilisation by hysterectomy,bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR c. < 50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels within local institution postmenopausal ranges. 10. Agreement to use adequate contraceptive measures.
1. Prior treatment with a PD-(L)-1 inhibitor for any malignancy,including earlier stage UC. 2. Prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a platinum containing regimen (cisplatin or carboplatin) in the neoadjuvant or adjuvant setting if more than 6 months since last cycle have occurred. 3. Pregnant and lactating female patients. 4. Known history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true: a. CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b. the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to C1D1 (if requiring steroid treatment); c. subject does not have leptomeningeal disease. 5. Prior allogeneic stem cell or solid organ transplantation. 6. Oral or IV steroids for 14 days prior to C1D1. The use of inhaled corticosteroids,physiologic replacement doses of glucocorticoids (i.e.,for adrenal insufficiency),and mineralocorticoids (e.g.,fludrocortisone) is allowed. Patients receiving treatment for CNS metastases at a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to screening are eligible. 7. Administration of a live,attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live,attenuated vaccine will be required during the study. 8. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug,whichever is shorter,prior to enrolment. 9. Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 10. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results,including significant liver disease (such as cirrhosis,uncontrolled major seizure disorder,or superior vena cava syndrome). 11. Malignancies other than urothelial carcinoma of the bladder within 3 years prior to Cycle 1,Day 1,with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix,basal or squamous cell skin cancer,or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive). 12. Significant cardiovascular disease,such as New York Heart Association cardiac disease (Class II or greater),myocardial infarction or cerebral vascular accident/stroke within 6 months prior to enrolment,unstable arrhythmias,or unstable angina. 13. Radiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment. 14. Major surgery (defined as requiring general anaesthesia and > 24-hour inpatient hospitalization) within 4 weeks prior to randomisation. Patients must have recovered adequately from complications from the intervention prior to starting study treatment. 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced pneumonitis,organizing pneumonia (i.e.,bronchiolitis obliterans,cryptogenic organizing pneumonia),or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted). 16. Active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. 17. Positive HIV test. 18. Active tuberculosis. 19. History of autoimmune disease including but not limited to myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis. 20. History of autoimmune-related hypothyroidism,unless on a stable dose of thyroid replacement hormone. 21. History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies. 22. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab. 23. Active infection requiring systemic therapy. 24. Persisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however,alopecia,sensory neuropathy Grade ≤ 2,or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable. 25. Any condition that,in the opinion of the investigator,would interfere with evaluation of study treatment or interpretation of patient safety or study results 26. Participants with previous or known history of allergic reaction to cisplatin, gemcitabine, carboplatin or other platinum containing compounds, or any component of the chemotherapy formulations 27. Patients with bleeding tumours 28. Any other contraindication for gemcitabine/ cisplatin or gemcitabine/carboplatin treatment as per SmPC.
Primary central nervous system lymphoma (PCNSL) is a rare type of brain tumour. It is an aggressive type of non-Hodgkin lymphoma that is found only in the brain or spinal cord. PCNSL is often treated with high-doses of chemotherapy. The first treatment doesn’t work for some patients (called ‘refractory’), and the lymphoma can come back (called ‘relapse’). Refractory or relapsed (RR) PCNSL is much more difficult to treat. There is currently no standard treatment for RR-PCNSL and further chemotherapy treatment is often unsuccessful. Radiation treatment to the brain can sometimes be used but can cause significant long-term side-effects. Clinical trials are now focused on testing new drugs that are better at targeting the tumour, and are likely to have fewer side-effects. The treatment being tested in the PRiZM+ trial is a drug called zanubrutinib. Zanubrutinib is a new type of drug (a Bruton’s tyrosine kinase inhibitor), which works by targeting lymphoma cells. Previous studies have shown that similar drugs can cause RR-PCNSL to shrink or disappear. It is thought that zanubrutinib could be a more effective treatment, which can be given safely without too many side effects. The aim of the study is to find out how effective and safe zanubrutinib is for patients with RR-PCNSL. We will be looking at the effects zanubrutinib has against lymphoma, how long these effects last, and what the side-effects of the drug are.
•> = 16 years of age •Histologically confirmed CD20+ DLBCL confined to the CNS •Relapsed or refractory PCNSL (defined as disease progression following CR/CRu/PR, or failure to achieve PR after one or more lines of therapy; one therapy line must have included at least 1 cycle of high-dose methotrexate (> = 1g/m2)) •Measurable disease on contrast-enhanced MRI of brain (and/or spinal cord) •ECOG performance status of 0 to 2, or 3 if attributed to lymphoma •Ability to swallow capsules •Adequate renal and liver function defined as: o Creatinine clearance > = 30 mL/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection) o Serum total bilirubin < 3.0 x ULN (unless due to Gilbert’s syndrome) o Up to and including moderate impairment (Child-Pugh class B) • Adequate bone marrow function, defined as unsupported platelets > 50 x109/L, neutrophils > 1 x109/L, haemoglobin > 80 g/L • Patient willing and able to comply with scheduled visits, treatment plan, investigations and other study procedures • Written informed consent for the trial
• Current evidence or prior history of systemic lymphoma • Exclusive intraocular involvement • Active infection requiring intravenous antimicrobials • Chemotherapy for lymphoma within 2 weeks of first dose of zanubrutinib • Whole-brain radiotherapy within 4 weeks of first dose of zanubrutinib • Contra-indication to lumbar puncture • Prior exposure to BTK inhibitor • Known bleeding disorder e.g haemophilia or severe Von-Willebrand Disease • Current use of warfarin, or dual anti-platelet therapy o Therapeutic anticoagulation with direct oral anticoagulants or low molecular weight heparin is permitted • Evidence of active HIV, HBV or HCV infection, except o HIV positive patients established on anti-retroviral treatment, with undetectable HIV RNA, after discussion with the patient’s HIV physician o HBV core antibody positive patients who are (i) surface antigen negative and (ii) HBV DNA PCR negative, who take prophylaxis as per institutional guidelines • Patients who are pregnant or breastfeeding (women of childbearing potential must have a negative urine or serum pregnancy test prior to trial entry) • Patients and patients with partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use highly effective contraception (see Section 9.6) during and for 12 months after cessation of therapy • Clinically significant cardiac or respiratory dysfunction that, in the opinion of the investigator, would jeopardise the safety of the patient in the trial • Active malignancy treated in the last 2 years, except o Non-melanoma skin cancer o Carcinoma in situ of the cervix or breast o Incidental finding of prostate cancer (T1a or T1b)
The MyMelanoma project is a large cohort study to which we will seek recruitment of at least 20,000 people treated by the NHS for melanoma of the skin and other body sites other than the eye. A study of great size is required to generate enough data to answer the current most important questions around the causes of melanoma, the factors governing outcomes for affected people, the effect of diagnosis and treatment on quality of life, the risk and nature of drug side effects in the short and long term. It is a key aim also to develop tests to better predict recurrence and response to treatment. Using the model of the UK Biobank this will use online data entry and linked NHS data, in order to build a resource of sufficient size and quality to address the very complex questions that remain for the management of melanoma. It will be an accessible data resource for all bona fide researchers on application to a data release committee. Melanoma survivors have been instrumental in the conceptionalization and design of the MyMelanoma project and will remain so.
Any patient treated for melanoma arising on the skin, mucosal membranes or around or under the nail, treated in the NHS 16 years or older. Melanoma is extremely rare before puberty. MyMelanoma does not feel that children would fully understand the nature of the consent they are giving.
Melanoma of the eye Unable to give informed consent No access to e-mail Unwillingness to allow linkage to NHS data as the study would not be possible without that linkage
For patients with advanced colorectal (bowel) cancer (aCRC) who have a gene (RAS) which is normal i.e. RAS wild-type (RAS-wt), standard first-line treatment is chemotherapy, sometimes given in combination with a type of drug called an anti-EGFR agent (cetuximab or panitumumab). However, not all RAS-wt patients benefit from anti-EGFR therapy. Anti-EGFR therapy has severe side-effects and is expensive. It should not be used for patients who will not benefit, or may even be harmed. Better selection of patients is therefore needed. We know that patients with tumours that start in the right side of the body (right-sided) in general do not respond very well to anti-EGFR treatment. In the UK, there is no agreed standard of care for the treatment of right-sided patients, some doctors routinely use an anti-EGFR drug, but some do not. However, we also know that patients who have high levels of the proteins epiregulin (EREG) and/or amphiregulin (AREG) respond well to anti-EGFR treatment. EGFR therapy decisions based purely on RAS status and tumour location, risk harming some patients through over-treatment, or risk withholding potentially beneficial therapy from others. By measuring levels of EREG and AREG, we may be able to identify patients with right-sided tumours who will benefit from anti-EGFR treatment, and also identify patients who will not benefit and may be harmed if given anti-EGFR therapy. However, before we can introduce this test into routine practice, we need to know that EREG and AREG levels can be measured and the results delivered to doctors quickly enough to inform treatment decisions. We also need to confirm that EGFR therapy is beneficial for patients with EREG/AREG-high, right-sided cancer. This trial aims to answer these questions.
Inclusion criteria for registration: • Age > = 18 years • Biopsy-confirmed adenocarcinoma of the colon with a right primary tumour location • aCRC defined as either M1 or locally inoperable disease. • Tumour RAS status either wild-type ( by local testing) or unknown • Tumour measurable by RECIST v1.1 criteria • Pre-registration laboratory tests: o Neutrophils > = 1.5 x10^9/l and platelet count > = 100 x10^9/l o Serum bilirubin < = 1.25 x upper limit of normal (ULN), alkaline phosphatase < = 5x ULN, and serum transaminase (either AST or ALT) < = 2.5 x ULN o Estimated creatinine clearance > = 50ml/min. • Medically fit for the trial treatments • Sufficient tumour material for EREG/AREG analysis • Written informed consent for registration Inclusion criteria for randomisation: • Registered in ARIEL • ARIEL central or local testing confirms tumour RAS-wt status • ARIEL central testing confirms tumour EREG/AREG high • Patients have had CT scan within the timeframes stipulated in protocol • WHO performance status (PS) 0, 1 or 2 • For women of childbearing potential, negative pregnancy test as per standard practice and adequate contraceptive precautions. • Effective contraception for male patients if the risk of conception exists. • Fit for combination chemotherapy plus cetuximab/panitumumab • Written informed consent for randomisation
Exclusion criteria for registration: • Tumour RAS-mutation present • Prior chemotherapy for mCRC (may have received neoadjuvant or adjuvant chemotherapy provided disease did not progress on treatment, and > 6 months since last dose) • Prior anti-EGFR agent therapy Exclusion criteria for randomisation: • Patient has received more than one cycle of chemotherapy since registration • Women who are breastfeeding • Patients with history of hypersensitivity to irinotecan, oxaliplatin, 5-fluorouracil or any of their excipients • Patients in receipt of live vaccine within four weeks prior to randomisation. • Patients with a history interstitial pneumonitis/idiopathic lung disease (ILD) • Patients with a history of keratitis, ulcerative keratitis or severe dry eye • Patients with a history of severe skin reaction which in the clinicians opinion could be exacerbated by EGFR Mab (cf Steven’s Johnson Syndrome)
The rate of well-differentiated thyroid cancer (DTC) is increasing faster than any other tumour. Currently, standard treatment for low-risk DTC is surgical removal of the whole thyroid gland called total thyroidectomy (TT), followed by radioiodine treatment. Recently, surgeons have started performing hemithyroidectomy (HT) (removal of the cancerous half of the thyroid) as international guidelines changed and studies suggested patients may benefit from less extensive surgery, whilst maintaining excellent cure rates. HT patients may not require life-long hormone replacement therapy, calcium and vitamin D supplements, and radioiodine treatment. However, results from these studies are biased and conflicting. There is uncertainty surrounding the most appropriate surgery causing variations in practice between different teams and hospitals. HoT is the first trial to directly compare TT versus HT in terms of the rate of cancer returning, impact on quality of life, surgery-related side-effects, need for thyroid hormone replacement therapy after surgery, health resources use and cost-effectiveness to the NHS. Patients who had a HT during diagnosis will be randomly assigned to receive regular surveillance only or have a second operation to remove the rest of their thyroid. Patients diagnosed with DTC but not undergone surgery, will be randomly assigned to have a HT or a single-stage TT. All patients will be followed-up regularly. HoT is funded by the National Institute for Health Research and plans to recruit ~456 patients over 4 years across UK hospitals. Patients will be monitored for up to 6½ years after surgery (last patient for ~2 ½ years). If we show HT is as effective as TT, HT would become nationally and internationally recommended for low-risk DTC patients. If HT proves less effective than TT, guidelines will make clear that HT should only be performed in selected cases, and TT preferred in most cases. This will improve treatment decision making.
Group 1 (Hemithyroidectomy already performed prior to diagnosis) The inclusion criteria represents those patients who are considered to have low-risk thyroid cancer, as defined by the American Thyroid Association 2015 and 8th AJCC TNM staging criteria. • Aged 16 or over Papillary thyroid cancer (PTC): • pT1b-2 (< = 4cm) irrespective of molecular genetic markers • R0 resection (clinically excised but microscopic R1 resected tumours at discretion of the local multidisciplinary team (MDT)) • cN0 or pN0, pNX & pN1a (< = 5 foci, no extranodal spread) • Confined to thyroid or minimal extrathyroidal extension • No higher risk histological variants on morphology (small foci allowed at the discretion of the local MDT) • No angioinvasion • Encapsulated follicular variant of PTC with capsular invasion only • Micro-PTC (< = 1cm) - multifocal - unifocal with pN1a (< = 5 foci; no extranodal spread) Follicular thyroid cancer and oncocytic/Hurthle cell carcinoma: • pT1b-2 (< = 4cm) irrespective of molecular genetic markers - Minimally invasive, with capsular invasion +/- minimal (< = 4 foci) vascular invasion (the latter is now called encapsulated angioinvasive and is at the discretion of the MDT) • Confined to thyroid or minimal extrathyroidal extension Group 2 (Differentiated Thyroid Cancer on cytology/core biopsy, who has not had prior thyroid surgery yet) • Aged 16 or over • ‘low risk’ differentiated thyroid cancer confirmed by cytology or core biopsy. • cT1b-2 irrespective of molecular genetic markers • cN0 • Contralateral lobe without suspicious nodule(s) (U2, or U3/U4 with Thy2 on FNAC) Eligibility criteria for nested sub-study on Navio’s web-based app (software): Patients are eligible for the nested sub-study on Navio's web-based app (software) if they: • have a SMS enabled mobile phone or handheld tablet with web access • are able to use the web-based app to complete the trial questionnaires without assistance
Group 1 (Hemithyroidectomy already performed prior to diagnosis) • tumour > 4cm • unifocal pT1a (< = 1cm) papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) (unless pN1a as listed in inclusion criteria) • non-invasive encapsulated follicular variant of PTC • Anaplastic, poorly differentiated or medullary thyroid carcinoma • R2 resection • gross extrathyroidal extension • pT4 or macroscopic tumour invasion of loco-regional tissues or structures • pN1a with > 5 foci or extranodal spread • pN1b • M1 • Aggressive PTC with any of the following features: - Widely invasive - Poorly differentiated - Anaplastic - predominance of Tall cell, Columnar cell, Hobnail, Diffuse sclerosing and other higher risk variants • FTC and oncocytic/Hürthle cell cancer with any of the following features: - Minimally invasive with extensive vascular invasion (now called encapsulated angioinvasive) (> 4 foci) - Widely invasive - Poorly differentiated - Anaplastic Group 2 (Differentiated thyroid cancer on cytology or after core biopsy, who has not had prior thyroid surgery yet) • M1
The FOxTROT platform is a rolling programme of molecularly stratified, randomised phase II/III, multi-centre, international, open-label studies patients with locally advanced but operable colon cancer (CC). FOxTROT 2 is a phase III,multi-centre,open-label,international,randomised-controlled trial of modified dose of OxFp compared to STS,in patients unsuitable for FOLFOXIRI with a left-CC or with a right-CC tumour confirmed to be pMMR or MSS, and not felt to be at risk of bowel obstruction. FOxTROT 3 is a phase III, multi-centre, open-label, international, randomised-controlled trial of 6 weeks of NAC with OxFp then surgery compared to 6 weeks of NAC with mFOLFOXIRI then surgery, in younger and non-frail patients with a left-CC or with a right-CC tumour confirmed to be pMMR or MSS, and not felt to be at risk of bowel obstruction. Patients diagnosed with locally advanced but operable CC will be identified at a CC multidisciplinary team meeting following radiological assessment of the primary tumour and histological assessment of endoscopic biopsy. Potential participants will then be reviewed by a clinician and asked for consent to send their tumour block for biomarker testing (if MMR/MSI status is unknown) and translational research. The clinician will assess whether they are suitable to be treated on a neoadjuvant pathway and which comparison is most appropriate and provide the patient with a PIS. If MMR/MSI status is known at first assessment,or if patients have left primary tumour location (PTL),patients can proceed directly to assessment of suitability for each comparison and consent/ randomisation. Although MMR/MSI status is not a requirement for randomisation for patients with a left-PTL,testing is strongly recommended. If MMR/MSI status is being tested centrally,potential participants will be assessed for eligibility and suitability for each comparison once the results are available,and proceed to consent/randomisation.
Patients will have met the following FOxTROT Registration inclusion criteria: • Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high for radiotherapy); high grade dysplasia is acceptable with unequivocal radiological evidence of invasive cancer* • Radiological stage T3-4, N0-2, M0 • Patient being treated with curative intent • Tumour tissue is available for molecular testing (local or central) • Age ≥18 at the time of registration • Patient able and willing to provide written informed consent for the study * Patients with synchronous tumours are eligible, if the most advanced tumour meets the criteria above (please note molecular testing will be of the most advanced tumour) For FoxTROT 2, patients will also have met the following protocol-specific criteria: • Patients will be unsuitable for mFOLFOXIRI due to oncologist assessed frailty or comorbidity • pMMR/MSS tumour status (for right sided tumours) • CC specialist-assessed fit to receive 6 weeks of NAC with OxFp (either full or modified dose) and surgery. • Adequate full blood count: WBC > 3.0 x10^9/l; Plts > 100 x10^9/l; neutrophils ≥1.5 x10^9/l. Anaemia (Hb < 10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams. • Adequate renal biochemistry: GFR > 50 ml/min as assessed by local standards • Adequate hepatobiliary function: bilirubin < 1.5 ULN (Patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study.) AST/ALT < 2.5 x ULN. • If female and of childbearing potential, must agree to avoid pregnancy during and for 6 months after last dose of study treatment • If male with a partner of childbearing potential, must: - Agree to use adequate, medically approved, contraceptive precautions during and for 6 months after the last dose of study treatment • Signed the Informed Consent Document for randomisation For FoxTROT 3, patients will also have met the following protocol-specific criteria: • Patients need to be fit and suitable for mFOLFOXIRI. There is no fixed age cut-off, but most patients will be under 70 years. • pMMR/MSS tumour status (for right sided tumours) • Adequate full blood count: WBC > 3.0 x10^9/l; Neutrophils ≥1.5 x10^9/l Plts > 100 x10^9/l. Anaemia (Hb < 100 g/l) is not an exclusion but should be corrected by transfusion prior to surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams. • Adequate renal biochemistry: GFR > 50 ml/min as assessed by local standards • Adequate hepatobiliary function: bilirubin < 1.5 x ULN (Patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study.) AST/ALT < 2.5 x ULN. • If female and of childbearing potential, must agree to avoid pregnancy during and for 6 months after the last dose of study treatment • If male with a partner of childbearing potential, must: - Agree to use adequate, medically approved, contraceptive precautions during and for 6 months after the last dose of study treatment • Signed the Informed Consent Document for randomisation
Patients will not have any of the following (as per FOxTROT Registration exclusion criteria): • Any patient for whom radiotherapy is advised by the MDT • Cases with a high index of suspicion of distant metastases or peritoneal nodules (cM1). However, cases with indeterminate abnormalities should be managed and investigated as per standard local MDT procedures and can be considered for trial entry if the MDT opinion is that these are considered most likely to be benign. • Colonic obstruction that has not been defunctioned* • Women who are pregnant or breastfeeding * Patients with symptomatic bowel obstruction cannot be included in the Foxtrot trial platform, unless the obstruction has been relieved. This would usually be by defunctioning. Patients may also be stented, but there is more limited safety data on this and these cases should be individually discussed with the TMG. For FOxTROT 2, additionally patients will not have met any of the following protocol-specific exclusion criteria: • Serious medical comorbidity,as assessed by leading clinician (such as uncontrolled angina) • Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer,carcinoma in situ and early stage disease with a recurrence risk < 10% • Known dMMR/ MSI-H tumour status • Known hypersensitivity to oxaliplatin or fluoropyrimidine therapy • Have a peripheral sensitive neuropathy with functional impairment • Known complete DPYD deficiency (homozygosity) • Recent or concomitant treatment with brivudine, sorivudine or their chemically related analogues. For FOxTROT 3, additionally patients will not have met any of the following protocol-specific exclusion criteria: • Serious medical comorbidity, as assessed by leading clinician (such as uncontrolled angina) • Any other malignant disease within the preceding 5 years except for non-melanomatous skin cancer, carcinoma in situ and early-stage disease with a recurrence risk < 10% • Known dMMR/ MSI-H tumour status • Known hypersensitivity to oxaliplatin, irinotecan or fluoropyrimidine therapy • Have a peripheral sensitive neuropathy with functional impairment • Have a severe chronic inflammatory bowel condition. • Known complete DPYD deficiency (homozygosity) • Recent or concomitant treatment with brivudine, sorivudine (or their chemically related analogues), St John’s Wort.
Immune checkpoint inhibitors are a type of drug used to treat patients with advanced cancers. They help the body’s immune system find cancer cells. The immune system is important in fighting infections and cancer. Immune checkpoint inhibitors can stop cancers growing for many months or years. Immune checkpoint inhibitors are given to patients through an injection into a vein every 3-6 weeks in a hospital or clinic. Blood tests are needed before each injection. This means that patients spend a lot of time (and money) on hospital visits. The drugs are expensive costing many thousands of pounds per month and use a lot of hospital resource. It is likely that immune checkpoint inhibitors work for a longer period of time than originally thought. This means it may be possible to give the drugs less often and still have the same effect on the cancer. The unwanted side effects of these drugs are unlike those of traditional chemotherapy drugs as they may cause auto-immune problems, meaning that the patients’ immune system attacks their normal tissues. The relationship between dose of drug and side-effect is not clear but it is possible that giving the drugs less often might limit the side-effects experienced by patients. REFINE is a clinical trial that tests whether patients can receive immunotherapy drugs less often whilst getting the same benefit in terms of treating their cancer with fewer side effects and improved quality of life. Giving these drugs less often may also allow the NHS to deliver equally effective treatment at a lower cost. The REFINE trial is an initial test of this concept and aims to understand the benefits to patients and to the health service from this approach, and may lead to a larger trial in due course. REFINE will start by testing this in groups of patients with advanced kidney cancer and melanoma but will then test this approach in patients with a range of other tumour types.
1. WHO Performance Status 0 or 1. 2. Patients with locally advanced or metastatic cancer whose clinician has determined they are candidates for treatment with standard of care immune checkpoint inhibitor. 3. Patients aged > = 18years. 4. Adequate normal organ and marrow function. a. Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria). b. Absolute neutrophil count (ANC) > = 1.5 x 109/L (> = 1500 per mm3). c. Platelet count > = 100 x 109/L (> = 100,000 per mm3). d. Bilirubin < = 1.5 x ULN (This will not apply to subjects with confirmed Gilbert’s syndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician). e. AST/ALT < = 3 x ULN. f. Calculated Creatinine Clearance level > 40mL/min by Cockcroft Gault formula (using actual body weight). 5. Resting 12-lead ECG on which QTcF must be < 450 ms. This will usually have been performed prior to commencement of the initial 12 weeks ICI. 6. Both men and women enrolled in this trial must be in agreement with trial policy on contraception during the treatment phase of the study. Egg donation, sperm donation and breastfeeding must be avoided. 7. Evidence of post-menopausal status or negative serum HCG pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: a. Women < 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy). b. Women > = 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). RENAL COHORT SPECIFIC INCLUSION CRITERIA: 1. Patients with un-resectable locally advanced or metastatic renal cell carcinoma (including clear cell and papillary histologies) 2. Intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria 3. Patient has received induction ipilumumab 1mg/kg (all four doses) and nivolumab 3mg/kg as first line treatment 4. Due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease on cross sectional imaging on completion of initial 12 weeks treatment with ICI) MELANOMA COHORT SPECIFIC INCLUSION CRITERIA 1. Patients with locally advanced or metastatic melanoma 2. Patients have received single agent pembrolizumab first line for 3 months, with no evidence of progression (i.e. response or stable disease), and due to commence maintenance Pembrolizumab every 6 weeks; OR induction ipilumumab 1mg/kg and nivolumab 3mg/kg as first line treatment, and due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease) on cross sectional imaging 12 weeks post initiation of ICI.
1. Patients who have received immune checkpoint inhibitors in a prior line of treatment 2. Patients whose planned treatment is the combination of anti-PD-1 and tyrosine kinase inhibitor eg, pembrolizumab-axitinib or the combination of traditional cytotoxic chemotherapy and anti-PD-1. 3. Patients with unresolved/untreated immune-related adverse events resulting from the first 3 months of treatment with standard of care immune checkpoint inhibitor 4. History of another previous malignancy, except for a) Malignancy treated with curative intent and with no known active disease > = 5 years before the first dose of IP and of low potential risk for recurrence. b) Adequately treated non-melanoma skin cancer without evidence of disease. c) Adequately treated carcinoma in situ without evidence of disease. d) Superficial bladder cancer 5. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study (see co-enrolment section for further details). 6. Current or prior use of immunosuppressive medication within 14 days before starting immune checkpoint inhibitor, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 7. Active infection including a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) b. Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. c. Hepatitis C. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. d. Human immunodeficiency virus (positive HIV 1/2 antibodies). 8. Receipt of live attenuated vaccine within 30 days prior to the start of treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving immune checkpoint inhibitor and up to 30 days after the last dose of immune checkpoint inhibitor. 9. Known allergy or hypersensitivity to immune checkpoint inhibitor 10. Pregnant or breastfeeding patients. 11. Uncontrolled adrenal insufficiency 12. Any serious or uncontrolled medical or psychiatric disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, interfere with participation and/or compliance in the trial, or interfere with the interpretation of study results. 13. Participants who have undergone any prior systemic anti-cancer treatment (previous participation in adjuvant studies allowed, providing the patient was on the observation/ placebo arm – this may require un-blinding of the patient) 14. Untreated brain metastases or brain metastases treated only with whole brain radiotherapy. (Patients are eligible if previous brain metastases treated with complete surgical resection, Stereotactic Brain Radiation Therapy (SBRT), or gamma knife with no subsequent evidence of progression and asymptomatic).
Treatments for breast cancer have been increasingly successful. However for patients who have recurrence of their cancer prognosis is still poor. This study will look at patients with treatable cancer that was estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-). Patients who have completed any surgery, chemotherapy and radiotherapy and are taking long-term endocrine (hormone) therapy will be approached. Participants will undergo up to 3 years of circulating tumour DNA (ctDNA) testing. It has been demonstrated in previous research that this can detect presence of cancerous cells that would not be detected by other means. The first objective of the study is to see how many participants are found to be ctDNA positive. Participants who test positive for ctDNA will be asked to participate in the therapeutic phase of the study. If they give consent they will be randomised to either palbociclib and fulvestrant or standard endocrine therapy. Those randomised to endocrine therapy will be given an option for their treatment to be changed from their previous therapy to an alternative endocrine therapy (see protocol). Palbociclib and fulvestrant is a standard treatment of patients with recurrent cancer, and this study will aim to investigate the introduction of this treatment early at the point of ctDNA detection. The objective is to demonstrate that early detection of recurrence through ctDNA and initiation of effective therapies can improve prognosis.
ELIGIBILTY CRITERIA FOR PATIENT REGISTRATION FOR CTDNA SURVEILLANCE 1. Written informed consent to participate in the trial and to donation of tissue and blood samples 2. Male or female patients aged 18 years or older 3. ECOG performance status 0, 1 or 2 (see https://ecog-acrin.org/resources/ecog-performance-status) 4. Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in > = 10% of cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ hybridization) breast cancer as determined by local laboratory 5. Patients with high risk early stage breast cancer according to at least one of the following criteria: Primary surgery (no other treatment prior to surgery) A. Four or more involved axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or B. Tumour size > 5 cm, regardless of lymph node status, or C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour size > 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx Recurrence Score > = 26, Prosigna score > = 60, EPclin risk score > = 4.0, or Mammaprint high risk category, or D. At least a 15% predicted residual risk of death within 10 years using NHS PREDICT (see appendix A3 on calculating predicted residual risk of death with PREDICT) Neoadjuvant chemotherapy (chemotherapy prior to surgery) E. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy F. Lymph node negative and tumour size > 3 cm after chemotherapy Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) G. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy H. Lymph node negative and tumour size > 3 cm after chemotherapy Use the primary surgery criteria - staging tumour size and lymph node status may be either the pathological staging after endocrine therapy or on the initial clinical staging prior to neoadjuvant therapy 6. Available tissue from one archival tumour tissue sample (either from diagnostic biopsy, primary surgery or where available residual disease post-neoadjuvant chemotherapy) A. Patients with bilateral tumours may enrol if both are ER+ and HER2- and if one archival tissue sample can be provided from each tumour B. Patients with multifocal breast cancer whose histopathologically examined tumours all meet pathologic criteria for ER+ and HER2- breast cancer, and two archival tissue samples can be provided. 7. No evidence of macroscopic distant metastatic disease or incurable locally advanced disease on staging scans conducted at any time since initial diagnosis. 8. Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole, anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6 months* and maximum of 7 years duration with an additional three years of endocrine therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues. * patients may enrol during the first 6 months of standard endocrine therapy, and wait until at least 6 months of endocrine therapy has been received prior to starting ctDNA surveillance 9. Patients must have had surgery achieving clear margins (as per local guidelines) 10. Female and male patients of reproductive potential must be willing to use an adequate method of contraception for the first three years of the trial, if randomised to standard endocrine therapy for the duration of trial treatment through to at least 4 weeks after the last dose of trial treatment, and if randomised to fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. 11. Patients willing to have frequent blood tests. ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE Please refer to the main protocol for inclusion criteria for treatment phase.
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate/denosumab. 2. Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may enrol only after at least 12 months from completing CDK4/6 therapy. 3. Prior exposure to fulvestrant is not permitted. 4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ 5. Patients previously entered into a therapeutic trial where experimental therapy is continued post-surgery. Patients who have entered a clinical trial of a CDK4/6 inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6 inhibitor only before an operation, with no post-operative adjuvant use, are eligible. 6. Treatment with an unlicensed or investigational product within 4 weeks prior registration to trial 7. Patient has not recovered to < = grade 1 (except alopecia or certain other toxicities, which in the opinion of the Investigator should not exclude the patient) from related side effects of any prior antineoplastic therapy, not including side-effects of endocrine therapy 8. Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medication (e.g. Crohn’s disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection) 9. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’ opinion cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol. 10. Clinically significant uncontrolled heart disease including any of the following: a. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry b. Symptomatic congestive heart failure c. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome. d. Cardiac arrhythmia. 11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis 12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of study screening) 13. Known active Hepatitis B or Hepatitis C (testing not required as part of study screening) 14. Females who are known to be pregnant or breastfeeding 15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting factor deficiency), other known abnormalities in coagulation or treatment with anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted. 16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min. ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE Please refer to the main protocol for exclusion criteria for treatment phase.
The HER2-RADiCAL study is for patients with HER2-positive breast cancer who: -started their course of drug treatment (chemotherapy + trastuzumab + pertuzumab) before surgery; -have had breast surgery; -and have been found to have the best possible response to treatment (a “pathological complete response” or “pCR”). A pCR means that there were no remaining living cancer cells in tissue removed at surgery. We already know that such patients have good outcomes with only a small chance of the cancer returning, and so it is possible that the side effects and risks of continuing all of these treatments in combination could outweigh any benefit. The study will investigate whether a more personalised treatment plan can be offered, with the aim of allowing patients with a pCR to safely receive less drug treatment after surgery. Study participants will continue treatment with trastuzumab to complete 9 cycles (rather than 18), including the cycles given before surgery. No more pertuzumab or any type of chemotherapy will be given after surgery. Some patients may avoid receiving a type of drug called an anthracycline (where the anthracycline-containing chemotherapy component is deferred after surgery). Any other treatment that might have been recommended (like hormone therapy or radiotherapy) will be given as normal. Patients will be asked to donate tissue samples removed during routine biopsy procedures or surgery. No new tissue samples will be taken for research purposes. The HER2-RADiCAL study aims to recruit around 720 patients with HER2-positive breast cancer and a pCR, to test whether these patients can safely receive less trastuzumab, pertuzumab and chemotherapy after surgery. This reduction of drug treatment may not only benefit the patient, but also save NHS resources. Data from routine NHS records on all patients with HER2-positive breast cancer in the UK will be collected in addition to the study data to assess the cost-effectiveness of this response-adapted approach.
1. Female or male, age ≥ 16 2. Histologically confirmed invasive breast cancer that is HER2-positive (IHC3+, and/or ISH positive/amplified) as determined by the local laboratory in accordance with national guidelines 3. Has received neoSACT chemotherapy with concomitant trastuzumab and pertuzumab 4. pCR (ypT0/is ypN0) in breast and sampled regional lymph nodes as per local pathology reporting 5. Imaging of breast and axilla prior to initiation of neoSACT and either: a) Breast primary radiological measurement ≤ 20mm prior to neoSACT and limited nodal involvement (cN1) confirmed by axillary core biopsy or FNA (cT1N1) OR b) Breast primary radiological measurement > 20mm but ≤ 50mm and node-negative (cT2N0) or limited nodal involvement (cT2N1) 6. Multiple ipsilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 7. Bilateral cancers are permitted provided at least one meets the tumour size and axillary node inclusion criteria and none meet any of the exclusion criteria 8. Pre-treatment diagnostic breast tumour biopsy sample available 9. Patient must be fit to continue treatment with trastuzumab and have no concomitant medical, psychiatric or social problems that might interfere with informed consent, adherence to the reduced treatment pathway or follow up 10. Provision of written informed consent to participate in HER2-RADiCAL
1. Evidence of metastatic disease at any time since diagnosis 2. Any residual invasive disease following neoSACT. This includes isolated tumour cells in axillary nodes or tissue or evidence of lymphovascular invasion in the breast. Persistent ductal or lobular non-invasive disease (DCIS or LCIS) is permitted. Resection margins must be deemed clear of any residual DCIS according to local MDT protocol. 3. Breast conserving primary surgery where it is known that breast irradiation will not be administered (e.g. due to contraindication or patient preference) 4. Intraoperative assessment of post-neoSACT axillary SLN using one stop nucleic acid amplification (OSNA) 5. Any planned further resectional surgery for breast cancer (including re-excision, mastectomy, or axillary surgery excluding reconstructive or risk reducing surgery) 6. HER2-negative invasive breast carcinoma 7. Breast cancer with clinical stage of T≥3 at diagnosis 8. Evidence of scarring (or other pathological features consistent with previous malignant involvement) in ≥4 axillary nodes or clinical nodal stage N≥2 at any time 9. Positive SLNB pre-neoadjuvant systemic therapy as this precludes determination of pCR 10. Pregnant and/or lactating women 11. Female patient of child-bearing potential, unwilling to use an effective form of contraception during trastuzumab treatment and for 7 months after their last dose of trastuzumab (NB. See section 5.5 for further guidance) 12. Previous diagnosis of invasive breast carcinoma 13. Previous diagnosis of any other (non-breast) malignancy unless disease-free for at least 5 years and considered to be at low risk of recurrence or treated basal cell or localised squamous cell carcinoma of the skin or cervical intraepithelial neoplasia 14. Chemotherapy administered following surgery (NB. Pertuzumab and/or trastuzumab may have been continued after surgery as per local practice prior to trial entry) 15. Has received > 9 cycles trastuzumab. In the event a patient has received 9 cycles prior to study entry then consent must occur within 3 weeks of last dose of trastuzumab. 16. Clinically significant cardiac disease within 12 months of starting trastuzumab, including unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident, or cardiac arrhythmia associated with haemodynamic instability 17. Left ventricular ejection fraction (LVEF) less than 50% on most recent cardiac imaging 18. History of interstitial lung disease 19. Any medical or other contra-indication to continuing trastuzumab
TRACC C is a prospective, randomised, multi-centre, study enrolling a total of 1681 patients Patients with high risk stage II or stage III colorectal cancer (CRC) whose pre-surgery blood test confirms presence of circulating tumour DNA (ctDNA) will be randomised to 1:1 with 810 patients treated in standard of care arm where patients are offered adjuvant chemotherapy according to national guidelines and 810 patients in the experimental arm, in which patients are treated based on ctDNA results . Patients will be stratified according to: 1. High risk stage II versus stage III 2. Site of primary tumour: right colon versus left colon versus rectum Hypothesis: ctDNA directed adjuvant chemotherapy administration will enable biomarker driven selection of patients who would benefit from adjuvant chemotherapy, thereby reducing the proportion of patients receiving adjuvant chemotherapy without compromising disease free survival. Background: There are 42,000 new cases of CRC, a top four cancer, diagnosed in the UK each year (CRUK Bowel Cancer Statistics, 2017). Approximately half of these cases are curable and include stage II (n= 9600/year) and III (n= 10,500/year). In patients with high risk stage II and stage III colorectal patients, adjuvant chemotherapy is currently determined by pathological features of the tumour resected at surgery. This is not a precise method of risk stratification of relapse and we are undoubtedly over-treating a proportion of patients already cured. Around 15-25% of patients offered standard oxaliplatin containing chemotherapy have permanent peripheral sensory neuropathy which can be quite debilitating and distressing (Grothey, Sem in Onc, 2003). Progress has been made in minimising unnecessary chemotherapy with the landmark UK-led publication (Iverson T et al, Lancet Onc, April 2018), confirmed by international meta-analyses (Grothey A et al, NEJM, March 2018) indicating that 3 months of post-operative chemotherapy was non-inferior to 6 months, without loss of benefit. The 3 year disease-free survival (DFS) in the 3-month group was 76.7% (95% CI 75.1–78.2) and in the 6-month group was 77.1% (75.6–78.6) [HR: 1.006 (0.909–1.114)]. The incidence of peripheral sensory neuropathy was of significantly less magnitude, with the rate being 58% in the 6 month group versus 25% in the 3 month group. The SCOT trial has changed clinical practice and our current standard of care is either 3 months of doublet capecitabine and oxaliplatin (CAPOX) or 6 months of single agent capecitabine chemotherapy in the adjuvant setting for patients with high risk stage II or stage III CRC. Liquid biopsies, in particular ctDNA, are emerging as an indicator of microscopic minimal residual disease following surgery. There is increasing evidence that postoperative ctDNA levels could potentially be a prognostic biomarker, identifying patients with high or low risk of recurrence. This represents the next step in individualising risk stratification and treatment minimisation, thereby truly delivering personalised care to patients. Multiple prospective studies have shown that time to recurrence, relapse free survival and overall survival were significantly shorter in patients who are ctDNA positive post-operatively compared to negative patients in stage II and stage III colon cancer (Tie et al., Science Translational Medicine, 2016; Diehn et al., ASCO 2017; Tie et al., ASCO 2018). Similarly, in patients with locally advanced rectal cancer (T3/T4 and/or N+) receiving chemo-radiotherapy recurrence-free survival was significantly worse in patients in whom ctDNA was detected after after surgery (HR 13.0; p< 0.001). (Tie et al., Gut Feb 2018). The technology for detecting ctDNA has advanced rapidly from the laborious droplet digital PCR (ddPCR) which involves designing individual probes for analysis, to next generation sequencing (NGS) directly in the blood by using suitable cutting edge gene panels. Our amendment now allows us to add TRACC C to the current TRACC protocol to use ctDNA analysis to guide therapy in high risk stage II and stage III patients with standard of care chemotherapy. This study will facilitate rapid implementation of this technology for assessment across the existing network of recruiting centres.
Eligibility criteria to be used prior to registration (for all patients, Part A and B): Inclusion Criteria: • New diagnosis of histologically confirmed CRC scheduled to undergo surgery with curative intent, with no radiological evidence of metastatic disease. • Patients with lesions with high degree of suspicion on histology but not confirmed to be an adenocarcainoma and whose imaging is strongly suggestive of colorectal carcinoma (CRC) will be included. This patients will be excluded post-surgery if carcinoma diagnosis is not confirmed • Age≥18 • Ability to give informed consent • Able to adhere to follow up schedule Additional eligibility criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy All patients proceeding to surgery Eligibility criteria at the first post-operative visit: Inclusion Criteria: • Stage I, II or III CRC based on the post-operative histopathology report • Availability of FFPE tumour tissue from surgery, for processing and analysis at the CMP For patients in the ctDNA guided interventional arm of the study only (Part C) Inclusion Criteria: 1. Subject ≥ 18 years of age 2. Subjects with histologically proven high risk stage II or stage III colon or rectal cancer treated with curative intent with surgery alone (any T, N1 or N2) with no evidence of metastatic disease. Subjects must be due to receive adjuvant chemotherapy following surgery. Subjects with histologically proven stage III rectal cancer are eligible, including patients treated with neoadjuvant chemoradiotherapy (any T, N1 or N2, M0) with no evidence of metastatic disease. Subjects must be due to receive adjuvant chemotherapy following surgery. 3. Fully surgically resected tumour with clear resection margins (i.e., > 1 mm) 4. Patients must have detectable levels of ctDNA (i.e., ctDNA positive) in blood samples at baseline; this is collected pre-operatively if being treated with surgery alone, or before chemoradiotherapy in patients with locally advanced rectal cancer being treated with neoadjuvant chemoradiotherapy before surgery 5. Adequate organ function - Absolute neutrophil function ≥1.0 x 109 / L - Platelet Count ≥ 75 x 109 / L - Haemoglobin ≥80g/L (blood transfusion before randomisation is allowed) - Adequate renal function as calculated by Cockcroft and Gault equation (GFR ≥ 30ml/min if FOLFOX chemotherapy chosen and GFR ≥ 50ml/min if single agent capecitabine or CAPOX chosen) - Aspartate aminotransferase/ Alanine aminotransferase levels ≤ 2.5 upper limit of normal 6. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would not contraindicate adjuvant chemotherapy 7. Patients should be assessed by Oncology team for suitability and assessment for adjuvant chemotherapy, be able to have post-operative ctDNA sample collected and be randomised by week 4-8 after surgery. 8. ECOG performance status 0- 2 9. Able to give informed consent
Eligibility criteria to be used prior to registration (for all patients, Part A and B): Exclusion Criteria: • Scheduled to have neoadjuvant chemotherapy, (neoadjuvant chemoradiotherapy for patients with rectal cancer is permitted) • Current or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix or other non-invasive malignancy. Additional eligibility criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy Patients scheduled to have further pre-operative treatment with chemotherapy • Patients that are no longer proceeding with surgery i.e. those in whom surgery is considered too high risk • Patients that are no longer proceeding with surgery as they are proceeding with a deferral of surgery approach Eligibility criteria at the first post-operative visit: Patients with no confirmed tissue diagnosis or high grade dysplasia included in the study based on imaging diagnosis but subsequent histopathology of surgical specimen confirms no carcinoma will be excluded • Scheduled to receive post-operative radiotherapy For patients in the ctDNA guided interventional arm of the study only (Part C) Exclusion Criteria: 1. History of concurrent and previous malignancy within the last 3 years, with the exception of non- melanomatous skin cancer and carcinoma in situ 2. Any major post-operative complications or other clinical conditions that in the opinion of the investigator would contra-indicate adjuvant chemotherapy 3. Any subject not due to receive adjuvant chemotherapy will not be eligible for Part C of the study 4. Hypersensitivity or contraindication to the drug(s) associated with the planned choice of systemic chemotherapy (CAPOX, FOLFOX or single agent 5-FU or capecitabine) as stated in the SPC for each of the drugs
Surgery is the only curative option for patients with oesophagogastric adenocarcinoma, but despite the use of multimodality therapy which combines it with chemo and/or radiotherapy, more than 50% of patients will relapse and die. Many of the UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab (a checkpoint blockade inhibitor) has been found to work in some advanced cancers. It is proposed for those where it hasn't worked - that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. In this trial we will aim to sensitize the tumour with temozolomide (TMZ) to increase its sensitivity to nivolumab. Patients will be treated for up to 3 months with TMZ prior to commencing nivolumab either in conjuction with TMZ or alone.
Patients ≥ 18 years of age • Pathologically confirmed advanced unresectable or metastatic OGA • MGMT methylation on archival tissue • Mismatch repair proficient (MSI-normal or MMR intact) • Previously treated with at least 3 months of platinum and fluoropyrimidine based chemotherapy for advanced disease and without evidence of disease progression. • Measurable disease per RECIST 1.1. • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 • Can swallow TMZ capsules • Adequate organ function assessed within 7 days before randomization: o White blood cell count (WBC) > 1.5 x 109/L o Absolute neutrophil count (ANC) > 1.5 x 109/L o Platelets ≥ 100 x 109/L o Haemoglobin ≥ 90 g/L o Measured/calculated creatinine clearance ≥ 60 mL/min (according to Cockroft-Gault formula). o Total bilirubin within normal limits (if the patient has documented Gilbert’s disease ≤ 1.5 x ULN or direct bilirubin ≤ 1.5 x ULN) o Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 1.5 x ULN • All toxicities (exception alopecia, and grade 2 fatigue, neuropathy and lack of appetite /nausea) attributed to prior anti-cancer therapy must have resolved to grade 1 (NCI CTCAE version 5.0) or baseline before administration of study drug. • Women of childbearing potential (WOCBP) may be included following a confirmed menstrual period and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)). Pregnancy test must be within 24 hours prior to starting treatment. (A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). • WOCBP should use one highly effective and one effective method of birth control during the study treatment period and for at least 5 months after the last dose of the study treatment. • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last dose of the study treatment. • Men who are sexually active with a WOCBP must adhere to contraception during and for a period of 7 months after the last dose of the study treatment. • Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. • Written informed consent
- Previous treatment with TMZ • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways • Active central nervous system metastases • Candidate for curative surgery • Previous malignancies are excluded unless a complete remission was achieved at least 5 years prior to study entry. Adequately treated cervical carcinoma in situ, and localized non-melanoma skin cancer are not exclusion criteria, regardless of timepoint of diagnosis. • Active, known, or suspected infectious or autoimmune disease (except for patients with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enrol) • Conditions requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration • Interstitial lung disease • > Grade 1 peripheral neuropathy • Positive test result for HBV or HCV indicating acute or chronic infection • Known history of testing positive for HIV or known AIDS • Known hypersensitivity to the components or excipients of co-trimoxazole, temozolomide or nivolumab. (Please refer to nivolumab IB and SmPC for TMZ and co-trimoxazole). • Known hypersensitivity to dacarbazine (DTIC) • Clinically significant abnormal 12-lead ECG. If clinically indicated, cardiac function assessment using either echocardiography or MUGA Scan, if clinically significant the patient is ineligible. • In the past 6 months serious cardiac illness or medical condition including but not confined to: o History of documented congestive heart failure (CHF) o High-risk uncontrolled arrhythmias o Angina pectoris requiring antianginal medication o Clinically significant valvular heart disease o Evidence of transmural infarction o Poorly controlled hypertension (e.g. systolic > 180mm Hg or diastolic greater than 100mm Hg) • Patients with severe liver parenchymal damage • Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed • Patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides. • Patients with acute porphyria • Patients with severe myelosuppression
Multi-parametric Magnetic Resonance Imaging (mp-MRI) has become the standard of care in the diagnostic work-up of patients with suspected prostate cancer (PCa). Using a 45-50 minute MRI protocol, the technique has high sensitivity (> 90%) for detection of clinically significant disease. However, it has several limitations that should be addressed, specifically: a) only about to 1 in 2 men with suspicious lesions at MRI have significant tumour at biopsy (i.e.: there is a need for improved specificity); b) mp-MRI often suffers from image artefacts causing difficulty in scan interpretation (i.e.: there is a need for improved image quality); c) there is growing concern on the safety of contrast agents used for MRI (i.e.: there is a need to reduce contrast usage). Recently, a new MRI technology named Luminal Index MRI (LI-MRI) has been introduced. LI-MRI can be easily set-up on any existing clinical MRI scanner and could replace the standard 45-50 minute mp-MRI with single 5-10 minute scan. Preliminary studies showed that, compared to mp-MRI, LI-MRI matches sensitivity, improves specificity, is significantly less prone to image artifacts and does not require the use of contrast agents. CLIMATE will be a prospective, multi-centre, non-randomised comparative study of mp-MRI and LI-MRI recruiting men with clinical suspicion of prostate cancer that should undergo mp-MRI as part of their standard clinical care. All participants will undergo both mp-MRI and LI-MRI with targeted biopsies performed when suspicious lesion are detected. The primary aim will be to compare the diagnostic accuracy of LI-MRI and mp-MRI for the detection of significant cancer. Secondary aims will be to compare the proportions of men over diagnosed with non-harmful tumours based on mp-MRI and LI-MRI, to determine the reproducibility between radiologists in scoring LI-MRI and to correlate LI-MRI quantitative metrics with tumour aggressiveness.
1. Men referred for prostate mp-MRI for a clinical suspicion of prostate cancer. 2. Men willing and able to provide written informed consent.
1. Prostate specific antigen (PSA) level > 20ng/ml within 6 months 2. Prior prostate cancer diagnosis 3. Ongoing hormone treatment MRI within the 3 month prior to MRI, excluding antiandrogens or 5-alpha reductase inhibitors 4. Contraindication for MRI scan 5. Contraindication to injection of gadolinium-based contrast agents
The assessment of quality of life (HRQOL) is a critical outcome measure for trials evaluating the risks and benefits of treatments for children with cancer. QOL assessment also plays an important role within clinical practice by facilitating communication between children, their parents and clinicians. It is therefore vital that QOL measures include questions which are of significance to children with cancer. While several paediatric QOL measures exist, previous research has identified shortcomings of those questionnaires when applied to children with cancer. The European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) has an international reputation for the development of cancer QOL questionnaires with a core quality of life questionnaire (EORTC QLQ-C30) and supplementary modules specific to a particular tumour, condition or age group (older adults, adolescents and young adults). There is currently no EORTC QLG questionnaire specific to children. The objective of this multi-centre study is to use EORTC QLG guidelines to develop a measure asking about QOL concerns of relevance and importance to children aged 8-14 years with cancer and identify optimal response options which are appropriate for this age group. The study is led by the Medical University in Innsbruck, Austria and involves two phases: Phase I consists of a literature review as well as qualitative semi-structured interviews with 60 children (8-14 years), 45 parents and 30 health-care professionals (HCPs). In Phase Ib, a further 60 children (8-14 years) will be interviewed to evaluate the best response format (Smiley faces- vs. Likert-Scale) for these age groups. In Phase II, the issues generated in Phase I will be operationalized and transformed into items and a preliminary questionnaire for children with cancer of 8-14 years will be constructed. In the UK a total of 30 children, 20 parents and 5 HCPs will be recruited.
The age group above relates to child participants (not parents or HCPs). Inclusion criteria: Diagnosis of any cancer and receiving treatment for cancer or palliative / supportive care Aged between 8 - 14 years No cognitive impairment Fluency in the native language of the local recruiting centre Willingness and ability of parents or guardians to give their fully informed consent Willingness and ability of children to give their assent HCPs: At least 5 years of clinical experience in paediatric oncology
Children with cognitive impairment and not able to give their assent or understand the nature of the study. Children / parents who are not willing to give their assent / consent. Children who have finished curative intent treatment and no longer have active disease.
Multi-centre open label randomised phase II trial,to evaluate haematological improvement in patients with low-risk MDS by comparing VBaP versus danazol in patients who have either received Erythropoiesis Stimulating Agents (ESAs) and lost response,not responded to ESAs or are deemed unlikely to respond to ESAs.
1. Provision of written informed consent 2. Age ≥ 18 years and able to give informed consent 3. Diagnosis of Myelodysplastic Syndrome with an IPSS-R score of less than or equal to 3.5 4. Haematological parameters: 1) Mean Haemoglobin < 100 g/l over 16 weeks (pre transfusion) OR 2) Mean Platelets < 100 x 109/L over 16 weeks + evidence of bleeding (assessed using the ISTH Bleeding Assessment Tool) OR 3) Mean neutrophils < 1.0 x 109/L over 16 weeks + history of infection (the requirement for antimicrobial therapy and hospital admissions associated with infection) 5. No response to Erythroid Stimulating Agents (ESAs) OR have ceased to respond to ESAs OR are Predicated not to Respond to ESAs by current UK guidelines (NB Patients with thrombocytopenia and/or neutropenia, without anaemia, are eligible as they are predicated not to respond). 6. ECOG performance status 0-3 7. Expected survival > 12months
1. Abnormal liver function (if patient has Gilbert’s syndrome, then abnormal direct Bilirubin is an exclusion) 2. Cockcroft Gault CrCl < 20ml/min 3. Current systemic treatment for low risk MDS 4. History of Allogeneic Bone Marrow Transplant 5. History of having received ESAs and/or G-CSF in the past 16 weeks 6. Currently receiving statin medication for Secondary Prophylaxis of Cardiovascular Disease, Cerebrovascular, or Peripheral Vascular disease (Please note patients receiving statin medication for Primary Prophylaxis of Cardiovascular Disease – i.e. the patient has no prior history of Ischaemic Heart Disease or Cerebrovascular Disease - can still be entered, please see section 1.4 Statin use) 7. Currently receiving fibrate medications 8. Currently receiving sodium valproate, carbamazepine or phenytoin for treatment of epilepsy 9. Prior cytotoxic chemotherapy or hypomethylating agents for AML/MDS (e.g. azacitidine) 10. Concurrent active malignancy requiring treatment 11. History of any Androgen Dependent Tumour (patients with Prostate Cancer are Excluded when a biopsy proven diagnosis of Prostate Cancer has been made OR their PSA is known to be elevated OR they are on active treatment for Prostate Cancer, including hormonal therapy). 12. Currently receiving Vitamin K-Antagonist Anticoagulation (though patients receiving DOACs (direct oral anticoagulants) can be included) 13. History of Venous Thrombo-Embolism (VTE) 14. Cardiac Failure NYHA Class III or IV 15. Women of childbearing potential, pregnant or lactating 16. The physician or patient consider VBaP or danazol to be inappropriate for the patient 17. Known HIV 18. Abnormally high CK level 19. Presence of isolated del 5q 20. Acute Porphyria 21. Contraindications to any of the trial medications or known hypersensitivity to any of the investigational products (see Appendix C for contraindications) 22. Previous randomisation in the REPAIR-MDS trial 23. Participation in a clinical trial of an investigational medicinal product in the last 16 weeks
PRIMROSE Tissue Study aims to collect and investigate archived tissue, excess CSF samples and related data (all collected as part of standard care) from patients with central nervous system disease secondary to breast cancer. This study does not involve additional procedures or interventions outside of standard care. Patients will be informed of the study and consented to participate in PRIMROSE Tissue. Following consent, arrangements will be made to request available archived FFPE tissue blocks of primary breast cancer tissue, non-cranial metastatic tissue or cranial metastatic tissue if available. CSF samples will be collected only if the patient has been scheduled to undergo a CSF collection procedure as part of their standard care. In this case, an excess 10ml of CSF will be collected for the PRIMROSE Tissue study. Prior to CSF collection, 10ml blood will be collected for the study (which would not otherwise be collected). The study can be carried out by trained clinical staff members, at sites with the appropriate and relevant facilities and this study does not involve experimental treatment or placebo treatment.
1.Male or female. 2.16 years of age or above 3.Histologically and/or cytologically confirmed breast cancer with CNS involvement, as defined as having one or more of the following: a)Metastases to the brain parenchyma b)Metastases to the leptomeninges c)Paraneoplastic Neurological Disorders 4.FFPE of biopsied or resected primary breast cancer, non-CNS metastasis and/ or brain metastasis is available or will be available. 5.Informed consent
1.Unable to comply with study procedures or give informed consent
Tumours require a blood supply to provide them with oxygen and nutrients and to enable spread of cancer to other organs (metastasis). New blood vessel formation is known as angiogenesis, which is controlled by a growth factor (like a hormone) called Vascular Endothelial Growth Factor (VEGF). Many drugs have been developed that block VEGF and, in most cancers, including ovarian cancer, the addition of VEGF inhibitors (VEGFi) to conventional anti-cancer therapy postpones recurrence of the disease and in some cases improves the overall outcome. VEGFi are widely used in cancer medicine. Yet, until now, there have been no biomarkers (tests) that could be used to tell patients and their doctors whether the drugs were working. In their initial studies in ovarian and bowel cancer, Prof Jayson’s team discovered the first biomarker that tells us whether a VEGFi is working. The test involves measuring a protein in the blood called Tie2, which can be measured from routine blood tests. When Tie2 decreases in the blood, we know that tumour blood vessels are blocked by VEGFi and the treatment is working; when the level increases, we know that the blood vessels have escaped the control of VEGFi and treatment should be changed. However, further research is required to establish the test in the NHS to support clinical decision making. In VALTIVE1 study, we would like to collect blood samples from patients with advanced ovarian cancer who are receiving a specific type of VEGFi called bevacizumab as part of their standard of care. The aim of VALTIVE1 is to generate a comprehensive biomarker data set that describes how Tie2 responds to treatment with bevacizumab. The data set will be used to design VALTIVE2, which will be a randomised trial with the aim of proving conclusively the value of Tie2 test.
In order to be eligible for participation in this trial, the patient must: 1. Be willing and able to provide written informed consent for the trial 2. Age 16 years or over on day of signing informed consent 3. Histologically proven ovarian, primary peritoneal or fallopian tube cancer (henceforth referred to collectively as Ovarian Cancer - OC) FIGO stage III with residual disease of more than 1cm; or stage IV; or stage III at presentation treated with neoadjuvant chemotherapy; or stage III with contraindication to debulking surgery chemotherapy 4. Planned to receive treatment with bevacizumab or biosimilar bevacizumab 5. Be scheduled to receive at least 2 successive doses of bevacizumab with 6 or more weeks of follow up blood samples after the first dose of bevacizumab if given pre-operatively; or to start bevacizumab post-operatively 6. Be eligible for receiving treatment with first line, 3-weekly carboplatin and paclitaxel chemotherapy 7. Be willing to provide blood samples and comply with trial-specific procedures
The patient must be excluded from participating in the trial if the patient: 1. Is unsuitable for treatment with VEGF inhibitors 2. Is unable or unwilling to comply with study procedures 3. Is participating in a clinical study with an investigational product other than carboplatin, paclitaxel and bevacizumab 4. Is judged by the investigator to be unlikely to comply with study procedures 5. Is pregnant or could become pregnant and is not using adequate contraception 6. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 7. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g. HCV RNA is detected). Testing only required if patient has a history of either of these
The primary aim of TARGET National is to establish a national framework to offer molecular profiling of circulating tumor DNA and/or tumour tissue (optional) to patients with advanced solid cancers referred to any of the Experimental Cancer Medicine Centres (ECMCs) across the UK, in order to help decision making for allocation to molecularly targeted experimental cancer treatments. Patients will be allocated treatment using a national Molecular Tumour Board to find the most suited therapies based on their molecular profiling results. The protocol has been written flexibly to allow additional samples to be collected (up to 60ml blood & up to 3 fresh biopsies) for further translational research. The TARGET steering board will oversee proposals for the collection and use of these samples to ensure all work remains within scope of the protocol and ethics approval. This study aims to recruit up to 6,000 patients with advanced solid tumours across 5 years and proposes to collect blood samples, archival tumour tissue and fresh tissue (optional). The data may also be used for future development of predictive cancer biological markers, the design of clinical trials involving new or existing drugs, discovery of new genetic targets and exploring how resistance to specific anticancer agents arises in patients to help improve future cancer treatment management.
1. Aged 16 years or over. 2. Written informed consent according to GCP and national regulations. 3. Patients with confirmed histological or cytological diagnosis of advanced solid cancer who have been referred to any of the ECMCs in the UK AND considered fit enough to receive an experimental therapeutic agent. 4. Availability of archival tumour sample (if tumour profiling is required) 5. Willingness to provide blood samples during the course of the study if allocated to a matched experimental therapy.
1. Known HIV, Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or Hepatits C virus (defined as HCV RNA detected), due to the difficulties in handling high-risk specimens. Routine testing for hepatitis is not required. Note: Patients with past/resolved Hepatitis B infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients with a history of Hepatitis C infection are eligible only if polymerase chain reaction (PCR) analysis is negative for HCV RNA at least 6 months after completing treatment for Hepatitis C infection. 2. Known current COVID19 positive (by PCR) or active symptoms for COVID19. Routine testing for COVID19 is not required. Patients with past infection who have fully recovered may be included. 3. Patients who are unable to provide fully informed written consent. 4. Patients not considered eligible by the investigator for early phase clinical trials. 5. Patients currently receiving systemic anti-cancer therapy (due to potential impact on ctDNA analysis), unless patient has clear evidence of progression on hormone-based therapies or tyrosine kinase inhibitors. A minimum of 3 weeks is required post completion of other systemic anti-cancer therapies. 6. Presence of any medical, psychological, familial or sociological condition that, in the investigator’s opinion, will hamper compliance with the study protocol and follow-up schedule. 7. Bleeding diathesis (patients’ on anticoagulation are permitted to enter the trial if anticoagulation can be safely managed to enable fresh tumour biopsies and blood sampling). 8. Conditions in which research biopsies or blood sampling may increase risk of complications for the patients and/or investigator.
This study is being carried out to see if the drug atezolizumab can reduce the size of tumours in patients with types of urothelial cancer before surgery. Atezolizumab is designed to stop a protein called PD-L1 (programmed death-ligand 1) being expressed on the cancer,allowing the immune system to recognise the tumour cells as foreign bodies and attack them. Atezolizumab has been shown to have activity in urothelial cancer which has spread. There two cohorts for this trial. One cohort will investigate the most common histological type of urothelial cancer (transitional cell carcinoma) outside the bladder,for example in the upper urinary tract. The other cohort will investigate rarer histological subtypes (such as such as squamous cell or adenocarcinoma) of urothelial cancer throughout the entire urinary system. This study will be recruiting patients from hospitals in the UK,France and Spain. If a patient is eligible for the study and decides to take part,they will receive up to two 3-weekly cycles of atezolizumab. 4-8 weeks after being enrolled,the patient will have an operation to remove the bladder (cystectomy) or the kidney,ureter and part of the bladder (nephroureterectomy or distal ureteral resection) as per normal practice. Following surgery,they will attend three hospital visits (4,12 and 24 weeks after surgery) and their disease progress/survival will be followed over the next 2 years. The clinical team will compare the patient’s tumour tissue samples,scan results and blood results from before and after treatment with atezolizumab in order to see how well the drug works and if it is safe. Many of the procedures involved in this study are offered as standard care and participation in this trial will not delay surgery.
Cohort-Specific Inclusion Criteria • Bladder cohort: Histopathologically confirmed carcinoma of the urothelium (T1 high grade -T4a) in the bladder with mixed or rare histological subtypes such as squamous cell or adenocarcinoma. Patients with mixed histologies are required to have a dominant non- transitional cell pattern. • UTUC cohort: Histopathologically confirmed,high grade or high risk upper urinary tract urothelial carcinoma (renal pelvis and ureter). This cohort includes all patients with upper tract malignancy who in the opinion of the investigators qualify for radical surgery (nephroureterectomy or distal ureter resection). Urothelial carcinoma of the upper urinary tract qualifies as high-risk disease if any of the below factors are present: - Hydronephrosis - Tumour size > 2cm on cross sectional imaging - High grade cytology - High grade biopsy - Multifocal disease - Variant histology - Previous radical cystectomy for urothelial cancer of the bladder All patients undergoing radical surgery with curative intent in the opinion of the investigator are eligible. Radical surgical interventions include nephroureterectomy or distal ureteral resection. General inclusion criteria: 1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Age ≥ 18 years 4. Residual disease after TURBT or URS (surgical opinion,endoscopy or radiological presence). 5. Fit and planned for radical surgery with curative intent in the opinion of the investigator (according to local guidelines). 6. N0 or M0 disease CT or MRI (within 4 weeks of registration) 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin- based therapy is not appropriate. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential. 11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of atezolizumab. 12. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: a) ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1,Day 1) b) WBC counts > 2500/μL c) Lymphocyte count ≥ 500/μL d) Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1,Day 1) e) Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f) AST or ALT,and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled). g) INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h) Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)
1. Pregnant and lactating female patients. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. 3. Previously intravenous chemotherapy for urothelial cancer. 4. Patients with prior allogeneic stem cell or solid organ transplantation. 5. Prior treatment with CD137 agonists,anti-CTLA-4,anti−programmed death−1 (PD-1),or anti−PD-L1 therapeutic antibody or pathway-targeting agents. 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids,physiologic replacement doses of glucocorticoids (i.e.,for adrenal insufficiency),and mineralocorticoids (e.g.,fludrocortisone) is allowed. 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g.,for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible). 8. Administration of a live,attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live,attenuated vaccine will be required during the study. 9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug,whichever is shorter,prior to enrolment. 10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results,including significant liver disease (such as cirrhosis,uncontrolled major seizure disorder,or superior vena cava syndrome). 12. Malignancies other than UC within 5 years prior to Cycle 1,Day 1,with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix,basal or squamous cell skin cancer,or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive). 13. Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection,bacteraemia,or severe pneumonia. 14. Significant cardiovascular disease,such as New York Heart Association cardiac disease (Class II or greater),myocardial infarction within 3 months prior to enrolment,unstable arrhythmias,or unstable angina. 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced pneumonitis,organizing pneumonia (i.e.,bronchiolitis obliterans,cryptogenic organizing pneumonia),or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted). 16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible. 17. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Positive test for HIV 19. Patients with active tuberculosis 20. History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug. 21. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > the institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study. 22. History of autoimmune disease including but not limited to myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis. 23. Patients with a history of autoimmune-related hypothyroidism,unless on a stable dose of thyroid-replacement hormone. 24. History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
The mechanism(s) by which the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-colorectal cancer (CRC) activity is not understood. Recent experimental data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota (gut bacteria), thereby reducing immunosuppressive mechanisms that allow CRC cells to ‘hide’ from the host anti-tumour immune response. The EMT2 trial is an ongoing randomized, double-blind, placebo-controlled phase 3 trial of the effect of EPA ethyl ester 4 g daily on CRC recurrence and survival after surgery for resectable CRC liver metastases (ClinicalTrials.gov NCT03428477). There is a unique opportunity to collect samples from participants in the trial in order to characterise the intestinal microbiota and immune response to CRC. We will collect biospecimens (faecal [stool] samples, CRC liver metastasis tissue, blood and urine) from EMT2 trial participants in a way that does not interfere with participation in the EMT2 trial. Using stool, blood and urine samples collected 1) after EMT2 trial randomisation, before starting active EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, we will interrogate immune and microbiome pathways in relation to survival in EMT2 trial participants. We will address causality and characterize the mechanisms by which EPA potentiates host anti-tumour immunity and suppresses CRCLM using a novel ‘avatar’ germ-free CRCLM mouse model humanized with faecal material from EMT2 trial participants. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximise the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalised use of EPA, which will be targeted at those most likely to benefit.
Only individuals recruited to the EMT2 trial are eligible.
There are no specific exclusion criteria. If an individual is recruited to the EMT2 trial, they would be automatically eligible for the biospecimen collection study.
Myelofibrosis (MF) is a cancer of the bone marrow that disrupts the production of blood cells. Symptoms of MF include anaemia (low red cell levels), weakness, tiredness and often an enlarged spleen. Standard treatment can involve chemotherapy, radiotherapy, a stem cell transplant or treatment with a drug called ruxolitinib. Ruxolitinib targets the specific cells that play a part in the development of MF, and is the only drug licenced to treat MF. Previous research has shown that ruxolitinib is good at reducing symptoms of MF and decreasing the size of the spleen. However, the majority of patients do not show a complete response to ruxolitinib, meaning that another treatment needs to be added to ruxolitinib to improve the outcome for patients. This study will test whether combining ruxolitinib with another drug called a bromodomain and extra terminal inhibitor (BETi) is safe for MF. Research has suggested that combining these two drugs will have a clinical benefit to patients. The main aims of the study are to find a suitable dose of PLX2853 when combined with ruxolitinib, and investigate the safety by looking at the side effects of treatment, and to see how well the combination treats MF.
• Age> = 16 years. • Primary or secondary myelofibrosis OR Dynamic International Prognostic Scoring System (DIPSS) defined risk groups intermediate-2 or high risk. • Treated with > = 24 weeks of ruxolitinib with ongoing residual splenomegaly > 5cm from costal margin. • Platelets > 75x109/L. • Neutrophils > 1.0x109/L. • < 10% blasts in peripheral blood and/or bone marrow. • Coagulation (INR or PT) and Activated partial thromboplastin time < = 1.5 x ULN. • Albumin > 3.0 g/dL. • Stable dose of ruxolitinib (no dose modifications) established for 4 weeks prior to trial entry. • Except as specified above for organ function, all drug-related toxicity from previous therapy for myelofibrosis must be resolved (to Grade < = 1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0]) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed). • Able to provide written informed consent. • Able to comply with trial treatment and follow-up. • Serum total bilirubin < = 2.0 × ULN OR Direct bilirubin < = ULN for patients with total bilirubin > 2.0 × ULN; o Exception for elevated total bilirubin secondary to Gilbert’s disease, in which case it must be < = 3 x ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < = 2.0 × ULN.
• Prior exposure to a bromodomain inhibitor such as OTX-015 or CPI-0610. • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to trial entry). • Patients and partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use effective contraception from the time of negative pregnancy test during screening to 90 days after the last dose of study drug. • Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for > = 1 year. • Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment. • ECOG Performance Status Score > = 3. • Clinically significant cardiac disease, defined as any of the following: o Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded. o Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval (drugs with a low risk of QTc prolongation that are needed for infection control or nausea may be permitted with approval from the Clinical Coordinator). o QT interval corrected for heart rate using the Fridericia method (QTcF) > = 450 msec males or QTcF > = 470 msec (females) at Screening. o History of clinically significant cardiac disease or congestive heart failure > New York Heart Association Class II. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months. o Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management. o Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring > 1 month before the start of study medication). • Inadequate renal function as defined by eGFR or CrCl < = 30 mls/min. • Current active viral hepatitis including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing. • Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry.). • Known or suspected allergy to the investigational agent or any agent given in association with this study. • Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption. • Patient is participating in any other therapeutic clinical study (observational or registry studies are allowed).
The European Organisation for Research and Treatment of Cancer Quality of Life Group Core measure (EORTC QLQ-C30) is the most widely used cancer health-related quality of life (HRQoL) questionnaire. We will be recruiting adolescents (12-17 years) (n= 300 minimum) who have been diagnosed with cancer and receiving treatment for curative intent or who are receiving palliative care. We would like to know whether the EORTC QLQ-C30 is acceptable, and if the content is relevant and representative for this age group. We will also be comparing young people and their parents'/ guardians' questionnaire responses. This current study has a target sample size of 300. There will be a good spread of participants according to language, culture (this is an international study), age sub-group (12-14 years and 15-17 years), on treatment and palliative care. For pragmatic reasons, we envisage recruiting fewer patients receiving palliative care compared with those on treatment with curative intent. Participants will be asked to complete the EORTC QLQ-C30 followed by a debrief interview asking about their experience of completing the questionnaire. They will also be asked to complete the 23 item PedsQL teen self-report form designed for adolescents aged 13-18 years. This measures physical, emotional, social and school (role) functioning thus it lends itself for comparison with the EORTC QLQ-C30. The young people will also be invited to complete a 15-item symptom checklist. Socio-demographic and clinical characteristics including the ECOG performance status will be completed. Participants will be recruited by a member of the research or clinical team while visiting the hospital as an inpatient or outpatient or they will be contacted by their clinician. Questionnaire completion will be carried out at the hospital, over the telephone, Microsoft Teams or at the participant’s home.
Diagnosis of cancer; awareness of diagnosis and management plan; treatment with curative intent or palliative care; age 12-17 years; comprehension of the language of the questionnaire; willingness and ability to give informed consent / assent (for participants aged 12-15 years), willingness and ability of parent / guardian to give consent.
Cancer survivors (i.e., participants who have completed treatment with curative intent and are now cancer free).
Locally recurrent rectal cancer (LRRC) – cancer which returns close to the original site - affects approximately 10% of patients following treatment of rectal cancer. LRRC can cause symptoms, such as pain, bleeding and anal discharge. The only curative treatment for LRRC is extensive surgery in the form of an extended pelvic resection with 5-year survival rates of 43-63% following complete surgical resection, which is associated with high post-operative morbidity of up to 60%. The true extent of the burden of LRRC and its treatments on patients is unknown. The clinical and cancer-related outcomes are well documented, however, the extent of the impact on patients overall quality of life (QoL) is poorly reported. The LRRC-QoL is a questionnaire specifically designed for patients with LRRC to measure QoL. The LRRC-QoL was developed and validated for use in England and Australia. The best way to document outcomes related to QoL in this group is to collaborate with a number of high-volume, specialist centres internationally and to report outcomes related to QoL over a length of time. This study aims to translate and validate the LRRC-QoL into a number of other languages to enable its international use. We will validate the LRRC-QoL questionnaire on an international platform. Validation means checking that the questionnaire is applicable across all the relevant patient groups. The data obtained from the serial measurements will be used to evaluate changes in quality in life over time. Comparisons in scores of quality of life will be examined between patients undergoing different treatments. Survivorship issues represent the healthcare needs experienced by patients who have survived cancer treatment. As survival continues to improve in patients with LRRC and the number of survivors of exenterative surgery improves, it is important to understand the QoL and survivorship issues relevant to this cohort of patients.
Inclusion criteria for phase I: • aged > = 18 years; • with radiological and/or histological diagnosis of LRRC; • or have undergone treatment (surgery/chemotherapy/radiotherapy) for LRRC within the last 2 years; • able to provide informed written consent to participate and; • able to read and write in the target language. For phase II: • aged > = 18 years; • with a new radiological and/or histological diagnosis of LRRC; • able to provide informed written consent to participate and; • able to read and write in the target language. For phase III: • aged > = 18 years; • treated for LRRC and are disease-free for more than 3 years; • able to provide informed written consent to participate and; • able to read and write in the target language.
For phases I and II: • have cognitive impairment • are in remission from treatment of primary rectal cancer with no evidence of local recurrence • receiving treatment for distant metastatic disease (i.e. liver, lung) following previous treatment of rectal cancer with no evidence of local recurrence. For phase III: • have cognitive impairment • have been treated for LRRC and disease-free for less than 3 years. • diagnosis or treatment for distant metastatic disease (i.e. liver, lung) or locally re-recurrent rectal cancer following previous treatment for LRRC.
Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin’s lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP a type of immunochemotherapy), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL. The main aims of this randomised phase II clinical study are: - To determine if combining Acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL. - To compare progression-free survival, overall survival, event free survival, disease free survival, time to progression, response duration and overall response rate between both treatment and molecular groups. - To assess differences in toxicity between the assigned treatments - To assess differences in quality of life in different treatment arms - To explore correlation of molecular characteristics in tumour material to clinical outcomes. - To explore correlation of baseline PET features including metabolic tumour volume, tumour lesion glycolysis, extranodal sites and bone marrow involvement with clinical risk factor and molecular characteristics in tumour material. - To compare metabolic response rates between molecular groups. Up to 558 patients (453 randomised) will be recruited to the clinical trial with 302 patients randomised to the experimental arm and 151 to the control arm in a 2:1 randomisation.
1.Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may be included: • DLBCL, not otherwise specified (NOS) • T-cell/histiocyte-rich large B-cell lymphoma • Epstein-Barr virus positive DLBCL, NOS • ALK-positive large B-cell lymphoma • HHV8-positive DLBCL, NOS • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) • High-grade B-cell lymphoma, NOS 2. At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter > 7.5cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be eligible. 5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma. 6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma. 7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault [(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (µmolL)]). 8. Serum bilirubin < 35μmol/L and transaminases < 1.5x upper limit of normal at time of study entry. 9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than institutional normal range. 10. No concurrent uncontrolled medical condition. 11. Life expectancy > 3 months. 12. Aged 16 years or above. 13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of study drug. 15. Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with < 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during the screening phase to control symptoms. 16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Women who can bear children must agree to use two highly effective forms of contraception or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for > = 2 years or which will not limit survival to < 2 years. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial.
Acute myeloid leukaemia (AML) is an aggressive blood cancer affecting 3000+ people per year in the UK. Patients who are relatively young and healthy are given potentially curative treatment with intensive chemotherapy (IC) which is fairly effective in inducing remission, and for some patients, long-term cure. IC has severe short-term side effects including decreasing white blood cell count (which can lead to potentially fatal infections), mouth ulcers, nausea, vomiting and hair loss. Long-term side effects include infertility, heart failure and secondary cancers. Side effects are often more severe in older patients who have pre-existing medical conditions; therefore these patients are given treatments to control (rather than cure) the disease; less than half of these patients survive for over one year. A new treatment (venetoclax) has been tested on patients with AML who were not suitable for IC, and the results have been extremely positive. Patients with a specific type of AML (called NPM1 mutated) had a particularly good response, with over 90% achieving a remission and over 75% alive after 2 years. This result seems as good as, if not better than results achieved with IC. Therefore, we would like to compare venetoclax to IC to see if the outcomes really are comparable. We will initially test this in patients aged 60+ who are healthy enough to receive IC. We may subsequently lower the age limit if venetoclax is showing to be as good as IC. We will monitor patients throughout treatment and those who are not responding well can switch treatments or receive a stem cell transplant. If successful, venetoclax treatment may replace IC, which would greatly benefit patient’s quality of life both during and after therapy. This study will be open at selected hospitals in the UK, Denmark and New Zealand and will be open for 2 years.
• Diagnosis of CD33 positive Acute Myeloid Leukaemia • Age > = 60 years (prior to the interim analyses performed after enrolment of 50 and 100 patients) • Genotype NPM1mut FLT3 ITDneg (FLT3- Tyrosine Kinase Domain mutation, TKD, is permitted) • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 • Serum creatinine < = 1.5 x ULN (upper limit of normal) • Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < = 2.5 ULN and bilirubin < = 2 x ULN • Able to provide written informed consent • Considered fit for intensive chemotherapy with anthracyclines by treating physician
• Previous chemotherapy for AML or any antedecent haematological condition, with the exception of hydroxycarbamide to control white blood cell count • Other active malignancy requiring treatment • Newly diagnosed or uncontrolled HIV or hepatitis B or C infection. Patients with known chronic infections may enrol if the last two tests for viral load have been negative and their current therapy does not include a protease inhibitor or a non-nucleoside reverse-transcriptase inhibitor • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) • Females of childbearing potential, and their partners, not willing to use adequate contraception during and for up to 6 months after treatment • Unable to swallow tablets whole • Known hypersensitivity to any of the IMPs • Patients known to require vaccination with a live vaccine during the treatment period
Squamous cell carcinoma (SCC) is a cancer that originates from the cells lining the body and can spread into the lymph glands and beyond. Some patients first present with an SCC which has moved to the lymph glands of the neck. Clinical examination and imaging investigations are performed to try and identify the site where the cancer has originated. However, if no original site can be identified, then we call these ‘cancers of an unknown primary’ (CUP) of the head and neck. One region where these cancers could have originated from is the oropharynx. There are two areas in the oropharynx were cancers commonly arise. One area is the palatine tonsils, which can be removed for analysis with an operation called tonsillectomy. The other area is the tissue lining the back of the tongue, known as the tongue base. A relatively new surgical technique called ‘tongue base mucosectomy’ (TBM) allows removal of this tissue to see if the primary cancer is contained within it. This study will then use a histological method called ‘step serial sectioning’ (SSS) to look in more detail at the tonsils and tongue base, hoping to increase the detection rate of the primary cancer. Centres performing TBM will be asked to participate. Patients will be asked to consent to their tissue being used for SSS after it has undergone conventional histology. Anonymised samples will be sent to a central laboratory in Newcastle for processing. Other anonymised data regarding the patients' diagnosis and care will be collated. Patients will be asked to complete questionnaires regarding pain and swallowing recovery following surgery. A smaller cohort of patients will also be interviewed as part of a qualitative research process to establish their views on CUP and the acceptability of the above treatment.
• Aged over 18 • Both sexes • Cervical metastatic SCC, confirmed with cytology or biopsy, undergoing TBM for identification of primary site
• Primary site identified by any means prior to being indicated for TBM • Patients undergoing targeted biopsies or resections
Bladder cancer is the 9th most common cancer in the world. In about 70% of patients the disease only involves the cells that line the inner layer of the bladder (i.e. the cancer has not invaded the muscular wall of the bladder) and is known as Non-Muscle Invasive Bladder Cancer (NMIBC). Patients with NMIBC that are at risk of the cancer invading the muscular wall usually have surgery to remove as much of their cancer, followed by BCG vaccine administered into the cells lining the bladder. However, in around 40% of patients the cancer returns and they require radical cystectomy (to remove the bladder) which carries significant risk of health issues or death. Immunotherapy has been used to treat bladder cancer for over 40 years and the addition of vaccine to immunotherapy is hoped to improve the way immunotherapy treatment works. Durvalumab is an immunotherapy treatment that works by stimulating the immune system to block cancer growth or other activities needed for cancer growth. S-488210/S-488211 are 2 vaccines that can potentially increase the number of different types of immune cells the immune system needs to stop cancer growth. DURANCE is a trial looking at the safety and activity of combining durvalumab with S-488210/S-488211 in patients with NMIBC whose cancer has returned. The study will be conducted in two parts. Phase Ib will recruit 14 patients to assess if it is safe to combine durvalumab and S-488210/S-488211. If considered safe, will recruit 50 more patients in phase II. Data collected from all 64 patients will be used to look at how the combined treatment works by measuring their disease at 1 year after starting treatment. Patients will receive up to 24 weeks of trial treatment provided the treatment appears to be working and then followed up for 5 years from the start of treatment.
1. Histologically proven high-risk non-muscle invasive bladder cancer (high-risk tumours include any of the following features: T1 lesions, high-grade disease, tumours larger than 3 cm, multiple or recurrent lesions, and CIS). 2. Adequate archival tissue sample available for histological assessment. 3. Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma. 4. BCG unresponsive disease (persistent high-risk NMIBC or recurrence of high-risk NMIBC after disease-free period at 6 months despite receiving adequate course of BCG). 5. Refused or deemed clinically inappropriate for radical cystectomy. 6. > = 18 years of age. 7. Body weight > 30 kg. 8.WHO performance status 0-1. 9. Must have undergone each of the following procedures within 8 weeks of registration: • Complete excision of all papillary disease (T1/TaHG) and demonstration of no muscle invasive disease in the resected specimen (muscle must be present in the tumour tissue sample); • Bladder ‘Mapping biopsies’ taken; • CT of the chest; • CT urogram or MRI of the abdomen and pelvis (if CT is not possible). 10. Adequate haematological status: • Haemoglobin > = 9.0 g/dL; • Absolute neutrophil count > = 1.5 x 10^9/L; • Platelet count > = 100 x 10^9/L; • INR and APTT < = 1.5 x ULN. NB: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. 11. Adequate liver function: • Total bilirubin < = 1.5 X ULN (< 3.0 x ULN for patients with Gilbert’s syndrome); • AST or ALT < = 2.5 x ULN. 12. Adequate renal function (measured creatinine clearance or calculated creatinine clearance using Cockcroft-Gault formula of > = 40 mL/min, or by 24-hour urine collection for determination of creatinine clearance). 13. Life expectancy of > = 6 months. 14. Willing and able to give informed consent (which includes compliance with the requirements and restrictions listed in the patient information sheet and in the protocol). 15. Patients of child-bearing potential and male patients with female partners of child-bearing potential must agree to use highly effective contraception methods from date of consent, which must be continued for up to 90 days after last treatment administration. 16. Female patients must not be pregnant. There should be sufficient evidence of post-menopausal status or a negative serum pregnancy test for pre-menopausal female patients. 17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and any other study procedures.
1. Any history of autoimmune or inflammatory disease including: inflammatory bowel disease, diverticulitis, SLE, sarcoidosis syndrome, wegener syndrome. Exceptions: thyroid disease on stable treatment, any chronic skin condition that does not require systemic corticosteroid therapy. Patients with a history of an autoimmune condition but without active disease in the last 5 years may be included after consultation with the CI/TMG. 2. Prior allogeneic stem cell or solid organ transplantation. 3. Prior treatment with anti- PD-1, PD-L1 or CTLA-4 monoclonal antibody or other novel immune-oncology agent(s). 4. Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. 5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest CT scan. 6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. 7. QTcF value of > 470 ms. If prolonged, should be confirmed by 2 further ECGs each at least 5 minutes apart. 8. Patients with risk factors for bowel perforation: history of acute diverticulitis or intra-abdominal abcess in the last 3 years, history of mechanical GI obstruction or abdominal carcinomatosis. 9. Any unresolved toxicity Grade > = 2 from previous anti-cancer therapy with the exception of alopecia, vitiligo and laboratory values defined in the inclusion criteria. Patients with any irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the CI/TMG. 10. Receipt of last dose of anti-cancer therapy within 30 days prior to first dose of trial treatment. 11. Treatment with any experimental drug within 30 days or 5 half-lives (whichever is longer) of the first dose of trial treatment. 12. Concurrent enrolment in another clinical study, unless it is an observational/ non-interventional clinical study or during the follow-up period of an interventional study. 13. Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial. 14. Received therapeutic oral antibiotics that cannot be discontinued at least 14 days prior to starting treatment or received IV antibiotics within 14 days prior to registration. 15. Any psychiatric or other disorder that impacts the ability to give informed consent or comply with trial treatment and activities. 16. History of leptomeningeal carcinomatosis. 17. Active infection of TB (clinically evaluated in accordance with local guidelines). 18. Patients must not have had systemic corticosteroid therapy (> 10 mg daily prednisone equivalent) within 14 days prior to registration or concomitant use of other immunosuppressive medications. 19. Administration of a live, attenuated vaccine within 4 weeks prior to planned start of treatment or anticipation that such a live, attenuated vaccine will be required during the study. 20. Evidence of significant uncontrolled concomitant disease that could substantially increase the risk of incurring AEs, affect compliance with the protocol or interpretation of results, including significant liver disease, uncontrolled hypertension, serious chronic GI conditions associated with diarrhoea and uncontrolled major seizure disorder. 21. Major surgical procedure within 28 days prior to first dose of treatment. 22. Significant cardiovascular disease (as outlined in the protocol). 23. Uncontrolled Type 1 diabetes (eligible if controlled on a stable insulin regimen). 24. Uncontrolled adrenal insufficiency. 25. Active hepatitis infection or hepatitis C (HCV). Patients with past hepatitis B virus infection or resolved infection are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 26. Known active primary immune deficiency, including uncontrolled HIV (detectable viral load) or AIDS-related illness. 27. Women who are pregnant or breast feeding. 28. Known allergy or hypersensitivity to any of the IMPs or their excipients. 29. Prior randomisation to, or treatment in a previous durvalumab clinical study. 30. Must not donate blood while participating in this study and for at least 90 days following the last dose of trial treatment.
In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as endocrine therapy) for at least five years after surgery is very effective at reducing the risk of the cancer returning. However, for some women their cancer may eventually become resistant to these drugs. POETIC-A Registration part will identify those who have a higher risk of developing resistance to standard endocrine therapy (ET). Approximately 8000 women diagnosed with early stage breast cancer and have not yet had surgery to remove the cancer will enter the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a type of ET, to treat the cancer for 2 weeks before surgery. A sample will be taken from the cancer during surgery and the study laboratory will measure a biological marker called Ki67. If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be less sensitive to endocrine therapy, and the study doctor will explore additional treatments after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage (2500 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or Group2: ET plus a new drug called abemacicilib. The first aim of the Treatment stage is to confirm whether abemaciclib given in combination with ET is more effective than giving ET alone in preventing the cancer coming back. The study laboratory will perform a second test on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib. Patients in Group 2 will receive ET plus abemacicilib for 2 years. Patients in both groups will have regular study visits during this period.
INCLUSION CRITERIA FOR THE REGISTRATION STAGE 1. Postmenopausal women defined as: 1a. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. or 1b. Documented bilateral oophorectomy. 2. Diagnosed operable invasive breast cancer with a palpable tumour of any size or an estimated invasive tumour size > = 1.5cm by imaging (ultrasound/MRI/mammogram) excluding those who are grade 1 and /or lobular histological type on diagnostic biopsy. 3. Tumour ER positive and HER2 negative. ER positivity is defined as > = 1% cells staining positive (or equivalent Allred Score of ER > = 3 out of 8). HER2 negativity will be defined as per the 2018 ASCO/CAP updated guidelines. 4. Baseline Ki67 and/or clinical pathological factors which predict for a high (20%) 5-year risk of relapse with AI alone (see Appendix 2) 4a. Baseline Ki67 > = 20% measured at the local site or 4b. Presence of clinicopathologic factors that have been previously shown to predict (> 50% chance) patients with Ki67 > = 8% after 2 weeks’ AI, defined as one or more of the following grade 3 clinical/radiological tumour size > 5cm PgR negative PgR unknown AND evidence of Vascular Invasion 5. No evidence of metastatic spread by standard assessment according to local guidelines. 6. Written informed consent to enter the registration stage of the trial and to donation of tissue (fresh tissue and surplus tissue from diagnostic procedures) and blood samples. 7. No medical condition or other factor likely to preclude entry to randomised stage of the study if eligible e.g. patient would not be suitable to receive abemaciclib due to concomitant medications or medical history. 8. The patient has given written informed consent prior to any study-specific procedures and is willing and able to make herself available for the duration of the study and amenable and able to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records. INCLUSION CRITERIA FOR THE RANDOMISATION STAGE 1. Patient previously consented and registered for screening component of POETIC A. 2. Centrally confirmed Ki67 > = 8% following 2 weeks of AI. 3. Aromatase Inhibitor Resistant-CDK4/6 Inhibitor Sensitive (AIR-CIS) signature has been derived in the central laboratory and confirmed to ICR-CTSU. 4. Patient must have undergone definitive surgery for the primary breast tumour with clear radial margins as judged by the multidisciplinary team. 5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection. 6. Adjuvant chemotherapy, if prescribed, must have been completed prior to randomisation and patients must have recovered (Common Terminology Criteria for Adverse Events version 5 [CTCAE v5 ] Grade < = 1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomisation. A washout period of a minimum of 28 days from day 1 of last cycle of treatment is required. 7. Adjuvant radiotherapy, if prescribed, must have been completed prior to randomisation, and patients must have recovered (Grade < = 1) from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomisation. 8. The patient should be randomised within 6 months of commencement of adjuvant endocrine therapy. 9. The patient is able to swallow oral medications. 10. The patient has adequate organ function for all of the following criteria defined as; ANC > / = 1.5 × 109/L (G-CSF / blood tranfusions cannot be administered to meet this ANC eligibility criterion) Platelets > / = 100 × 109 / L Hemoglobin > / = 8g/dL Total bilirubin < / = 1.5 × ULN (Patients with Gilbert’s syndrome with a total bilirubin < = 2.0 times ULN and direct bilirubin within normal limits are permitted) ALT and AST < / = 3 × ULN 11. The patient intends to take adjuvant endocrine therapy for at least 5 years. 12. The patient has given written informed consent prior to any study-specific procedures (for the randomised intervention stage) and is willing and able to make herself available for the duration of the study and amenable and able to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records.
EXCLUSION CRITERIA FOR THE REGISTRATION PHASE 1. Men and pre/perimenopausal women. 2. Grade 1 tumours 3. Invasive lobular carcinoma. 4. Concurrent use (defined as use within 4 weeks prior to diagnostic tissue sample being taken) of HRT or any other oestrogen-containing medication (including vaginal oestrogens). 5. Prior endocrine therapy for breast cancer or breast cancer prevention. 4. Evidence of metastatic disease. 6. Locally advanced breast cancer not amenable to surgery. 7. Bilateral breast cancer. 8. Multiple unilateral tumours with different ER/PgR/HER2 status, grade or type (e.g. ductal vs lobular) i.e. anything that suggests two or more different cancers. Multifocal disease with homogenous ER/PgR/HER2 status, grade and type is allowed if at least one lesion is palpable or at least 1.5cm on ultrasound; the largest lesion should be used for sample collection and CRF completion. 9. Previous invasive breast cancer except for ipsilateral DCIS or LCIS treated > 5 years previously by locoregional therapy alone or contralateral DCIS/LCIS treated by locoregional therapy at any time. 10. Any invasive malignancy diagnosed within previous 5 years (other than non-melanoma skin cancer or cervical carcinoma in situ). 11. Any other medical condition likely to exclude the patient from subsequent randomisation stage. (See exclusion criteria: Eligibility for Randomisation). EXCLUSION CRITERIA FOR THE RANDOMISATION STAGE 1. Patient has received prior CDK4 / 6 inhibitor. 2. Any patient with a history of VTE (for example, DVT of the leg or arm and/or PE) will be excluded. Patients with a history of venous catheter occlusion by thrombus that did NOT surround the catheter, and the lumen could be made patent by appropriate measures (for example, saline or thrombolytic agent), are not excluded. 3. The patient has serious/or uncontrolled pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (such as severe renal impairment, [for example, estimated creatinine clearance < 30 mL/min], interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or pre-existing Crohn’s disease or ulcerative colitis or a pre-existing chronic condition resulting in baseline Grade 2 diarrhoea). 4. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: patients with controlled atrial fibrillation diagnosed more than 30 days prior to randomisation are eligible. 5. The patient has active systemic bacterial infections (requiring IV antibiotics at time of initiating study treatment),systemic fungal infection or detectable viral infection ( such as known HIV positivity or with known active hepatitis B or C (e.g. hepatitis B surface antigen positive). Screening is not required for enrolment.
Myeloma is a cancer of the bone marrow cells. Combining stem cell transplantation (SCT) with new drug treatments has shown to improve outcomes in myeloma patients. Some patients have been found to have genetic abnormalities in the myeloma cells and these ‘high-risk’ patients do not respond well to standard treatment. Some patients without these genetic abnormalities are also known to not respond as well to initial therapy. This study will investigate different treatment combinations for these two groups of patients. It will also investigate whether a third group of patients, who do respond well to initial treatment, can receive treatment for a shorter period of time without coming to harm. This study gives access to new treatments (the unlicensed drug isatuximab) and treatment combinations. All participants will receive the same initial induction treatment and during this time will have genetic tests to determine whether they have ‘standard-risk’ or ‘high-risk’ disease. Following this chemotherapy treatment participants will receive ASCT (A stands for autologous, meaning that the participant's own stem cells are used). After induction treatment participants will be allocated to a second stage treatment group based on their genetic risk, high-risk or standard-risk, and on how well the myeloma has responded to the initial treatment. Each treatment group will then receive different combinations of medication to investigate their benefit. Treatment will comprise of combinations of isatuximab, bortezomib, cyclophosphamide, lenalidomide and dexamethasone. Newly diagnosed myeloma patients, above the age of 18 who are suitable for SCT will be eligible for the study. Patients will be required to have bone marrow, blood and urine tests throughout the trial. Participants will also be asked to complete questionnaires about their quality of life. The study will be conducted in multiple hospitals throughout the UK. RADAR study is funded by Cancer Research UK, Celgene and Sanofi.
Inclusion criteria for registration 1.Previously untreated patients with multiple myeloma requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to IMWG diagnostic criteria 2.Eligible for stem cell transplant 3.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression); 4.Total bilirubin < 3 x upper limit of normal (ULN) 5.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 6.adequate marrow function: •neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 109/L is allowed), •haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted, •platelets > = 75 × 10^9/L (in the case of heavy bone marrow infiltration (> 50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of > = 50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted. 7.Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 8.Able to swallow oral medication 9.Aged at least 18 years 10.Agree to follow the pregnancy prevention guidelines 11.Able to provide written informed consent Inclusion criteria for starting isatuximab maintenance, R1, R2 and R3 1.4 cycles of RCyBorD received 2.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression); 3.Total bilirubin < 3 x upper limit of normal (ULN) 4.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 5.Adequate marrow function: •neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed), •haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted, •platelets > = 75 × 10^9/L (in the case of heavy bone marrow infiltration (> 50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of > = 50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted. 6.Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 7.Agree to follow the pregnancy prevention guidelines Additional inclusion criteria for starting isatuximab maintenance 1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q), as confirmed by the CTRU. 2.4 cycles of RCyBorD received 3.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R1 treatment pathway Additional inclusion criteria for R1 1.12 cycles of isatuximab maintenance received 2.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) after 12 cycles of isatuximab Additional inclusion criteria for R2 1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as confirmed by CTRU. 2.4 cycles of RCyBorD received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.MRD-positive (proportion of malignant cells in the bone marrow is > = 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT 5.Received > = 100mg/m^2 high-dose melphalan and ASCT 6.Signed the Informed Consent Document for the R2 treatment pathway Additional inclusion criteria for R3 1.High-risk (participant is confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q)) as confirmed by CTRU 2.4 cycles of RCyBord received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R3 treatment pathway
Exclusion criteria for registration (and for starting isatuximab maintenance, R1, R2 and R3) 1.Smouldering MM, monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM) 2.Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160mg dexamethasone. This criteria is not applicable at R1, R2 and R3 when participants will have received previous treatment for MM as part of this trial. 3.Unstable angina or myocardial infarction within 4 months prior to registration (or at any time since registration for participants starting isatuximab maintenance, R1, R2 and R3), NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker 4.Cardiac disorder identified according to local practice (eg left ventricular ejection fraction, LVEF; results from formal measurements acceptable within 28 days prior to registration) 5.Significant neuropathy (Grade > = 3, or Grade 2 with pain) 6.Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to registration. Cancer treated with curative intent for > 5 years previously and without evidence of recurrence will be allowed 7.Pregnant, lactating or breastfeeding female participants (within 28 days prior to starting isatuximab maintenance, R1, R2 and R3 8.Known resistance, intolerance or hypersensitivity to any component of the planned therapies, except in the case of hypersensitivity which is amenable to premedication with steroids or H2 blocker. Intolerance includes hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 9.Major surgery within 14 days before registration (or starting isatuximab maintenance, R1, R2 and R3). This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty. 10.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 11.Active systemic infection 12.Participant is hepatitis B surface antigen positive, hepatitis C antibody positive or HIV positive. Participants must have hepatitis and HIV screening conducted within 28 days prior to registration. 13.Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 14.Receipt of live vaccination within 30 days prior to registration, for the duration of the study and for 3 months after the last dose of study drug. Exclusion criteria for starting isatuximab 1.Disease progression 2.MRD-positive at 100 days post-ASCT 3.Registration exclusion criteria Exclusion criteria for R1 1.Disease progression 2.MRD-positive at 100 days post-ASCT or after 12 cycles of isatuximab 3.Registration exclusion criteria Exclusion criteria for R2 and R3 1.Disease progression 2.Registration exclusion criteria in Section
There is a paucity of data on the aetiology of myeloproliferative neoplasms (MPNs). The research group will conduct a UK wide case-control study of 560 patients with classic MPNs and up to 560 non-blood relative or friend controls to investigate the causes (aetiology) of MPNs and to evaluate quality of life2 (QoL). DNA and RNA samples from MPN patients and controls who participate in the case-control study will be collected and retained to evaluate gene-environment interactions upon receipt of additional funding.
• Have clinically confirmed MPN diagnosis (PV, ET or PMF); see definitions above. • Have been informed that they have a MPN. • Diagnosed within the previous 24 months. • Aged 18 years and over. • Capable of giving informed consent as determined by the treating clinician. • Physically and cognitively capable of completing the questionnaire as determined by the treating clinician. • Capable of completing the questionnaire in English language as determined by the treating clinician.
• Patients under 18 years old. • Where the clinician does not agree to inclusion • Incapable of giving informed consent as determined by the treating clinician. • Physically or cognitively incapable of completing the questionnaire as determined by the treating clinician. • Incapable of completing the questionnaire in English language as determined by the treating clinician. • Too ill to participate. The WHO performance evaluation scale will be used at the stage of participant identification by the clinician and retained. Only those scoring 0-3 will be considered eligible for inclusion in the study. Those scoring 3 are described as “Symptomatic > 50% in bed but not bedbound”. • Patients not expected to live more than 2 months. • Those who do not speak English language.
At the time of diagnosis of pancreatic cancer, an estimated 65% of patients have diabetes mellitus (DM). Whilst a small proportion of DM in pancreatic cancer patients is long standing (present more than 3 years) the remainder is new-onset-DM. This often goes undiagnosed, and when it is diagnosed, in the majority of cases this comes within one year prior to pancreatic cancer being identified. In effect, new-onset diabetes can be an early warning sign of the presence of pancreatic cancer, and individuals with new-onset diabetes are a high-risk group for pancreatic cancer. Approximately 1% of individuals (1 in 100) diagnosed with new onset type 2 DM (T2DM) have undiagnosed pancreatic cancer. This group of individuals actually has pancreatic cancer associated DM, although it is mistakenly diagnosed as T2DM. Currently individuals with new-onset DM are not screened for pancreatic cancer as there are no reliable tests to distinguish between T2DM and pancreatic cancer associated DM. Developing methods for pancreatic cancer detection in individuals with new-onset DM will require early-stage, pre-diagnostic samples and corresponding patient data. In this study we aim to recruit 2500 Individuals from hospitals and GP surgeries who are 50 years old or over and newly diagnosed with DM. Blood samples and questionnaire/clinical data will be collected at appointments every six months for two years. We will collect and store samples in a standardised way so that they can be used to identify biomarkers in the blood that will distinguish between DM caused by pancreatic cancer and type 2 DM. This may ultimately enable a screening programme in the future. As part of this study we will also attempt to gain a better understanding of risk factors associated with pancreatic cancer and to determin the cost effectiveness of screening for pancreatic cancer.
1. Age > = 50 at time of study entry. 2. New-onset diabetes (defined as HbA1C > = 48mmol/mol (6.5%)) diagnosed within 6 months of study entry. 3. Written informed consent obtained from the participant prior to performing any protocol-related procedures. 4. Participant is willing and able to comply with the protocol for the duration of the study including scheduled follow-up visits.
1. Diagnosis of pancreatic cancer within 5 years of study entry. 2. Treatment for digestive or endocrine cancer within 5 years of study entry. 3. Previous Surgical resection of the pancreas. 4. A known history of hyperglycaemia/pre-diabetes (HbA1c: 42-47 mmol/mol (5.9% - 6.4%)) of greater than three years duration. 5. Diagnosis of diabetes > 6 months before study entry. 6. Pregnancy. 7. Condition preventing study investigation and follow-up. 8. Inability or incapacity to give informed consent.
Acute Lymphoblastic Leukaemia (ALL) is the commonest cancer of children and young adults with over 400 cases diagnosed each year in the UK. While over 90% of children with ALL are cured, some people’s disease is harder to treat than others. ALLTogether1 investigates whether treatment can be reduced for children with the highest chance of cure, and whether the addition of new drugs improves the chance of cure for those whose disease is most likely to relapse. In the UK, ALLTogether1 will be open to patients aged 1-29 with newly-diagnosed ALL. Initially, patients will have standard chemotherapy and be registered for data collection only. Based on routine tests carried out before and during the early stages of chemotherapy, patients will be put into one of four risk groups based on how likely their disease is to relapse, for whom standard treatment and the questions that we want to ask will differ. There will also be further research questions for patients with specific needs, such as those whose leukaemia has genetic changes that can be targeted with particular drugs and patients with down syndrome. Children with standard risk and intermediate risk-low disease can take part in randomisations about whether one or two drugs can safely be removed from their standard treatment. Patients with intermediate risk-high disease can take part in a randomisation about whether adding Inotuzumab Ozogamicin to treatment can safely improve their chance of cure. We will be collaborating with researchers undertaking CAR-T cell trials and will aim to signpost young people with high risk disease to such studies. The trial will recruit approximately 8000 children and young people across Europe over a six-year period. Each patient will be on trial for at least 5 years (2 years of treatment, then a minimum of 3 years follow-up).
NB: The upper age limit of participants for the international trial is 45 years. However, the age limit for the UK is 29 years. Please see Performance Management Note in 'Notes' section of CPMS dated 20/07/2020 for explanation. 1. Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre. 2. Age ≥ 365 days and < 46 years (one day before 46th birthday) at the time of diagnosis. 3. Informed consent signed by the patient and/or parents/legal guardians according to country-specific age-related guidelines (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199 234.pdf ). 4. The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre. 5. The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries. 6. The patient should be a resident in one of the participating countries on a permanent basis or should intend to settle in a participating country, for instance by an application for asylum. Patients who are visiting the country as tourists should not be included. However, returning expatriots and patients who intend to stay at least for the duration of the treatment with primary diagnosis abroad may be included if no treatment has been administered and the diagnostic procedures are repeated at a participating centre. 7. All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment. 8. For each intervention/randomisation an additional set of inclusion-criteria is provided.
1. Age < 365 days at diagnosis (infant ALL) or > 45 years at diagnosis. 2. Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN). 3. Relapse of ALL. 4. Patients with mature B-ALL (as defined by Surface Ig positivity or documented presence of one of the t(8;14), t(2;8), t(8;22) translocations and breakpoint as in BALL). 5. Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR-ABL1 fusion transcript). These patients will be transferred to an adequate trial for t(9;22) if available. 6. ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory. 7. Treatment with systemic corticosteroids (> 10mg/m2 /day) for more than one week and/or other chemotherapeutic agents in a 4-week interval prior to diagnosis (pretreatment). 8. Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment). 9. Any other disease or condition, as determined by the investigator, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures. 10. Women of childbearing potential who are pregnant at the time of diagnosis. 11. Women of childbearing potential and fertile men who are sexually active and are unwilling to use adequate contraception during therapy. Efficient birth control is required, see section 17.7. 12. Female patients, who are breast-feeding. 13. Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair). For each intervention/randomisation an additional set of exclusion-criteria is provided. Patients who are not eligible according to the in- or exclusion criteria above will not be protocol-patients. However, in the case the treating physician considers the ALLTogether protocol their best available SOC, they may be treated according to the protocol at the discretion of the treating physician. Furthermore, they may be registered in a separate database of the ALLTogether consortium for non-protocol patients if this registration is compatible with the legal framework of the country in question and informed consent for this registration is obtained.
There is increasing evidence that the bacteria that live naturally in our mouth and gut (called our ‘microbiome’) influence our immune system and how it works. The mix of bacteria living in your microbiome is unique to you and this is affected by various factors, including your diet, your medications and where you live. Recently, some small studies have linked the presence of certain bacteria in a patient’s microbiome with the effectiveness of immunotherapy for cancer, particularly immune checkpoint inhibitor drugs that they have taken. Immune checkpoint inhibitor drugs are improving outcomes for cancer patients, these drugs work by reactivating immune cells to recognise and kill cancerous cells. However, these drugs do not work for everyone and they can also cause some people side effects that are difficult to tolerate. We would like to be able to identify patients who are likely to either benefit or experience side effects from these drugs, which we cannot do currently. Previous research has mainly focussed on looking for markers in blood and tumour samples that these drugs are working or causing toxicity. We plan to undertake a detailed study of the mouth and gut bacteria of patients receiving treatment with these drugs by collecting an oral swab sample prior to treatment as well as a series of stool samples prior to and during treatment. We will collect blood samples and also tumour tissue, if it is available to us. After we analyse these samples, we hope to better understand how the microbiome contributes to the effectiveness of immune checkpoint inhibitor drugs as well as potential side effects. We hope we can use this knowledge to tailor patient treatment and potentially develop better treatments in the future. We plan to recruit up to 1800 patients and 360 household controls over a 5 year period.
CANCER PATIENT • Signed informed consent and ability to comply with the study protocol • Aged > = 18 years old • Histological or cytological confirmation of invasive malignancy • Due to commence palliative, adjuvant or neoadjuvant systemic therapy including an anti-PD-(L)1 antibody ± anti-CTLA-4 antibody • Patients with unresectable disease must have radiologically and/or clinically measurable disease, by RECIST version 1.1; target lesions must not have been previously irradiated; baseline tumour assessments must be performed within 28 days prior to starting immune checkpoint inhibitor treatment. • Received no prior immune checkpoint inhibitors (previous treatment with other types of anti-cancer therapy is determined by patient cohort; for patients with unresectable disease, prior adjuvant therapy with immune checkpoint inhibitor(s) is allowed if completed at least 6 months previously). • Willingness and ability to comply with scheduled visits, treatment plans, sample collections and other study procedures.
CANCER PATIENT • Other invasive malignancies diagnosed within the last year which are not fully resected, or in complete remission, or for which additional therapy is required • Significant acute or chronic medical or psychiatric condition, disease, or laboratory abnormality, which in the judgment of the investigator would place the patient at undue risk, or interfere with their ability to comply with the study. Examples include, but are not limited to: o Patients with uncontrolled ischaemic heart or other cardiovascular event eg. myocardial infarction, new angina, stroke, transient ischaemic attack, or new congestive cardiac failure within the last 6 months o Presence of active infection o Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C o Current active, severe, or uncontrolled autoimmune condition, including but not limited to Crohn’s disease and ulcerative colitis. • Women who are pregnant, plan to become pregnant, or are lactating during the study period • Requirement for daily non-physiological dose of oral steroids, or regular use of any other immunosuppressive agents; less than 10mg prednisolone or equivalent doses are allowed. Use of inhaled or topical steroids is allowed. HOUSEHOLD CONTROLS Confirmation of suitability to be a household control participant will be determined by completing a self-assessed questionnaire either at home or in clinic. Household controls must: • NOT have had any gastrointestinal infections i.e., parasites, viruses or diarrhoeal episodes during the last 6 months. • NOT have taken antibiotics for at least 6 months • NOT have or be recovering from any chronic intestinal disease such as: o Crohn’s disease o Ulcerative colitis o Coeliac disease o Irritable bowel syndrome o Stomach ulcers • NOT have a chronic autoimmune disease or significant allergies e.g., multiple sclerosis, asthma requiring regular medication, psoriasis. • NOT have and NOT be recovering from any form of cancer. • NOT take proton pump inhibitors, steroids, other non-steroidal anti-inflammatory drugs such as ibuprofen or aspirin. In addition, household controls must sign informed consent and be aged > = 18 years old.
Some patients with early breast cancer are treated with chemotherapy before or after surgery. Chemotherapy is given with the aim of eradicating any cancer cells that may have escaped into the general circulation and reduce the risk of the cancer returning. Chemotherapy treatment in this setting is most effective if patients receive the optimum dose, on time and without delays or reductions in their treatment doses. Chemotherapy doses are calculated from a patient’s height and weight. However, these calculations were designed for normal weight patients which has resulted in uncertainty as to whether patients with different amounts of blood, muscle and fatty tissue (body composition) are being dosed with chemotherapy correctly. For example, obesity is defined by body mass index calculated from height and weight but this does not take into account that people of the same size can have differing body compositions which can affect the behaviour of drugs. Approximately 26% of British women are considered to be obese and obese breast cancer patients have a higher risk of disease recurrence than healthy-weight patients. Our pilot study, CANDO-2, has confirmed that body composition data from early breast cancer patients attending routine chemotherapy out-patients can be collected quickly and easily by asking patients to stand on a sBIA analyser for a few minutes and that these measurements may help predict when patients might need to unexpectedly return to hospital during chemotherapy for side effects or problems. In the Cando-3 study we will be collecting body composition data from over 300 women receiving routine chemotherapy before or after breast surgery across seven UK hospital sites. We will collect information on the chemotherapy drugs and doses each patient receives and the side effects they experience to investigate how different patterns of body composition are associated with intolerance and side effects from chemotherapy.
1) Early invasive breast carcinoma 2) Stage I-III disease 3) Tumour grade, ER and HER 2 status available from core biopsy 4) Clinical or pathological tumour size and lymph node status available 5) Neo-adjuvant or adjuvant systemic chemotherapy recommended by local breast multi-disciplinary meeting 6) No prior systemic anti-cancer treatment 7) No evidence of metastatic disease 8) Patient agrees to receive neo/adjuvant chemotherapy 9) Planned to receive 4-6 21 day cycles of anthracycline or taxane based combination chemotherapy 10) Aged> = 18 years and< 80 years 11) Female 12) Able to complete written records in English
1) Previous invasive malignancy (with the exception of non-melanomatous skin cancer) 2) Any other medical conditions preventing physical participation in the study procedures 3) Patients receiving single agent or weekly neo/adjuvant chemotherapy regimens eg weekly paclitaxel with trastuzumab
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.
Myeloma is a cancer diagnosed in around 5500 patients within the UK, each year. The development of treatments have increased life expectancy in all patients, but these have been less effective in older and frailer patients. There is no evidence to suggest their Myeloma is more aggressive, so it needs to be asked why this is the case. Research is beginning to look at older Myeloma patients who are ineligible for transplants. Myeloma XI, a trial previous to this run at the CTRU, where 1840 of these patients were recruited, has shown that treatment outcomes were not necessarily associated with different combinations of treatment. Frailty-adjusted can potentially show how problems developed during treatment that are not responding effectively so it can be minimised. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomised on a 1:1 basis at trial entry to either frailty score-adjusted treatment vs.standard up-front treatment followed by toxicity dependen dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomisation. In the second phase of the trial, patients will be tested to assess whether lenalidomide and ixazomib is effective as a maintenance treatment. Patients will either receive lenalidomide and ixazomib, or lenalidomide and placebo (something that has a similar taste and appearance to ixazomib but has no effect on the person) to test this. Participants and their treating physicians will be blinded to maintenance allocation. Aims: This trial aims to determine and compare: a) Frailty adjusted dosing induction treatment compared to standard dosing induction treatment with modifications allowed where toxicity is seen b)If there is an improved response rate and overall survival rate when patients receive lenalidomide plus ixazomib vs lenalidomide alone. Methods: A phase III, multi-centre, randomised controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant.
Inclusion criteria for Randomisation 1 (R1): 1. Newly diagnosed as having multiple myeloma (MM) according to the updated International Myeloma Working Group (IMWG) diagnostic criteria 2014 (see Appendix 1 in protocol for criteria) requiring treatment. 2. Not eligible for stem cell transplant. 3. Aged at least 18 years. 4. Meet all of the following blood criteria within 14 days before R1: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L, or, in the case of heavy bone marrow infiltration (> = 50%) which in the opinion of the investigator is the cause of the thrombocytopenia and provided appropriate supportive measures and patient monitoring are in place, platelet count > = 30 x 10^9/L is permitted. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN. 5. Meet the pregnancy prevention requirements: Female participants who: a) Are not of childbearing potential (Appendix 8 in protocol), OR b) If they are of childbearing potential, agree to practice 2 effective methods of contraception (Appendix 8 in protocol), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a) Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Contraception for female and male participants must be in accordance with (and participants must consent to) the Celgene-approved Pregnancy Prevention Programme. If female and of childbearing potential (see Appendix 8 in protocol), they must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Pregnancy Prevention Programme. 6. Able to provide written informed consent. Inclusion criteria for Randomisation 2 (R2): 1. Randomised into the FiTNEss (Myeloma XIV) trial and received induction chemotherapy with ixazomib and lenalidomide continued for 12 cycles. 2. Achieved at least MR at the end of IRD induction according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol), with no evidence of progression prior to R2. 3. Meet all of the following blood criteria within 14 days before R2: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN.
Exclusion criteria for Randomisation 1 (R1): 1. Smouldering MM, MGUS, solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM). 2. Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160 mg dexamethasone. 3. Known resistance, intolerance or sensitivity to any component of the planned therapies. 4. Prior or concurrent invasive malignancies except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention; ‐ Any cancer from which the subject has been disease-free for at least 3 years. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Any concomitant drug therapy which, in the opinion of the investigator, may lead to an unacceptable interaction with any of the agents ixazomib, lenalidomide, dexamethasone, and that cannot be safely stopped prior to trial entry. Full details of interactions can be found in the SPCs. 9. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 10. > = Grade 2 peripheral neuropathy. 11. Known HIV positive 12. Participant has current or prior hepatitis B surface antigen positive or hepatitis C antibody positive. Participants must have screening conducted within 14 days before R1. 13. Active systemic infection. 14. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. Exclusion criteria for Randomisation 2 (R2): 1. Received any anti-myeloma therapy other than their randomised trial treatment, with the exception of local radiotherapy to relieve bone pain (in the absence of disease progression), or bisphosphonate treatment. 2. SD or disease progression according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol). 3. Known resistance, intolerance or sensitivity to ixazomib or lenalidomide that required cessation of either agent during induction. 4. Developed any malignancy since R1 except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 9. > = Grade 2 peripheral neuropathy, or grade 1 with pain. 10. Known HIV positive 11. Current or known hepatitis B surface antigen positive or hepatitis C antibody positive. 12. Active systemic infection. 13. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s continued participation in this study.
Cancer diagnosis/treatment results in unwanted symptoms/toxicity so assessing the risks and benefits of new treatments requires knowledge of both effectiveness against the cancer and impact on quality of life. Several research groups, including the EORTC, have developed questionnaires to measure quality of life so that patients can be monitored and their treatment side effects investigated. These groups are now looking to enhance the use of their questionnaires more efficiently. It would be helpful to pool results from studies using different questionnaires investigating the same symptoms, but because the questions on each questionnaire are subtly different, this is not easy. In this study patients complete several widely used similar questionnaires. Their scores are then compared with those from the EORTC questionnaires. Using statistical analysis we will produce an algorithm (mathematical equation) 'converting' scores between questionnaires. The algorithm could be useful in clinical research when two groups of researchers are investigating a new drug with a side effect of fatigue but are using different questionnaires to assess this e.g EORTC Fatigue Scale versus FACT Fatigue Scale. The algorithm will link the scores by ‘predicting’ the score on one questionnaire using the score on the other. The two studies can then be compared, or their results pooled, giving a larger sample for analysing any effect. Using other statistics we will compare all the questionnaires and see how good (or not) they are at detecting symptoms (validity and reliability) and how sensitive they are to changes over time as the symptoms worsen or improve . Knowing which are the most sensitive questionnaires for different domains of quality of life and side effects is critical because fewer patients would then need to be recruited in future research.
Cross Sectional Sample: 1. Any cancer diagnosis and any (previous) treatment 2. > 18 years of age 3. Ability to provide written informed consent 4. Good literacy skills Longitudinal Sample: 1. Any cancer diagnosis 2. Patients about to start first line chemotherapy (Previous treatment e.g surgery/radiotherapy or no prior treatment is acceptable) 3. > 18 years of age 4. Ability to provide written informed consent 5. Good literacy skills Survivorship Sample: 1. Any cancer diagnosis and any (previous) treatment 2. Completed primary curative treatment at least 12 months previously or receiving maintenance therapies (hormonal therapies) 3. > 18 years of age 4. Ability to provide written informed consent. 5. Good literacy skills
Cross-sectional sample 1. Patients with brain metastases 2. Patients with serious cognitive impairment 3. Patients participating in other competing quality of life studies 4. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. Longitudinal Sample: 1. Previous chemotherapy 2. Patients not having chemotherapy or whose chemotherapy has already commenced. 3. Patients with brain metastases 4. Patients with serious cognitive impairment 5. Patients participating in other competing quality of life studies 6. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. Survivorship Sample: 1. Patients with brain metastases 2. Patients with serious cognitive impairment 3. Participating in other competing quality of life studies 4. Poor literacy skills - inability to read and understand the PIS, consent and questionnaires which will only be available in English. 5. Patients currently on treatment
FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS). It is a multi-arm, multi-stage format, involving several different trial questions. FaR-RMS is intended to be a rolling programme of research with new treatment arms being introduced dependant on emerging data and innovation. This study has multiple aims. It aims to evaluate the impact of new agent regimens in both newly diagnosed and relapsed RMS; whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent (in metastatic disease) and timing of radiotherapy improve outcome and quality of life. In addition the study will evaluate risk stratification through the use of PAX-FOXO1 fusion gene status instead of histological subtyping and explore the use of FDG PET-CT response assessment as a prognostic biomarker for outcome following induction chemotherapy. Newly diagnosed patients should, where possible, be entered into the FaR-RMS study at the time of first diagnosis prior to receiving any chemotherapy. However, patients can enter at the point of radiotherapy or maintenance, and those with relapsed disease can enter the study even if not previously entered at initial diagnosis. Patients may be entered into more than one randomisation/registration, dependant on patient risk group and disease status.
Inclusion Criteria for study entry 1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS) 2. Written informed consent from the patient and/or the parent/legal guardian Inclusion criteria for all randomisations and registrations: • Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active • Written informed consent from the patient and/or the parent/legal guardian • Medically fit to receive treatment Frontline chemotherapy specific inclusion: • Entered in to the FaR-RMS study at diagnosis • No prior treatment for RMS other than surgery • Documented negative pregnancy test for female patients of childbearing potential • Adequate hepatic function: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome Phase 1b Specific Inclusion • VHR disease • Age > 12 months and ≤25 years • Adequate hepatic function: ALT or AST < 2.5 X ULN for age • Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 • Absolute neutrophil count ≥1.0x 10^9/L • Platelets ≥ 80 x 10^9/L CT1a specific inclusion • VHR disease • Age ≥ 6 months • Available for randomisation ≤60 days after diagnostic biopsy/surgery • Fractional Shortening ≥ 28% • Absolute neutrophil count ≥1.0x 10^9/L (except in patients with documented bone marrow disease) • Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) CT1b specific inclusion • HR disease • Age ≥ 6 months • Available for randomisation ≤60 days after diagnostic biopsy/surgery • Absolute neutrophil count ≥1.0x 10^9/L • Platelets ≥ 80 x 10^9/L Radiotherapy Inclusion • Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) • VHR, HR and SR disease • ≥ 2 years of age • Receiving frontline induction treatment as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen • patients for whom. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible • Documented negative pregnancy test for female patients of childbearing potential • RT1a and RT1b Specific Inclusion • Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy • (6 cycles for metastatic disease) • Adjuvant radiotherapy required in addition to surgical resection (local decision). • Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised • disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease RT1b and RT1c Specific Inclusion • Higher Local Failure Risk (HLFR) based on presence of either of the following criteria: • Unfavourable site • Age ≥ 18yrs RT1c Specific Inclusion • Primary radiotherapy indicated (local decision) • Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease RT2 Specific Inclusion • Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy. • Unfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4 Maintenance specific Inclusion • Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy • regimen • Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible • No evidence of progressive disease • Absence of severe vincristine neuropathy – i.e requiring discontinuation of vincristine treatment) CT2a specific inclusion • VHR disease • Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens) CT2b specific Inclusion • HR disease • Completed 5 cycles of VnC maintenance treatment Relapse CT3 specific Inclusion • Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse) • Age ≥ 6 months • First or subsequent relapse of RMS • No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks • Documented negative pregnancy test for female patients of childbearing potential
Phase 1b specific exclusion • Weight < 10kg • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) CT1a and CT1b specific exclusion • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) Radiotherapy specific exclusion • Prior allo- or autologous Stem Cell Transplant • Second malignancy • Pregnant or breastfeeding women • Receiving radiotherapy as brachytherapy CT2a and CT2b specific Exclusion • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter current illness or active infection • Second malignancy • Pregnant or breastfeeding women • Urinary outflow obstruction that cannot be relieved prior to starting treatment • Active inflammation of the urinary bladder (cystitis) CT3 specific exclusion • Active > grade 2 diarrhoea • Prior allo- or autologous Stem Cell Transplant • Uncontrolled inter-current illness or active infection • Pre-existing medical condition precluding treatment • Known hypersensitivity to any of the treatments or excipients • Second malignancy • Pregnant or breastfeeding women
Pancreatic cancer has one of the worst overall survival of malignancy (five year survival under 10%). The main reason for this is late detection. Symptoms are non- specific and screening of asymptomatic individuals is impractical as no current screening system has adequate specificity to avoid false positives exceeding true positives, treatment for pancreatic cancer involves surgical resection of the organ with very high associated morbidity and even mortality. In order to develop and validate improved screening modalities these need to be applied to high risk individuals. Current guidelines only allow research screening in individuals with an autosomal dominant predisposition for pancreatic cancer. The European Registry for heredity pancreatitis and familial pancreatic cancer (EUROPAC) was established in 1996 in order to identify individuals at high risk of pancreatic cancer. We wish to continue recruitment to this registry and to continue to pilot secondary screening for pancreatic cancer in the individuals registered. The registry has also proved an invaluable resource in order to study pancreatic diseases in general: diabetes, acute and chronic pancreatitis as well as cancer. We also wish to continue this analysis. The screening we propose to carry out will be based on established methods of pancreatic imaging including Endoluminal Ultrasound, Computed Tomography and Magnetic Resonance Imaging. This will be supplemented by use of biomarkers which will at first be purely experimental but following validation will be used to phase subsequent screening. Epidemiological and demographic data as well as clinical reports will be used to stratify cancer risk and to monitor disease progression: acute pancreatitis can progress to chronic pancreatitis with endocrine and exocrine failure; diabetes mellitus can be both an early sign of pancreatic cancer and also a risk factor.
Inclusion Criteria for Registry: Cancer families: Two first degree relatives with pancreatic adenocarcinoma. A family with three or more relatives with pancreatic ductal adenocarcinoma. Families with pancreatic cancer and other cancers (e.g. bowel, breast/ovarian, melanoma, gastric) that suggest a known cancer predisposition syndrome: Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Familial atypical mole melanoma (FAMMM). Lynch Syndrome. Breast Ovarian Cancer Peutz-Jegher's syndrome Li Fraumeni syndrome Families with a causative mutation in a gene linked to pancreatic cancer (e.g. PALB2 BRCA2 or genes prospectively discovered to be linked to pancreatic cancers) and at least one case of pancreatic cancer in the family. Pancreatitis families: Families with two or more relatives with idiopathic pancreatitis. Families with at least one case of pancreatitis and a confirmed causative mutation in the PRSS1 gene. Cyst surveillance: Individuals already enrolled on surveillance due to identification of a pancreatic cystic lesion NOD individuals: Individuals over the age of 40 with diabetes mellitus diagnosed in the last 6 months Disease control Individuals with: diagnosed pancreatic ductal adenocarcinoma; acute or chronic pancreatitis of any aetiology; and individuals with long term (over two years) type 2 or 3c diabetes mellitus Inclusion Criteria for Screening: Individuals over 40 years of age from an established pancreatic cancer family where the family is consistent with predisposition with high penetrant autosomal dominant inheritance (for example, at least two first degree relatives with pancreatic ductal adenocarcinoma, where no non-penetrant carriers have to be assumed over the age of 75). Individuals with Peutz-Jeghers syndromes, or individuals with affected relatives under the age of 50 will be considered for inclusion below the age of 40. Unaffected members of a family with an associated cancer syndrome and at least one case of pancreatic cancer, who are over 40 years of age and who have been shown to carry the relevant genetic alteration. Any member of a Hereditary Pancreatitis (HP) family (autosomal dominant predisposition for pancreatitis) who have been confirmed to carry a causative PRSS1 mutation or (where no causative mutation is known) have symptoms of pancreatitis. Individuals incidentally found to have cystic lesions or other clinical features that indicate an increased risk of pancreatic cancer may also be included. There will be adaptation to risk models as the study progresses to fit the needs of the study outcomes.
Any individual who is incapable of providing informed consent. For genetic testing: Any individual who does not consent to be informed of clinically significant results. Genetic testing specifically for research purposes at a specific locus with no actionable clinical significance can be carried out (e.g. for a polymorphism that may associate with disease but is not causative), but only with explicit consent from the individual. For screening: Individuals of less than 40 years of age or 10 years younger than the youngest case in the family will be excluded. Risk assessment will be made using progressively developed models any individual deemed to have less than 2% chance of developing PDAC in the next three years will be excluded (this will depend on the evidence supporting the models and the exclusion will only apply if the steering committee agrees on the risk assessment). Any female participant able to bear a child but who has not taken appropriate contraceptive measures.
An increasing number of patients with early rectal cancer in the UK are being identified through the bowel screening programme. There is a growing number of patients who may not be suitable for surgery, due to other medical comorbidities and factors. These patients may suffer from symptoms as their cancer grows, including pain, diarrhoea and the need for a stoma (bowel bag). For these patients, radiotherapy combined with chemotherapy, or radiotherapy only is used. A standard dose of radiotherapy given over 5.5 weeks can lead to the cancer disappearing in about one third of patients. In this trial we want to find out if a higher radiotherapy dose given over the same time will give greater benefit to patients with acceptable side effects. This could lead to better treatment and improved quality of life.
- Biopsy confirmed adenocarcinoma of the rectum - Age 18 or over - Able to provide written informed consent - MDT deems patient unsuitable for radical TME surgical resection of their tumour either because they are considered to be at increased surgical risk from TME (for example due to general frailty or due to specific co-morbidities which make anaesthetic or surgery hazardous, such as cardiac disease, pulmonary disease, renal failure, previous anaesthetic problems or previous pelvic surgery), or they have marked anxiety at the prospect of a stoma, or because of anticipated difficulty managing a stoma post-operatively (including physical causes such as arthritis, Dupuytren’s contracture and visual problems). - Patient is suitable for either pelvic radiotherapy or chemoradiation in the opinion of the treating oncologist - ECOG PS 0-2 - Primary tumour is < = 4 cm in maximum diameter - Primary tumour is staged at T1-T3b. (TNM staging as per UICC 8th Edition (Appendix B), with additional T3 subdivisions) - Tumour is visible on MRI - Superior aspect of tumour is at or below a horizontal line drawn from the anterior aspect of the S2/3 junction on pre-treatment MRI - No unequivocally involved lymph nodes, i.e. NX (nodes too small to characterise as to say equivocal nodes) and N0 are both eligible - For low rectal tumours superior to the puborectalis sling, patients are eligible if the mesorectal fascia or levator are: o Clear (> 1 mm from disease to levator ani or mesorectal fascia) o or threatened (< = 1mm from disease to levator ani or mesorectal fascia) o or mesorectal fascia is involved but not breached - Estimated creatinine clearance > = 50 mls/min (estimated using a validated creatinine clearance calculation e.g. Cockroft and Gault (Appendix D) or Wright formula) - Absolute neutrophil count > 1.5 x 109/l; platelets > 100 x 109/l - Serum transaminase concentration < 3 x Upper Limit Normal (ULN) - Bilirubin concentration < 1.5 x ULN
- Nodal involvement identified by nodes showing irregular margins and or heterogeneous signal on the high resolution MRI (i.e. N1-N2) - The presence of EMVI discontinuous with the primary tumour - Discontinuous tumour deposits (N1c) - Dominant mucinous tumour on MRI - Signet ring carcinoma or tumours histopathologically containing a neuroendocrine component - Tumour has grown through and breached mesorectal fascia - Tumour involves or breaches the levator ani (as this would be T4b disease) - Involvement of anal intersphincteric plane or external anal sphincter or adjacent organs (If the participant has a low rectal tumour extending inferior to the puborectalis sling, involvement of the internal anal sphincter is permitted) - Undergone an attempt at complete local resection of their cancer - Previous pelvic radiotherapy - Definite distant metastases (equivocal distant metastases on the CT scan are permitted, e.g. indeterminate lung modules, sub-centimetre retroperitoneal nodes or indeterminate liver lesion) - Defunctioning colostomy or ileostomy has been fashioned - Prior invasive malignancy unless disease free for a minimum of 3 years (excluding basal cell carcinoma of the skin or other in situ carcinomas) - Prior systemic chemotherapy for colorectal cancer - Women who are pregnant, breastfeeding or a women of child bearing potential who are unwilling to use effective contraceptive methods
This trial is being carried out to explore the safety, tolerability and anti-tumour activity of a combination of gemcitabine and a new anti-cancer drug called AZD6738 in patients with solid tumours. Gemcitabine is anti-cancer drug which is routinely used as a treatment for various types of cancers. There are 2 parts to this trial. All participants will receive both study drugs. Part 1 is a dose escalation phase. During this phase AZD6738 will be given in combination with gemcitabine. Doses will be increased as participants are recruited. Within part 1 there are 2 treatment schedules, continuous and intermittent. Participants will be allocated to either the continuous administration schedule (AZD6738 once daily for 21 days and gemcitabine administered on days 3, 10 and 17 of every 28 days cycle) or the intermittent administration schedule (AZD6738 once daily on days 1 to 4, 8 to 11 and 15 to 18, and gemcitabine administered on days 3, 10 and 17 of every 28 days cycle). Part 2 is a dose expansion phase and will only recruit patients with inoperable, locally advanced or metastatic pancreatic cancer. The schedule(s) and dose levels determined from Part 1 will be allocated to all participants. Up to 55 evaluable participants will be recruited across approximately 4 participating sites. Up to forty (40) participants will be registered in to the dose escalation phase of the trial, followed by up to fifteen (15) participants in the treatment expansion phase. Participants will undergo routine and research tests and assessments. Participation is expected to last a maximum of 1 year, plus a 28 day screening period. Participants that have withdrawn or completed the study will be referred back to their usual hospital doctor.
To be included in the trial the participant must meet all of the following criteria: • Written informed consent to participate. • Aged 18 years and over. • ECOG performance status of 0 or 1. • Dose escalation phase only: Patients with inoperable/unresectable, histologically proven, locally advanced or metastatic solid tumour that has progressed on standard therapy, or patients unwilling to receive standard therapy. • Treatment expansion phase only: Patients with inoperable, histologically proven, locally advanced or metastatic pancreatic adenocarcinoma that has progressed on conventional chemotherapy, or patients unwilling to receive standard therapy. • Documented evidence of progression (radiological or clinical) prior to trial entry. • Estimated life expectancy of > = 12 weeks. • Measurable tumour lesions that can be accurately assessed at baseline by computed tomography (CT) and are suitable for repeated assessment as per RECIST 1.1 and considered accessible for core biopsy. • Women of childbearing potential, male participants and their partners are required, and must be willing, to use 2 highly effective forms of contraception for the duration of the trial and for six (6) months after the completion of the trial treatment. Women of non-childbearing potential must meet one of the following: • Documented postmenopausal (defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments). • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy with last menses > 1 year ago (excluding tubal ligation, radiation-induced oophorectomy). • Documented amenorrhoeic for 12 months (defined as women under the age of 50 years with serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution). • Patient is willing and able to comply with the protocol for the duration of the trial.
• Diagnosis of ataxia-telangiectasia syndrome. • Women who are pregnant or breast-feeding. • Women of child-bearing potential and male participants who are unwilling to use 2 highly effective forms of contraception during the trial and for 6 months after the completion of the trial treatment. • Cytotoxic chemotherapy within 21 days of start of treatment (greater than five half-lives is allowed for washout in patients treated with non-cytotoxic drugs). Exposure to a small molecule IMP within 30 days or 5 half-lives (whichever is longer) prior to the start of treatment. • Palliative radiotherapy within 21 days of start of treatment. • Immunotherapy within 42 days of start of treatment. • New treatment with bisphosphonates or denosumab for bone metastases within 5 days of start of treatment (patients can receive a stable dose of bisphosphonates or denosumab for bone metastases before and during the trial as long as these were started at least 5 days prior to start of treatment). • Major surgery within 2 weeks of start of treatment (patients must have recovered from any effects of major surgery). • Current treatment with steroids (doses of > 10mg of prednisone or equivalent) or other immunosuppressive drugs within 14 days of start of treatment. • Any other malignancy which has been active or treated within the past three years (with the exception of cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively treated with no evidence of disease for > = 5 years prior). • Current treatments with known potent cytochrome P (CYP) 3A inhibitors, potent CYP3A inducers, CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index or Pgp modulators (wash out period of five half-lives, but three weeks for St. John’s Wort, see Appendix 5). The use of herbal supplements or ‘folk remedies’ is not permitted. • Impaired hepatic or renal function defined as: o AST or ALT > 2.5 x ULN (or 5 times if liver metastasis). o Total bilirubin > 1.5 x ULN. o Glomerular filtration rate (GFR) (calculated by Cockcroft-Gault) of < 41 ml/min. • Inadequate bone marrow reserve or organ function defined as: o Absolute neutrophil count < 1.5 x 10*9/L. o Platelet count < 100 x 10*9/L with no blood transfusions in the past 28 days. o Haemoglobin < 90 g/L with no platelet transfusions in the past 28 days. • INR > = 1.25 above the normal range. • Haematuria +++. • Known history of cardiac dysfunction within the last 6 months defined as: o Myocardial infarction o NYHA Class II/III/IV heart failure o Unstable angina pectoris o Unstable cardiac arrhythmias not controlled with a pacemaker or medication (e.g. complete left bundle branch block or third degree heart block). • Any of the following cardiac criteria: o Mean resting corrected QT interval (QTc) > 470 msec for women, and > 450 msec for men obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula. o Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mmHg. o Patients with known reduced LVEF < 55%. o Patients at risk of brain perfusion problems (e.g. medical history of carotid stenosis, pre-syncope, syncope episodes or a history of transient ischaemic attack). o Uncontrolled hypertension (grade 2 or above) requiring clinical intervention. • Patients unable to swallow orally administered medication and with gastrointestinal disorders likely to interfere with absorption of AZD6738. • Any other concurrent severe and/or uncontrolled medical condition that places the patient at unacceptable risk of toxicity or non-compliance (examples include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome, extensive bilateral lung disease on high resolution CT scan, severe Parkinson’s disease, active inflammatory bowel disease, psychiatric condition, or active infection (including any patient known to have hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral drugs)). Screening for chronic conditions is not required. • Prior exposure to an ATR inhibitor. • A known hypersensitivity to AZD6738 or gemcitabine (e.g. excessive myelosuppression), any excipient of the products, or any contraindication to the combination of anti-cancer agents. • Any unresolved toxicities from prior therapy of CTCAE grade > 1 (with the exception of alopecia and CTCAE grade 2 neuropathy). • Spinal cord compression (unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of treatment). •Brain metastases. • Judgment by the Investigator that the patient should not participate in the trial.
-What is the problem? Although sarcoma patients have higher survival rates with different treatments, they often experience side-effects and psychosocial issues that negatively impact health-related quality of life(HRQoL) during and long after treatment. Therefore, it is important to assess treatment effectiveness both in terms of objective outcomes (survival, recurrence) and in terms of subjective patient reported outcomes including HRQoL. Generic HRQoL instruments are available, but questionnaires capturing all of the unique experiences of sarcoma patients is currently lacking. -What are our aims? To be able to develop a HRQoL instrument specifically for sarcoma-patients, this study aims to provide insight into the relevant HRQoL issues in this patient-group. Furthermore, we will investigate how to design the questionnaires: one list for all sarcoma patients or items based on patient and sarcoma-characteristics. -How will we do this? This study has a mixed method design. In the first phase of this study, semi-structured interviews will be conducted with sarcoma patients and health care professionals about the HRQoL issues that they experience. Subsequently, the respondent will be asked to review the EORTC QLQ-C30 and a site-specific module, if available, for topic and item relevance. These results will be combined with data from previous literature to create an extensive issue-list. In the second phase, we will present the list of HRQoL issues to another group of sarcoma patients and health care professionals and ask them to rate the issues on relevance and to prioritize the 10 most important issues. -What can we learn? The results of this study will help to develop a HRQoL instrument that can be used in future studies to assess not only adverse events and efficacy of new treatments, but also their impact on common functional health problems reported by sarcoma patients.
A confirmed diagnosis of sarcoma; age 18 years or older; informed consent provided. Although sarcoma is a disease of all ages, we decided to include only those 18 years and older because the EORTC QLQ-C30 is only validated among cancer patients 18 years and older. Age-specific questionnaires are available for those patients under 18 years.
-Having any psychiatric condition or cognitive impairment that would hamper participation in interview/completion of self-reported questionnaires. -Patients who are too ill (death is imminent), as determined by the referring health care professional, will be excluded. -Patients with a GIST diagnosis, who are quite unique in terms of type of disease and treatment. For example, while localised GISTs respond well to surgery, large unresectable or metastatic tumours are resistant to conventional chemotherapy and radiotherapy. -Patients with Kaposi sarcoma, as this disease occurs quite often in people with AIDS -Patients with Carcinosarcoma as this disease is generally seen as a carcinoma
This ethics application is a continuation of the project titled: Generation of ductal carcinoma in situ prognostic gene signature using retrospective archived paraffin embedded tumour samples. The study was given ethical approval on November 2008 by West Glasgow Ethics Committee 1 ( REF 08/S0703/147) The Sloane Project is a UK wide prospective audit of screen detected non-invasive and atypical breast hyperplasias. Non invasive breast neoplasia accounts for 25% of all ‘breast cancers’ detected through breast screening and includes ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Atypical hyperplasias are high risk benign lesions and are found in 10% of benign biopsies performed through the screening programme. The importance of these lesions rests on the increased risk of subsequently developing invasive breast cancer with DCIS at highest risk ( 20 times greater than the general population) followed by LCIS (2-11 times greater) and atypical breast hyperplasia (4 times greater). The Sloane project data are held by Public Health England (PHE) and provide full and detailed information about the patients' journey from diagnosis to treatment and outcome. The project aims to increase the understanding of these early breast lesions which can lead to breast cancer. All NHS breast screening units in the UK are invited to send in data for the Sloane Project. The objective of this research protocol is the collection of formalin fixed paraffin embedded (FFPE) tissue blocks from women whose data is held within the Sloane Project in order to allow detailed analysis of the genomic changes in cases of in situ and atypical hyperplasia and how these relate to the corresponding annotated clinical, pathological and radiological data collected by PHE in order to identify a particular signature that define which cases are likely to develop invasive disease.
Women of screening age identified through the Sloane project with ductal carcinoma in situ, lobular carcinoma in situ or atypical hyperplasia.
Women with a previous history of invasive breast cancer
Men diagnosed with prostate cancer that has spread to other organs are currently treated with drug therapy alone usually androgen deprivation therapy (ADT). ADT suppresses the male hormone, testosterone, which the prostate cells need to grow.Some men also have chemotherapy with ADT Recent evidence shows treating the main cancer in the prostate itself might prolong the time ADT control the cancer and might improve survival.Treatment directed to the metastases has also shown some initial promising data.There are no randomised controlled trials (RCT) that have shown this yet so we need better evidence to see if local treatment to the prostate might be beneficial in combination with treatment to metastases in some men. This is important since local radical therapy(surgery or radiotherapy)can have side-effects.Ablation therapy using heating or freezing has shown to have lower side-effects when used in men whose cancer has not spread so might be a alternative to radical therapy in men with metastatic cancer. Eligible men will be asked to participate in a RCT comparing standard drug therapy to radical therapy (surgery or radiotherapy) or local ablation (heating or freezing) therapy,in combination with metastases directed therapy in select men. 80 men will be approached in 10 UK centre to estimate recruitment rate, acceptability of the trial randomisation, reported toxicities and adherence to trial interventions in a pilot phase. They will also be included into the Main phase where 918 will be recruited. Participants will remain in the study for a maximum of 4 years. Our aims are to see whether men will participate in this trial (pilot) before we continue to run a larger trial (Main), and the impact of these treatments on quality of life. [68Ga]PSMA-11 PET-CT substudy: Embedded within the pilot phase this sub-study assesses the role of [68Ga]PSMA-11 PET in metastatic prostate cancer as this unknown. Blood and urine taken from patients will establish prognostic & predictive factors
1. Diagnosed with prostate cancer within 6 months of screening visit 2. Metastatic disease (Tany, Nany, M1+) any grade, stage or Prostate Specific Antigen (PSA) level 3. Fit to undergo standard of care treatment for metastatic disease and both minimally invasive therapy and prostate radiotherapy/prostatectomy. 4. Performance status 0-2 5. Histologically proven local tumour Embedded [68Ga]PSMA-11 PET sub study Patients must meet all the criteria listed in the main protocol and the following criteria for sub-study entry. Signed separate consent for participation in the ATLANTA PET Sub-study is required. Main Inclusion Criteria: 1. Confirmed newly diagnosed metastatic prostate cancer as per PCWG3 guidelines (MPC is defined as extrapelvic disease e.g. retroperitoneal, mediastinal, thoracic), who are due to start ST (physician directed). 2. Age > = 18 years 3. WHO performance status < = 2 4. Clinically acceptable full blood count, renal and liver function (as judged by the investigator)
1. Patient did not undergo and/or is unable to undergo standard of care baseline imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest Xray (or CT chest) AND radioisotope bone scan (or whole body imaging such as MRI or PET imaging as alternative to all preceding scans mentioned here) AND prostate MRI. 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for the treatment of prostate cancer unless started within 3 months of randomisation. 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer (apart from ADT or hormonal therapy as outlined above) Embedded [68Ga]PSMA-11 PET sub study: Main Exclusion Criteria 1. Metastatic prostate cancer patients who have had previous surgery and or radiotherapy treatment. 2. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry.
The purpose of the study is to monitor patients with early stage lymphoproliferative disorders not meeting criteria for treatment, including early stage Chronic Lymphocytic Leukaemia (CLL), Monoclonal B-cell Lymphocytosis (MBL), Monoclonal Gammopathy of Uncertain Significance (MGUS), asymptomatic Waldenstroms Macroglobulinaemia (WM) and Smouldering Myeloma (SM). Each of these disorders has a pre-cancerous phase when abnormalities can be seen in the blood however treatment may not be required. A minority of people with early stage lymphoproliferative disorders will go on to need chemotherapy or other treatment for blood or bone marrow cancer. Currently we do not have a reliable way to predict which of these individuals with these disorders are more likely to develop a blood or bone marrow cancer. By studying a large group of individuals over time we hope to discover more about what factors might predict progression. We may be able to identify markers which identify individuals who are more or less likely to develop blood or bone marrow cancer. These markers might be particular symptoms, gene changes called mutations or levels of particular molecules or cells in the blood or bone marrow. In the longer term this may enable us to identify those people who would benefit from certain types of treatment or from receiving treatment at an earlier stage and also to confidently reassure those who will never progress. Patients will be studied for up to 5 years with blood, bone marrow and saliva samples taken at key time-points to help answer these questions. In addition to looking for these markers we will also collect information about: •What it is like to live with one of these conditions •How many people with these conditions develop other significant medical conditions, such as serious infections, thrombosis (blood clots) or other types of cancer.
1.Patients diagnosed within the previous two years with one of the following: a.High count monoclonal B-cell lymphocytosis (MBL) i.e. clonal B-cell population 0.5-4.9 10*9/L b.Low risk Rai Stage/ Binet Stage A Chronic Lymphocytic Leukaemia not meeting the IWCLL criteria for treatment c. IgG or IgA Monoclonal Gammopathy of Uncertain Significance meeting one of the following criteria: i. IgA paraprotein > 10g/L or ii. IgG paraprotein > 15g/L or iii. IgA/IgG paraprotein below these cut-offs but kappa:lambda light chain ratio of < 0.1 or > 3.0 iv. Patients not meeting the cut-offs defined in points i) to iii) but who are referred to secondary care e.g. due to GP concern or for investigation of symptoms d. IgM Monoclonal Gammopathy of Uncertain Significance meeting one of the following criteria: i. IgM paraprotein > 10g/L or ii. IgM paraprotein < 10g/L and difference between the kappa and lambda light chains of > 50mg/L iii. Patients not meeting the cut-offs defined in point i) and ii) but who are referred to secondary care e.g. due to GP concern or for investigation of symptoms e. Asymptomatic smouldering Waldenstroms Macroglobulinaemia not meeting the criteria for treatment f. Smouldering myeloma not meeting the criteria for treatment 2. ECOG performance status of 0,1 or 2 3. Age 16 years and over 4. Signed written informed consent 5. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations. 6. Haematological and biochemical indices within the ranges shown below: Haemoglobin (Hb) > 110g/L Platelet count > 100 x 10*9/L
1. Pregnant or breast-feeding women. Pregnant or breast-feeding women may be re-screened following delivery and/or cessation of breastfeeding, as appropriate. 2. Previous chemotherapy or immunotherapy for any haematological cancers 3. Treatment with any other investigational agent, or participation in an interventional clinical trial within 28 days prior to enrolment. 4. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor study candidate or could interfere with protocol compliance or the interpretation of study results. 5. Any other malignancy that requires active surgical or chemotherapeutic treatment. Patients on long term hormone therapies (e.g. tamoxifen) are permitted to enrol at the discretion of the investigator, after considering the overall clinical context. 6. Any significant concurrent medical condition resulting in a life-expectancy of less than 5 years (including but not limited to renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease)
Healthy bone marrow produces blood cells, including infection-fighting immune cells. These blood cells originate from stem cells. In cancer, the bone marrow can no longer function properly. To restore healthy blood cell production and to fight the cancer, some patients are given healthy stem cells from a donor’s bone marrow. Although this can cure many patients, it can have serious side effects, including ‘graft versus host disease’ (GvHD). This happens because the bone marrow contains donor immune cells (the ‘graft’) that see the patient’s healthy cells (the ‘host’) as foreign and attacks them. It mainly affects the tissues of the skin, the liver and the gut and can be life threatening. Drugs that prevent GvHD by suppressing the donor’s immune cells in the patient’s body renders the immune system weak and unable to fight infections. These infections are sometimes very severe and can lead to patients dying. This trial aims to find out if giving patients additional infection fighting immune cells from the donor (Tem cells) will reduce their chance of getting an infection without causing GvHD. Patients will receive additional donor immune cells about one month after the transplant. They will also receive the standard GvHD prevention treatment. Different doses of the donor immune cells will be given to individual patients to work out which dose is best. All patients will be closely monitored for signs of GvHD or infection. They will also have blood tests to determine how well and quickly their immune systems recover. Patients will be followed up for 12 months post treatment. The study will recruit a maximum of 18 patients. The study will be conducted at NHS hospitals and is expected to last 22 months.
Patient: - Severe aplastic anaemia or - Primary immune deficiency or - Haematological cancer which can be ONE OF the following: o Non-Hodgkin’s lymphoma (NHL) in CR or PR; o Hodgkin’s lymphoma (HL) in CR or PR; o Chronic (Pro-)lymphocytic leukaemia (CLL or PLL) in CR or PR o Plasma cell myeloma (PCM) in CR, VGPR or PR; o Acute myeloid leukaemia (AML) in CR; o Acute lymphoblastic leukaemia (ALL) in CR; o Myelodysplastic syndrome (MDS) < 10 % blasts in bone marrow; o Chronic myelomonocytic leukaemia (CMML) < 10% blasts in bone marrow - Have undergone disease reassessment within 8 weeks prior to registration - Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based conditioning regimen with calcineurin-inhibitor based immunoprophylaxis - Aged > = 16 years, < 70 years - Written informed consent Donor: - Aged > = 16 years - HLA-identical sibling - Have met transplant centre criteria regarding suitability for cell therapy donation - Negative for HIV 1 and 2, hepatitis B, hepatitis C, HTLV-1 and 2, syphilis serology - Written informed consent
Patient: - Women who are pregnant or breast feeding - Life expectancy of < 8 weeks - Currently taking part in any other interventional clinical research study (involving any IMP, ATIMP or cellular therapy) - Proposed use of any other method of GvVHD prophylaxis other than alemtuzumab and calcineurin inhibitor - Organ dysfunction: o LVEF< 45% o Glomerular filtration rate (corrected) < 50ml/min o Bilirubin > 50µmol/l o AST or ALT > 2.5 x ULN (NB: If both are performed then both must be < = 2.5 x ULN) Trial Treatment Exclusion Criteria (patient eligibility check 2 days prior to CD62L- Tem Infusion) - Prior or active acute pattern GvHD of any grade - Relapse or progression - Primary or secondary graft failure - Has received other cellular therapies Donor: - Pregnant/lactating women
There has been little improvement in outcome for patients with osteosarcoma (OS) over the last 20 years. There have been only a few clinical trials of new treatments and no major new therapies introduced recently. This is in part because we do not have a good understanding of the biology of osteosarcoma, but also trials have only included subgroups of patients. The more we understand about how and why osteosarcoma arises and grows the better we will be able to decide what treatments are most likely to work best. The purpose of this project is to collect high quality clinical data about patients of all ages with osteosarcoma, such as information about the size of the disease, how it was diagnosed and where it is at diagnosis, what treatments were given and how the disease responded the treatments. We will also collect blood and tissue samples for analysis in research laboratories. By looking at the results of the laboratory findings and the clinical data together, we will start to answer the questions about why osteosarcomas arise and grow, what makes it spread, and why some patients respond to treatment better than others. As time goes on, we plan to use this information to develop clinical trials of new treatments. Alongside this, we want to find out more about how osteosarcoma and its treatments affect the lives of those living with this disease. This information will help us to provide the most appropriate care and support that will meet the needs of each patient. Ultimately, our aim is to improve the care and treatment of osteosarcoma patients so that they may live longer and better lives.
• New histological diagnosis of osteosarcoma or in the absence of osteoid seen on biopsy, pathology and imaging supportive of a diagnosis of osteosarcoma. It is well recognised that some patients may present with features suggestive of osteosarcoma (under 40, radiological abnormality compatible) but in whom no osteoid is detected in needle biopsy. Although categorised as spindle cell tumour of bone, such patients are usually treated in an identical approach to osteosarcoma. A definite diagnosis of osteosarcoma is then often possible after surgery when the entire resection specimen is available. • Written informed consent of patient or parent/legal guardian
• Osteosarcoma diagnosis more than three months prior to registration
In the UK, prostate cancer is the most common cancer in men and with about 1 in 8 men diagnosed with prostate cancer in their lifetime. Up to a third of prostate cancer deaths occur when cancer spreads to other parts of the body known as metastatic prostate cancer, which is a major healthcare burden. Currently, physicians use a maximum of six cycles of Docetaxel and continue abiraterone until disease progression with long term androgen deprivation therapy (ADT). There is no early test to indicate if treatment is working for patients with metastatic prostate cancer. Currently Prostate Specific Antigen (PSA) is not sensitive enough to guide treatment alone. Studies in colorectal, lung and prostate cancers have started looking at substance called Plasma tumour deoxyribonucleic acid (ptDNA) and correlated presence of ptDNA will early relapse. Therefore, this study will investigate if the detection of ptDNA after initiating treatment is associated a worse clinical outcome. Our ultimate aim, is to identify which of the current treatment options will work best for patients in the future. This research may also identify new targets for the development of new drugs to test in clinical trials in the future. Assessments will include blood taken before and during treatment and at cancer progression. In selected centres, an optional Whole Body Magnetic Resonance Imaging (WBMRI) will be performed before and during treatment for those patients who are eligible. Patients will be followed up for a maximum of 5 years at the time they register onto the study. We expect recruitment duration to be 18 months.
1. Able and willing to provide written informed consent 2. Prostate adenocarcinoma confirmed on biopsy obtained in previous 6 months 3. Polymetastatic disease defined as two of the following: i. Gleason score of > = 8, ii. Presence of > = 3 lesions on bone scan, iii. Presence of measurable visceral lesion 4. Eastern Cooperative Oncology Group (ECOG) Performance status 0 to 2 5. No medical contra-indications to abiraterone or docetaxel 6. Patients should be either of the following: A. Planned to start long-term Luteinizing hormone (LH) suppression, or B. within 10 weeks of starting long-term luteinizing hormone releasing hormone (LHRH) antagonist, or C. within 12 weeks of starting LHRH agonist or an anti-androgen when the latter is used in combination with or prior to LHRH agonist for flare protection. 7.Patients should be planned for addition of docetaxel (PARADIGM-D) or abiraterone (PARADIGM-A) 5 to 10 weeks after start of LHRHa (or 7 to 12 weeks if LHRH agonist is started without anti-androgen ) with a target of 6 cycles or continuation until progression respectively. 8.No concomitant medical conditions likely to reduce life expectancy. 9.Patient agrees to be followed up in the recruiting centre and to having sequential plasma samples collected as per the study protocol.
1. Medically unsuitable for either abiraterone, prednisolone or docetaxel. 2. Concurrent or planned for (within the first 5 cycles of docetaxel or abiraterone) treatment with any experimental drugs, oestrogen patches radiotherapy or surgery to the primary tumour. Patients randomised to the standard of care (SOC) arm in open-label clinical trials are eligible. Patients who are still to be randomised to STAMPEDE may be included where the randomisation will be limited to SOC or arm K. Patients can participate in other observational studies. 3.Prior systemic therapy for prostate cancer other than for LHRHa +/- anti-androgen (started within the time limits defined in inclusion criterion 6). 4.Metastatic brain disease or leptomeningeal disease. 5.Any surgery planned prior to Cycle 3 Day 1 (C3 D1) 6.Other current malignancy or malignancy diagnosed or relapsed within the past 5 years (other than non-melanomatous skin cancer, stage 0 melanoma in situ and non-muscle invasive bladder cancer) 7.Patients who consent to the whole-body magnetic resonance imaging (WBMRI) translational sub-study should have no contraindications to MRI as per local guidelines.
Triple negative breast cancer (TNBC) can have a high/moderate risk of returning (relapsing) after standard treatment; usually within the first 2 years after finishing treatment. In some patients with TNBC who receive chemotherapy before surgery, if there is cancer remaining after chemotherapy (called residual disease) that risk of relapse is higher. PHOENIX aims to investigate the biology of this residual disease in the 2-week time window between completing chemotherapy and surgery to see if giving trial treatment in this window changes the biology of the cancer. TNBC patients who have cancer remaining at their mid-point assessment during chemotherapy will be invited to register for PHOENIX. After registration, a post-chemotherapy MRI scan will confirm presence of residual disease and eligible patients will be randomly allocated into a cohort: Cohort A: standard care (no trial treatment) Cohort B: AZD6738 Cohort C: olaparib Cohort D: durvalumab A pre-treatment research biopsy and blood sample will be collected, followed by trial treatment before surgery. After trial treatment, a second research biopsy and blood sample will be collected. Pre- and post-treatment samples will be compared to see if there is a difference that may provide an early signal that warrants further investigation of the trial treatment. Patients may resume trial treatment after surgery for a period of 12 months (adjuvant treatment) to investigate whether any signals seen in the tumour/blood after short exposure to trial treatment prior to surgery are also seen after longer exposure to trial treatment in the adjuvant setting.
INCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Signed Informed Consent Form (ICF) for Trial Registration; 2. Aged > = 18 years old; 3. Histologically confirmed invasive triple negative breast cancer (TNBC). TNBC defined as ER negative, PgR negative (ER and PgR negative as defined by Allred score 0/8, 1/8 or 2/8 or stain in < 1% of cancer cells) or PgR unavailable, and HER2 negative (immunohistochemistry 0/1+ or negative in situ hybridization) as determined by local laboratory and recorded in the patients notes; 4. Planned definitive surgical treatment after at least 6 cycles of neoadjuvant chemotherapy (NACT); 5. Radiographically measurable tumour mass assessable for new distinct radio-opaque marker insertion and repeated biopsies on the NACT mid-assessment standard of care imaging modality; 6. Eastern Oncology Cooperative Group (ECOG) performance status 0-1; 7. Considered fit enough to have breast cancer surgery with curative intent; 8. Considered fit to complete at least 2 weeks of pre-operative trial treatment in the WOP; 9. Patients must be suitable for a mandatory pre-treatment baseline biopsy performed Day -1 or 1 of the window of opportunity (WOP) and a post-treatment biopsy performed on Day 14 of the WOP. Registered patients who are approached for Trial Entry will be required to consent to the pre- and post- WOP treatment biopsy. If it is deemed unsafe to proceed with biopsy upon Trial Entry the patient will not be eligible for participation in the trial. 10. Patients with clinical stage II disease or clinical suspicion of metastatic disease must have staging studies as per standard of care to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 11. Patients with stage III disease must have staging studies as per standard of care at any point after diagnosis but before Trial Registration, to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease), even if asymptomatic. 12. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed > 5 years prior to Trial Registration, and there is no evidence of recurrent disease; 13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before Trial Registration; 14. Patients must be: a) surgically sterile (i.e. if female have undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy; if male have undergone a bilateral orchidectomy); b) have a sterilised sole partner; or c) be post-menopausal; or d) must agree to practice total/true abstinence; or e) use a condom and one highly effective form of contraception in combination during the period of trial treatment and be willing to do so for a period of at least 6 months following the end of trial treatment. Post-menopausal is defined in Protocol Section 6.3.1. INCLUSION CRITERIA FOR TRIAL ENTRY: 1. Signed Informed Consent Form (ICF) for Trial Entry; 2. Residual disease is confirmed as at least one viable disease focus > = 1cm on trial-specific imaging performed at least 1 week following day 1 of the final cycle of NACT. 3. Recovery from all acute adverse events of prior NACT to baseline or NCI CTCAE Grade < = 1, except for alopecia. Patients with irreversible toxicity not reasonably expected to be exacerbated by trial treatment may be included only after consultation with the CI or Coordinating Investigator. 4. Patients must have adequate haematological, renal and hepatic function as defined in Protocol Section 9.1.1. 5. Women of childbearing potential must have a confirmed menstrual period and a negative urinary or serum pregnancy test prior to Trial Entry. This should be repeated as applicable to ensure a negative pregnancy test is performed within 3 days prior to commencing trial treatment (or on the day of planned trial treatment for Cohort C) 6. Confirmation that all Trial Registration inclusion criteria listed in Section 6.3.1 remain satisfied.
EXCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Definitive evidence of metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 2. Patients with bilateral tumours; 3. History of another primary malignancy within the last 5 years prior to Trial Registration, except for: a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; b. Adequately treated carcinoma in situ without evidence of disease; 4. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML; 5. Severe concurrent disease, infection or co-morbidity that, in the judgment of the local Investigator, would make the patient inappropriate for Trial Registration; 6. Resting ECG with QTc > 470msec for females and > 450 msec for men on 2 or more time points within a 24 hour period, factors which increase the risk of QTc prolongation or family history of long QT syndrome; 7. A diagnosis of ataxia telangiectasia; 8. Patients unable to swallow orally administered medication; 9. Patients receiving formal anti-coagulation treatment; 10. Patients with gastrointestinal disorder affecting absorption; 11. History of seizure or any condition that may predispose to seizure; 12. Other non-malignant systemic disease that would preclude trial treatment or would prevent required follow-up; 13. Pregnant or breast-feeding; 14. Prior exposure to ATR inhibitor (including AZD6738), PARP inhibitor (including olaparib), anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab); 15. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that in the investigators opinion would cause reasonable suspicion of a disease or condition, that contraindicates the use of trial treatment, that may increase the risk associated with trial participation, that may affect the interpretation of the results, or that would make this trial inappropriate for the patient; 16. Patients with a known hypersensitivity to the trial treatments or any excipients of the products; 17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT); 18. Active or prior documented autoimmune or inflammatory disorders (examples & exceptions are listed in Protocol Section 6.3.1). 19. Active infection including tuberculosis (TB), hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV) as described in Protocol Section 6.3.1. EXCLUSION CRITERIA FOR TRIAL ENTRY: 1. History of clinically significant or uncontrolled cardiovascular disease as described in Protocol Section 9.1.2; 2. History of loss of consciousness or transient ischemic attack within 12 months prior to Trial Entry; 3. Patients with Grade > = 2 neuropathy, as defined by NCI CTCAE v5.0 will be evaluated on a case-by-case basis after consultation with the CI or Coordinating Investigator; 4. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 2 weeks prior to Trial Entry. Patients must have recovered from any effects of any major surgery prior to commencing trial treatment. 5.Use of any investigational agent within 30 days prior to commencing trial treatment. 6. Concomitant use of known strong CYP3A inhibitors. 7. Concomitant use of known strong CYP3A inducers. The required washout period prior to commencing trial treatment is 5 weeks; 8. Whole blood infusion or erythropoietin within 28 days prior to trial entry (packed red blood cells and platelet transfusions are acceptable); 9. Current or prior use of immunosuppressive medication within 14 days prior to commencing trial treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisolone, or an equivalent corticosteroid. 10. Receipt of live attenuated vaccine within 30 days prior to commencing trial treatment. 11. Confirmation that none of the Trial Registration exclusion criteria listed in Section 6.3.2 are met.
It is particularly difficult to treat some groups of children diagnosed with cancer, including very young infants in the first weeks of life and children with poor kidney function. It can be especially difficult to know how much chemotherapy (anti-cancer drugs) to give to these children. Doctors often have to make difficult decisions about the most appropriate dose of drug, without enough scientific information to help them decide. This can mean that patients might not get enough drug or get too much, and this can be harmful in terms of causing long term health problems due to under or over dosing. Our research group is a national centre for carrying out cancer drug trials in children. Over the past 10 years we have gained a reputation for expertise in supporting the treatment of ‘hard to treat’ children through the use of therapeutic drug monitoring. This involves the measurement of drug levels in individual patients following a request from the treating clinician. A limited number of blood samples are collected following drug administration and sent to our laboratory for analysis. The results are fed back to the treating clinician who can use this information alongside information on patient response and side effects to make informed decisions regarding the continued treatment of the individual patient. Based on the positive impact on patient treatment of this approach, we now aim to conduct a study to allow the formal collection of clinical data following the treatment of these challenging patient populations. The findings of this research programme will be made available to doctors treating children with cancer about what doses of drugs to prescribe. This will positively impact on the treatment of future childhood cancer patients by providing data that will inform future dosing guidelines.
Inclusion criteria to be utilised for patient recruitment; a) age < 18 years b) confirmed diagnosis of cancer c) patient receiving 'modified' chemotherapy (see below for patients who fall into this category)* d) central venous catheter in place e) willingness to participate and written informed parental/patient consent (signed and dated) f) request from the treating clinical for therapeutic drug monitoring approach to treatment * Patients receiving 'non standard' chemotherapy dosing regimens will include the following groups: - neonates and infants including pre-term infants - anephric patients - patients receiving high dose myeloablative chemotherapy and autologous stem cell rescue - obese patients (BMI at or above the 995th percentile for children of the same age and sex)
a) Failure to meet the inclusion criteria
Prostate cancer (PrCa) is the most common cancer in men in the UK with over 47,000 men diagnosed every year. Research shows the main contributing factors to PrCa development are age, a family history of PrCa, and being from certain ethnic backgrounds. These risk factors can be grouped into environmental and inherited factors (i.e. genetic changes). The team's previous research shows that defects in certain genes are not only associated with higher rates of PrCa development, but are associated with more aggressive disease. It is likely that it is not simply a family history of PrCa that is linked with this phenomenon, but also the presence of mutations in a persons DNA (genetic material) from birth. Genetic 'panel' tests can detect mutations in known PrCa genes and ‘genetic profiling’ can be used to look at a person's DNA for many common genetic changes involved in PrCa and adding them together to give an overall genetic risk score. This study is a non-interventional single-site study, at the Royal Marsden Hospital (RMH). It will offer PrCa-specific genetic testing to men with, or at high-risk of, PrCa to identify the prevalence of genetic defects in 2 high-risk cohorts. 1. Men with PrCa AND diagnosed young (ie under 70, OR with a family history, OR with disease that has spread (metastatic). 2. Unaffected men with a family history PrCa defined as: a. A first degree relative(FDR) diagnosed < 70 years b. Two FDR/second degree relative(SDR), one diagnosed < 70 years c. Three FD/SDR diagnosed at any age(on the same side of family) This study will evaluate the usefulness of this knowledge within a clinical setting to determine how it informs management of these men, in terms of screening and/or treatment. Identifying men with such mutations earlier in their disease trajectory will offer new insights into the role these genes play within PrCa progression and treatment response.
Two cohorts of men will be recruited, 1000 subjects in each i.e. a total of 2000 men. AFFECTED 1. Affected with PrCa < 70 years 2. Affected with metastatic castration-resistant PrCa (mCRPC) at any age 3. Affected with PrCa and a family history defined as a. two or more cases in the family with one case < 70 b. three or more cases any age (FDR or SDR) UNAFFECTED Aged > 40 and with a family history defined as:: a. FDR diagnosed < 70 b. 2 or more cases in First or Second Degree Relatives (FDR/SDR) with one case diagnosed < 70 years c. 3 or more cases at any age (on the same side of the family)
WHO performance status 4
Polycythemia vera (PV) is a rare blood cancer characterised by a high-risk of thrombosis (clotting) and haemorrhage (bleeding). Average survival in high-risk patients receiving contemporary care is 10.9 years. Current treatments include aspirin, venesection (blood drawing) and selected use of standard therapies (hydroxycarbamide (HC) or interferon alpha (IFNa)). The strategies remain less than perfect, with on-going risks of developing blood clots, bleeding, dying early due to either these events or to the disease progressing into leukaemia or a more aggressive form (myelofibrosis). Approximately 9 out of 10 people who have PV have a change in the JAK2 gene. The JAK2 gene makes a protein that controls how many blood cells the stem cells make. Ruxolitinib, the drug being tested in this trial, targets the JAK pathway to stop the JAK2 gene signalling to the stem cells to make blood cells. Ruxolitinib appears to help patients with PV whether they have the JAK2 mutation or not. MITHRIDATE is therefore an important trial as it aims to answer whether ruxolitinib, is better than the Best Available Therapy (BAT) HC or IFNa to improve outcomes for patients with PV. Patients will be randomised between ruxolitinib and BAT. 586 patients with high risk PV who meet the eligibility criteria will be recruited from the UK and France. All patients will be assessed for response throughout and will attend clinic visits seven times in the first year and every 3 months throughout year 2 and 3. Patients on either treatment will continue on the drug until the last patient finishes treatment or until the primary endpoint is reached,or end of study is declared, whichever is sooner. The research is funded mainly by Novartis who will be providing the drug free of charge. There is also some funding from MPN Voice (a charity) and The French National Cancer Institute.
1. Patient > = 18 years of age 2. Diagnosis of PV meeting the WHO criteria within the past 10 years 3. Meets criteria of high risk* PV ( High risk PV defined as WBC > 11 x 109/l* AND at least ONE of the following: -Age > 60 years -Prior thrombosis or major haemorrhage related to disease -Platelet count > 1000 x 109/l* -Diagnosed < 10 years -Received treatment for < 5 years) 4. Patients may have received antiplatelet agents and venesection 5. Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy) 6. Able to provide written informed consent.
1. Diagnosis of PV > 10 years previously 2. Absence of JAK-2 mutation 3. Patients with any contraindications to any of the investigational medical products 4. Treatment with > 1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy 5. Active infection including hepatitis B, hepatitis C, Tuberculosis 6. Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry) 7. Patients and partners of childbearing potential not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication 8. ECOG Performance Status Score > = 3 9. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (within the last 6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease > NYHA ( New York Heart Association) Class II 10. Patients who have transformed to myelofibrosis 11. Previous treatment with ruxolitinib 12. Previous (within the last 12 months) or current platelet count < 100 x 109/L or neutrophil count < 1 x 109/L not due to therapy 13. Inadequate liver function as defined by ALT/AST > 2.0 x ULN 14. Inadequate renal function as defined by eGFR < 30 mls/min 15. Unable to give informed consent
IRONMAN is an international registry study of men with advanced prostate cancer. The treatment of advanced prostate cancer has changed significantly over the past 10 years. There are now multiple drug treatments available for men with advanced prostate cancer. The use of these drugs has resulted in improved survival and quality of life for many patients. However a number of questions still remain including the observation that some patients have an excellent and long response to treatment, whilst others do not. We also do not have any biomarkers helping chose the best treatment for an individual patient. The aim of this research study is to learn more about prostate cancer and to describe the use of different therapies for advanced prostate cancer internationally. The study also aims to identify associations between treatment sequences and outcome and investigate biomarkers which could be helpful with deciding which treatment is best for which patient. Finally this study will also investigate the patient experience of men with advanced prostate cancer and identify any unmet needs in their treatment. World wide 5,000 patients will be recruited to IRONMAN, including the UK, US, Canada, Brazil, Australia, and Europe. Patients will be recruited from hospitals treating patients with advanced prostate cancer. This registry study does not involve a new drug or treatment but will focus on collecting real-life information on a patient’s cancer, treatment, symptoms, and quality of life. Hospital visits will be every 3 months and these will coincide with routine visits. Blood samples will be taken for biomarker research and this will take place at study entry, after 1 year and at each point a patient changes prostate cancer treatment. Patients will be followed up for at least 3 years.
To be included in the IRONMAN Registry, subjects should meet the following criteria at the time of registration: 1. Willing and able to provide written informed consent and privacy authorisation for the release of personal health information 2. Males 21 years of age and above 3. Histological or cytological confirmed prostate cancer from prostate biopsy, radical prostatectomy or Transurethral Resection of the Prostate (TURP) Or Documented histopathology or cytopathology of prostate cancer from a biopsy of a metastatic site Or Metastatic disease typical of prostate cancer (i.e. involving bone or pelvic/extra pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA > 20ng/mL 4. Metastatic hormone sensitive prostate cancer (mHSPC): a) No more than 1 year of continuous androgen deprivation therapy (ADT) exposure prior to consent, with documented recovery of testosterone as determined by investigator. b) No more than 90 days of active systemic therapy at the time of consent c) Metastatic disease M1a, b, or c stage as defined by the American Joint Committee on Cancer Or Castration resistant prostate cancer (CRPC) a) A rising PSA indicating progressing disease or new metastatic disease as determined by the investigator I. While on ADT (or orchidectomy) or II. With castrate level of testosterone as determined by investigator b) No more than 6 weeks of continuous systemic therapy for CRPC at the time of consent I. NOTE: Prior systemic therapy for any length of time for mHSPC is allowed for patients currently with CRPC 5. No active systemic treatment for a diagnosis of a second, non-prostate malignancy 6. For both mHSPC and CRPC, prior treatment with bisphosphonate or denosumab will be permitted.
1. Previous diagnosis of a second, non-prostate malignancy that requires additional systemic therapy. 2. Men with mHSPC who have received active systemic therapy for longer than 90 days prior to consent. 3. Men with CRPC who have received continuous systemic therapy for CRPC for longer than 6 weeks prior to consent.
THIS STUDY WILL RECRUIT PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS FOR ALL FORMS OF CANCER Immune Checkpoint Inhibitor Genetics Summary Title: Toxicites caused by immune checkpoint inhibitors used to treat cancers: are there differences in the genetic make-up of those patients who suffer side effects and those who do not? All anti-cancer therapies cause toxicity and some individuals appear especially susceptible to the side-effects of particular treatments. This might be because of genes that we inherit. We can find out whether those genes exist by studying the clinical features and blood samples of a large set of cancer patients who have been treated with immune system boosters and looking for differences between those who develop severe toxicity, those who have mild toxicity and those who have no toxicity. We can also look at people with different types of toxicity, for example affecting different parts of the body. We will also study the clinical features and bloods samples of a group of participants who have autoimmune diseases but have not been treated with immune system boosters to assess whether there are any similarities in their inherited genes. If we find genes that affect the chances of toxic side-effects, we may be able to find out who is at greatest risk before they take the drugs and develop ways of preventing or minimising the side-effects. Clinical details will be collected from the participant and clinical team in the form of a questionnaire, blood sampling will occur on a single occasion, either within routine clinical management or at the participants convenience.
Patients that have been treated with Immune Checkpoint Inhibitors for any malignancy. Able and willing to provide informed consent and a sample of blood (or saliva). Aged 16 or over. Family members of participants with autoimmune disease.
Unable or unwilling to provide informed consent and a sample of blood (or saliva) Aged less than 16 years old
This study is looking to see if adding the drug nivolumab to the current standard treatment will be better for treating patients with liver cancer. The current treatment TACE (Transcatheter Arterial Chemoembolisation) with drug eluting beads puts a large dose of chemotherapy drugs directly into the tumour. Putting the drug directly into the tumour gives less side effects and less damage to other tissues nearby. Current evidence suggests that adding an immunotherapy drug like Nivolumab at the same time as TACE may help increase the time taken until the tumour begins to grow/spread. The study is looking at patients who have liver cancer (Hepatocellular carcinoma (HCC)) which is classified as intermediate. Patients will need to undergo some tests and a biopsy of their Liver to confirm it is safe and they are suitable to be included in the trial. The study will be conducted across NHS hospitals in the UK and in hospitals in France. In this study we will treat half the patients with TACE on its own and the other half with TACE and the new drug nivolumab. Patients will have regular scans to look at their cancer and will be treated until the cancer has grown. Nivolumab will be given once before a patient’s first TACE therapy and then every 4 weeks alongside any further TACE therapy given. Patients will be on study treatment for a maximum of 2 years. We will look at how long it takes for patient’s cancer to grow, how long patients survive, the side effects patients suffer and also Quality of Life. The study is split into two parts. If the first part (phase II) of the study shows that the drug maybe working to control patient’s cancers, we will expand the study to recruit more patients in part two (phase III).
1. Histological diagnosis* of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI. 2. Not a candidate for surgical resection or liver transplantation** 3. Aged > = 16 years and estimated life expectancy > 3 months 4. ECOG performance status 0-1 5. Adequate haematological function: • Hb > = 9g/L • Absolute neutrophil count > = 1.0x109/L • Platelet count > = 60x109/L 6. Bilirubin < = 50 μmol/L, AST,ALT and ALP < = 5 x ULN 7. Adequate renal function; Creatinine < = 1.5ULN (Using Cockcroft-Gault Formula) 8. INR < = 1.7 9. Child-Pugh A (score < = 6) (Appendix D) 10. HAP score A, B or C (Appendix E) 11. No contra-indications to T-cell checkpoint inhibitor therapy (use of immunosuppressive drugs including steroids at dose equivalent to prednisolone > 10mg/day unless used as replacement therapy; organ transplantation; subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol). 12. Women of child-bearing potential should have a negative pregnancy test prior to study entry. Both men and women must be using an adequate contraception method, which must be continued for 5 months after completion of treatment for women and 7 months for men 13. Written informed consent *All patients are required to under a MANDATORY biopsy prior to entry onto the study. **Criteria which establish ‘intermediate’ HCC
1. Extrahepatic metastasis* 2. Prior embolisation, systemic or radiation therapy for HCC* 3. Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis 4. Investigational therapy or major surgery within 4 weeks of trial entry 5. History of variceal bleeding within the past 4 weeks 6. Child-Pugh cirrhosis B or C (score > = 7) 7. HAP score D 8. Hepatic encephalopathy 9. Ascites refractory to diuretic therapy 10. Documented occlusion of the hepatic artery or main portal vein5 11. Hypersensitivity to intravenous contrast agents 12. Active clinically serious infection > Grade 2 NCI-CTC 13. Pregnant or lactating women 14. Known history of HIV infection 15. HBV chronic infection with HBV DNA > 500IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated. 16. History of serious autoimmune disease. 17. History of second malignancy except those treated with curative intent more than three years previously without relapse and non-melanotic skin cancer or cervical carcinoma in situ 18. Evidence of severe or uncontrolled systemic disease, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial 19. Psychiatric or other disorder likely to impact on informed consent 20. Patient is unable and/or unwilling to comply with treatment and study instructions *Criteria which establish ‘intermediate’ HCC
Stratified Medicine Paediatrics (SMPaeds) is a UK research study testing tumour (somatic) and normal (germline) DNA and RNA for genetic and gene-expression changes in children, teenagers and young adults with relapsed/refractory cancer. The results of the tests performed will identify patients who may be eligible for new targeted anti-cancer therapies and will aid research that will help us to more precisely diagnose cancer and understand why some patients do not respond to standard treatments. All children, teenagers and young adults with solid paediatric tumours (including brain tumours and lymphoma) whose disease has come back (relapsed) or not responded to treatment (refractory) will be eligible to take part. In addition, the patient must have had a recent biopsy/operation to obtain tumour tissue on which molecular tests can be performed. The results of the testing will be relayed back to the patient’s doctor via an expert group of doctors who will make recommendations on any available treatments. Patients and/or their parents will be asked in advance to consider what information they which to receive in relation to any abnormal genetic results either in the tumour or their normal (germline) genetic code. In addition, the data collected will be used and shared for the purposes of clinical research.
Inclusion • Patients with a relapsed or refractory paediatric tumour (all solid tumours, central nervous system (CNS) tumours and Lymphoma) • Formalin fixed paraffin embedded (FFPE) tumour available from a biopsy, resection or other surgical procedure that was taken within 8 weeks of trial entry* • Written informed consent of patient/parent/guardian/legal guardian** * To allow full multi-omic analysis both fresh frozen and Formalin fixed paraffin embedded (FFPE) tumour plus a blood sample for constitutional (germline) and circulating tumour (ct) DNA will need to be available. Original diagnostic slides should be submitted at the same time as block from current relapse/refractory episode either in same shipment or via PathXL (see laboratory manual for further details). ** Some adult patients with brain tumours or brain metastases may be incapable of providing their own consent due to the neurological effects of their disease. In such cases, these patients will be classed as an incapacitated adult and a consultee will be sought.
None
Throughout the 20th century, the global incidence of pancreatic cancer has steadily increased. It is currently the 4th most common cause of cancer death in Western societies. In the period 1930-1970, the rate of mortality associated with pancreatic cancer doubled in the UK and, as the incidence of the disease continues to rise, it is expected to become the 2nd most common cause of cancer death within a decade. Pancreatic cancer is often diagnosed late and therapy options for patients are limited. This means that exceedingly poor patient outcomes remain the norm for people affected by pancreatic cancer. To put this into numbers: of the people diagnosed with pancreatic cancer in 1970, only 3% survived for five years or more. Forty years later, that figure remains more or less unchanged. Shockingly, this means that of the ~9,000 people who will be diagnosed with pancreatic cancer in the UK this year, only around 270 people are expected to survive for more than five years. Despite some incremental advances, we have not shifted the outlook for pancreatic cancer in any significant way. Due to its aggressive nature, and the lack of efficacy of chemotherapy (with combination regimens associated with more toxicity) only about 50% of patients with advanced pancreatic cancer receive any therapy. Of those that receive therapy,few benefit in any significant way, and at best, only half of them are well enough to receive a second line of treatment. Less than 5% of patients receive a third treatment. It is reasonable to argue that due to the lack of tissue for research purposes and lack of efficacy of current therapies,there is no “standard-of-care” for pancreatic cancer, and if it is to be called that, then the standard is very poor. The lack of effective therapies and bleak outlook for patient survival makes this particular cancer type an ideal target for the exploration of models of molecular phenotype guided cancer care. Precision-Panc aims to identify, test and implement tailored therapeutic approaches for individuals affected by pancreatic cancer by using a master protocol approach to obtain tissues for study. A range of clinical trials (PRIMUS) will be linked to the master protocol so that each and every patient will have real options. The goal is to “find the trial for the patient” rather than “the patient for the trial”. Patients will be profiled using state of the art molecular phenotyping approaches. We aim to offer patients, and their doctors, the ability to identify therapeutic opportunities that have a real chance of increasing the patient's survival time. We will achieve this through the use of experiments (genome/DNA sequencing approaches) to identify changes (mutations) present within the tumour of patient that could be targeted by known drugs. If such changes are identified as drug targets, patients will then be given information about any relevant clinical trials for them (should they, following discussions with their oncologist, wish to pursue that option).
Patients with a suspected or confirmed diagnosis of pancreatic ductal adenocarcinoma and its variants who consent to additional biopsies to obtain tissue for next generation sequencing analyses will be included in this study. Patients will also be deemed suitable for chemotherapy and/or chemoratiotherpay, and/or surgery pending on the disease clinical stage
Participants without a confirmed diagnosis of pancreatic ductal adenocarcinoma will not be eligible for this study. Patients who do not consent to additional biopsy to obtain tissue for research purposes will be excluded. Pregnant or breast-feeding individuals will also be excluded. Patients deemed to be unsuitable or too frail for chemotherapy or targeted therapy will also be excluded.
There are approximately 16,000 new cases of rectal cancer in the UK per year. Surgery is the mainstay of treatment which is associated with peri-operative mortality and long-term morbidity. Locally advanced disease is treated initially with preoperative radiotherapy, in the main using long-course chemo-radiotherapy (LCCRT) at 45 to 50 Gy, followed by major surgery 8 to 15 weeks later (referred to in this protocol as standard surgical pathway) or selectively by short-course radiotherapy (SCRT) at 25 Gy, traditionally followed by major surgery within 10 days, but based on modern trial results, increasingly major surgery is being delayed for 6 to 8 weeks. In 10% to 20% of cases, chemo-radiotherapy (CRT) may result in a complete disappearance of the rectal tumour. In patients without residual tumour on imaging and endoscopy (clinical complete response [cCR]), a watch-and-wait (W&W) policy (omission of surgery with follow-up) might be considered as an alternate to major resection. This represents a new paradigm for treating rectal cancer. But there are concerns that this approach is oncologically unsafe outside published series from selected specialised centres. While randomised trials would represent the ideal way to evaluate the natural history and efficiency of W&W in patients with cCR, there is a general international option that such trials are “unlikely” and that investigators have observed that “many patients ….. express a strong preference not to undergo major surgery”. Thus, there is a continuing need to prospectively collect clinical data in a standardised manner to monitor the natural history of patients with CCR managed by W&W.
Inclusion criteria for this protocol The intended core future prospective data will be those required to meet the primary aim – namely, routinely collected clinical data: i) In patients with rectal cancer following clinical complete response to chemoradiotherapy or radiotherapy and managed by watch-and-wait used internationally recognised criteria defined by Habr-Gama and colleagues (8). These criteria are a set of clinical, endoluminal, and radiological (typically with magnetic resonance imaging, MRI). The core future data include follow-up within the dates set under the heading ‘Follow-up’. ii) In patients rectal cancer who on histological examination after surgical resection are deemed to have a pathological complete response following chemo-radiotherapy or radiotherapy i.e. ypT0. iii) In addition, we seek to include prospectively routinely collected clinical data in patients with rectal cancer and determined through MDT to have: a clinical near complete response following chemo-radiotherapy or radiotherapy – and treated either by W&W; transanal endoscopic micro-dissection (TEM); or contact radiotherapy or brachytherapy; or major resection. Again, these prospective data include follow-up within the datesets under the heading ‘Follow-up’
not stated.
The STELLAR trial will assess the effect of acalabrutinib taken in combination with CHOP-R compared to taking CHOP-R alone in patients with newly diagnosed Richter’s Syndrome (RS). It will also be a platform to test other new drugs that show potential for treating RS. Chronic lymphocytic Leukaemia (CLL) is the most common blood cancer in adults, usually in their 70s or older. In a few patients, CLL can transform from a slow-growing cancer into an aggressive lymphoma called Richter’s Syndrome. RS is very difficult to treat and patients have a short life-expectancy - usually a few months after diagnosis. Treatment for Richter’s Syndrome in the UK is CHOP (four chemotherapy drugs) plus rituximab (‘R’ - an antibody treatment). The CHOP-R treatment is given as a standard of care for RS but has limited benefit - it is often temporary to extend life. Richter’s Syndrome returns in most patients who then die from this disease. The STELLAR trial will investigate if a new drug called acalabrutinib, which is effective used by itself in patients with relapsed CLL and also some with Richter’s Syndrome, will improve outcomes for newly diagnosed patients with RS. Acalabrutinib blocks a protein in CLL which can stop the cancer growing. Participants who have Richter’s Syndrome and are suitable for CHOP-R will be recruited by specialised hospitals across the UK. People with another cancer, heart problems, or recent stroke cannot take part. Participants will have a lymph node biopsy, 3-4 bone marrow biopsies, blood samples, and PET-CT and CT scans. CHOP-R is given in a hospital every three weeks up to 6 times. All participants will receive CHOP-R; half will also receive acalabrutinib. When treatment with CHOP-R ends the patients who had acalabrutinib can continue to take it; patients who had CHOP-R alone may have acalabrutinib if their Richter’s Syndrome returns after CHOP-R.
Inclusion criteria for the Randomised Trial -Suitable for anthracycline-containing chemo-immunotherapy. -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures Inclusion criteria Cohort 1 (progressive RS following chemo-immunotherapy) -Patients with relapsed/refractory RS who received anthracycline based chemotherapy with anti-CD20 monoclonal antibody. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures Inclusion criteria Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib) -Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within four weeks of last dose of ibrutinib. -No previous anthracycline treatment and suitable for anthracycline-containing chemo-immunotherapy. -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. -ECOG performance status of 0, 1, 2 or 3. -Age 16 years and over. -Signed written informed consent prior to performing any study-specific procedures
Exclusion criteria ALL -Known central nervous system (CNS) involvement of CLL or DLBCL. -Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin. -Chronic or ongoing active infectious disease -Positive serology for Hepatitis B (HBKnown human immunodeficiency virus (HIV) positive. -Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease). -Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenoprocoumon). -Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) > 2 x the upper limit of normal (ULN). -Major surgery within 30 days prior to randomisation and/or inadequate recovery from any prior major surgery, toxicity or complications. -Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function. -Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. -Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. -History of significant cerebrovascular disease in the 6 months prior to randomisation, including intracranial haemorrhage. -Known or suspected hypersensitivity to components of the investigational products -Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment -Current participation in any other interventional clinical study. -Patients known or suspected of not being able to comply with a study -Breast feeding women or women with a positive pregnancy test at screening. -Women of childbearing potential and men not willing to use adequate contraception during study and for 3 months after last dose of study therapy Additional exclusion criteria for the Randomised Trial -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation. -Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop RS are not excluded from the randomised trial component). -Previous acalabrutinib exposure. Additional exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy) -Previous acalabrutinib exposure. Additional exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib) -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation. -Previous acalabrutinib exposure.
Upper gastrointestinal tumours have some of the worst survival rates of all cancer subtypes. 85% of Gastric cancer patients will not survive for 10 years and the figure is 88 % for oesophageal cancer. Cancer research UK has identified oesophageal cancer as an unmet need and a priority for research. More recently oesophageal and stomach cancer were both included in the less survivable cancers taskforce (a collaboration between 5 charities to improve outcomes in 6 cancers that are responsible for more than 50% of cancer deaths and receive only a fifth of the funding of more survivable cancers). Our work is also supported by the leading UK charity, Heartburn Cancer UK and our Chief Investigator is a trustee of the charity. The aim of this study is to increase understanding of the biology of upper gastrointestinal tumours with the eventual hope of identifying targets for new therapies. Our focus will be on the interplay between cancer cells and the normal cells that surround them in the tumour micro-environment. The study will be run from the Southampton Cancer Research UK centre and we will recruit patients undergoing treatment for upper gastrointestinal tumours at the Southampton and Portsmouth regional referral centres. Tissue will be used to identify and create a database of all of the normal and cancerous cell types present in upper GI tumours. We will examine the interplay between them with particular emphasis on immune cells and inflammatory cells. We will identify signalling pathways and interactions that can be manipulated with new therapies with the aim of improving survival across upper gastrointestinal cancer.
INCLUSION CRITERIA All patients over 18 years old with solid tumours arising from the GI tract between the pharynx and the Ampulla of Vater undergoing surgical resection. All patients over 18 years old attending for Endoscopy (OGD/EUS) for clinical, diagnostic or therapeutic reasons.
EXCLUSION CRITERIA Patients younger than 18 years old. Patients unable to give informed consent
Ovarian cancer is the leading cause of deaths from gynaecological cancers. Despite massive funding in drugs and new treatment strategies, survival rates remain poor. Only 3 in 10 women are alive at 10years. Women with a > 10% risk of getting ovarian cancer are considered high-risk. 10% ovarian cancers are familial. The commonest cause is a fault/alteration in BRCA1/BRCA2 genes. BRCA1/BRCA2 carriers have a 17-44% risk of developing ovarian cancer and 69-72% risk of developing breast cancer. There is currently no NHS screening programme for ovarian cancer. Best current practice is to offer women at increased-risk, an operation to remove their fallopian tubes and ovaries on completing their family. This significantly reduces the risk of ovarian cancer by 90% but leads to early menopause. Early menopause has serious implications including, hot flushes, sweats, mood changes and pain during intercourse. Additionally, it increases the risk of thinning of the bones, heart disease, stroke and dementia. Many women avoid/delay prevention due to this. However, a significant number of ovarian cancers actually start in the fallopian-tube. This has led to an attractive alternative ‘two-stage’ proposal to prevent ovarian cancer. The first-stage involves removing the fallopian-tubes (earlysalpingectomy) alone. This is followed by a second-operation (delayed oophorectomy) to remove the ovaries after they have gone through the menopause. This offers protection against ovarian cancer in younger women whilst avoiding the negative health consequences of early menopause. However, long term consequences of this new approach have not been adequately studied. Our UK-wide study compares old and new strategies for ovarian cancer prevention. The study evaluates the impact on sexual function, endocrine function, quality-of-life and cost-effectiveness of this new strategy in high-risk women by comparing it to the traditional strategy of removing both tubes and ovaries as well as outcomes in women who don’t have an operation (controls). Women entering the study can choose whichever strategy they prefer.
1. Women at high-risk of ovarian cancer (BRCA1/BRCA2 mutation carriers, or deemed to be at increased risk from a strong family history of breast and/or ovarian cancer or RAD51C/ RAD51D/ BRIP1 mutation carriers. 2. Premenopausal ≥30years. 3. Completed family (for early surgical arms only).
1. Previous bilateral-salpingectomy or bilateral-oophorectomy. 2. Postmenopausal (amenorrhoea ≥1year (uterus insitu) / FSH > 40). 3. Previous tubal/ ovarian/ peritoneal malignancy. 4. < 12 months post cancer treatment. 5. Pregnancy** 6. Clinical suspicion of tubal/OC at baseline. 7. Inability to provide informed consent.
Prostate cancer accounts for 25% of new cancer diagnoses in the UK, and is the most common cancer diagnosis in men. Patients with intermediate and high risk localised prostate cancer are recommended to have either radical prostatectomy or radical radiotherapy combined with hormone therapy. 20-30% of those in higher risk groups are likely to recur following radiotherapy. Intensity modulated radiotherapy(IMRT) and image guidance techniques provide scope for intensifying prostate radiotherapy treatment whilst minimising any associated increase in radiotherapy related side effects. It is, however, currently uncertain whether promising results from planning and cohort studies of these approaches would translate into improved outcomes, without substantial increase in toxicity, in the context of a randomised controlled trial. PIVOTALboost aims to determine whether the addition of pelvic node IMRT and/or prostate boost to standard prostate IMRT improves failure-free survival (FFS) compared to standard prostate IMRT alone in patients with high or intermediate risk localised prostate cancer. PIVOTALboost is a randomised controlled parallel 4-arm phase III multicentre trial in men with localised high and intermediate risk prostate cancer. Consenting patients will be randomised to receive either: A) Prostate IMRT (control) B) Prostate and pelvic IMRT C) Prostate IMRT and prostate boost D) Prostate and pelvic IMRT and prostate boost All radiotherapy will be delivered using image guidance. Prostate boost will be delivered to the whole gland using High-Dose Rate Brachytherapy (HDRB), or to focal disease using focal HDRB or focal Intensity Modulated Radiotherapy (IMRT). Patients will be followed up for disease outcome, acute and late toxicity and quality of life; health economic details will also be captured. The study will recruit 1952 patients.
1. Histologically confirmed, adenocarcinoma of the prostate using the Gleason scoring system (histological confirmation can be based on tissue taken at any time, but a re-biopsy should be considered if the biopsy is more than 12 months old). 2. PSA < 50ng/ml prior to starting ADT. 3.1. NCCN localised high risk or locally advanced disease • T3a, T3b or T4 N0M0 (clinical and/or MRI) and/or • dominant Gleason 4 or 5 and/or • PSA > 20; or 3.2. NCCN intermediate risk disease • T2b-c N0M0, and/or Gleason 3+4 and /or PSA 10-20 ng/ml and • Adverse feature, for example: Maximum tumour length (MTL) > 6mm and/or 50% biopsy cores positive and / or PI-RADS score 3, 4 or 5, lesion > 10mm on staging MRI. 4. Age > = 18 years. 5. Signed, written informed consent. 6. WHO performance status 0-2.
1. Prior radiotherapy to the prostate or pelvis. 2. Prior radical prostatectomy. 3. Prior ADT for > 6 months at consent (as patients will need to commence radiotherapy at months 3-5 (maximum 7) following start of ADT). 4. Adjuvant docetaxel chemotherapy. 5. Radiologically suspicious or pathologically confirmed lymph node involvement. 6. Evidence of metastatic disease. 7. Life expectancy < 5 years. 8. Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artifacts and would make pelvic node planning more difficult. 9. For patients having fiducials inserted: Anticoagulation with warfarin/ bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician. 10. For patients being considered for randomisation options C2 and D2 only and are undergoing a planning MRI scan: Contraindication to undergo a MRI scan. 11. For undergoing HDR brachytherapy: long-term anticoagulation therapy which cannot be temporarily stopped, prostate surgery (TURP) with a significant tissue cavity, a history of recent deep vein thrombosis or pulmonary embolus, significant cardiovascular comorbidity, unfit for prolonged general anaesthetic. 12. Medical conditions likely to make radiotherapy inadvisable e.g. inflammatory bowel disease, significant urinary symptoms. 13. Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival. 14. Any other contraindication to external beam radiotherapy to the pelvis.
Malignant melanoma is the fifth most common cancer in the UK, 14,500 new cases were diagnosed in 2013. In metastatic melanoma, cancerous cells spread around the body to sites distant from the original skin tumour. Up to 45% of individuals suffering with metastatic melanoma will develop skin deposits (metastases). If left untreated they can grow in size, ulcerate or cause distress through their appearance. Current treatment options include surgery and radiotherapy which can involve separate hospital visits as well as follow up appointments for aftercare. Unfortunately, despite these treatments, the response by metastases is very variable and although some patients improve, others do not show a good response. Microwave ablation (MWA) is the thermal destruction of cells through the generation of heat from oscillating water molecules. It is already used in the management of internal malignancies. Melanoma skin metastases represent an ideal target for MWA treatment due to their accessible nature. Recent advances in systemic immunotherapy for melanoma have shown the effectiveness of treatments aimed at enhancing the immune response to melanoma. We have previously shown in a study of Human Papilloma Virus (HPV) skin infection that microwave therapy is well tolerated and induces an anti-HPV immune response. It is possible that MWA may be able to stimulate and augment a systemic anti-melanoma response as well providing local destruction of melanoma metastases. We propose a pilot study to establish if MWA can successfully treat metastatic melanoma deposits using the Swift device manufactured by Emblation. We hypothesise that precise delivery of microwave energy onto a melanoma deposit will lead to its destruction. In this biomarker driven study we will analyse the treated melanoma tumours for histological, morphological and gene expression changes before and after treatment. We will assess circulating T-cells for antimelanoma activity before and after treatment.
1. Stage 4 or inoperable stage 3 metastatic melanoma 2. Age > 18yrs 3. Targeted treatment of cutaneous metastases deemed inappropriate or unwanted
1. Aged under 18 2. Inability to provide informed consent 3. Unable to fulfil study requirements
Follicular lymphoma (FL) is a slowly growing cancer of the lymph glands. It often responds well to treatment but has a tendency to come back again (relapse) and therefore needs to be treated more than once. Initial treatment is usually with a 6-month course chemotherapy combined with an antibody drug called rituximab (R+chemo). Most patients who respond to R+chemo are offered further (maintenance) therapy with rituximab alone over a period of 2 years with the aim of delaying relapse. However, there is growing controversy about the routine use of rituximab maintenance after initial R+chemo for the following reasons: (1) It does not prolong survival; (2) It is associated with an increased risk of infection (responsible for 7-8% of all deaths in FL); (3) It prolongs remissions only in the minority of patients whose disease was destined to relapse within 2-3 years. A one-size-fits-all approach to rituximab maintenance is therefore not ideal as many patients will experience complications without deriving any benefit. The PETReA trial will use a new scanning technique called Positron Emission Tomography (PET) to identify which patients are more or less likely to benefit from rituximab maintenance after initial R+chemo treatment. We know that patients whose PET scans return to normal have a low-risk of early relapse, and the trial will therefore investigate if rituximab maintenance can be omitted in this group. In contrast, patients whose PET scans remain abnormal have a high risk of early relapse. The trial will investigate whether this group will benefit from the addition of a drug called lenalidomide to rituximab maintenance. PETReA, which is funded by Cancer Research UK, aims to recruit more than 800 patients from across the UK over a period of 4.5 years and is potentially available for any patient with FL who requires initial R+chemo treatment.
1. Must be > = 18 years of age at the time of signing the informed consent form. 2. Must be able to adhere to the study visit schedule and other protocol requirements. 3. Must have a documented diagnosis of follicular lymphoma (grade 1, 2 or 3a). 4. Must be at non-contiguous stage II, stage III or stage IV. 5. Must fulfil at least one of the Groupe d'Etude des Lymphomas Folliculaires (GELF) GELF criteria for high tumour burden: a. Systemic symptoms (> 10% weight loss, temperature > = 38°C for more than 5 days, abundant night sweats) b. Performance status (PS) greater than 1 according to the Eastern Cooperative Oncology Group (ECOG) scale c. Elevated lactate dehydrogenase (LDH) level d. β2-microglobulin level greater than 25.5 nM/L (3 μg/mL) e. A single lymph node larger than 7 cm f. Involvement of at least 3 nodal sites, each with diameter greater than 3 cm g. Marked splenomegaly h. Organ failure i. Pleural effusion or ascites j. Orbital or epidural involvement k. Blood infiltration l. Cytopenia 6. Must not have received prior systemic therapy (local radiotherapy is permitted). 7. Must have a WHO performance status score of less than or equal to 2. 8. Must agree to adhere to the Celgene guidance on pregnancy prevention.
1. Any serious medical condition that would prevent the subject from participating in the study. 2. Known active infection with HIV, HBV or HCV. 3. Pregnant or lactating females. 4. Central nervous system involvement as documented by spinal fluid cytology or imaging. 5. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer (TNM stage of T1a or T1b) 6. Any of the following laboratory abnormalities: a. Absolute neutrophil count (ANC) < 1,000/μL (1.0 X 109/L) b. Platelet count < 50,000/μL (50 X 109/L) c. Serum alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN) d. Serum total bilirubin > 1.5 x ULN unless due to Gilbert's Syndrome or biliary obstruction by lymphoma
A prospective interventional multi-centre study, COMET aims to prove the accuracy of imaging diagnosis of extranodal tumour deposits (TD) and their adverse effect on prognosis of colorectal cancers. The proposed intervention will be additional radiological and pathological assessment and the reporting of supplementary diagnostic information which would not otherwise have been available. This may affect treatment according to local MDT protocols and also affect the provision of prognostic information to patients in subsequent discussions. Any patient with a suspected primary adenocarcinoma of the colon, sigmoid or rectum undergoing surgery are eligible. The date of surgery must be known prior to registration. This trial aims to determine if image mapping techniques can improve the concordance between imaging and pathology detection of tumour deposits. Lymph nodes and tumour deposits will be identified on pre-operative scans and mapped by radiologists then shared with pathologists prior to processing the resected specimen. Patients will be managed at their local hospital with standard follow-up. Patients will be followed up for 5 years.
Patients with rectal cancer who are going to have surgery Over 18 Able to undergo an MRI
Under 18 Unable to give informed consent Unable to undergo surgery Unable to undergo MRI
An adaptive phase II study of FOLFOX-A (FOLFOX and nab-paclitaxel) versus AG (nab-paclitaxel and gemcitabine) in patients with metastatic pancreatic cancer, with integrated biomarker evaluation
1 Patient has been enrolled in the Precision Panc Master Protocol and their tissue has been deemed suitable for NGS analysis 2 Patient has provided signed information consent for the PRIMUS 001 study 3 Age ≥ 16 years 4 Histologically-confirmed metastatic pancreatic ductal adenocarcinoma and its varients, with measurable metastatic lesion(s) according to RECIST 1.1. 5 Eastern Cooperative Oncology Group (ECOG) 0-1 with life expectation of no less than 12 weeks. 6 Patients must have received no previous chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with a fluoropyrimidine and/or gemcitabine administered in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no ongoing toxicities are present. 7 Adequate liver/bone marrow function as defined by: a. Neutrophils (ANC) ≥ 1.5 x 109/l b. Platelets ≥ 100 x 109/l c. Haemoglobin ≥ 9.0 g/dL d. WBC ≥ 3 x 109/l e. Total bilirubin ≤ 1.5 x institutional ULN unless bilirubin rise is due to Gilbert’s syndrome f. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (and < 5 ULN in the presence of liver metastases) g. Estimated creatinine clearance ≥ 60 mL/min (as calculated by Cockcroft and Gault or Wright formula or measured by EDTA clearance) NHS R&D Form IRAS Version 5.5.1 10 221370/1121060/14/694 8 Negative serum Human Chorionic Gonadotropin (HCG) test for females with child bearing potential. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential 9 Woman of child bearing potential, and men with female partners of child bearing potential, must agree to use adequate contraceptive measures (see section 8.1.8.1) for the duration of the study and for up to 6 months after the completion of study treatment. 10 Compliant, and can be followed up regularly The following additional inclusion criteria is ONLY required if recommended by the independent Data Monitoring Committee after interim review of study data (sites will have been informed by the CRUK CTU if this is the case) 11 Patient must be biomarker positive as fed back after central Precision-PANC diagnostic testing
1 Prior treatment with nab-paclitaxel or oxaliplatin 2 Prior chemotherapy for metastatic pancreatic cancer 3 Known hypersensitivity for any component of any study drug 4 Active infection including Herpes Zoster and chickenpox 5 Current neuropathy ≥ grade 2 6 Uncontrolled brain metastatsis or mental illness 7 Uncontrolled congestive heart failure (CHF), or history of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months. 8 Uncontrolled serious contraindicated medical condition or illness 9 Known or suspected dihydropyrimidine (DPD) deficiency 10 Pregnant of breastfeeding 11 History of physical or psychiatric disorder that would prevent informed consent and compliance with protocol 12 Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, of receiving the first dose of trial treatment 13 Any systemic anti-cancer therapy, or major surgery within 28 days of randomisation 14 Any minor surgery or radiotherapy within 7 days of randomisation 15 Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial protocol and follow up schedule. 16 Any patients receiving treatment with brivudin, sorivudin and analogues 17 History of another malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated earlystage cervical cancer or treated/bio 18 chemically-stable, organ-confined prostate cancer). 19 Any patient with severe diarrhoea (defined as ≥grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection
Cancer of the large bowel (colorectal cancer) is common in the general population and the lifetime risk for someone living in the UK is 1 in 17. Whilst modern surgery, radiotherapy and chemotherapy treatments have impacted beneficially on survival outcome, many patients still die from their disease. Hence, there is a pressing need to understand the causes of colorectal cancer and to intervene early. Colorectal cancer under the age of 40 years of age is particularly rare, with less than 1.2% of all cases aged < 40 years. We have published extensively that patients within this age group are highly enriched for underlying major genetic effects. A number of genes have been identified over the past 20 years, but much of the genetic aetiology remains to be discovered. We now plan a major initiative to conduct “next-generation” sequencing of the whole genome of young patients and both parents where there is no evidence of cancer “running in the family”. Our aim in this study is to look at samples (blood and tissue removed from tumours) from individuals who have developed bowel cancer at a young age and also blood samples from each of their parents. These samples will be analysed using a technique called “Next-Generation Sequencing” (NGS). NGS is a scientific technique that gives us a “read-out” of all the genetic information that is stored in our DNA within each of our cells within the body. It is this information that makes every person unique. We aim to identify changes in patients DNA (mutations) that may not be present in parents. We aim to collect this information to help us identify mutations that are causing bowel cancer. This will in the long term help us to develop new treatments and predict who will be susceptible to cancer and so be able to prevent disease progression.
PATIENT INCLUSION CRITERIA •Patients who have developed colorectal cancer at aged 40 years of age or younger at the time of diagnosis. (Individuals OVER the age of 40 years ARE eligible if they were previously diagnosed with colorectal cancer when aged 40 years or younger). •Patients will not have a known molecular genetic predisposition to the development of colorectal cancer or a strong family history of cancer consistent with known dominant disorders. •Patients are able to provide written informed consent for whole genome sequencing and blood/saliva biomarkers. •Documentary evidence of a pathologically confirmed adenocarcinoma of colon or rectum along with consent to access archived tumour material from the time of operation. •Demographic and drug history are available or can be ascertained from patient. •If the patient is under the age of 16 years, both parents are available to sign/countersign a consent form. Whilst cases under the age of 16 years are extremely rare, these cases greatly enhance the value of their contribution to the study. •Inclusion can be from any part of mainland GB and Northern Ireland and of any ancestry. •Patients will be asked if they agree to being re-contacted if further confirmatory samples are required and/or results are of clinically significant relevance. PARENTS INLCUSION CRITERIA •Neither parent will have had a past or present diagnosis of colorectal cancer or other cancer relevant to CRC predisposition such as endometrial cancer. •Both parents will be alive and are contactable within the United Kingdom and Northern Ireland. •Both parents will not have a known genetic predisposition to the development of colon cancer. •Both parents will be able to provide written informed consent for sampling. •Both parents will provide a simple blood sample for whole genome sequencing & blood or saliva biomarkers. •Demographic and drug history are available or can be ascertained from parents. •Both parents will be asked to agree to being re-contacted if further confirmatory samples are required and/or results have clinical implications.
Exclusion criteria – PATIENTS - BOTH parents unable to provide samples. - The inability to provide informed consent. - Patients who have developed CRC aged over 40 years at diagnosis. - Tumour that has shown loss of DNA mismatch repair gene protein expression or tumour that has exhibited MSI (micro satellite instability). - Familial CRC (a strong family history) Exclusion criteria – PARENTS - Both parents are unable to provide samples. - The inability to provide informed consent. - Known mutations in colorectal susceptibility genes within the family (eg APC,MLH1, MSH2, MSH6, PMS2, MUTYH, POLE1, POLD1, SMAD4/BRCA/STK11).
Neuroblastoma is an embryonal childhood tumour derived from cells which go on to form the sympathetic nervous system. It most often develops in the adrenal medulla but can occur anywhere from the neck to the pelvis. It is one of the most difficult childhood cancers to cure with around 40% five-year survival in high risk cases (50% of all cases). Despite advances in neuroblastoma therapy relapse still occurs in 50% of high risk cases and in most high risk cases cure is no longer possible. Knowledge of factors which influence subsequent response and length of survival following relapse in neuroblastoma are important to determine which, if any, treatment at relapse is appropriate in individual cases, and may significantly affect the results obtained when evaluating new therapies for neuroblastoma in Phase I and II clinical trials. Recent studies report an increased frequency of recurrent, genetic abnormalities at relapse including segmental chromosomal abnormalities (SCA) and gene mutations for which a targeted treatment exists. The present study is a retrospective epidemiological and genetic study which aims to determine clinical and genetic factors associated with neuroblastoma relapse and length of survival following relapse. This will be done by linking epidemiological data, clinical and existing genetic data analysed by multiplex ligation PCR dependent amplification (MLPA) or array comparative genomic hybridisation on recurrent chromosomal losses and gains and treatment information. We will also compare existing genetic profiles on patients on the current high risk neuroblastoma trial who have relapsed with those who haven’t to determine whether particular types and number of segmental chromosomal abnormalities are associated with an increased risk of relapse. The study will also investigate whether the median survival time following relapse is associated with the time interval from diagnosis to relapse. The outcomes from this study will be used to inform future Phase I, II and III clinical trials for children with neuroblastoma.
All cases of relapsed/refractory neuroblastoma in the UK and Ireland diagnosed in children and young people aged 0-40 years from the year 2000 onwards. For the second aim of work package I of the study we will include all cases of high risk neuroblasoma who are registered on the high risk trial and who have had genetic studies in addition to MYCN undertaken at diagnosis. Based on numbers of patients registered on the current high risk neuroblastoma trial to date from the UK (around 500) and the numbers on which genetic analyses have been performed (around 250) it will be possible to identify at least 100 relapsed and non-relapsed patients (based on 50% relapse rate). Work package II - cases of neuroblastoma where the tumour cell content is > 30% (30 cases) from diagnosis and relapse (partly from a previous study from our group) and the remainder from the neuroblastoma genetic reference centre work undertaken in Dr Nick Bown's laboratory).
N/A
Neuroblastoma is one of the commonest childhood malignancies and accounts for 15% of paediatric cancer deaths. Prognosis for children with metastatic disease remains poor. In recent years antibody based immunotherapies have shown considerable promise in this area. This is a phase 1 study to test the toxicity and tolerability of combining i) radiotherapy targeting neuroblastoma cells (131-I mIBG therapy) ii) antibody targeting the ganglioside molecule GD2 on neuroblastoma cells (Dinutuximab beta Apeiron) iii) Nivolumab, an antibody that binds to the immune molecule PD-1. This novel combination is based on pre-clinical work demonstrating that these agents may work together to kill neuroblastoma cells and generate long term immunity against the tumour. Both 131-I mIBG therapy and Dinutuximab beta have been widely used in neuroblastoma, with therapeutic activity as single agents. Nivolumab has undergone paediatric phase I testing, but has not been widely used in neuroblastoma. This study will be performed in patients with relapsed or refractory neuroblastoma, for whom there are no other curative options. The first cohort of patients will receive 131-I mIBG therapy followed by treatment with Nivolumab. If there is no unexpected toxicity, the next cohort of patients with received 131-I mIBG, Nivolumab and a reduced (50%) dose of Dinutuximab beta. If this is tolerated then a larger cohort of patients will receive all 3 agents at the full dose. Imaging of the tumour, as well as detailed monitoring of the immune response will be performed (by serial blood tests) to seek evidence of anti-tumour effects.
• At study entry patients must be > 1 year • Relapsed or refractory high risk neuroblastoma (as defined by INRG criteria) • MIBG avid disease on imaging within 4 weeks to study entry. • > = 3 months since any myeloablative chemotherapy / stem cell rescue • > = 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half-lives since last dose of any monoclonal antibody therapy. • Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky, see Appendix 1: Performance Scales) • Estimated life expectancy > = 12 weeks • Adequate bone marrow function: ANC > 1.0 x 109/L, platelets > = 50 x 109/L and haemoglobin > 8.0 g/dL • Adequate renal function: serum creatinine < 1.5 mg/dL or a estimated creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73m2 • Adequate cardiac function: shortening fraction of > = 28 % by echocardiogram • Adequate hepatic function: ALT or AST < 5 x ULN and a total bilirubin < 1.5 x ULN • Adequate lung function: FEV1 and FVC > 60% of predicted by pulmonary function tests. Children unable to do PFTs should have no dyspnea at rest and a pulse oximetry > 94% on room air • Adequate pancreatic function: serum lipase < 1.5 x upper limit normal • Patients may have had prior CNS metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema • Patients must consent to the placement of a central venous line, if one has not already been placed. • Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery. • Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method to avoid pregnancy for 5 months after last dose of trial medication. Female patients who are lactating must agree to stop breast-feeding. Male patients who are sexually active must be instructed to use contraception throughout treatment and for a period of 7 months after last dose of trial medication. • Patients with seizure disorders may be enrolled if seizures are well controlled. • All patients and/or their parents or legal guardians must sign a written informed consent • All institutional and national requirements for clinical trials must be met. • Expression of PD-L1 by tumour is not a pre-requisite • Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration • Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy • Patients who have previously received Dinutuximab beta (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously. • Patients who have had previous 131-I mIBG therapy will not be excluded • At least 1 x 106 /Kg autologous stem cells stored and available if needed • Patients and/or their parents or legal guardians must agree that no standard or experimental anti-tumour treatment, except when specified in the protocol, is allowed any time during the study treatment.
• Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study • Previous allogeneic stem cell transplant or solid organ transplant • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger • Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry. Local steroid treatments (e.g. dermal, mucosal, inhaled) are allowed. • Unable to maintain platelets > = 50 x 109/L without transfusion • HIV or Hepatitis B or C infection • Patients who have had major surgery (e.g laparotomy or thoracotomy) within the past 2 weeks. • Patients with significant intercurrent illnesses and/or any of the following: o Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance. o Patients with significant psychiatric disabilities or uncontrolled seizure disorders. o Patients with active infections, or active peptic ulcers, unless these conditions are corrected or controlled. o Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade > 2) are ineligible. o Patients with clinically significant, symptomatic, pleural effusions. Patients with uncontrolled hypertension
Germ cell tumours (GCTs) account for 98% of all testicular cancers. Germ cell tumours also arise in the ovary, accounting for 1% to 2% of ovarian neoplasms. Germ cell tumours also rarely arise in the mediastinum, retroperitoneum, ovary and brain. Post-pubertal germ cell tumours represent 14% of all cancers in older adolescents. Outcomes are excellent for most patients, however over a third of patients with metastatic disease will relapse and die despite being on best available therapy. There is a need to improve 1st line therapy results for patients classified as intermediate & poor risk. Treatment currently involves the use of a chemotherapy regimen comprising of bleomycin, etoposide, & cisplatin (BEP); coupled with surgical resection of residual metastatic disease post chemotherapy. Early trials have demonstrated the safety, feasibility & tolerability of accelerated BEP for metastatic GCTs. These trials also indicated that the chemotherapy related toxicities were no worse than those expected from standard BEP regimen. This is an open-label, randomised, stratified 2-arm multicentre phase 3 clinical trial in patients with intermediate or poor risk categorised GCTs undertaken in two stages. The patients will be given either 4 x 21-day cycles of BEP or 4 x 14-day cycles of BEP, followed by 4 doses of weekly bleomycin monotherapy. The aim of the study is to determine if accelerated BEP is superior to standard BEP as a 1st line therapy for these patient groups by comparing progression-free survival in the two arms. The research team will also compare the two arms for protocol specific response, adverse events, quality of life and treatment preference, delivered dose-intensity of chemotherapy & overall survival.
Patients will be eligible for inclusion into this study if they meet all of the following criteria. 1. Able and willing to provide signed, written informed consent/assent 2. Male or female 3. Aged between 11 and 45 years inclusive on the date of consent 4. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or exceptionally raised tumour markers (AFP > = 1000ng/mL and/or HCG > = 5000IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases is consistent with GCT, high tumour burden, and a need to start therapy urgently 5. Primary arising in the testis, ovary, retro-peritoneum or mediastinum 6. Metastatic disease or non-testicular primary 7. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma and inclusion of ovarian primaries). 8. Adequate bone marrow function with ANC > = 1.0 x 109/L 9. Adequate liver function where bilirubin must be < = 1.5 x ULN, - except if the elevations are due to hepatic metastases, in which case ALT and AST must be < = 5 x ULN - except participants with Gilbert’s Syndrome where bilirubin must be < = 2.0 x ULN; ALT and AST must be < = 2.5 x ULN 10. Adequate renal function with estimated creatinine clearance of > = 60 ml/min according to the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline, in the opinion of the investigator, in which case GFR should be formally measured, e.g. with EDTA scan 11. ECOG Performance Status of 0, 1, 2 or 3 12. Study treatment both planned and able to start within 14 days of randomisation 13. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments.
Patients will be excluded from this study if they meet any of the following exclusion criteria; 1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumour, or other malignancy treated at least 5 years previously with no evidence of recurrence) 2. Previous chemotherapy or radiotherapy, except: - Pure seminoma relapsing after adjuvant radiotherapy of adjuvant chemotherapy with 1-2 doses of single agent carboplatin - Non-seminoma and poor prognosis by IGCCC criteria in the rare case where low-dose induction chemotherapy is given prior to registration because patient is not fit enough to receive protocol chemotherapy (e.g. organ failure, vena cava obstruction, overwhelming burden of disease). Acceptable regimens include cisplatin 20 mg/m2 days 1-2 and etoposide 100 mg/m2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m2 days 1-2; or baby-BOP.37 Patients must meet all other inclusion and exclusion criteria at the time of registration - Participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation. Such patients must be discussed with the coordinating centre prior to registration, and must be registered within 10 days of commencing study chemotherapy 3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin 4. Significant co-morbid respiratory disease that contraindicates the use of bleomycin 5. Peripheral neuropathy > = grade 2 or clinically significant sensorineural hearing loss or tinnitus 6. Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety 7. Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and 12 months post treatment. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration 8. Known allergy or hypersensitivity to any of the study drugs 9. Presence of any psychological, familial, sociological or geographical condition that in the opinion of the investigator would hamper compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
Colorectal cancer (CRC) remains an important cause of morbidity and mortality. Identifying those at higher risk is important in targeting preventive measures, such as screening colonoscopy, to those most likely to benefit. Much of the risk of CRC and its precursor lesions (mostly polyps) is genetic, but a great deal of the heritability of CRC remains unexplained. Some of the remaining genetic risk probably results from rare genes with large effects, some from uncommon genetic variants with moderate effects and some from common differences with modest or very modest effects. The sub-division between these categories is extremely difficult to predict in advance of successful searches for these genes. The principal aim of this study is to identify additional susceptibility genes for CRC and cancers genetically related to CRC, such as endometrial cancer. This will involve studying CRC patients, their families, patients with other cancer types and controls. Secondary aims include determining the extent of that genetic risk, building risk models that incorporate multiple risk factors, and performing functional studies to work out how CRCs develop and how inherited risk factors act. Blood samples, tumour samples, non-cancer material and medical information from study participants is required to perform molecular and statistical analyses. Dysregulation of DNA repair pathways is known to be involved in the development of colorectal cancer and other cancers. Analysis of additional non-bowel samples from participants with and without germline mutations will aid in understanding why particular germline mutations lead to the development of tumours specifically in the bowel. Characterisation of inherited predispositions is further aided by analysis in the context of other cancers and conditions, which will be assessed by inclusion of other cancers and healthy controls, and by means of questionnaires focusing on cancer history, fertility and birth defects.
• Index patient o > 6 years, male or female; o with a colorectal tumour (malignant or benign) or with a cancer or disease strongly related to colorectal tumours (e.g. endometrial cancer). o Individual and/or parent/guardian willing and able to give informed consent for participation in the study. In practice, recruitment centres may be asked to focus on patients who are more likely to have a genetic basis to their disease (e.g. early onset, multiple tumours, syndromic features). • Blood relative of the index patient o Age > 18 years, male or female; o Willing and able to give informed consent for participation in the study. • Control o Non-blood relative or other individual who has never had a colorectal tumour/ cancer or cancer in any other site; o No first degree relatives with bowel cancer; o Age > 18 years, male or female; o Willing and able to give informed consent for participation in the study.
An individual may not enter the study if ANY of the following apply: • For adults/parents: unwilling to provide informed consent • For children: expressing dissent An individual may not supply additional research-only skin sample if they • Have a history of bleeding disorders • Are taking any medications that would preclude safe skin biopsy
Langerhans Cell Histiocytosis (LCH) is a rare disorder with highly variable clinical presentation and biological behaviours. It can affect a single system/organ (SSLCH) or multiple systems/organs (MSLCH). Patients with SSLCH of the skeleton, skin or the lymph nodes have an excellent prognosis and may need no, or minimal treatment. MSLCH is unpredictable upon diagnosis, ranging from spontaneous resolution to rapid progression and fatal outcome. Previous research has shown that combination therapy with vinblastine and prednisolone is effective for MSLCH however more than a third of patients suffer disease reactivation. LCH patients may also suffer permanent consequences including hormone deficiencies, a neurodegenerative syndrome and lung fibrosis. This study aims to improve overall survival, reduce reactivation rates and reduce the permanent consequences. The trial is split into seven strata, designed to tailor treatment based on disease features at diagnosis and on response to treatment. Stratum I is investigating a prolongation (12 vs. 24 months) and intensification (addition of mercaptopurine) of first line therapy (vinblastine and prednisolone) via a randomisation. In stratum II, the response to a uniform initial second line therapy (prednisolone, cytarabine and vincristine) for those patients without risk organ involvement is studied following a randomised comparison of maintenance therapy with either indomethacin or mercaptopurine and methotrexate. Stratum III (cladribine/cytarabine based salvage treatment) and stratum IV (reduced intensity haemapoietic stem cell transplant) are single arm studies of second line therapy for those patients withrisk organ involvement. Stratum V explores the course and treatment of Central Nervous SystemLCH (CNSLCH). Stratum VI is an observational stratum for SSLCH which does not require systemic treatment at diagnosis.
Each stratum has its own exclusion criteria. Stratum I: Pregnancy (patients of childbearing age must be appropriately tested before chemotherapy) LCHrelated permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis etc.) in the absence of active disease Prior systemic therapy Stratum II: Patients with progressive disease in risk organs Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis etc.) without evidence of active LCH in the same organ or in any other locations Stratum III: Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of organ involvement Inadequate renal function as defined by serum creatinine > 3 x normal for age. Stratum IV: Pulmonary failure (requiring mechanical ventilation) not due to active LCH Isolated liver sclerosis or pulmonary fibrosis, without active LCH Uncontrolled active lifethreatening infection Decreased renal function with a GFR of < 50ml/1.73m2/min. Pregnancy or active breast feeding Stratum VI: Patients with SSLCH who have an isolated tumorous CNS lesion (eligible for stratum V) Patients with isolated "CNSrisk" or multifocal bone lesions (eligible for stratum I, group 2).
This research project will study a group of rare blood disorders in children, called Paediatric Myelodysplastic Syndromes (MDS).Paediatric MDS is characterised by failure of normal blood cells production. Without treatment these syndromes are usually fatal and can lead to leukaemia.The aim of this project is to improve our current understanding of the molecular pathways that lead to the disease development;identify all the disease related genetic abnormalities;document the natural history of the disease;create correlations between the clinical presentations and genetic defects and create targets for future therapies .Children with a diagnosis of Paediatric MDS from across all specialist paediatric haematology centres in the UK will be invited to participate in this project. From the study of these cases we aim to built a comprehensive picture of paediatric MDS,which is something that has not been achieved so far. We will record how these disorders present, all their clinical characteristics; laboratory tests results, how the disorders progress with time and the response of the different subgroups of patients to the current treatments.The samples collected will be in the form of blood,bone marrow,nail clippings,skin biopsies, saliva and hair follicles.These samples will be tested for all genetic abnormalities that have been previously described in different types of MDS. In cases that no known genetic abnormality is detected, further genetic testing(called whole genome sequencing) will be performed, after appropriate consent, in order to identify new genetic defects linked with MDS.This will enable us to provide an accurate diagnosis for each family, but also to select the most appropriate treatment for each case.We will study the behaviour of blood cells from children with MDS,using stateof-the-art technology,with the objective to identify the molecular pathways that lead to the disease development.
1. Age from birth to 21 years 2. Probable diagnosis of MDS ie a. Sustained (> 3 months) unexplained cytopenia b. Bi/trilineage morphological myelodysplasia c. Acquired clonal cytogenetic abnormality in haematopoietic cells d. Bone marrow blasts > 5% 3. Children with syndromic MDS or suspected syndromic MDS 4. Children with secondary MDS: chemotherapy, radiotherapy, toxic agents 5. Children with IBMFS and features of myelodysplasia 6. Children with suspected familial MDS 7. Denovo MDS (hypocellular or hypercellular ) 8. Juvenile Myelomonocytic Leukaemia 9. MDS/MPS 10. MDS with systemic disease 11. Children with Downs MDS
1. Patients who do not fulfil inclusion criteria 2. Patients who have not consented for the study 3. Children with known CBF AML translocations
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
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.
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
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.
The primary objective of Phase I is to identify a recommended dose of olaparib to be administered in combination with radiotherapy. The primary objective of Phase II is to determine the effect of olaparib administered in combination with radiotherapy compared with placebo administered in combination with radiotherapy on life expectancy (overall survival) in patients with newly diagnosed glioblastoma who are not fit enough to receive aggressive treatment with both chemotherapy and radiotherapy.
1. Age 18 – 69: WHO performance status 2 at initial oncology consultation or performance status 0-1 but otherwise unsuitable for radical radiotherapy with concomitant and adjuvant temozolomide 2. Age ≥70: WHO performance status 0 or 1 at initial oncology consultation 3. Histologically confirmed diagnosis of glioblastoma 4. Life expectancy greater than 12 weeks 5. No previous radiotherapy or chemotherapy for primary or secondary CNS malignancy 6. Adequate haematological, hepatic and renal function defined as below: •Haemoglobin ≥ 10 g/dL (no blood transfusions in the 28 days prior to trial entry) •Absolute neutrophil count ≥ 1.5 x 109/L •White Blood Cells > 3x109/L •Platelet count ≥ 100 x 109/L •Bilirubin ≤ 1.5 x upper limit of normal (ULN) •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN •Adequate renal function with creatinine clearance / glomerular filtration rate > 50 ml/min. If the creatinine clearance / glomerular filtration rate is less than 50 ml/min as calculated by the Cockroft-Gault/ Wright formula, then the creatinine clearance / glomerular filtration rate should be measured by either a radioisotope technique or by 24-hour urine collection 7. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed 8. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures 9. Ability to swallow oral tablets/capsules 10. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of trial treatment, confirmed prior to treatment on day 1 Posmenopausal is defined as: •Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments •LH and FSH levels in the postmenopausal range for women under 50 •Or surgical sterilisation (bilateral oophorectomy or hysterectomy)
1. WHO performance status > 2 2. Life expectancy less than 12 weeks 3. Active concurrent malignancy (except non-melanoma skin cancer or in situ carcinoma of the cervix). If history of prior malignancy, must be disease-free for > 5 years 4. Prior treatment for primary or secondary CNS malignancy 5. Confusion or altered mental state that would prohibit understanding and giving of informed consent 6. Concomitant treatment with medicines detailed in section 5.10 of protocol 7. Female patients who are able to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intrauterine device and condom, diaphragm with spermicidal gel and condom) effective at the first administration of either IMP, throughout the trial, and for six months afterwards, are considered eligible 8. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] effective at the first administration of IMP, throughout the trial, and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate 9. Administration of any investigational drug within 28 days prior to receiving the first dose of trial treatment 10. Any previous treatment with a PARP inhibitor, including olaparib 11. Blood transfusions within 1 month prior to trial start 12. Patients with myelodysplastic syndrome/acute myeloid leukaemia 13. Major surgery within 14 days of starting trial treatment and patients must have recovered from any effects of major surgery 14. Patients with a known hypersensitivity to olaparib or any of the excipients of the product 15. Patients with uncontrolled seizures 16. Patients who are known to be HIV positive, or who are known to have positive Hepatitis B or C serology
Advanced cancers of the stomach or oesophagus are normally treated with 2drug or 3drug combination chemotherapy regimens. In patients with tumours that are negative for a protein called HER2, the normal management after completion of the chemotherapy is to proceed with regular follow up ‘surveillance’ to monitor for any signs of the cancer starting to regrow. In patients with tumours that are positive for HER2, the normal treatment after completion of the chemotherapy is to proceed with an antibody drug called trastuzumab on its own and continue to monitor for evidence of the cancer starting to regrow. In both cases, the break from chemotherapy will usually allow patients to recover from any treatment side effects. Further chemotherapy may be given at the time of the cancer starting to regrow. However, there is interest in developing drugs which may be more tolerable than traditional chemotherapy, and which could be administered during this surveillance period to try and prolong the length of time until the tumour starts to regrow. Within the PLATFORM study, researchers are evaluating a number of different drugs which could be added in this ‘maintenance’ setting to see whether any of them may improve disease control and the length of time that somebody lives with advanced cancer of the stomach or oesophagus.
• Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach. • Completion of at least 6 cycles of firstline chemotherapy for locally advanced / metastatic disease (this must have included a platinum and fluoropyrimidine in all cases; HER2 positive patients must have received trastuzumab alongside chemotherapy) with > stable disease on the end of treatment CT scan. • Disease which, following firstline chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy. • Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy. • Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis. • Unidimensionally measurable disease (CT or MRI as per RECIST). • Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease. • No prior radiotherapy in the advanced disease setting. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator. • Male/female patients aged ≥18 years. • WHO Performance status 0, 1 or 2. • Patients should have a projected life expectancy of at least 3 months. • Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be posttransfusion). • Adequate renal function: calculated creatinine clearance ≥50ml/minute. • Adequate liver function: serum bilirubin ≤1.5x ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present). • Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 60 days following the last dose of assigned study drug(s). • Written informed consent must be obtained from the patient before any study-specific procedures are performed.
• Concurrent enrolment in another clinical trial unless it is an observational (noninterventional) clinical study. • Tumours of squamous histology. • Documented brain metastases, central nervous system metastases or leptomeningeal disease. • Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other antineoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be < grade 2 according to NCI CTCAE version 4.0. • Any major surgery within 4 weeks prior to the start of study treatment. • Uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 100 mm Hg). • Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior history of clinically significant cardiac failure are excluded from study entry. • History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan. • Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication. • Patients who are pregnant or lactating. • Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection. • Other clinically significant disease or comorbidity which may adversely affect the safe delivery of treatment within this trial. • Any other malignancies within the last 3 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). • Treatment with another investigational agent within 30 days of commencing study treatment.
The Ependymoma Program is a comprehensive program to improve the accuracy of the primary diagnosis of ependymoma and explore different therapeutic strategies in children, adolescents and young adults accordingly. This program is open to all patients diagnosed with ependymoma below the age of 22 years. After surgery and central review of imaging and pathology, patients will be enrolled in one of 3 different studies according to the outcome of the initial surgical resection, their age or eligibility/suitability to receive radiotherapy.
Overall program Main residence in one of the participating countries Age < 22 years old at diagnosis Newly diagnosed intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary myxopapillary, clear-cell and tanicytic or anaplastic ependymoma Delivery to national referral pathology centre of FFPE tumour tissue blocks (or charged slides with sufficient interpretable material and curls in an Eppendorf tube) Written informed consent for data and study biological samples collection All patients and / or their parents or legal guardians willing and able to comply with protocol schedule and agree to sign a written informed consent Patients must be affiliated to a Social Security System in countries where this is mandatory After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy. Patients with centrally and histologically confirmed intracranial ependymoma (histology confirmed by National Reference centre for Biology and Pathology review) meeting the following criteria will be enrolled into one of interventional strata: •Main residence in one of the participating countries, •Age below 22 years old at the diagnosis, •Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: cellular, papillary, clear-cell and tanycytic or anaplastic ependymoma. •Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial, •Males and females of reproductive age and childbearing potential with effective contraception (see section 4.1.2.4 Definition of highly effective methods of contraception) for the duration of their treatment and 6 month after the completion of their treatment, •Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure Specific inclusion criteria have been defined for each stratum of the program. Stratum 1: •Age > 12 months and < 22 years at time of study entry •No residual measurable ependymoma based on the central neuroradiological review (detailed in protocol) •Histologically confirmed WHO Grade II-III ependymoma by central pathological review •No metastasis on spinal MRI and on CSF cytology assessments •No previous radiotherapy •No previous chemotherapy (except steroids) •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry •No medical contraindication to radiotherapy and chemotherapy, •No signs of infection •Adequate bone marrow function(detailed in protocol) •Adequate liver function (detailed in protocol) •Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) Stratum 2: •Age > 1 year and < 22 years at time of entry to study •Residual non reoperable measurable ependymoma based on central neuro-radiological review (detailed in protocol) •Histologically confirmed WHO Grade II III ependymoma by central pathological review •No metastasis on spinal MRI and on CSF cytology assessments •No previous radiotherapy •No previous chemotherapy (except steroids) •No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry •No medical contraindication to radiotherapy and chemotherapy, •No signs of infection •Adequate bone marrow function (detailed in protocol) •Adequate liver function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) Stratum 3 •Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician/parent decision and according to national criteria •Histologically confirmed WHO Grade II-III ependymoma by central pathological review •Adequate bone marrow function(detailed in protocol) •Adequate liver function (detailed in protocol) •Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol) •No previous chemotherapy •No previous radiotherapy •No contraindication to chemotherapy Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed
All interventional stata •Tumour entity other than primary intracranial ependymoma •Primary diagnosis predating the opening of SIOP Ependymoma II •Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas •Patients with spinal cord location of the primary tumour •Participation within a different trial for treatment of ependymoma •Age ≥ 22 years •Contraindication to one of the IMP used in this stratum according to the SmPC related to the products used in the country concerned. (see SmPC in appendix 4) •Concurrent treatment with any anti-tumour agents •Inability to tolerate chemotherapy •Unable to tolerate intravenous hydration •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the Investigator •Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion •Pregnancy and breast feeding Stratum 1 and 2: •Ineligible to receive radiotherapy •Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator Stratum 3: NHS R&D Form IRAS Version 3.5 12 130101/737949/14/8 •Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion •Pregnancy and breast feeding Stratum 1 and 2: •Ineligible to receive radiotherapy •Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator Stratum 3: •Pre-existing severe hepatic (liver) and/or renal (kidney) damage Family history of severe epilepsy •Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial •Elevated blood ammonium level ≥ 1.5 x upper limit of the normal •Elevated Blood lactate level ≥ 1.5 x upper limit of the normal Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgement of the Investigator
• Histologically confirmed diagnosis of squamous cell carcinoma of the oropharynx. • HPV positive on central testing. • UICC TNM (7th edition) stage T1T3, N0N2b tumours of the oropharynx. Staging should be based on cross sectional imaging investigations carried out within 6 weeks of study entry*. • Local MDT decision to treat with primary transoral resection and neck dissection. • Patients considered fit for surgery and adjuvant treatment by the local MDT. • Aged 18 or over. • Written informed consent provided. * Please Note: Current smokers with N2b disease (including smokers up to 2 years before diagnosis) are not eligible to be included.
• HPV negative squamous cell carcinomas of the head and neck. • Patients with T4 primary oropharyngeal tumours and/or T1T3 tumours where transoral surgery is considered not feasible. • N2cN3 nodal disease. • Unresectable retropharyngeal node involvement. • Current smokers with N2b disease (including smokers up to 2 years before diagnosis). • Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction. • Patients with distant metastatic disease (UICC TNM stage IVC disease) as determined by routine preoperative staging radiological investigations e.g., CT thorax and upper abdomen or PETCT. • Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix. • Pregnant or lactating women and fertile women who will not be using contraception during the trial.
A study of prognostic factors in cutaneous lymphoma with the aim of developing a prognostic index to identify high risk patients
All patients within 6 months of a new diagnosis of MF/SS
Patients diagnosed with MF/SS more than 6 months prior to assessment. Patients unable to give informed consent.
A randomised phase II multicentre trial, IMPRESS will determine whether the use of MRI imaging in staging sigmoid cancers results in a change to the treatment plan by identifying more high risk tumours compared to those patients who were staged using CT imaging. The proposed intervention will be additional radiological and pathological assessment and the reporting of supplementary diagnostic information which would not otherwise have been available. This may affect treatment according to local MDT protocols and also affect the provision of prognostic information to patients in subsequent discussions. Patients with suspected or proven sigmoid colon adenocarcinoma, eligible for curative treatment whose MRI can be reviewed prior to surgery and has no decision regarding radical treatment are eligible. Patient are randomised to the control arm which the standard care of preoperative CT imaging and subsequent discussion by the Multidisciplinary Team or the interventional arm which has the additional use of MRI imaging and subsequent discussion by the Multidisciplinary Team. Patients are followed up at 1 and 3 years together with QoL questionnaires.
- All patients with pelvic sigmoid cancer (demonstrated on colonoscopy and biopsy) who are eligible for curative treatment.
- Less than 18 years old - Unable to consent - Consent witheld or withdrawn - Unable to have an MRI (e.g. pacemaker, metal implant in major viscera, severe claustrophobia) - A previous history of colorectal cancer - Presence of irresectable distant metastases - Severe comorbidities that prevent the application of eventual chemo/radiotherapy
A phase II multicentre, interventional study to determine if additional staging at diagnosis with liver DW-MRI will diagnose more synchronous metastases than CT alone in patients with high risk colorectal cancer. Liver metastases found on the additional DW-MRI scans will be discussed at MDT and treated according to local policy. Eligible patients with high risk colorectal malignancy (T3/4, spread greater than 5mm, EMVI positive) will have additional surveillance of breath hold T1, T2 and DW-MRIs (no IV contrast) post surgery six monthly for three years. Findings of liver MRIs as reported by radiology PI will be shared with their local MDT who make decisions as appropriate, including the management of any identified liver metastases, according to local protocol.
1. High risk primary colorectal cancer (as determined by CT or MRI). 2. CT which is negative for, or no confirmatory evidence of, metastatic disease . 3. Patient aged over 18 years
1. Patients who are unable to give consent, who withhold consent or who withdraw consent will be excluded. 2. Patient is undergoing active treatment or follow-up for another malignancy (excluding basal cell carcinoma). 3. Patient has a contraindication to CT or MRI (e.g. intraocular metal fragments, pacemaker, severe claustrophobia), iodine or gadolinum based contrast agents (documented allergy to iodine, renal impairment with GFR < 30mL/min) 4. Patients who are pregnant or breast feeding. 5. Patients who have received systemic treatment for colorectal cancer. 6. Patients with any metastatic disease.
rEECur is a randomised study to compare four chemotherapy regimens to see which is the best at treating recurrent or refractory Ewing sarcoma. Ewing sarcoma is a type of bone cancer. Recurrent Ewing sarcoma means Ewing sarcoma that has come back after being treated. Refractory Ewing sarcoma means Ewing sarcoma that has grown or progressed while being treated. Ewing sarcoma is rare and running a study such as this requires funding and collaboration across many different treatment centres and countries. The logistics behind running such a study are not trivial and as a result rEECur is the first study to directly compare different chemotherapy regimens in this disease setting. Most doctors treat recurrent and refractory Ewing sarcoma with chemotherapy. However, although several chemotherapy regimens are available to treat this disease, we do not know which is the best regimen to use. We are primarily interested in finding out which regimen is most effective at making tumour deposits shrink and, in the longer term, at curing the disease or providing prolonged disease control. We will also determine which regimen has the most side effects, which is associated with the most time spent in hospital and which has the greatest effect on quality of life. The results will help us to know which chemotherapy regimen is the best to use for patients with this disease. It will also allow us to inform patients about the relative burden of side effects associated with each regimen, allowing individual patients and/or parents to make an informed choice about how to be treated.
1. Histologically confirmed Ewing sarcoma. 2. Disease recurrence or progression after completion of first line treatment OR Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on Response Evaluation Criteria In Solid Tumors (RECIST). The appearance of new bone lesions on bone scan will require confirmation with crosssectional imaging. 3. Soft tissue disease component evaluable by crosssectional imaging. Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure. 4. Age ≥4 years and < 50 years. 5. Patient assessed as medically fit to receive cytotoxic chemotherapy. 6. Documented negative pregnancy test fr female patients of childbearing potential. 7. Patient agrees to use effective contraception during therapy and for 12 months. after last trial treatment (females) or 5 months after last trial treatment (males), where applicable. 8. Written informed consent from the patient and/or legal guardian.
1.Bone marrow infiltration resulting in absolute neutrophil count (ANC) < 1.0 x 109/l or platelets < 75 x 109/l 2.Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previosu two weeks. 3.Myeloablative therapy within previous eight weeks. 4.Radiotherapy to target lesion within previous six weeks. 5.Pregnant or breastfeeding women. 6.Followup not possible due to social, geographic or psychological reasons.
This project aims to improve short and long term outcomes for children and young people with Wilms (WT) and other childhood renal tumours through the introduction of a more ‘personalised’ approach to risk stratification. This will include biological characterisation of tumour, blood and urine samples to better define the molecular pathways involved, particularly in high risk, ‘blastemal type’ Wilms tumour. There will be central review of tumour pathology and of any imaging studies (scans) performed in ‘real time’, to test the feasibility of integrating all of these complex datasets within a newly developed e-health tool project known as “P-medicine”, that will be used to improve clinical decision making in a future clinical trial. Each patient’s treatment will be according to the currently accepted best practice, that is based on the recently closed phase III clinical trial run by the International Society of Paediatric Oncology (SIOP) Renal Tumours Study Group, in which the UK was a major participant.
All children, adolescents or young adults with a primary renal tumour (or extrarenal Wilms tumour) diagnosed and treated at a participating Children’s Cancer and Leukaemia Group (CCLG) treatment centre. There is no strict upper age limit nor requirement for the patient to be a UK resident provided that follow up information is anticipated to be available.
Patients who do not give/whose parents do not give consent for inclusion of their clinical/imaging or biological sample data. (note that patients/parents can consent separately to the biological studies so may still be registered if they consent for inclusion of their clinical/imaging data but will be excluded from the biological studies if they so wish).
Mesothelioma is a relatively uncommon cancer that accounts for 1% of all cancers with an annual death rate in the UK of around 2100. Mesothelioma is different from other cancers as it is driven by the body's inability to deal with asbestos fibres. There is increasing evidence that links particular immune cells (macrophages and other inflammatory cells) with encouraging tumour growth and for this reason the study of mesothelioma may offer new insights into the role of these immune cells in cancers driven by inflammation. Therapy that targets the immune system has established itself as a relevant treatment in an increasing number of cancers with benefit in controlling disease and patient survival. The successful approaches include stimulating immune cells (antibodies) and also vaccination, which has been used in other cancers like colorectal and prostate cancer. Little is known about how and whether events in the immune system affect outcome in mesothelioma. Some steps in the process that cause mesothelioma, like acquisition of proteins that prevent the cancer cells being destroyed by the body have been found. There are also some studies that show mesothelioma may be able to be targeted by the immune system when vaccination against a protein called Wilms-Tumour antigen 1 (WT1) is undertaken. A DNA vaccine against WT1 has been developed in Southampton and is in clinical testing in leukaemia. The identification of specific immune cells that recognise WT1 may provide useful markers for diagnosing mesothelioma and may be used to evaluate how effective a vaccine may be in this disease. This study aims to identify specific immune cells that may be useful as markers in mesothelioma to predict clinical outcome in patients and and identify cells and pathways that may be targeted to treat mesothelioma.
For the study of retrospective paraffin embedded tissue: Known diagnosis of mesothelioma Patient aged 18 or over For the prospective collection of pleural fluid/pleural biopsies/blood: Suspected diagnosis of mesothelioma Presence of pleural fluid in control group Patient aged 18 or over Patients with the ability to understand the study requirements and provide written informed consent
None identified (other than absence of consent)
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
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
tbc
To quantitatively analyse the relative expression of known and novel tumour associated antigens in the peripheral blood and bone marrow samples of haematologically normal donors and myeloid leukaemia patients. Also we will investigate anti-tumour immune responses by T cells from patients.
• Male and female adults, aged 18 and over • Acute myeloid or lymphoblastic leukaemia patients, newly diagnosed or in remission • Chronic myeloid leukaemia patients, newly diagnosed, in chronic phase or at transformation to blast crisis • Myelodysplastic Syndrome patients, newly diagnosed or in remission Myeloma patients, at diagnosis or following treatment including autologous or allogeneic stem cell transplantation. • Normal haematopoietic stem cell donors for stem cell transplantation • Able to provide written informed consent (understanding of the form and what they are signing at a level which reassures the consenting medic that they are competent to do so)
• Known positivity for HIV • Inability to obtain informed consent.
Oral cancer (OSCC) is the 8th most common cancer worldwide, representing about 4% of all malignancies. In the UK, the incidence has increased dramatically over the last 20 years, particularly in young non-smokers, with around 5,000 new cases each year. Compared with many cancers, OSCC remains a relatively understudied disease. And despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained unchanged for decades, with a 5-year survival rate of around 50%. Oral cancer may be preceded by a premalignant, histologically dysplastic lesion, usually presenting clinically as a white or red patch in the mouth. However, only around 10-15% of patients diagnosed with oral dysplasia will develop oral cancer.
- Clinical suspicion of premalignant oral/oropharyngeal/laryngeal lesion and/or condition. - Clinical and histopathologic diagnosis of oral/oropharyngeal/laryngeal cancer.
N/A
To identify mutation carriers in collaboration with the NHS Regional Genetics Services and recruit them and their relatives. This will allow the identification of genetic and environmental modifiers on colorectal cancer.
Mismatch repair gene mutation carriers (and tested relatives) will be identified in collaboration with the Regional Genetics Centre.
Unknown
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.