Bladder Cancer Breast Cancer Lung Cancer
Breast Cancer Colorectal Cancer Lung Cancer
Haematological Oncology Haematology
Head and Neck Cancer
Brain Cancer Breast Cancer
Breast Cancer Genetics
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
Low grade gliomas (LGG) are the most frequent brain tumour in children. More than 50% of these tumours will progress within the first 5 years and need further treatment. As most patients are young, the risks of radiotherapy to the developing brain are high, further medical treatment options are urgently needed. Vinblastine is an effective chemotherapy drug for LGG and has been shown to improve survival. Nilotinib is type of biological therapy called a tyrosine kinase inhibitor. Vinblastine and Nilotinib have different antiangiogenic mechanisms, limited and non-overlapping toxicities, and are thought to play an interesting role in the treatment of paediatric LGG. The phase I part of the trial has already been completed and identified the recommended doses (RD) of each agent when given in combination. The main objective of the phase II part is to evaluate the efficacy of vinblastine in combination with nilotinib at the RD, as compared to vinblastine alone, in children, adolescents, and young adults with refractory or recurrent LGG. This is an open label, randomised, study of the combination of nilotinib and vinblastine versus vinblastine alone 122 patients with LGG will be randomised to receive either: • Vinblastine and nilotinib OR • Vinblastine only Vinblastine will be given as an intravenous injection on days 1, 8, 15 and 22 of each 28 day cycle. Nilotinib will be taken as a capsule orally twice a day on each day of the cycle. Patients will receive up to 12 cycles of treatment in the trial as long as they are benefitting from it and are well. This trial is being funded in the UK by Cancer Research UK (including funding from the Brain Tumour Charity). Nilotinib is being provided free of charge by Novartis. This trial will open at 6 sites in the UK plus others within Europe. The Sponsor of this international study is Gustave Roussy, France.
• Written informed consent signed by the patient, or parents or legal representative and assent of the minor child where appropriate. • Age: 6 months to < 21 years of age at time of study entry • Diagnosis: one of the three conditions listed below - Refractory or recurrent low-grade glioma after at least one first-line therapy with pathological documentation in non NF1 patients (no further biopsy is needed at study entry) - Refractory or recurrent low-grade glioma after at least one first-line therapy in NF1 patients, with or without pathological documentation. For patients with NF1 and optic pathway glioma, no biopsy is required to confirm the radiological diagnosis of the low grade glioma. - Low grade glioma at diagnosis in NF1 patients when the use of chemotherapy is considered for the treatment in case of threat to vision or unequivocal radiological tumor progression. Pathological documentation is advised but not mandatory. • Evaluable Disease on morphologic MRI • Karnofsky performance status score > = 70% for patients > 12 years of age, or Lansky score > = 70% for patients < = 12 years of age, including patients with motor paresis due to disease. • Life expectancy > = 3 months. • Administration of stable dose of steroids for at least one week • Adequate organ function: - Adequate hematopoietic function: neutrophils 1.0 x 109/L, platelets 100 x 109/L; hemoglobin 8 g/dL - Adequate renal function: serum creatinine < 1.5 x ULN for age - In other cases where serum creatinine > 1.5 ULN according to age, Glomerular filtration rate or creatinine clearance has to be > 70ml/min/1.73m2 or > 70% of the expected value. - Adequate electrolytes levels: potassium, magnesium, phosphor phosphate, total calcium > = Lower Limit of Normal (LLN) - Adequate hepatic function: total bilirubin < = 1.5 x ULN; AST and ALT < = 2.5 x ULN. - Absence of peripheral neuropathy > = grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0) • Adequate cardiac function: - Shortening Fraction (SF) > = 28% (35% for children < 3 years) and Left Ventricular Ejection Fraction (LVEF) > = 50% at baseline, as determined by echocardiography - Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the QTcF formula) or other clinically significant ventricular or atrial arrhythmia • Wash-out period of at least - 3 weeks in case of preliminary chemotherapy, - 6 weeks in case of nitrosourea-containing chemotherapy, - 2 weeks in the case of treatment with vincristine only - 6 weeks in case of radiation therapy • Possibility of receiving the therapeutic schedule as indicated in the protocol • Patients with reproductive potential must use effective/acceptable birth method control (as defined per CTFG guidelines) during their treatment and for up to 90 days after the last dose. Females with reproductive potential must have a negative pregnancy test < = 7 days before randomization. • Patients already treated with one of the two drugs can be enrolled in the trial provided that rechallenging them with the same drug could be considered acceptable
• Concomitant anti-tumor treatment • Not recovered to < Grade 2 from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy • Known intolerance or hypersensitivity to Vinblastine • Existence of another severe systemic disease • Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines, • Any concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib. • Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors (e.g. antiepileptic drugs, see complete list in the Appendix 5). • Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (Appendix 6) • Impaired cardiac function including any one of the following: - Clinically significant resting brachycardia (< 50 beats per minute). - QTc > 450 msec on baseline ECG. If QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. - Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension). - History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT syndrome or a known family history of congenital long QT syndrome) • Positive test for Hepatitis B virus surface antigen
Brain Cancer Children's Cancer and Leukaemia Teenage and Young Adult's Cancer
Aim 1B. (precursor-B lineage) To determine if the addition of monoclonal antibody (or antibodies – arms B1 to B2) to standard induction chemotherapy results in improved EFS in patients with precursor B-cell lineage ALL. Aim 1T (T lineage) To determine if the addition of nelarabine following standard induction therapy (arms T 1 and T2) improves outcome for patients with T cell ALL. Aim 2 To determine the tolerability of pegylated asparaginase in induction (for all patients) and to compare anti-asparaginase antibody levels between patients in the 2 randomisation groups from aim 1B. Aim 3 To determine whether risk-adapted introduction of unrelated donor HSCT (myeloablative conditioning in patients aged up to and including 40 years at time of study entry and non-myeloablative conditioning in patients aged greater than 40 years, ie having reached their 41st birthday at time of study entry) result in greater EFS for patients at highest risk of relapse. Aim 4 To compare 2 schedules of administration (standard P1 vs., ‘collapsed’ P2) of keratinocyte growth factor (palifermin) for efficacy in preventing the severe mucosal toxicity of etoposide/TBI HSCT conditioning regimen.
a)Subjects must be aged ≥ 25 and ≤ 65 years old with acute lymphoblastic leukaemia OR ≥ 19 and ≤ 65 years old with Philadelphia Chromosome. b)Newly diagnosed, previously untreated ALL (a steroid pre-phase of 5-7 days is acceptable and can be started prior to registration) c)Written informed consent
a) Known HIV infection b) Hepatitis B infection (defined as positive HBsAg and/or HBcAb). Antibodies to Hep B surface antigen only is acceptable c) Hepatitis C infection (antibodies against hepatitis C or a PCR evaluation which is positive for hepatitis C DNA) d) Pregnant or lactating women e) Blast transformation of CML f) Mature B-cell leukemia i.e. Burkitt’s disease t(8,14)(q24 ;q32) and all disorders amplification of c-myc e.g. t(2;8)(p12’q24), t(8;22)(q24;q11)
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
Gynaecological Cancers Teenage and Young Adult's Cancer Testicular Cancer
Patients with PTCL have a poor outlook. Current first line treatments are inadequate and are associated with high rates of early relapse. Despite the recent introduction of novel agents for patients with relapsed disease prognosis is again very poor. There are currently no targeted treatments although monoclonal antibodies directed against Tfh surface markers including PD1 are available (Ansell et al, 2014) and have been trialled in other conditions. Similarly therapeutic anti-ICOS antibodies (MedImmune, MEDI-570) have been trialled in autoimmune conditions and a phase 1/2 trial for PTCL is about to start recruitment in Canada (Clinical Trials Identifier: NCT02520791). Over the next few years, therefore, treatment for PTCL is anticipated to change radically. A PTCL Biobank will be a valuable resource to expedite the development of diagnostic tests, based on the new genetics of these diseases and biobank samples will also be used to investigate biomarkers for response to specific therapies and the prediction of relapse.
Newly diagnosed and relapsed/refractory PTCL patients including: Angioimmunoblastic T-cell lymphoma ALK+ anaplastic large-cell lymphoma ALK- anaplastic large-cell lymphoma PTCL-NOS Male or Females, aged 18 years or above. Participants willing and able to give informed consent for participation in the study. Able (in the Investigators opinion) and willing to comply with all study requirements.
Male or Female patients < 18 years. Patients with NK disease, EATL and cutaneous T-cell lymphoma Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study.
Prostate cancer is a global problem of great impact in both human and financial terms. Men diagnosed with prostate cancer are subject to large variations in quality and outcomes of care. This variation is in part due to differences in the quality and outcomes of medical care men receive for prostate cancer. Comparative effectiveness research, often using large population registries, is emerging as a potential solution to improve comparisons and optimize outcomes and quality of care. In recent years, longitudinal registries in prostate cancer and other conditions have allowed meaningful assessment of effectiveness, costs, and safety; which has, at least in some countries, led to changes in practice and more cost-efficient care. International collaboration in creating and maintaining disease registries has allowed bench marking of process measures and some high level outcomes on a large scale. At present the UK does not have a nationwide cancer registry that collates routinely collected clinical data for all men with localised prostate cancer. We hope that this study will help to establish a registry to allow comparisons of patient-relevant outcomes in order to identify novel approaches to improving quality and outcomes of care in men with localised prostate cancer. Prostate Cancer Outcomes Global Initiative to Compare and Reduce Variation (PCO-CRV) will recruit men with localised prostate cancer to capture their health outcomes through routinely collected clinical information and patient completed questionnaires. Participants will be recruited from approximately eight NHS secondary care Trusts. Questionnaires will be completed before treatment (baseline) and again at 12 months. Data from the UK NHS sites will be anonymised and transferred securely to Monash University where it will be combined with data from around the world and analysed to learn more about outcomes for prostate cancer patients.
Patients will be eligible to be recruited to the PCO‐CRV if they meet the following criteria: Diagnosed with localised or locally advanced prostate cancer disease (any T, any N and M0) after the date on which ethical approval to contribute data to the PCO‐CRV Registry has been provided; Diagnosed or managed within a Participating Site or Local Data Centre recruiting patients which has appropriate ethical approval for the study.
Patients will be excluded if they meet the following criteria: Aged < 18 years at diagnosis Diagnosed with advanced prostate cancer disease The patient’s treating clinician advises that they not be included on the basis of poor mental and/or physical health They are unable to receive information about the study in a language they understand They decline participation.
All patients attending the Royal Marsden Hospital prostate clinics with a diagnosis of prostate cancer. Additionally, outside referrals of single cases of prostate cancer diagnosed at age 60 or under, first degree related pairs with at least one diagnosed at age 65 or under and any family with three or more cases of prostate cancer, at any age.
Men who do not have prostate cancer or who do not fall within the inclusion criteria.
Genetics Prostate Cancer Surgical Urology
Approximately half of patients diagnosed with rectal cancer are offered chemotherapy and radiotherapy treatment (CRT) before surgery. There is great variability in how each tumour responds to CRT. Approximately 30% of tumours completely respond to and no cancer cells can be found in the cancer specimen. Other tumours do not respond at all or occasionally continue to grow during treatment. In many hospitals patients receive an MRI scan before and after CRT treatment. Emerging evidence suggests that by viewing the MRI scans in a smarter way by assessing ‘mrTRG’ (MRI Tumour Regression Grade) it is possible to assess how the tumour has responded to treatment. The TRIGGER Trial aims to evaluate mrTRG as a tool for stratifying patients according to their response to treatment. Patients will be randomised (1:2 ratio) to a control and intervention arm. Patients in the control arm will receive best current practice of surgery at 6-8 weeks after CRT and then a standard course of chemotherapy. Patients in the intervention arm will receive a treatment plan according to their response to CRT, assessed using the MRI tumour regression grade (mrTRG). Patients who have a good response to CRT will defer surgery until the cancer stops reducing in size or avoid surgery altogether if the cancer cannot be detected with repeat scans and assessments. Patients who have a poor response to CRT will have additional pre-operative chemotherapy. We will be able to see if this reduces the size of the tumour further, before a decision is made about proceeding to surgery, and if this lowers the risk of the tumour spreading. TRIGGER is a randomised, controlled, multicentre trial to evaluate mrTRG as an imaging biomarker for the stratified management of patients with rectal cancer. The feasibility trial will involve the recruitment of approximately 90 patients and if feasibility is demonstrated the trial will proceed to Phase III and involve ~ 630 patients.
1) Have a biopsy-confirmed adenocarcinoma 0-15cm from the anal verge (on MRI or rigid sigmoidoscopy) 2) Have locally Advanced Rectal Carcinoma diagnosed by MRI (mrCRM unsafe or ≥mrT3c [> 5mm beyond muscularis propria] or mrEMVI positive disease) 3) Be deemed to require chemoradiotherapy 4) Scheduled to receive 45Gy - 55Gy long course radiotherapy 5) Be aged 18 years or over.
1) Have metastatic disease (including resectable liver metastases) 2) Are contraindicated for MRI eg. non-mr compatable hip prosthesis, cardiac pacemaker 3) Are scheduled to receive less than 45Gy or more than 55Gy long course radiotherapy 4) Are contraindicated for chemoradiotherapy (CRT) or systemic chemotherapy 5) Are receiving or planned to receive treatment outside of that stipulated by the protocol,such as an alternative cytotoxic or investigational drug. 6) Are pregnant, breastfeeding or unable / unwilling to comply with pregnancy prevention guidelines 7) Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with < 5% recurrence risk
Colorectal Cancer Colorectal Surgery
Men who choose radical surgery for prostate cancer (radical prostatectomy) can experience side effects, including urine leakage and problems with erections. This project aims to develop a new questionnaire for measuring urinary and sexual function following radical prostatectomy in men in the UK. We hope that this will help us to: • Allow a man to track his progress over time in a way that he can share the information with his clinical team so that reassurance can be given if things are likely to get better over time, or treatments can be started if needed. • Compare outcomes from different surgeons, so that any factors associated with improved outcomes can be learnt more widely • Use the data to help inform men who are considering radical prostatectomy what their functional outcomes could be This will be done by: Developing a new questionnaire • Using a combination of the best questionnaires available to collect data on men in the UK having radical prostatectomy • Carrying out focus groups in men who are due to have, or have had radical prostatectomy, to see where the current questionnaires are helpful and where they can be improved • Using the questionnaire and focus group data to develop a new questionnaire • Using the new questionnaire in men in the UK having radical prostatectomy Comparing outcomes across groups • Collecting details of the operation • Comparing functional outcomes from the questionnaires with the operation details • Having a surgical forum to help surgeons discuss and develop the best ways to do the operation to get the best outcomes for men Using the data for men considering prostatectomy • The results of the study will be fed back to the True NTH UK Understanding consequences project which is developing a decision aid for men who need to decide between different treatment options which include surgery
• A diagnosis of prostate cancer and scheduled to have radical prostatectomy. • Access to the internet. • An understanding of the English language sufficient to understand and complete on line CRFs. • An understanding of the English language sufficient to understand written and verbal information about the trial and consent process. • Signed informed consent.
• Men who are unable to give informed consent.
Prostate Cancer Surgical Urology
Patients with cancers of the blood often develop low blood cell counts either as a consequence of the disease or the treatment by chemotherapy or stem cell transplantation. Platelet transfusions are commonly given to raise any low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). But recent studies have indicated that many patients continue to experience bleeding, despite the use of platelet transfusions. Tranexamic acid is a type of drug that is called an antifibrinolytic. These drugs act to reduce the breakdown of clots formed in response to bleeding. These drugs have been used widely in both elective and emergency surgery and have been shown to decrease blood loss and the use of red cell transfusions. The purpose of this study is to test whether giving tranexamic acid to patients receiving treatment for blood cancers reduces the risk of bleeding or death, and the need for platelet transfusions. Patients will be randomised to receive tranexamic acid (given intravenously through a drip, or orally) or a placebo. We will measure the rates of bleeding daily using a short structured assessment of bleeding, and we will record the number of transfusions given to patients.
1. At least 18 years of age 2. Confirmed diagnosis of a haematological malignancy 3. Undergoing chemotherapy or haematopoietic stem cell transplantation 4. Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count of ≤10x10 to the power of 9/L for ≥ 5 days 5. Able to comply with treatment and monitoring
1. Diagnosis of acute promyelocytic leukaemia and undergoing induction chemotherapy 2. History of ITP, TTP or HUS 3. Patients receiving L-asparginase as part of their current cycle of treatment 4. Patients with a past history or current diagnosis of arterial or venous thromboembolic disease including myocardial infarction, peripheral vascular disease and retinal arterial or venous thrombosis 5. Patients with a diagnosis/previous history of veno-occlusive disease (also called sinusoidal obstruction syndrome) 6. Patients receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor VIIa or Prothrombin Complex Concentrates (PCC) within 48 hours of enrolment, or with known hypercoagulable state 7. Known inherited or acquired bleeding disorder. E.g. acquired storage pool deficiency; paraproteinaemia with platelet inhibition; known inherited or acquired prothrombotic disorders 9. Patients receiving anticoagulant therapy or anti-platelet therapy 10. Patients with overt disseminated intravascular coagulation 11. Patints with visible haematuria at time of randomisation 12. Patients requiring a platelet transfusion threshold > 10x10 to the power of 9/L at time of randomisation 13. Patients with anuria (defined as urine output < 10mls/hr over 24 hours) 14. Patients who are pregnant 15. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth factors or other pro-coagulant agents 16. Allergic to tranexamic acid or epsilon amino caproic acid 17. Previously randomised in this study at any stage of their treatment
Haematological Oncology Haematology
TIGER is a multi-centre study in germ cell patients whose cancer has returned or become resistant to their initial chemotherapy. Its primary aim is to compare the overall survival in patients treated with high-dose chemotherapy, plus collection and reinfusion of the patients own stem cells, with those treated with conventional-dose chemotherapy. Germ cell tumours (GCT) represent the most common cancer affecting adolescents and young adult men in both Europe and the United States. Early stage disease, which affects the majority of GCT patients, is nearly universally curable with surgery or short-course chemotherapy therefore current efforts are focused on finding curative treatments which are less toxic. There is no international standard treatment in this setting and routine practice differs between countries. At present, the two major approaches for patients who require further treatment are high-dose chemotherapy with a stem cell transplant of the patients own cells or conventional-dose chemotherapy; due to a lack of conclusive randomised trials, it remains unclear which option represents the best treatment approach for these patients. Defining standards and optimising outcomes of salvage treatment thus represents one of the most pressing issues in the management of GCT at present
- Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment. Tumour may have originated in any primary site. - Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatinbased chemotherapy, defined as meeting at least one of the following criteria: * Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study. * Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease. * Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase. - Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy. Prior POMBACE, CBOP-BEP, or GAMEC are allowed. - No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy). - Must have adequate recovery from prior surgery (e.g., healed scar, resumption of diet, etc.). - Age ≥ 14 years. - ECOG Performance Status 0 to 2. - Male gender. - Required Initial Laboratory Values: *Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 *Platelet Count ≥ 100,000/mm3 *Calc. Creatinine Clearance ≥ 50 mL/min *Bilirubin ≤ 2.0 x upper limits of normal (ULN) *AST/ALT ≤ 2.5 x upper limits of normal (ULN) unless due to hepatic metastases in which case levels of ≤ 5 x ULN are allowed. - Negative Serology (antibody test) for the following infectious diseases: a. Human Immunodeficiency Virus (HIV) type 1 and 2 b. Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe) c. Hepatitis B surface antigen d. Hepatitis C antibody - Patient must not father a baby whilst in this study. - Written informed consent must be given prior to patient randomisation.
-Prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue). - Prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed. - Concurrent treatment with other cytotoxic drugs or targeted therapies. - Contraindications to the use of paclitaxel, ifosfamide, cisplatin, carboplatin and etoposide as per the summary of product characteristics (SPC). - Radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy. - Previous chemotherapy within 16 days prior to enrollment except for bleomycin which cannot have been given within 5 days prior to enrollment. - Concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia. Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed. - Late relapse with completely surgically resectable disease. Patients with late relapses (defined as relapse ≥ 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable are not eligible. Patients with late relapses who have unresectable disease are eligible. - Large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery). Treatment may begin ≥ 7 days after completion of local treatment. Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated. Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide. - Secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression. - Although they will not be considered formal eligibility (exclusion) criteria, physicians should recognise that the following may seriously increase the risk to the patient entering this protocol: *Psychiatric illness which would prevent the patient from giving informed consent *Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous to the patient *Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years *Patients who cannot swallow oral formulations of the agent(s)
Teenage and Young Adult's Cancer Testicular Cancer
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
Colorectal Cancer Colorectal Surgery
Is it feasible to ask children with brain tumours, and their parents, about their health, well-being, and concerns, online and then discuss this information with clinicians during routine appointments in outpatient clinics with the aim of enhancing child-clinician-parent communication, the child's quality of life (QoL), and to improve follow-up treatment plans? The QoL of these children is often impaired and not assessed early. Systematic feedback of patient reports into patient care is beneficial and now easier with computer assistance but the processes linking feedback to patient benefit are complex. This three year study, funded by the Brain Tumour Charity (BTC), will focus on these processes to strengthen the links, tailor the methods of feedback to the service providing care, and thus maximise the benefits to the QoL of affected children. In the development phase of the study, we will recruit 18-20 families with children aged 5-17 years treated for a brain tumour and also clinicians from three Children's Cancer Treatment Centres (Nottingham, Great Ormond Street, and Southampton) and using qualitative methods ask them which questions should be included in an assessment of QoL using the online platform KLIK (https://www.youtube.com/watch?v= 4A2vF0k2-jM#t= 32). We will then develop KLIK and in the feasibility phase of the study, pilot it with another 45 families across the three hospitals to see which aspects of the system work well and what the barriers are to the implementation of the platform in clinical practice. Families and clinicians will work with us in a collaborative way to gradually refine the system to develop a high fidelity feedback intervention that could be scaled up and rolled out across the UK in a subsequent project.
Children aged 8-17.9 years with a brain tumour diagnosed within the previous five years, off treatment but receiving outpatient care > = 6 monthly, and their parents. Also parents of children with a brain tumour who are aged less than 8 years and not younger than 5 years. Children and parents who are able to communicate in the English language at a level to enable them to participate in discussions and interviews and who are able to read questionnaires in the English language. Clinicians involved in the outpatient care of children treated for brain tumours at three Children's Cancer Treatment Centres (CCTCs): University Hospital Southampton, Great Ormond Street Children’s Hospital, and Queens Medical Centre, Nottingham. Participants who have given informed consent.
Families who are not sufficiently fluent in the English language to read text and to express their views in discussions and interviews. Families who were deemed to be ineligible by their treating clinician.
Brain Cancer Children's Cancer and Leukaemia Teenage and Young Adult's Cancer
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
Cardiothoracic Surgery Lung Cancer Respiratory Disorders
Despite advances in breast cancer treatments, a subgroup of patients, especially young women, remain at a significant risk of cancer returning in the breast (recurrence) after receiving the standard breast conserving surgery and post operative course of radiotherapy. In this group of patients, standard radiotherapy would have been given several months after surgery and would normally consist of a 3-5 week course of daily radiotherapy to the whole breast, as well as a shorter 5-8 day course to the tumour bed (the normal breast tissue immediately around the tumour); it is difficult to accurately aim the boost at the tumour bed. We developed a new radiotherapy technique- TARGeted Intraoperative radioTherapy (TARGIT), in 1998 and have accumulated considerable experience through worldwide collaboration in over 30 centres. With TARGIT, radiotherapy is delivered accurately to the tissues at highest risk of recurrence- the tumour bed- at the time of surgery in a single session. The long-term analysis of the first 300 patients treated with this technique found a remarkably low recurrence rate, less than half of the expected rate. Hence we have designed a randomised trial of 1796 patients to compare TARGIT boost with conventional boost to test its superiority. The research will be a global collaborative effort of over 30 centres co-ordinated from London. The primary outcome will be local recurrence of cancer at 5 years. We shall also be looking at breast appearance, patient satisfaction and quality of life, and whether or not the intervention represents good value for money to the NHS and to patients and families (cost and cost-effectiveness).
Patients diagnosed with breast cancer and suitable for conserving surgery and whole breast radiotherapy, with a histological confirmation of carcinoma can be included in the study once a written informed consent is obtained. All patients should be available for regular follow-up (according to local policies) for at least ten years. At least one of these criteria must be satisfied: 1. Less than 46 years of age 2. More than 45 years of age and with one or more of the following poor prognostic factors: a) Grade 3 histology b) ER and/or PgR negative c) lobular carcinoma d) extensive intraductal component (EIC) e) lymphovascular invasion f) axillary nodal involvement g) more than one tumour in the breast but still suitable for breast conserving surgery through a single specimen h) any factor or a combination of factors that puts the patient at a higher risk of local recurrence as per the current local guidelines : e.g., those who need a tumour bed boost or those not suitable for TARGIT-Alone as standard treatment. 3. Those patients with large tumours which have responded to neo-adjuvant chemo- or hormone therapy that is given in an attempt to shrink the tumour, and are now suitable for breast conserving surgery as a result. Note. It is recommended that hormone receptor status (at least ER) is known before randomisation. Patients with either HER2 positive or HER2 negative tumours can be included.
1. Bilateral breast cancer at the time of diagnosis. 2. Patients with any severe concomitant disease that may limit their life expectancy 3. Previous history of malignant disease does not preclude entry if the expectation of relapse-free survival at 10 years is 90% or greater (e.g., non-melanoma skin cancer, CIN etc.).
Breast Cancer Radiotherapy
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. Systemic AL amyloidosis, which is the commonest amyloid type, occurs in a small proportion of individuals with monoclonal B cell dyscrasias. AL amyloid has a lifetime incidence and is the cause of death of between 0.5-1 per thousand individuals in the UK. It occurs equally in men and women and the median age at diagnosis is 65 years. Without therapy it is inexorably progressive and until recently the median survival was just 6-15 months. This is an open labelled Phase I/IIa Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis (TRALA). There are three treatment levels with step-wise increase of the infused [90Y]- labelled anti-CD66 radiation activity which will be given prior to autologous stem cell transplantation. The total number of participants planned is twelve (12), with a maximum of 18 if all treatment levels are expanded. The objectives of the trial is to review safety and toxicity using [90Y]-anti-CD66 as the sole conditioning prior to autologous stem cell transplantation for AL-amyloidosis and disease response as determined by changes in the free light chain assay (FLCa) pre and post [90Y]-labelled anti-CD66 and post transplantation.
• Aged ≥18 years. • Have a diagnosis of systemic AL-amyloidosis, either as a new diagnosis or recurrent disease. • Measurable clonal plasma cell dyscrasia. • Amyloid related organ dysfunction or organ syndrome. • Estimated life expectancy of at least 6 months (as defined at trial entry). • Sufficient stem cells for two transplant procedures . • Bone Marrow (BM) cellularity > 20%. • Eligible for ASCT in AL amyloidosis defined as fulfilling all of the following criteria : o ECOG Performance Status of 0 or 1 o Cardiac troponinT< 0.07 μg/L o NYHA heart failure class of < 3 o No more than 3 organs involved by amyloidosis by consensus guidelines. o Creatinine clearance or isotope GFR ≥30ml/min. o Bilirubin ≤1.5 times and alkaline phosphatase ≤3 x upper limit of normal. o AST or ALT < 2.5 x upper limit of normal range. o Mean left ventricular wall thicknesses of < 16mm by echocardiography. o Absence of clinically important amyloid related autonomic neuropathy . o Absence of clinically important amyloid related gastro intestinal haemorrhage. • Capable of providing written, informed consent. • Women of child bearing potential should use adequate forms of contraception. o Intrauterine Device (IUD) o Hormonal based contraception (pill, contraceptive injection etc.) o Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap with spermicide) o True abstinence
Patients with poor performance, advanced organ involvement or significant cardiac involvement will be excluded from the study. Patients with the following characteristics are ineligible for this study: • Overt symptomatic multiple myeloma. • Amyloidosis of unknown or non AL type. • Localised AL-amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the bladder or larynx, in association with a clonal proliferative disorder within that organ). • Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome). • NYHA Class III or IV heart failure (appendix 1). • Liver involvement by amyloid causing bilirubin > 1.5 times upper limit of normal. • Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas. • Pregnant, lactating or unwilling to use adequate contraception as listed above • Intolerance / sensitivity to any of the study drugs. • Known positive Human anti-murine antibodies (HAMA). • Unable to provide written informed consent • Involved in another IMP trial
To establish whether dose escalated, hypofractionated radiotherapy (36 Gy in 6#) increases the proportion of MPM patients experiencing a clinically significant improvement in pain compared with standard radiotherapy (20 Gy in 5#)
• Histological and/or MDT diagnosis of MPM • Performance status 0-2 (ECOG) • Predicted life expectancy of > 12 weeks • CT scan within 8 weeks of starting radiotherapy • Worst Pain ≥4/10 (0-10 Numerical Rating Scale) • Ability to provide written informed consent prior to participating in the trial and prior to any trial related procedures being performed • Willingness to comply with scheduled visits, treatment plans, laboratory tests and other study procedures • Patients must have a radiotherapy plan compatible with the treatment arm (30-36 Gy in 5-6 fractions).
• Patients who have received anti-cancer therapy within the 4 weeks prior to study entry that is likely to alter pain at the index site during the duration of the study. • Patients who are planned to have further anti-cancer therapy within 6 weeks post radiotherapy treatment • Psychotic disorders or cognitive impairment. • Co-existing lung tumours at the time of study entry. • Pregnant or breastfeeding. • Patients of child-bearing potential, who are unwilling to use 2 effective methods of contraception during radiotherapy treatment
Lung Cancer Supportive and Palliative Care
Neuroendocrine tumours (NETs) are rare, and there are many different subtypes. For example they can arise in bowel, pancreas or lung, but they can also be found in the skin, thymus and other sites. The prognosis of NETs is generally favourable, with a median overall survival of 75 months. However, survival is very variable. The primary treatment for Grade 1 and Grade 2 NETs is surgery, although long-acting octreotide, radiolabelled octreotide (Peptide Receptor Radionucleotide Therapy or PRRT), chemotherapy and tyrosine kinase inhibitors or mTOR inhibitors can also be considered. Unfortunately due to the rare and heterogeneous nature of this disease there aren’t any head-to-head trials comparing different treatment strategies e.g. chemotherapy vs everolimus. There are three key reasons why we are embarking on a project to improve understanding of the molecular, immunological and genetic features associated with NET dissemination, prognosis and response to treatment. 1. There has been only minimal improvement in outcomes for patients with NETs over the last 30 years. Large clinical trials have not been possible due to the rare and heterogeneous nature of the disease. Evidence to guide treatment selection for patients with NETs is urgently required. 2. We need to improve our ability to prognosticate accurately for patients with NETs. 3. A better understanding of NET biology may lead to a greater range of treatment options for patients with this rare disease, for example immunotherapy. There are two parts to the study Part A: To study archival tissue in consort with clinical data from our NET patients, to develop a molecular classification for NETs Part B: To collect fresh tissue from tumour and healthy tissue, and blood samples, to perform testing including immune profiling and single cell sequencing to further explore specific hypotheses identified from Part A.
There are two parts to the research Part A: Any patient with a histologically proven neuroendocrine tumour who has given consent for their tissue to be used for research. Part B: Any patient aged over 16 with a clinical or pathological diagnosis of a neuroendocrine tumour who understands and is willing and able to comply with study procedures.
Children under 16 and vulnerable groups will be excluded.
The Study 15 trial is a phase II trial to examine whether the addition of hydroxychloroquine (HCQ) to chemotherapy can improve progression free survival in patients with small cell lung cancer (SCLC). Lung cancer, the leading cause of cancer-related death, accounting for nearly 1.4 million deaths worldwide every year, and has an annual incidence of over 41,000 in the UK. 10-15% are SCLC, representing about 4500 new cases per annum in the UK. Compared with non-small cell lung cancer (NSCLC), patients with SCLC are more responsive to chemotherapy (with an objective response rate of about 70-80%) and radiation treatment but relapse quickly with treatment-resistant disease. The survival rates are poor, with less than 10% of patients alive by 5 years. In a previous CR UK & UCL Cancer Trials Centre trial involving 724 patients, the median survival was 10.3 months. The standard first line chemotherapy treatment remains a platinum-based chemotherapy and this has been unchanged for 20 years. Novel active treatment approaches are urgently needed to improve survival in SCLC. There is increasing interest in targeting autophagy as a means of selectively killing cancer cells. Numerous pre-clinical studies have demonstrated that small molecule inhibitors of autophagy including chloroquine (CQ) and its analogue, hydroxychloroquine (HCQ), enhances the activity of a broad array of anticancer agents. These results have recently led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. More recently, CQ was found to have tumour vasculature normalising properties, thereby increasing platinum delivery to tumour tissue and improved chemosensitivity. The advantage of using HCQ instead of CQ is less cumulative retinal toxicity issue. Previous preclinical studies demonstrate that HCQ and etoposide are mutually antagonistic. Study 15 will combine HCQ with gemcitabine/carboplatin chemotherapy in the investigational arm to avoid the antagonistic interaction with etoposide. The control arm remains carboplatin/etoposide due to the fact that this remains the Standard of Care for patients at sites throughout the UK. We previously demonstrated carboplatin-gemcitabine is as effective as standard carbo/etoposide and associated with a better toxicity profile and cognitive function. The Study 15 trial will therefore investigate whether the combination of HCQ with carboplatin-gemcitabine compared with standard chemotherapy (carboplatin/etoposide) confers additional survival benefit. Each patient will be randomised between the control arm (carboplatin/etoposide) and the investigational arm (carboplatin/gemcitabine + HCQ). All eligible patient that consent to take part in the trial will be randomised onto the trial and will receive 4-6 cycles of chemotherapy, those randomised to the investigational arm will also receive HCQ alongside chemotherapy for up to 30 months. All patients will be followed up for up 36 months after the last trial treatment is administered to the last patient or until death. The trial will be undertaken throughout the UK in approximately 30 NHS sites. The target accrual is 112 patients. The trial is funded by the London Lung Cancer Group (LLCG), endorsed by Cancer Research UK and sponsored by University College London. The trial will be coordinated by the CR UK & UCL Cancer Trials Centre.
• Histologically or cytologically confirmed SCLC • Stage IV disease • Performance status ECOG 0-2 • Life expectancy > 8 weeks • Age 18 or over • Willing and able to give informed consent • Patient considered able to tolerate chemotherapy • Adequate renal function - defined by GFR ≥50mL/min as measured by EDTA or C&G • Adequate bone marrow reserve: Absolute neutrophil count ≥1.5 x 109/L, haemoglobin ≥90 g/L, platelet count ≥100 x 109/L • Negative pregnancy test for WCBP • Effective contraception is mandatory for all patients of reproductive potential • At least one site of measurable disease (target lesion) for RECIST 1.1 evaluation • Able to swallow medication
• Mixed cell histology (i.e. NSCLC and SCLC) • Prior macular degeneration or diabetic retinopathy • Patients with abnormal LFTs (ALP, ALT/AST*) that are ≥3 x ULN (≥5 x ULN for patients with liver metastases) • Patients with abnormal bilirubin levels that are ≥1.5 x ULN • Prior treatment for this disease e.g. chemotherapy, surgery, radiotherapy (expect palliative radiotherapy to bone metastases) • Documented side effects to chloroquine or related agents • Treatment with chloroquine or related agents within the last year prior to randomisation • Glucose-6 phosphate dehydrogenase (G6PD) deficiency • Concurrent psoriasis unless the disease is well controlled and patient is under the care of a specialist for the disorder who agrees to monitor for exacerbations • Evidence of significant medical condition or laboratory finding which, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial • Previous medical history of prolonged QT interval • A history of prior malignant tumour, unless the patient has been without evidence of disease for at least 3 years or the tumour was a non-melanoma skin tumour or early cervical cancer • Patients with symptomatic brain metastases • Women who are pregnant or breastfeeding • Concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs e.g. phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine • Patients who are unable to have their digoxin levels regularly monitored • Infection with blood borne viruses (BBVs) such as Hepatitis C, Hepatitis B and HIV * if both ALT and AST performed then both need to be recorded and reviewed
At present bladder cancer accounts for 10,000 new diagnoses and 5,000 deaths per annum in the UK. The current standard of care is to treat with cisplatin based chemotherapy combined with gemcitabine (GC) in both newly diagnosed and advanced disease groups. Progression or relapse following cisplatin treatment is common, however new information have suggested that DNA demethylating agents could synergise with cisplatin and in turn bypass cisplatin resistance. SGI-110 is a DNA demethylating agent which will be added to the standard GC combination in this trial. This trial will take place in four NHS trusts in England and is looking to recruit a maximum of 56 patients. The dose escalation phase will follow a rolling six (3+3) design in patients with advanced disease only. There will be four dose levels of SGI-110 given with the standard dose of GC. Patients will receive up to 6 cycles (each cycle lasts 21 days) of the combination chemotherapy and SGI-110. They will remain on trial until all side effects have been resolved. Once the optimum dose has been established the trial will open in to a randomised dose expansion phase. Patients with bladder cancer who are receiving GC chemotherapy prior to planed radical cystectomy will be eligible for this part of the trial. 20 patients will be randomised to receive the combination of SGI-110 and GC or GC alone. Prior to surgery, patients will receive 3-4 cycles of GC and SGI-110 or GC alone. They will remain on trial until all side effects have been resolved. The results will be analysed to see if there is a significant difference between the two groups and if they are positive, we will potentially open in to phase III trial.
All Patients: 1. ECOG performance status of 0 or 1 2. Glomerular filtration rate estimation of ≥ 60 mL/min according to either the Cockcroft and Gault formula or by Cr-51 EDTA or Tc-99m DTPA clearance 3. Adequate haematological parameters • Haemoglobin ≥ 90 g/dL • Neutrophil count ≥ 1.5 x109/L • Platelets ≥ 100 x109/L 4. Adequate biochemical parameters • Bilirubin ≤ 1.5 x ULN • ALT and ALP ≤ 2.5 x ULN (ALP ≤ 5 x ULN if caused by liver or bone metastases) 5. Aged 16 years or over 6. Life expectancy > 3 months 7. Provision of written informed consent Patients In The Dose Escalation Phase: 8. Incurable histologically or cytologically confirmed, locally advanced or metastatic, solid cancer, for which the use of gemcitabine and cisplatin is a clinically appropriate treatment in the view of the local principal investigator. Any number of previous lines of systemic chemotherapy is permitted. Patients In The Dose Expansion Phase: 9. Bladder cancer with a pure or a predominant component of transitional cell carcinoma 10. Clinical stage T2-4a N0 M0 11. Planned to commence GC for 3 or 4 cycles with neoadjuvant (i.e. curative) intent prior to a planned radical cystectomy
All Patients: 1. Unresolved toxicities from prior therapy greater than CTCAE v4.03 grade 1 (with the exception of alopecia) at the time of registration 2. Prior radiotherapy to > 30% of bone marrow 3. Major surgery within 30 days 4. Any investigational medicinal product within 30 days 5. Allergy or other known intolerance to any of the proposed study drugs including supportive agents and inclusive of G-CSF and locally utilised anti-emetics 6. Previously-identified central nervous system metastases unless treated and clinically stable and not requiring steroids for at least 4 weeks prior to the start of trial treatment 7. Coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris or congestive cardiac failure (New York Heart Association ≥ grade 2) within the last 6 months 8. Women who are pregnant or breast feeding. (Women of child-bearing potential must have a negative pregnancy test performed within 7 days prior to the start of trial treatment) 9. Patients of child-bearing potential who are not using, or who are unwilling to use, a highly effective method of contraception 10. Any patient who, in the judgment of the local investigator, is unlikely to comply with trial procedures, restrictions or requirements 11. Any patient who has received a live vaccine within 4 weeks of initiation of their treatment. Patients In The Dose Expansion Phase: 12. Recent or current separate other malignancy. Current non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer is permissible. Participants with a history of a separate other malignancy having completed all active treatment 2 or more years previously may be entered
Added as of 23/01/2013: Prostate cancers depend upon the male hormone testosterone for their growth. Lowering testosterone levels (either by removing all or part of both testes, or by giving anti-hormone treatment) slows the growth of prostate cancers. This type of treatment is called hormone treatment and is often used when prostate cancers have spread outside the prostate gland. Although hormone treatment is usually successful at stopping the cancer growing for a period of time, the cancer will begin to grow again in most men. There are increasing numbers of treatments available for advanced prostate cancer. These treatments are usually used in prostate cancer when hormone treatment is no longer effective and the cancer has started to grow again. The aim of this trial, which is called STAMPEDE, is to assess some of these treatments, given earlier in the course of the disease in combination with hormone treatment. The treatments currently assessed inthe trial are: - Radiotherapy to the prostate - Abiraterone and enzalutamide combination Treatments previously assessed but now closed to recruitment: Zoledronic acid, Docetaxel, Celecoxib and Abiraterone alone. The trial information can also be found at the following MRC CTU web page: http://http://stampedetrial.org/
PATIENT INCLUSION CRITERIA Patients must fulfil both of the criteria in Section 1 or one criterion in Section 2 or at least one criteria in Section 3. Additionally, all patients must fulfil the criteria in Section 4. 1. HIGH-RISK NEWLY DIAGNOSED NON-METASTATIC NODE-NEGATIVE DISEASE Both: - At least two of: Stage T3/4, PSA≥40ng/ml or Gleason sum score 8-10 - Intention to treat with radical radiotherapy (unless there is a contra-indication; exemption can sought in advance of consent, after discussion with MRC CTU) OR 2. NEWLY DIAGNOSED METASTATIC OR NODE-POSITIVE DISEASE At least one of: - Stage Tany N+ M0 - Stage Tany Nany M+ OR 3 PREVIOUSLY TREATED WITH RADICAL SURGERY AND/OR RADIOTHERAPY, NOW RELAPSING1 At least one of: - PSA ≥4ng/ml and rising with doubling time less than 6 months - PSA ≥20ng/ml - N+ - M+ AND 4. FOR ALL PATIENTS I. Histologically confirmed prostate adenocarcinoma II. Intention to treat with long-term androgen deprivation therapy III. Fit for all protocol treatment2 and follow-up, WHO performance status 0-23 IV. Have completed the appropriate investigations prior to randomisation V. Adequate haematological function: neutrophil count > 1.5x109/l and platelets > 100x109/l VI. Estimated creatinine clearance > 30ml/min VII. Serum potassium ≥3.5mmol/L VIII. Written informed consent IX. Willing and expected to comply with follow-up schedule X. Using effective contraceptive method if applicable SELECTION CRITERIA FOR COMPARISON OF RESEARCH (M1) RT FOR METASTATIC DISEASE All patients meeting criteria are eligible for the trial, but not all can be allocated to the research (M1) radiotherapy arm. The selection criteria for this “RT to the prostate” comparison are: - Newly diagnosed prostate cancer - Demonstrable M1 disease - No contraindication to radiotherapy e.g. no previous pelvic radiotherapy, - No previous radical prostatectomy
Patients must not fulfil any of the criteria, below. I. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in Section 4.1.3 II. Metastatic brain disease or leptomeningeal disease III. Abnormal liver functions consisting of any of the following: Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN IV. Any other previous or current malignant disease which, in the judgement of the responsible physician, is likely to interfere with STAMPEDE treatment or assessment V. Patients with contra-indications to prednisolone, including active peptic ulceration or a history of gastrointestinal bleeding VI. Patients with active inflammatory bowel disease VII. Symptomatic peripheral neuropathy grade 2 (NCI CTC)5 VIII. Any surgery (e.g. TURP) performed within the past 4 weeks IX. Patients with significant cardiovascular disease such that, in the investigator's opinion, the patient is unfit for any of the study treatments. This might include: Severe/unstable angina Myocardial infarction less than 6 months prior to randomisation Arterial thrombotic events less than 6 months prior to randomisation Clinically significant cardiac failure requiring treatment (NYHA II-IV)6 Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 2 years prior to randomisation Patients with uncontrolled hypertension defined as systolic BP greater or equal than 160 mmHg or diastolic BP greater or equal than 95 mmHg X. Patients receiving treatment with drugs known to induce CYP3A4 (including phenytoin, carbamazepine, Phenobarbital)7 XI. Prior exposure to abiraterone XII. Prior exposure to enzalutamide XIII. Prior chemotherapy for prostate cancer XIV. Prior therapy with zoledronic acid or other bisphosphonates other than treatment for hypercalcaemia or low bone density XV. Prior exposure to policy of long-term hormone therapy before randomisation (unless as described in Section 4.4.2) XVI. History of seizure including any febrile seizure, loss of consciousness, or transient ischaemic attack within 12 months of randomisation or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization) XVII. Unexplained history of loss of consciousness within 12 months of randomisation XVIII. Operation of heavy machinery during treatment
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.
Children's Cancer and Leukaemia Teenage and Young Adult's Cancer
The Show RESPECT study is trying to find practical ways to share the results of clinical trials with the people taking part in it. It is doing this by testing several different approaches within a large ovarian cancer trial (the ICON8 trial). Each site that is taking part in ICON8 in the UK will be allocated at random to share the results of the study in one or more of the following ways: - a link to a basic webpage that contains a simple summary of the results. - Ga link to an ‘enhanced’ webpage that contains a simple summary of the results, links to further information, a short video of a doctor explaining the results, and a ‘frequently asked questions’ section that answers questions people send in. - a simple printed summary of the results. - Inviting people taking part in the trial to join an email list, where a summary of results and updates will be sent out. We will collect information from people taking part in the trial on how satisfied they are with how the results were communicated to them, including whether they found out the results, how easy it was to understand, and whether it told them everything they wanted to know. We will also collect information from research nurses on how easy it was to share the results using these methods, how much time it took, and what they think of them. We will also carry out interviews with a small number of people taking part in the trial and research nurses to explore their experience and views on this in more detail.
1. Participant in the ICON8 trial 2. Currently being followed up at an ICON8 trial site in England, Scotland, Wales or Northern Ireland 3. Aged 18 years or older
Exclusion criteria for quantitative and qualitative research: 1.Participant has previously informed their site that they do not wish to attend any further visits in relation to the ICON8 trial, or provide any further data (sometimes referred to as ‘withdrawal of consent’); participants who previously stopped ICON8 trial treatment earlier than expected but continue in ICON8 follow-up will not be excluded, nor will participants who have reduced follow-up arrangements but still contribute data to the ICON8 trial. 2.Lost to follow-up from the ICON8 trial 3.Site staff consider the patient to be too unwell to be contacted about this study For the qualitative research further to the above exclusion criteria, participants will also be excluded if patients do not adequately understand verbal explanations.
Psychosocial Oncology and Survivorship
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 126.96.36.199 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
Contrast enhanced CT is the standard imaging modality for the diagnosis of liver metastases in patients with colorectal cancer, but patients in the SERENADE trial will receive an additional Diffusion Weighted MRI (DW-MRI) scan of the liver which may identify more patients with synchronous liver metastases. Identification of liver metastases in an accurate and timely fashion allows the early identification of patients for surgical metastectomy and neoadjuvant therapy, or may possibly identify more patients who are suitable for trials of the treatment of metastatic disease.
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.
Colorectal Cancer Other
1.17 years of age or older. 2.Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT. 3.Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma. 4.Tumours of the cervical, thoracic oesophagus, or gastrooesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm aboral and distal extent of primary tumour no more than 2 cm beyond the GOJ. 5. Tumours staged with spiral CT scan, PETCT with/without endoscopic ultrasound (EUS), to be T14, N/+ (provided total tumour length including nodes is ≤10). To be eligible for PET randomisation, the PETCT must be within 4 weeks of start date of treatment. 6. Total contiguous disease length ≤10cm defined by CT, EUS and/or PET. This includes ≤8cm primary tumour plus nodes within 2cm. 7. WHO performance status 0 or 1. 8. Adequate haematological, renal, respiratory, cardiac and hepatic function, and are fit to receive all protocol treatment. 9. Patients with reproductive potential (male or female), who are sexually active during the duration of the trial, should be prepared to use a highly effective method of contraception preferably with low user dependency for at least six months after the last dose of chemoradiotherapy. 10. Patients who have provided written informed consent prior to randomisation. Additional inclusion criteria for patient eligibility for PET randomisation: 11.Baseline SUVmax ≥ 5. 12.PET scan 14 days after start of chemo (2/+3 days from this date is acceptable) 13.Not responding to early cis/cape chemotherapy (< 35% reduction in SUVmax) 14.For diabetics, fasting Blood glucose ≤12 mmol/L.
1. Patients who have had previous treatment for invasive oesophageal carcinoma or gastrooesophageal junction carcinoma 2. Patients with metastatic disease 3. Patients with other active malignancy or past malignancy in remission for less than 3 years except patients that have been curatively treated from the following conditions; basal cell carcinoma, Carcinomainsitu breast and carcinomainsitu cervix 4. Patients with > 2cm mucosal extension of tumour into the stomach or where the superior extent is proximal to 15 cm ab oral. 5. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease. 6. Patients who need continued treatment with a contraindicated concomitant medication or therapy. 7. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. 8. Patients with hearing impairment or sensorymotor neuropathy of WHO grade ≥2. 9. Known hypersensitivity to IMPs. 10. Women who are pregnant or breastfeeding.. 11. Oesophageal stent (Patients requiring a PEG/RIG/feeding jejunostomy for nutritional purposes are eligible). 12. Any other situation, which in the opinion of the local PI, makes the patient an unsuitable candidate for this trial (eg with profusely bleeding tumours where the PI has concerns about randomisation to paclitaxel/carboplatin arm where there is risk of aggravation of bleeding due to higher risk of thrombocytopenia)
Breast, Colorectal, Melanoma, Bladder, Brain, Kidney, NonHodgkins, Oesophageal, Pancreatic: men and women diagnosed at age 18-69 years Endometrial, Ovarian: women diagnosed at age 18-69 years Prostate: men diagnosed at age 18-69 years
Breast Cancer Cancer Primary Care
The SARON trial is a phase III trial looking to see if adding radiotherapy (conventional, stereotactic radiotherapy and / or stereotactic radiosurgery (give to the brain)) to standard chemotherapy can improve overall survival in non-small cell lung cancer (NSCLC) patients with 1- 3 metastases. The target accrual is 340 patients. The trial is funded by Cancer Research UK and sponsored by University College London. The trial will be coordinated by the CR UK & UCL Cancer Trials Centre. • All patients in the trial will receive 4 cycles of standard doublet-platinum chemotherapy. • After two cycles of chemotherapy, patients will be assessed for progression. Those that have not progressed, have a performance status of 0, 1 or 2 and continue to meet eligibility will be randomised. • Patients randomised to the control group (chemotherapy only) will receive 2 more cycles of chemotherapy. • Patients randomised to the investigational group (chemotherapy plus radiotherapy) will receive 2 more cycles of chemotherapy followed by radiotherapy to all sites of disease. • All patients will be followed up for 3 years after completing trial treatment or until death. A safety substudy will look at the first 20 patients receiving conventional radiotherapy to the primary and stereotactic radiotherapy to thoracic metastases to assess the level of lung inflammation within the first 3 months after the end of treatment. A feasibility substudy will make an assessment after the first 50 patients have been randomised. This will review the practicality of achieving recruitment targets, assess the logistics of delivering the radiotherapy treatment, and the potential for patients seeking stereotactic radiotherapy off study if randomised to the control group. Primary Endpoint: Main trial Overall survival SubStudies: Feasibility Sub Study • Recruitment rate • Logistical practicalities • Assess if patients seek stereotactic radiotherapy outside of the trial. Safety Sub Study Grade 3-5 lung inflammation Secondary Endpoint: Main trial: • Progressionfree survival • Local control of lung tumour and all metastases • New distant metastases
1) Histologically or cytologically confirmed NSCLC. 2) Negative or unknown EGFR and ALK mutation status EGFR testing is mandatory and ALK testing to be performed if part of local policy. 3) Staging with FDG PETCT whole body scan and MRI brain or CT brain with IV contrast within 42 days prior to registration. 4) ECOG performance status 0 to 1 at time of registration. 5) Patient presenting with synchronous primary disease and oligometastatic disease. 6) Patient is fit to receive four cycles of platinumbased doublet chemotherapy, cisplatin or carboplatin, according to local guidelines and assessment. 7) Primary tumour and nodes included in the radical RT volume must suitable for radical RT (either conventional RT or SABR). Conventional RT fields do not need to be contiguous. 8) Patient is deemed fit to receive conventional RT and SABR/SRS according to local guidelines and assessment. 9) Between one and three metastatic lesions, assessable according to RECIST v1.1 and suitable for SABR/SRS (only one site of metastases OR the primary tumour needs to be measurable according to RECIST v1.1) i. Nodes included in the radical RT volume will not count towards the number of sites of metastases ii. Nodes not treated in the radical RT volume are counted as metastases. The patient, though, must have stage IV disease. The same RT dose constraint eligibility criteria will apply to these nodes as to other metastases. iii. Only station 1 neck nodes (Foundation system) are considered N3. Higher neck nodes are considered as metastases. Note: If brain metastasis present, at the time of randomisation, the largest lesion must be no more than 3cm in maximum diameter. A second lesion must be no more than 2cm maximum in diameter. 10) Acceptable lung function for radical lung radiotherapy. 11) No relevant comorbidities, including pulmonary fibrosis and connective tissue disorders.
1) Patient has had palliative radiotherapy to any tumour site prior to registration or requires palliative radiotherapy prior to randomisation. 2) One or more metastases previously treated with alternative ablative treatment, e.g. RFA or surgery 3) Patient has received any previous treatment for this NSCLC malignancy 4) Patients who present with brain metastasis only and no sites of extra cranial metastatic disease i.e. the presence of more than 2 brain metastases is an exclusion criteria. 5) Metastasis in sites where normal radiotherapy constraints cannot be met 6) Brain metastasis within the brainstem 7) Patients who have more than three metastases prior to trial registration. 8) Primary tumour or metastases causing direct invasion or high clinical suspicion of direct invasion of the wall of a major blood vessel. 9) Malignant pleural or pericardial effusion 10) Patients with bilateral adrenal metastases 11) History of prior malignant tumour likely to interfere with the protocol treatment or comparisons, unless the patient has been without evidence of disease for at least 3 years or the tumour was a nonmelanoma skin tumour or early cervical cancer 12) Women who are pregnant or breast feeding 13) Stage III disease even with extensive nodal disease or the tumour was a nonmelanoma skin tumour or early cervical cancer 14) Leptomeningeal disease
Oesophageal cancer is relatively common in the UK. If detected early, it may be cured with surgery (oesophagectomy). The operation to remove the cancer is complex with large incisions made to the abdomen, chest and, sometimes, neck. 30% of patients experience complications, and about 3% of patients die soon afterwards. Surgery improves survival rates but there is a reduction in quality of life. The limited available data suggest that minimally invasive ‘keyhole’ surgery for oesophageal cancer may achieve the same survival benefit as open surgery, but with better recovery. It is possible that the improved recovery seen in these studies may be due the selection of fitter patients for the minimally invasive procedure. A pilot study has enabled us to refine the trial methodology for a robust RCT, designed to detect clinically important improvements in recovery with minimally invasive surgery at in 406 patients at 7 UK centres. Patients with localised oesophageal cancer, referred for surgery by their multi-disciplinary cancer care team, will be invited to join the study. Patients will be excluded if they have previous surgery or cancer that would make the oesophagectomy more difficult or are pregnant. Following informed consent, patients will be randomly allocated to open oesophagectomy (OO) or “laparoscopically-assisted” oesophagectomy (LAO). The abdominal surgery in the LAO group will use minimally invasive methods. The primary outcome will be a validated measure of physical function. Data will also be collected on survival, days in hospital, complications, pathological specimen quality, health-related quality of life and resource use data. Follow-up is for at least two years post-randomisation. A sub-study at two centres will also randomly allocate patients to a fully minimally invasive oesophagectomy, this will provide unbiased early information on this novel approach.
Participants may enter study if ALL of the following apply: 1. 18 years of age or above 2. Referred for primary oesophagectomy by the multi-disciplinary team (MDT) or oesophagectomy following re-staging after neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (N.B, in this any type of neoadjuvant treatment may be used) 3. Confirmed MDT evidence of at least adenocarcinoma or at least squamous cell cancer of the oesophagus or oesophago-gastric junction 4. Fit for pre-operative anaesthesia and surgery, assessed by the MDT 5. Able to provide written informed consent. 6. Measurement (endoscopic or otherwise) that the tumour starts more than 5cm below crico-pharyngeus 7. Measurement (endoscopic or otherwise) that the tumour involves less than 4 cm of the gastric wall 8. The final pre-treatment tumour stage is between T1N0M0 and T4aN1M0, i.e. including all stages (T1N0M0, T1N1M0, T1N2M0, T2N0M0, T2N1M0, T2N2M0, T3N0M0, T3N1M0, T3N2M0, T4aN0M0 and T4aN1M0) in which T4a is a resectable tumour invading pleura, pericardium, or diaphragm.
Participants may not enter study if ANY of the following apply 1. Patients with high grade dysplasia (squamous cell or adenocarcinoma) 2. Stage 4 disease 3. Type 3 tumours of the oesophago-gastric junction that are scheduled for total gastrectomy 4. Patients with squamous cell cancer of the oesophagus who the MDT recommends or who individually elect to undergo definitive chemoradiotherapy 5. Evidence of previous complex thoracotomies or laparotomies that preclude a minimal access approach 6. Evidence of previous/concomitant malignancy that would interfere with this treatment protocol 7. Pregnancy 8. Patients participating in other trials that would interfere with the implementation of this protocol at a particular site.
Upper GI Upper GI Surgery
Neoadjuvant chemotherapy (NAC), for early breast cancer reduces the amount of surgical treatment required, often avoiding the need for mastectomy. A pathological complete response (pCR) is generally associated with excellent prognosis and no pCR is associated with poor outcomes. To maximise pCR patients are treated with both epirubicin and docetaxel containing combinations increasing toxicity due to exposure to both drugs. Retrospective analysis of adjuvant chemotherapy trials strongly suggests that a combination of two genetic markers (CEP17 and TOP2A) predict for epirubicin sensitivity. It may be unnecessary to treat all patients with both epirubicin and docetaxel. Current standard of care in patients with involved axillary nodes before chemotherapy is an axillary dissection. When there is no residual cancer this becomes an unnecessary procedure. The data on the use of sentinel lymph node biopsy post NAC is controversial. In ROSCO 1056 patients with early breast cancer will be randomised from hospitals around the UK to initial chemotherapy with either epirubicin based or docetaxel based chemotherapy. They will be stratification by CEP17 and TOP2A status. On completion of 4 cycles of chemotherapy patients will undergo surgery and pCR assessment. Where pCR is not achieved patients will receive the alternative chemotherapy as adjuvant treatment. The aim is to determine if CEP17 and TOP2A status can be used to select the appropriate chemotherapy, resulting in higher pCR rates and a requirement for less chemotherapy. Patients with axillary node involvement prechemotherapy will undergo a post NAC, sentinel node biopsy (SLNB) and axillary clearance as a single procedure to determine if post NAC SLNB is sufficiently accurate to be used as a routine staging tool in this context. Patients will be followed up for 5 years.
ROSCO Main Trial • Patient with histological diagnosis of invasive breast cancer • Suitable for neoadjuvant chemotherapy in opinion of investigator • Unifocal tumour: - Radiological size greater than or equal to (≥) 20 mm by ultrasound (or in some cases Magnetic Resonance Imaging (MRI) is allowed) -T4 tumour of any size with direct extension to (a) chest wall or (b) skin or both - Inflammatory carcinoma with tumour of any size OR Multifocal tumour: The sum of each tumour’s maximum diameter must be ≥20 mm (total sum of multifocal deposits ≥20 mm by ultrasound) OR Other locally advanced disease Biopsy confirmed axillary lymph node involvement or large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes and primary breast tumour of any diameter Involvement of large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes without a primary breast tumour identified: in this case the presence of breast cancer in a lymph node must be histopathologically confirmed by lymph node biopsy (trucut or whole lymph node) • Patients with bilateral disease are eligible to enter the trial, if one of the criteria above is met for disease in at least one breast • Any HER2 status • Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician. The following recommendations must be taken into account when making this assessment: Patients with HER2 positive disease must not have clinically significant cardiac abnormalities. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of Left Ventricular Ejection Fraction (LVEF) by Multi Gated Acquisition (MUGA) scan or echocardiogram (ECHO). LVEF must be within the normal range as defined locally by the treating hospital Patients must have adequate bone marrow, hepatic, renal and haematological function • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 • Women of childbearing potential, or men in a relationship with a woman of childbearing age, prepared to adopt adequate contraceptive measures if sexually active • 18 years or older • Male or female • Written informed consent for the trial • Availability of embedded paraffin tumour blocks from prechemotherapy biopsy is required • Willing and able to comply with scheduled visits, treatment plan and other study procedures Sentinel Lymph Node Biopsy Study (in addition to above) • Biopsy/fine needle aspiration proven involved ipsilateral axillary lymph nodes at diagnosis
ROSCO Main Trial • Tumours of low or intermediate grade (Grade 1 or 2) which are also Oestrogen Receptor (ER) rich and Progesterone Receptor (PgR) rich or PgR unknown, whatever the size or nodal status • Previous invasive breast cancer • Unequivocal evidence of metastatic disease • Previous diagnosis of other malignancy unless: Diseasefree for 5 years; or Previous basal cell carcinoma, cervical carcinoma in situ, superficial bladder tumour; or Contralateral or ipsilateral DCIS of the breast treated by surgery alone • Previous chemotherapy • Prior extensive radiotherapy (as judged by the investigator) to bone marrow • Previous neoadjuvant endocrine therapy (unless less than 6 weeks duration) • Concomitant hormonal therapies/chemotherapy or any other medical treatment in relation to treating the breast cancer • In HER2 positive patients risk factors precluding coadministration of trastuzumab and FEC75 Previous myocardial infarction during the 6 months prior to recruitment LVEF below institutional lower limit of normal and no echocardiographic evidence of heamodynamically Significant valvular heart disease or ventricular contractility • Prior diagnosis of cardiac failure • Uncontrolled hypertension, coronary heart disease other significant cardiac abnormality • Bleeding diathesis • Presence of active uncontrolled infection • Any evidence of other disease which in the opinion of the investigator places the patient at high risk of treatment related complication • Pregnant (female patients of child bearing potential should have a urine or blood Human Chorionic Gonadotropin test performed to rule out pregnancy prior to trial entry) • Lactating females • Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent completion of treatment or followup Sentinel Lymph Node Biopsy Study (in addition to above) • Negative nodes at diagnosis • SLNB at diagnosis • Allergy to patent blue dye
Breast Cancer Breast Surgery
The ROCkeTS project aims to derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This project will be conducted in four interlinked Phases 1. Phase 1 will be to undertake systematic reviews of the accuracy of tests and risk prediction models used for identifying OC in women with suspected OC. 2. Simultaneously, in Phase 2 we will undertake refinement of an existing risk prediction model based on additional predictions within existing large datasets. For Phase 2, we have identified 3 datasets UKCTOCS, UKOPS and InternationalOvarian Tumour Analysis (IOTA) that are relevant to primary care and secondary care settings in post and premenopausal women. 3. Phase 3 Prospective study, based on the evidence from Phases 1 and 2 , the most promising tests and risk prediction models for post and menopausal women will be externally validated, in a prospective study comprising newly presenting premenopausal and postmenopausal patients. In order to conduct this complex project as effectively as possible, we will start recruitment to the Phase 3 study and banking of samples from patients concomitant with Phases 1 and 2. 4. In Phase 4, we will develop models of pathways and cost comparisons of alternative testing. Pathways will incorporate the differences in patient management guided by different thresholds of the risk prediction models, that inform the minimum predicted probability that flags a diagnosis of OC.
Pre and postmenopausal women with symptoms of suspected OC and either raised Ca125 or abnormal USG.
USG reveals nonovarian pathology e.g. fibroids or simple ovarian cysts < 5cm in size (very low risk of malignancy). Patients with normal pelvis USG. Patients who decline transvaginal scan. Patients unable to provide informed consent.
General Surgery Gynaecological Cancers Reproductive and Sexual Medicine
RomiCar is a prospective, single arm, multicentre phase I/II clinical trial for patients with relapsed or refractory peripheral T-cell lymphoma. The following designs will be used in each phase: Phase I: Continual Reassessment Method (CRM) to determine the Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib. Phase II: A’Hern’s single stage design to assess the activity (best overall response rate (PR + CR)) of the combination of romidepsin and carfilzomib over 8 cycles of treatment.
• Age ≥ 16 years of age • Life expectancy > 12 weeks • ECOG performance status ≤ 2 • Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma, extranodal NK/T-cell lymphoma, transformed mycosis fungoides, hepatosplenic T-cell lymphoma • Failed at least 1 prior therapy (but no upper limit of prior regimens) • Patients MAY have had a prior allogeneic stem cell transplant but must not require systemic immunosuppression for graft-versus-host disease (local treatments are permitted) • Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x10^9/l and platelets ≥ 100x10^9/l or ≥ 75x10^9/l if marrow involvement documented) • Adequate liver function (bilirubin ≤ 1.5 x ULN, AST / ALT ≤ 2x ULN) • Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) • Serum potassium ≥ 3.8 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ LLN prior to trial entry • CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in craniocaudal length attributable to relapsed lymphoma • Ability to give informed consent * For all relapsed patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 6 months and preferably to confirm refractory disease.
• Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2 • Previous treatment with histone deactylase inhibitor or proteasome inhibitor • Need for any other concurrent anticancer drug (apart from corticosteroids at a dose equivalent to prednisolone ≤ 7.5mg daily). A steroid prephase may be used but should be stopped by the first day of cycle 1. • Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant • Previous systemic malignancy within the last 3 years unless treated with curative intent with no sign of recurrence. Other exceptions include non-melanotic skin cancer or carcinoma in-situ of the uterine cervix • Coexisting active infection requiring parenteral antibiotics • Patients unable to swallow oral medication • Active infection with HIV, hepatitis B or hepatitis C • Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigational agents within 28 days prior to trial entry (or a longer period depending on the defined characteristics of the agents used, please contact the trials office for confirmation). *Limited field radiotherapy to an isolated lesion in bone or soft tissue must be completed 2 weeks prior to trial entry • Major surgery within 4 weeks of trial entry • Patients with proven CNS involvement • QTc interval of ≥ 450ms or patients taking medications that significantly prolong the QT interval • Patients taking any inhibitors or strong inducers of CYP3A4, with the exception of dexamethasone. • Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry and within 7 days prior to the start of treatment. Postmenopausal females (> 45 years old and without menstruation for > 1 year) and surgically sterilised females are exempt from a pregnancy test) • Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy • Concurrent Pulmonary Hypertension • Left Ventricular Ejection Fraction (LVEF) of< 40%
Each year, 12,000 people in the UK are diagnosed with B-cell malignancies. B-cell cancers can be divided into high grade or low grade based on how quickly the cancer grows. Although high grade lymphomas (e.g. diffuse large B-cell lymphoma (DLBCL)) are potentially curable, approximately 30% of patients will relapse after frontline therapy. There is no established standard for second line therapy but consolidation therapy with autologous stem cell transplant is undertaken if a patient is fit enough. Even with transplantation, only 50% of patients will achieve durable remissions. Thus the great majority of patients with relapsed DLBCL will eventually succumb to the disease. Whilst low grade diseases lead a less aggressive course, successive remissions become increasingly shorter, necessitating different therapies with each relapse. Thus there is a clear clinical need for more novel therapeutic agents in B-cell lymphoma. In this trial, patients with high grade or low grade B-cell lymphoma whose cancer has come back after initial response or has not responded to treatment will be treated with rituximab and varlilumab. Varlilumab is an immunostimulatory antibody. It binds to the normal immune cells and enhances their anti-tumour effect. Rituximab is an antibody that targets the tumour cells directly. It binds to the CD20 molecule that is present on the surface of normal and malignant B-cells and engages the immune effector cells, leading to killing of the tumour cell. Our hypothesis is that varlilumab enhances rituximab-mediated killing of tumour cells by increasing the number of immune effector cells. Patients will receive 6 cycles of treatment, with administration of rituximab on day 1 of each cycle and of varlilumab on day 2 of cycles 1, 3 and 5. Each cycle is 2 weeks long. Patients will be followed up 2 weeks after they complete the trial treatment and then every 2 months for one year.
1. Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). • High grade subgroup: Diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL) grade 3b, transformed Follicular Lymphoma • Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL, e.g. Mantle cell lymphoma (MCL), Lymphoplasmacytic lymphoma (LPL) and Follicular Lymphoma (FL) grade 1, 2 and 3a 2. Disease must be recurrent or treatment refractory, and received at least one line of treatment. Rituximab-refractory patients are eligible for entry into the study. 3. At least one measurable lesion by CT scan (defined as > 1.5 cm in one axis) that is also easily accessible for biopsy. 4. Histological confirmation of relapse within 12 months of treatment. 5. 16 years of age or older. 6. Haematological and biochemical indices with the ranges shown below: • Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible) • Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (or ≥0.5 x 10^9/L if bone marrow involvement) G-CSF support is not permissible at screening • Platelet count ≥75 x 10^9/L (or ≥30 x 10/L if bone marrow involvement) • Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert’s syndrome in which case up to 3 x ULN is permissible • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to hepatic involvement • Calculated creatinine clearance (Cockroft-Gault formula) ≥30 ml/min (uncorrected value) 7. Ability to understand the purpose and risks of the study and provide written informed consent. 8. Willing and able to participate in all required evaluations and procedures in this study protocol. 9. Women of childbearing potential, must be willing to participate in appropriate pregnancy prevention measures: a. Female patients who have a negative serum or urine pregnancy test during screening (within 14 days prior to the start of trial treatment) and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible. b. Male patients with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception and condom; an intrauterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible. Male subjects must also refrain from donating sperm during this period. c. Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 10. Life expectancy ≥ 12 weeks. 11. ECOG performance status 0-2.
1. Known central nervous system involvement by lymphoma, that is not in remission, are excluded from the study. 2. History of other malignancy within the last 2 years except for: • Noninvasive malignancies such as adequately treated ductal carcinoma in situ of the breast, non-melanoma skin cancer or lentigo maligna, cervical carcinoma in situ and urothelial papillary noninvasive carcinoma or carcinoma in situ, and • Prostate intraepithelial neoplasia without evidence of prostate cancer. 3. Receiving treatment (or within a month of) with chemotherapy, immunotherapy or immunosuppressive agents. This includes any systemic steroids at dose exceeding 10 mg prednisolone (or other steroid equivalent) within 2 weeks prior to first dose of varlilumab. 4. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study. 5. Active and documented autoimmune disease (including, but not limited to, inflammatory bowel disease, coeliac disease, haemolytic anaemia, or immune thrombocytopenic purpura) prior to first dose of varlilumab. 6. Active infection requiring systemic therapy. 7. Women who are pregnant or lactating. 8. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, the results of hepatitis serology should be known prior to commencement of immunochemotherapy. • Positive test results for chronic HBV infection (defined as positive HBsAg serology and positive HBcAb) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. • Positive test results for hepatitis C (HCV antibody serology testing) will not be eligible. 9. Previous recipient of an allogeneic bone marrow transplant at any time. 10. Autologous bone marrow transplant within 100 days of first dosing. 11. Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks prior to first dosing. 12. Subjects known or suspected of being unable to comply with the protocol. 13. Ongoing toxic manifestations of previous treatments. Exceptions are to this are alopecia or certain Grade 1-toxicities, which in the opinion of the Investigator should not exclude the patient. 14. Uncontrolled congestive cardiac failure, cardiac ischaemia or cardiac arrhythmia. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV). 15. Subjects with a known hypersensitivity to rituximab (≥Grade 3) or murine proteins, or any other excipients used in the formulation of rituximab.
The aim of this study is to investigate patient recovery after surgery for gynaecological cancer. Patients will complete health-related quality-of-life questionnaires following open, Key hole (laparoscopic) and robotic surgery. In addition they will complete a walking test. These investigations will be administered before the operation and at fortnightly intervals in the six weeks following the operation. The theory being tested is that patients undergoing robotic surgery will have a better rate of recovery compared to the other surgical approaches.
All women undergoing surgery to treat a gynaecological cancer, including cancer of the uterus, cancer of the cervix, cancer of the fallopian tubes/ovaries.
Individuals will be excluded if they are aged < 16 years, are unfit for surgery, have a benign diagnosis, if surgery is possible only by an open approach, if surgery is anticipated to require a midline laparotomy incision beyond 4 cm above the umbilicus, if the patient is being treated for a large ovarian tumour, if the patient requires radical de-bulking surgery, if the patient requires more than hysterectomy and oophorectomy (e.g. bowel resection) or if they are unable to complete the outcome measures due to cognitive impairments or an inability to speak or understand English due to the requirement to complete the questionnaires.
Gynaecological Cancers Gynaecological Surgery
Renal cell carcinoma is a type of kidney cancer that starts from the kidneys. It is the 8th most common cancer in the UK and an increase of new cases of 2% has been seen in the last twenty years. About half of the new cases of kidney cancer are among people aged 70 and above. Patients whose disease has not spread outside the kidneys typically have surgery to remove a part or all of their kidney (called a partial or radical nephrectomy). After surgery, patients are seen by their doctor with regular check-ups to look for signs of the cancer coming back or spreading to other parts of the body; this is generally called ‘active monitoring’ or ‘active surveillance’. Unfortunately, it is estimated that the cancer will return in 30-40% of the patients who have undergone surgery. Many clinical studies have been carried out to find if a new treatment after surgery might slow the cancer coming back or prevent it from coming back altogether. However, to date no treatment is available. Immunotherapy is a type of cancer treatment that ‘wakes up’ the patient’s own immune system so it can fight the cancer. New drugs which act in this way have worked well in patients with skin cancer (melanoma), lung cancer and in patients with kidney cancer that has spread outside the kidney. RAMPART is a study looking at two new immunotherapy treatments. We aim to find out whether taking one drug (durvalumab) or a combination of two drugs (durvalumab and tremelimumab) for one year can prevent or delay kidney cancer from coming back compared to the current standard of care (active monitoring after surgery). Durvalumab is sometimes referred to as an anti-PDL1 drug, and it is currently being tested (alone or in combination with other drugs) in many types of cancer. Tremelimumab is sometimes called anti-CTLA4 drug. It is also being tested in different types of cancer. Like all drugs, these treatments have side effects and patients will have regular blood tests, scans and appointments with their study doctor and nurse. Around 1,750 patients from the UK, Australia, France and the US will join the study. It will take approximately 5.5 years to reach this number. The first results from the study are expected 6.5 years after the study starts, with more results following later. If positive, the results of the study will change the current standard of care for the treatment of kidney cancer after surgery.
1.Histologically proven RCC (all cell types of RCC are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); no evidence of residual macroscopic disease on post-operative CT scan after resection of RCC. Patients with treated bilateral synchronous RCCs are eligible. 2.At the start of recruitment patients with Leibovich score 3-11 will be eligible for randomisation. MRC CTU will monitor accrual and stop recruiting intermediate risk patients (Leibovich Score 3-5) after three years or when intermediate risk patients contribute 25% of the total accrual target, whichever is earlier. Recruitment of patients with Leibovich Score 6 11 will continue until the accrual target is reached. 3.Patients should have had surgery at least 28 days but no more than 91 days prior to randomisation date. 4. Post-operative scans should be performed within 28 days prior to randomisation 5.WHO Performance Status 0 or 1. 6.Patient has archival FFPE pathology tissue available, and agrees to provide at least one sample (FFPE tumour block from nephrectomy, or a minimum of 10 unstained slides), as well as a baseline EDTA blood sample for future translational research 7.Adequate normal organ and marrow function a.Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks of randomisation in order to achieve the entry criteria). b.Absolute neutrophil count (ANC) > = 1.5 x 109/L (> = 1500 per mm3). c.Platelet count > = 100 x 109 (> = 100,000 per mm3). d.Bilirubin < = 1.5 x ULN (This will not apply to subjects with confirmed Gilbert’s syndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician). e.AST/ALT < = 2.5 x ULN. f.Calculated Creatinine Clearance level > 40mL/min by Cockcroft Gault formula 8.12-lead ECG on which QTcF must be < 470 ms. In case of clinically significant ECG abnormalities, including a QTcF value > = 470 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. 9. Patient must weight > = 30Kg at the time of randomisation 10.Subjects must be > = 18 years in age. 11.Written Informed Consent obtained from the patient 12.Both men and women enrolled in this trial must use adequate contraception during the treatment phase of the study and for 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided. 13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age specific requirements apply: a. Women < 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy). b. Women > = 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy induced menopause with last menses > 1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
1.Previous diagnosis of RCC. 2.Metastatic or macroscopic residual disease. 3.Patients with a single pulmonary nodule > = 5mm diameter are not eligible unless the nodule has had a definite benign diagnosis. Patients with multiple small, less than 5 mm nodules may be eligible if nodules have been shown to be radiologically stable for at least 8 weeks. 4.Prior anticancer treatment (other than nephrectomy) for RCC. 5. Any unresolved toxicity NCI CTCAE Grade > = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria a. Patients with Grade > = 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician. 6. History of another primary malignancy except for: a) Malignancy treated with curative intent and with no known active disease > = 5 years before the first dose of IP and of low potential risk for recurrence. b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c) Adequately treated carcinoma in situ without evidence of disease. 7. History of leptomeningeal carcinomatosis. 8. Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow up period of an interventional study. 9. Major surgical procedure (as defined by the Investigator) within 28 days prior to the start of treatment. Local surgery of isolated lesions for palliative intent is acceptable. 10. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years may be included but only after consultation with the RAMPART Trial Management Team e. Patients with coeliac disease controlled by diet alone 12. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty. 13. History of allogeneic organ transplant. 14. Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection b. Symptomatic congestive heart failure c. Uncontrolled hypertension d. Unstable angina pectoris e. Uncontrolled cardiac arrhythmia f. Active peptic ulcer disease or gastritis g. Active bleeding diatheses h. Psychiatric illness or social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. 15.Active infection including a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) b. Hepatitis B (known positive HBV surface antigen (HBsAg) result) c. Hepatitis C d. Human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti HBc] and absence of HBsAg) are eligible. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 16. Receipt of live attenuated vaccine within 30 days prior to the start of treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving investigational medicinal product and up to 30 days after the last dose of investigational medicinal product. 17. Pregnant or breastfeeding patients. 18. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 19. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients. 20. Previous investigational medicinal product assignment in the present study.
Prostate cancer is the most common male cancer in the UK with more than 11,000 deaths every year. The two most common genetic defects in this disease are androgen receptor (AR) driven rearranged oncogenes and PI3K/AKT pathway activation. Currently in the UK docetaxel followed by abiraterone is the standard of care for patients with advanced prostate cancer (APC). For patients with disease progression after treatment with abiraterone and docetaxel, options are cabazitaxel, participation in clinical trials or supportive care. About 50% of post-chemotherapy patients with APC will be eligible for REAKT; a trial of enzalutamide with the novel AKT inhibitor AZD5363. Enzalutamide is an antiandrogen with distinct properties that blocks testosterone binding to the AR, impacts AR transport into the nucleus and inhibits binding of the AR to DNA. AZD5363 inhibits the AKT protein which helps cancer cells grow, multiply and spread.. By combining enzalutamide and AZD5363 it is hoped the cancer cells stop growing and the growth and spread of those that do is slowed. REAKT has three parts;Phase I safety run-in phase to determine the dose of AZD5363 to use; Phase II randomised, double blind trial to measure how effective the combination treatment is; Single stage phase II expansion cohort where AZD5363 is added to enzaluatmaide at progression to explore whether AZD5363 can reverse resistance to enzalutamide. Enzalutamide and AZD5363 are taken orally and are taken as long as they are helping to prevent the cancer getting worse. Participants will have regular checkups at the hospital. Participants will be asked to donate blood, urine, tumour, hair, buccal (cheek) swab and saliva samples during the study to see if there are any drug to drug interactions and to see if there is anything that will predict who this combination treatment will work best for.
1)Written informed consent. 2)Histological diagnosis of adenocarcinoma of the prostate and with archival tumour tissue 3)Metastatic CastrationResistant Prostate Cancer (mCRPC). 4)Progressed after 1 or 2 lines of taxane based chemotherapy. 5)Progressed after at least 12 weeks of abiraterone 6)Age 18 years or above. 7)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 02. 8)PSA greater than or equal to 10ng/ml. 9)Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment 10)Documented ongoing castrate serum testosterone < 50 ng/dL (< 2.0 nM). 11)Received prior castration by orchiectomy and/or ongoing Luteinizing HormoneReleasing Hormone (LHRH) agonist treatment. 12)Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria; a.disease progression as defined by at least 2 new lesions on bone scan. b.Soft tissue disease progression defined by modified RECIST 1.1. c.Clinical progression (worsening pain & the need for palliative radiotherapy). PHASE I SAFETY RUN IN and EXPANSION COHORT inclusion criteria: 13)Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment. SINGLE STAGE PHASE II EXPANSION COHORT ONLY inclusion criteria: 14)Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression 15)Archival tumour tissue available for the analysis of PTEN loss by the central laboratory
1)Prior treatment with enzalutamide (not applicable for the phase I safety run in or for the single stage phase II expansion cohort). 2)Prior treatment with PI3K, AKT, TOR kinase or mTOR inhibitors 3)Surgery, chemotherapy, or other anticancer therapy within 4 weeks prior to trial entry / randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug. 4)Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation. 5)Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry / randomisation. 6)History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism. 7)History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry / randomisation. 8)Known brain or leptomeningeal involvement. 9)Use of potent inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 2 weeks before trial entry / randomisation (3 weeks for St John¡¯s Wort) must be avoided. 10)Clinically significant abnormalities of glucose metabolism as defined by any of the following: a.Diagnosis of diabetes mellitus type I or II b.Glycosylated haemoglobin (HbA1C) ≥8.0% at screening c.Fasting Plasma Glucose ≥8.9mmol/L at screening. 11)Inadequate organ and bone marrow function as evidenced by: a.Haemoglobin < 8.5 g/dL b.Absolute neutrophil count < 1.0 x 109/L c.Platelet count < 75 x 109/L d.Albumin ≤25 g/dL. e.AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥5 x ULN if liver metastases) f.Total bilirubin ≥ 1.5 x ULN (except for patient with Gilbert's disease) g.Serum Creatinine > 1.5 x ULN 12)Inability or unwillingness to swallow oral medication. 13)Malabsorption syndrome or other condition that would interfere with enteral absorption. 14)Any of the following cardiac criteria; a.Mean resting corrected QT interval (QTcF) > 470msec obtained triplicate ECGs b.Clinically important abnormalities(rhythm/conduction/morphology)resting ECG c.Factors that increase risk of QTc prolongation or risk of arrhythmic events d.Experience of any of the following in the preceding six months: coronary artery bypass graft angioplasty vascular stent myocardial infarction angina pectoris congestive heart failure NYHA ≥ Grade2 e.Uncontrolled hypotension 15)Clinically significant history of liver disease consistent with ChildPugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis. 16)Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications. 17)Need for chronic corticosteroid therapy of > 10 mg of prednisolone or > 0.5mg of dexamethasone per day or an equivalent dose of other anti inflammatory corticosteroid. 18)Malignancies other than prostate cancer within 5 years prior to trial entry / randomisation, except for adequately treated basal or squamous cell skin cancer. 19)Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy. 20)Inability to comply with study and follow up procedures.
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.
Patients will either be involved in a collaborating national trial: including but not limited to RT01, CHHIP, PIVOTAL or ART-DECO. Alternatively, patients may be enrolled in a single centre Royal Marsden study (e.g. Pelvic IMRT), single centre Addenbrookes study (Cambridge breast IMRT) or be recruited prospectively with breast, prostate or gynaecological cancer (N.B. sites undertaking prospective recruitment is strictly limited). Must be over 18 years of age and give written informed consent to be involved and gift a blood sample.
Volunteers from the above trials/ studies who are in poor health due to cancer or non-cancer related conditions or who are unable to give informed consent or a blood sample.
Breast Cancer Prostate Cancer
RAIDER is a multicentre two stage randomised phase II trial investigating Dose escalated Adaptive tumour boost radiotherapy (DART) for patients with muscle invasive bladder cancer. Participants will be randomised between standard whole bladder radiotherapy (WBRT), Standard dose Adaptive tumour focused radiotherapy (SART) and DART. Stage I will establish the feasibility of delivering DART in a multi-centre setting, and stage II will establish the toxicity of DART. Participants will be permitted to receive concomitant chemotherapy. 72 patients will be recruited in stage II, with an additional 168 patients in stage II. Both fractionation regimens in standard use in UK are included – 32f and 20f. 120 participants will be recruited per fractionation cohort. Primary endpoints will be assessed in each fractionation cohort separately with the flexibility to drop either a fractionation cohort or an experimental treatment group (on advice of Independent Data Monitoring Committee) following completion of stage I.
1. Written informed consent 2. Age ≥16 years 3. Histologically or cytologically confirmed transitional cell carcinoma (TCC) of the bladder 4. Unifocal bladder TCC staged T2-T4a N0 M0 5. Fit to receive a radical course of radiotherapy 6. WHO performance status 0-2 7. Willing and able to comply with study procedures and follow up schedule
1. Nodal or metastatic disease 2. Widespread carcinoma in situ (CIS) or CIS remote from muscle invasive tumour or multifocal invasive disease 3. Simultaneous TCC in upper tract or urethra 4. Pregnancy 5. Active malignancy within 2 years of randomisation (not including non melanomatous skin carcinoma, previous non muscle invasive bladder tumours, NCCN low risk prostate cancer (T1/T2a, Gleason 6 PSA < 10), in situ carcinoma of any site) 6. Any other conditions that in the Principal Investigator’s opinion would be a contra-indication to radiotherapy (e.g. previous pelvic radiotherapy / inflammatory bowel disease)
We are asking patients with a rare gynaecological cancer if they would like to take part in the RaNGO study. We are researching how these cancers are currently diagnosed, treated and managed. By definition, numbers of women being diagnosed with rare cancers are very small – about 50 in the UK each year. It is therefore very difficult for individual clinicians or even Cancer Centres to build up a knowledge base on how best to treat these patients. We will not be able to improve the outlook in the UK unless we can collect such information together in one place over a number of years and then review the results of the different treatments . We hope to encourage all UK gynaecological cancer centres to join the study. Patients will continue to be treated there as usual, any of their tissue samples etc being kept in local laboratories as at present. However during the study these samples, along with the patients’ anonymised details, including treatments and outcomes, will be virtually recorded on a central index as well. If one of these rare cancers recur, we would also like patients to consider giving permission for more blood and / or fluid samples, biopsies or tissue to be taken for this study. The plan is that in 5-10 years’ time, we will have collected enough information in some of these rare gynaecological cancers to give us a clearer idea of which treatments are useful. The information collected will enable us to provide more information to individual patients and perhaps to consider starting clinical trials of new agents for these rare cancers. For laboratory work we will have information about the location of the rare tissue and blood / fluid samples for important scientific evaluation.
Inclusion criteria Queries about the eligibility criteria should be addressed prior to registration. Patients are eligible for trial if all the inclusion criteria are met and none of the exclusion criteria applies: 1. Patients > = 16 years with one (or more) of the specified rare gynaecological cancers listed in Appendix 1 of the study protocol 2. Patients (or in rare circumstances any guardian or next of kin) must be able to give adequate informed consent agreeing to the collection and retention of anonymised data about their rare gynaecological cancer to RaNGO 3. Patients must provide informed consent to the exchange/release of their data from all relevant National Cancer Registries and other National Organisations, now and in the future, to allow comparison with data that are held on RaNGO, and to update information as it becomes available through these agencies. 4. Formalin-fixed, paraffin-embedded tissue taken at the time of original diagnosis of the specific rare gynaecological cancer (Appendix 1) must be available for inclusion in a virtual tissue bank for legitimate use in research and trials in the future. The tissue may have originated from a range of surgical procedures, including biopsies. For those patients with only a biopsy at the time of primary diagnosis, availability of tissue from specimens taken at interval debulking surgery and repeat biopsies at relapse or maintained remission is desirable. Laboratory accession numbers and block keys must be available at registration.
Exclusion criteria 1. Rare gynaecological cancers that are not listed in Appendix 1of the study protocol 2. Diagnosis of a rare gynaecological cancer listed in Appendix 1 made on cytology only, AND no subsequent formalin-fixed paraffin embedded tissue available to confirm the diagnosis. 3. Absence of consent to inclusion of data on RaNGO or specific consent to access information from National Cancer Registries or Databases
Atypical meningioma is an intermediate grade brain tumour that arises from the linings of the brain. These are very rare tumours and there are approximately 150 new cases per year in the UK, and tend to affect adults with a peak incidence at age 40-60 years. The 5-year tumour recurrence rates are reported as between 39 and 58%. The primary treatment for atypical meningioma is surgery and in patients with residual solid tumour, radiotherapy is administered to reduce the risk of recurrence. In patients with complete resection of the tumour, some clinicians give early radiotherapy, whilst others advise active monitoring with radiotherapy given only at recurrence. Whilst radiotherapy has been shown to be an effective adjuvant treatment in some studies but not others, there is no consensus as to which of these approaches is best. Following resection surgery for atypical meningioma, eligible patients will be randomised to receive either radiotherapy or active monitoring. Patients in both arms will typically have an early postoperative follow-up within 2 weeks of resection surgery to discuss the histopathology results and assess wounds and clinical status. Follow-up thereafter would be at 6 months, 12 months and annually until tumour recurrence or trial closure. EORTC C30 and BN20 quality of life, EQ5D health outcome, and resource use questionnaires will be administered at each follow up visit. All participants will be followed up for a minimum of 5 years post-surgery.
a) Histologically confirmed newly diagnosed solitary atypical meningioma (WHO grade II) based on the 2016 WHO criteria  b) Age >/= 16 years c) All anatomical locations allowed except optic nerve sheath tumour d) Complete resection (Simpson 1, 2 or 3) as assessed by the surgeon e) Able to commence radiotherapy between within 12 weeks of surgery (ideally 8-12 weeks) f) WHO performance status 0, 1 or 2 (Appendix 1) g) Women of reproductive potential must use effective contraception for the whole duration of the treatment h) Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
a) Neurofibromatosis type II (NF-2) b) Optic nerve sheath tumours c) Multiple meningiomas d) Radiation-induced meningioma e) Clinical evidence of second malignancy, except for cervix carcinoma in situ or basal cell carcinoma, and history of invasive malignancy unless treated with curative intent and the patient has been disease free for the last five years f) Previous intracranial tumour in the last 10 years treated with radiotherapy or chemotherapy g) Pregnant or lactating women.
Brain Cancer Neurosurgery
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 188.8.131.52) 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
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.
Some breast cancers are considered low risk. Low risk means there is a small chance of the breast cancer returning after it has been removed during surgery. Currently, patients with low risk breast cancer have radiotherapy after surgery, followed by drug treatment (hormone therapy tablets) for 5 years. Radiotherapy reduces the risk of cancer returning in the breast (local recurrence). However for patients with a low risk breast cancer, the risk of radiotherapy side effects may start to outweigh its benefit. The PRIMETIME study aims to identify a group of women who can safely avoid radiotherapy because the risk of their cancer returning is so low. A research calculation called IHC4+C will be used to calculate a woman's risk of cancer returning 10 years after surgery. 'Very low' risk patients are those where the chance of their cancer returning 10 years after surgery is less than 5%. This means that out of 100 women with 'very low' risk breast cancer, cancer will return in less than five women. In the PRIMETIME study women with 'very low' risk breast cancer can avoid having radiotherapy. All other women will be recommended to have radiotherapy according to standard care. Patients who are eligible to take part are those with a small, slow growing breast cancer which has not spread beyond the breast. Patients will be 60 years or over, have had surgery to remove their cancer with a plan to receive at least 5 years of drug treatment (hormone therapy) for their cancer. The study will be conducted in NHS hospitals in the UK. Participating patients will be followed up by their treating hospital for 10 years following surgery.
1.Provision of written informed consent to participate in the PRIMETIME study 2.Provision of slides for research testing and availability of Ki67 result (contact ICR-CTSU to confirm Ki67 result is available) 3.Women aged ≥ 60 years (younger patients are eligible if they are post-menopausal and have co-morbidities that imply a high risk of radiotherapy toxicity (e.g. significant cardiovascular disease with left sided breast cancer); 4.Women having had breast conserving surgery with complete resection of tumour tissue (≥1 mm microscopic, circumferential margins of normal tissue from invasive cancer and DCIS); 5.AJCC staging of pT1/pN0/M0 (DCIS is allowed in combination with invasive breast cancer, providing whole tumour size (in-situ and invasive ≤2cm); isolated tumour cells in axillary nodes are allowed); 6.Histological confirmation of grade 1 or 2 invasive breast cancer; 7.Oestrogen receptor (ER) positive according to local practice. The H score must be available; 8.Progesterone receptor (PR) positive according to local practice. The percentage positivity must be available; 9.Human epidermal growth factor receptor (HER2) negative according to local practice; 10.Patients must be recommended for ≥5 years adjuvant endocrine therapy according to local policy, they must also be willing to start endocrine therapy and in the investigator’s opinion, deemed able to comply with the duration of treatment.
1.Patients known to have lymphovascular space invasion and/or axillary nodal micrometastases or macrometastases. 2.Patients with a past history of malignancy except (i)basal cell skin cancer and CIN cervix uteri or (ii)treated, localised squamous cell carcinoma of the skin or (iii)malignancies treated with curative intent and the patient has been disease free ≥5 years; 3.Patients who have had an ipsilateral mastectomy; 4.Patients who have received neoadjuvant therapy (endocrine or cytotoxic chemotherapy with therapeutic intent) or who are deemed by the MDT to require adjuvant cytotoxic chemotherapy. NB. In most instances treatment within a window of opportunity study is not considered of therapeutic intent and will therefore be allowed: please check with the PRIMETIME trial manager if a patient has participated in a window of opportunity study. 5.Patients with mammographically occult breast cancers, ie. present with lump, but not visible on mammogram
Each year more than 48,000 women are diagnosed with breast cancer in the UK. Currently women having surgery to treat their cancer undergo removal of the first one or two lymph glands (called sentinel nodes) from the armpit (axilla) to check if the cancer has spread to these. This procedure is called sentinel node biopsy. For about a quarter of women, this test shows that the breast cancer has spread to their sentinel nodes. These women then undergo treatment to their armpit (axillary treatment). This is either a second operation to remove all the lymph glands in the armpit (axillary node clearance) or radiotherapy to the armpit (axillary radiotherapy) depending on their hospital practice. After recovery from this treatment, they have chemotherapy and/or endocrine therapy. Some women may also have radiotherapy to their breast or chest wall. This chemotherapy, endocrine therapy, breast and chest wall radiotherapy is called adjuvant therapy. We now know that adjuvant therapy is very good at preventing the cancer from coming back. So, armpit treatment may no longer be needed. Armpit treatment damages the drainage channels of the lymphatic system. Fluid called lymph begins to collect in the arm and doesn't drain. The arm and hand swell and this swelling is called lymphoedema. One in 5 women will get lymphoedema in the arm after armpit treatment. Lymphoedema can be painful and make it difficult to move the arm. It cannot be completely cured, and without treatment it may get worse. Also, 1 in 3 people will have numbness or pain after armpit treatment and 1 in 5 may experience shoulder stiffness. These problems can be upsetting and difficult to cope with. If armpit treatment is no longer needed, it would be important to know this. We could then spare women unnecessary treatment, and avoid the long term problems it causes.
Women will be eligible for inclusion only if ALL of the following criteria apply: • 18 years or older • Unifocal or multi-focal invasive tumour with lesion ≤5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound (tumour size should be based only on the single largest tumour; do not add the sizes together from the multiple foci) • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit > 2.0mm in largest dimension or defined as macrometastasis on molecular assay) • Fit for axillary treatment and adjuvant therapy • Have given written informed consent
Women will be excluded if they have: • bilateral breast cancer • more than 2 nodes with macrometastases • neoadjuvant therapy for breast cancer • previous axillary surgery on the same body side as the scheduled sentinel node biopsy • not receiving adjuvant systemic therapy • previous cancer less than 5 years previously or concomitant malignancy except o adequately treated basal or squamous cell carcinoma of the skin o adequately treated in situ carcinoma of the cervix o adequately treated in situ melanoma o contra- or ipsilateral in situ breast cancer
Breast Cancer Breast Surgery
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.
Hepatobiliary Surgery Upper GI
In locally advanced colon cancer the standard of care is surgical resection and chemotherapy. Most patients are cured however not all of them are. To improve the cure rate we need to target sub groups of patients who are likely to respond to new drugs. We aim to look at 2 sub groups of patients - Mismatch repair deficient and POLE exonuclease mutant. We think that because of these tumours having a high mutational load, they are likely to respond to a new group of treatments called checkpoint inhibitors. This study will compare the standard of care - surgery and chemotherapy with this plus Avelumab - an immune checkpoint inhibitor. It will be a randomised study.
1. Male or female subjects aged > = 18 years 2. ECOG PS 0/1 3. Histologically proven, stage III (i.e., any T, N1 or N2, M0) adenocarcinoma of the colon (as defined by the presence of the inferior pole of the tumour above the peritoneal reflection - that is, at least 15 cm from the anal margin). 4. Fully surgically resected tumour with clear resection margins (i.e., > 1 mm) 5. Locally confirmed defective mismatch repair (dMMR) tumour (as defined by the lack of staining on either the pre-operative biopsy samples or resection specimens of at least one of the following proteins: MLH1, MSH2, MSH6, PMS2) or centrally confirmed POLE exonuclease domain mutated tumour (in subjects < 50 years old with pMMR tumours) 6. Absence of metastases as shown by post-operative CT scan 7. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would contraindicate adjuvant chemotherapy 8. Adequate hematological function defined by absolute neutrophil count (ANC) > = 1.5 × 109/L, platelet count > = 100 × 109/L, and hemoglobin > = 9 g/dL (blood transfusion before recruitment is allowed) 9. Adequate hepatic function defined by a total bilirubin level < = 1.5 × the upper limit of normal (ULN) range and AST and ALT levels < = 2.5 × ULN 10. Adequate renal function defined by an estimated creatinine clearance > = 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) 11. Negative serum or urine pregnancy test at screening for women of childbearing potential 12. Fertile men and women must agree to take highly effective contraceptive precautions during, and for 6 months after the last dose of chemotherapy or for 1 month after the last dose of Avelumab
1. Rectal tumours (as defined by the presence of the inferior pole of the tumour below the peritoneal reflection - that is, < 15 cm from the anal margin). 2. Inability to start adjuvant chemotherapy within 12 weeks after surgery 3. Administration of neoadjuvant systemic chemotherapy or radiotherapy before surgical resection of colon cancer 4. Prior organ transplantation, including allogeneic stem cell transplantation 5. Significant acute or chronic infections including, among others: - known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - positive test for HBV surface antigen or anti-HCV antibody and confirmatory HCV RNA test 6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: - Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible - Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses < = 10 mg/day of prednisone or equivalent - Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade > = 3 NCI CTCAE v4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) 8. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.0; however, alopecia and sensory neuropathy Grade < = 2 is acceptable unless oxaliplatin administration is planned as part of the adjuvant treatment 9. Pregnancy or lactation 10. Known alcohol or drug abuse 11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (> = New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication 12. Known history of colitis, pneumonitis and pulmonary fibrosis (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment. 13. Any psychiatric condition that would prohibit the understanding or rendering of informed consent 14. Vaccination within 4 weeks of the first dose of Avelumab and while on trial is prohibited except for administration of inactivated vaccines 15. Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured. Cancer subjects with incidental histological findings of prostate cancer (tumour/node/metastasis stage of T1a or T1b or prostate-specific antigen ˂10) who have not received hormonal treatment may be included, pending a discussion with the study physician.
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.
Anal cancer is rare, but its incidence is rising rapidly. Approximately 1000 cases are diagnosed each year in the UK. Standard treatment usually involves a combination of chemotherapy and radiotherapy (chemoradiotherapy (CRT)). Often the same radiotherapy dose is given regardless of disease stage. Recent improvements in radiotherapy means altered doses can now be given to the tumour whilst sparing normal tissues. PLATO is an integrated protocol, comprising 3 separate trials (ACT3, ACT4 and ACT5) which aims to optimise radiotherapy dose for low-, intermediate- and high-risk disease. ACT3: a prospective non-randomised phase II trial which will evaluate a treatment plan in patients with early, small tumours who have undergone surgery (local excision). Patients with no tumour cells close to the cut edge of the removed tissue (margins > 1mm) have no further treatment, and those with tumour cells close to the cut edge (margins ≤1mm) receive additional lower-dose CRT (41.4Gy in 23 fractions). We aim to determine whether this treatment strategy results in acceptably low rates of the cancer coming back ACT4: a randomised phase II trial. Compares standard-dose CRT (50.4Gy in 28 fractions) with reduced-dose CRT (41.4Gy in 23 fractions) in patients with intermediate-risk disease, to see if less radiotherapy is able to maintain the excellent success rates in treating the cancer, while reducing the side effects of treatment. ACT5: a seamless randomised pilot, phase II and phase III trial that compares standard-dose CRT (53.2Gy in 28 fractions) with two higher doses of CRT (58.8Gy and 61.6Gy, both in 28 fractions), in patients with locally advanced anal cancer, to see if giving a higher dose of radiotherapy reduces the chance of the cancer coming back, whilst not causing too many extra side effects. One of the two higher-dose experimental arms will be selected for the phase III component of the study.
Key inclusion criteria for all three trials include: - written informed consent; - histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anus; - adequate bone marrow, hepatic and renal function; - HIV negative or HIV positive and receiving effective antiretroviral therapy and CD4 count > 200; - - aged 16 years or over; - fit for all protocol defined treatments; - prepared to practice methods of contraception during treatment and until 6 months post end of treatment - able to undergo all mandated staging and follow-up investigations, including MRI Trial-specific inclusion criteria: ACT3 – T1 N0 or Nx anal margin tumour treated by local excision; ECOG performance status 0-2 ACT4 – T1-2 up to 4cm N0 or Nx anal canal or anal margin tumour; ECOG performance status 0-1 ACT5 – T2 N1-3 or T3-4 Nany anal canal or anal margin tumour; ECOG performance status 0-1
Key exclusion criteria for all three trials include: - definite evidence of metastatic disease; - prior invasive malignancy unless disease-free for a minimum of 3 years (exluding basal cell carcinoma of the skin or other in situ carcinomas); - prior systemic chemotherapy for anal cancer; - prior radiotherapy to the pelvis; - uncontrolled cardiorespiratory comorbidity; - pregnant or lactating; - immunocompromised (organ transplant) Trial-specific exclusion criteria: - ACT3 - where a piecemeal local excision precludes assessment of tumour size and margin status
There are many different types of breast cancer defined by the genetic code present within cancer cells. The genetic code is stored in the form of DNA, and changes within DNA are called mutations. Mutations are usually identified by analysis of tumour samples obtained through surgery or biopsy. Treatments that target specific mutations (known as targeted therapies) have led to improvements in the treatment of breast cancer. DNA from cancer cells is found in the blood of over 90% of patients with advanced breast cancer (breast cancer that has either reappeared following treatment, known as recurrent or locally advanced breast cancer, or breast cancer that has spread to another part of the body, known as metastatic breast cancer). DNA from cancer cells found in the blood is called circulating tumour DNA (ctDNA). Patients with advanced breast cancer will be asked to provide a blood sample which will be analysed for several specific mutations in the ctDNA. Depending on the ctDNA screening results, the patient may be invited to enter a treatment cohort and receive a treatment targeted to their type of disease. Patients will receive treatment until their cancer gets worse (progresses). The main aims of plasmaMATCH are to assess whether ctDNA screening can be used to detect patient subgroups who will be sensitive to targeted therapies and then to assess the safety and activity of the targeted treatments. Treatment cohorts: Cohort A: Patients with an ESR1 mutation will receive extended-dose fulvestrant. Cohort B: Patients with a HER2 mutation will receive neratinib. Patients with estrogen receptor (ER) positive breast cancer in this cohort will also receive fulvestrant. Cohort C: Patients with ER positive breast cancer and an AKT1 mutation will receive AZD5363 and fulvestrant. Cohort D: Patients with one of several mutations that activate a process called the ‘AKT pathway’ will receive AZD5363. Cohort E: Patients with triple negative breast cancer on their most recent tumour biopsy who do not have a targetable mutation identified by ctDNA screening or tumour sequencing that would allow entry into Cohorts A to D, or who have an actionable mutation identified but are not otherwise eligible for Cohorts A to D, will be invited to enter Cohort E and receive AZD6738 and olaparib.
1. Female. 2. Aged ≥ 18 years old. 3. Histologically confirmed invasive breast carcinoma. 4. Metastatic or recurrent locally advanced breast cancer that is not suitable for treatment with radical or curative intent. 5. Demonstrated progression of disease by radiological assessment or by clinical assessment within the last 6 weeks. 6. Measurable disease by RECIST v1.1. 7. Patients must have completed at least one prior line of treatment for advanced breast cancer and/or relapse within 12 months of completing (neo)adjuvant chemotherapy. Patients with HER2 positive breast cancer must have been treated with at least two courses of HER2 targeted therapy in the advanced setting (or one course if no further courses of HER2 targeted therapy are available locally). 8. Patient must either be suitable for a baseline biopsy of recurrent disease or have an archival biopsy of recurrent disease available. Patients are requested to consent to a baseline biopsy but if deemed unsafe by the Investigator, an archival biopsy of recurrent disease can be used instead. If it is deemed unsafe to proceed with baseline biopsy, and no archival recurrent disease biopsy is available, the patient will not be eligible for entry into the treatment cohort. 9. ECOG performance status ≤ 2. 10. Life expectancy > 3 months. 11. Patients must be surgically sterile, be postmenopausal or must agree to use effective contraception during the period of trial treatment and be willing to do so for 6 months following the end of trial treatment. Effective contraception is defined as double barrier contraception (e.g. condom plus spermicide in combination with a diaphragm, cervical cap or intrauterine device). Ovarian suppression with an LHRH agonist is not a method of contraception. 12. Patients of childbearing potential should have a negative serum pregnancy test within 14 days prior to initiation of trial treatment. 13. At least 4 weeks washout period after the end of trial treatment on a different cohort within plasmaMATCH. 14. Adequate haematological, renal and hepatic function as defined by: • Haematology: - Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 x 109/L) - Platelet count ≥100,000/mm3 (≥100 x 109/L) - Haemoglobin ≥9g/dL (≥90g/L) • Renal function: - Serum creatinine ≤1.5 x upper limit of normal (ULN) and calculated creatinine clearance more than 30ml/min • Liver function tests: - Total bilirubin ≤1.5 ULN - Alanine aminotransferase (ALT) ≤3 ULN. In the presence of liver metastases ALT ≤5 ULN. For patients in Cohort B, C and D: aspartate aminotransferase (AST) ≤3 ULN. In the presence of liver metastases AST ≤5 ULN. 15. For patients with ER positive breast cancer in Cohorts A, B and C: EITHER postmenopausal, as defined by at least one of the following criteria: • Age > 60 years; • Age < 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females; • Documented bilateral oophorectomy; medically confirmed ovarian failure. OR Pre-/peri-menopausal (i.e. not meeting the criteria for being postmenopausal) if being treated with an LHRH agonist that was commenced at least 4 weeks prior to Cycle 1 Day 1, and continues on the LHRH agonist throughout the trial period. NB. Additional eligibility criteria apply for entry into each treatment cohort.
1. Prior treatment with radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy or IMPs during the previous 4 weeks (6 weeks for nitrosoureas, Mitomycin-C) before trial treatment, except for hormonal therapy with LHRH analogues, which are permitted, and bisphosphonates or RANK ligand antibodies that are permitted for the management of bone metastases. 2. Uncontrolled CNS disease (brain metastases or leptomeningeal disease). Patients with prior diagnosis of CNS metastases must be stable by clinical assessment having ceased steroids after prior treatment. 3. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction within the last 6 months or ventricular arrhythmia. Patients with a history of any of the above listed cardiac conditions judged not to be clinically significant by the local investigator must be notified to the trial team at the ICR-CTSU for approval by the CI and/or Cohort Lead. 4. Ongoing toxic manifestations of previous treatments Grade ≥1. Exceptions to this are alopecia or toxicities which in the opinion of the Investigator should not exclude the patient. Such cases should be clearly documented in the patient’s notes by the Investigator. 5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of trial treatment. 6. Pregnant or breastfeeding. 7. Any condition that according to the treating physician may compromise the patient’s safety or the conduct of the trial. 8. Current malignancies of other types, with the exception of adequately treated in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy and have no evidence of the disease for 3 years or more are eligible for the trial. NB. Additional eligibility criteria apply for entry into each treatment cohort.
To establish the maximum tolerated dose (MTD) and safety of ruxolitinib in combination with 5-azacitidine
For the Interventional component: •Age ≥16 years old •A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP) •In need of treatment in the opinion of the investigator •Eastern Cooperative Oncology Group (ECOG) performance status 0-3 •Adequate liver and renal function, defined as: - Liver transaminases ≤3 × ULN (AST/SGOT and ALT/SGPT) - Bilirubin < 4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible) - GFR ≥40 ml/min •Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments •Able to give valid informed consent For the Observational Component •Age ≥16 years old •A prior diagnosis of ET, PV or MF with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP) - Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients previously treated post transformation into MPN-AP/MPN-BP, or entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only. - Able to give valid informed consent
For the Interventional Component: •Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial •New York Heart Association Class II, III, or IV congestive heart failure •On-going cardiac dysrhythmias of grade 3, QTc prolongation > 480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium < 3.0 mEq/L, family history of long QT interval syndrome) •Erythropoietic agent within 28 days prior to registration •Thrombopoietic agent within 14 days prior to registration •CYP3A4 inhibitor within 7 days prior to registration •Experimental treatment within 14 days prior to registration •Previous treatment for MPN-AP or MPN-BP, including stem cell transplant and low intensity AML chemotherapy •Previously received 5-azacitidine. Ruxolitinib can be taken up until study entry at the pre-study dose. Hydroxycarbamide prescribed prior to study entry must be stopped before the first scheduled day of trial treatment •Known contraindications to receiving azacitidine or ruxolitinib •Known HIV seropositivity •Known to have active hepatitis A, B, or C •Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry •Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose. For the Observational Component: No Exclusions planned.
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.
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
PEACE is a multi-centre prospective observational study intended to facilitate tissue donation from multiple tumour sites in the post-mortem setting. Potential study sites will be assessed to ensure that they have the infrastructure and ability to consent an adequate number of patients for the study so that at least 10-15 tumour harvests are performed per year. This has taken into account a likely attrition rate as a result of missed cases from consent to death. The PEACE protocol has been written in collaboration with oncologists, palliative care teams, molecular and histopathologists, ethicists, medical lawyers, and the patient advocate group ‘Independent Cancer Patients’ Voice’ (ICPV). The study consent and tumour harvesting procedure have been developed in accordance with the Human Tissue Act 2004, and the consent allows for the use of collected samples in future ethically approved studies.
1. Age 18 years or older 2. Confirmed diagnosis of a solid malignancy with metastatic disease 3. Oral and written informed consent from patient to enter the study and to undergo post-mortem tissue sampling
1. Medical or psychiatric condition that would preclude informed consent 2. History of high-risk infections (e.g. HIV-positive, hepatitis C, tuberculosis and Creutzfeldt-Jacob disease)
This is a clinical trial for patients diagnosed with early stage breast cancer i.e. that has not spread to other organs such as the lungs, liver or bones, who have been advised to receive chemotherapy before surgery (neoadjuvant) chemotherapy. The trial investigates the safety and effectiveness of olaparib, a drug which targets part of the pathway that repairs damaged DNA, in addition to platinum-based neoadjuvant chemotherapy. The trial is open to patients who have breast cancer caused by an inherited mutation (change from the normal DNA sequence) in the BRCA 1 or BRCA 2 genes. In addition, it is open to patients who do not have hormone-responsive (oestrogen) breast cancer that also does not over-express a protein called HER2. These breast cancers are called triple negative breast cancers (TNBC). BRCA–mutated (gBRCA) and TNBC are considered to have a higher risk of disease recurrence after surgery and are usually treated with chemotherapy. The chemotherapy to be given are drugs called paclitaxel (given weekly) and carboplatin (given once every 3 weeks) followed by drugs called anthracyclines. Both of these drugs have been used in breast cancers of these types and stage previously but not in combination with olaparib. However, they have been used in combination with olaparib in women with more advanced breast cancers with good results. So this trial investigates whether introducing olaparib at an earlier stage of breast cancer might produce more shrinkage of the breast cancer before surgery, which may allow a better chance of avoiding mastectomy and may lead to a better chance of avoiding recurrence of the breast cancer.
• Written informed consent. • Aged between 16 and 70 • Histologically confirmed invasive breast cancer. • Clinical stage T1-4 N0-2 (tumour or metastatic node diameter > 10mm) • Confirmed ER-negative and HER2-negative. or • Germline BRCA mutation positive, irrespective of hormone status but HER2 negative. • Performance Status 0-1
T0 tumour in absence of axillary node > 10mm • TNBC with a non-basal phenotype and over-expressing Androgen Receptor • Not suitable for neoadjuvant chemotherapy • Distant metastases apparent prior to randomisation • Prior history of invasive breast cancer within the last 5 years • Previous PARP inhibitor use or any previous chemotherapy or targeted agent. • Any previous chemotherapy or agent used for the treatment of cancer within the last 5 years
• 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.
Head and Neck Cancer
Surgical removal of part of the liver is primarily indicated as a treatment for cancer, either a cancer which has arisen in the liver or has spread from elsewhere, commonly the bowel. The number of such operations performed is increasing year on year due to improvements in non-surgical treatments for cancer and in surgical expertise which yields more patients suitable for surgery. The standard method by which this surgery is performed is through a large abdominal incision. Increasingly the keyhole approach is advocated as resulting in less pain after surgery, better cosmesis and a quicker recovery. However to date there is a lack of good quality evidence to support the use of keyhole surgery over the traditional open approach. The proposed research trial should address this knowledge gap. The research will be carried out in centres in the UK capable of performing such specialist surgery, Southampton and Cardiff. A random process will be used to allocate patients to either the open or keyhole approach. The main determinant of which operation is superior will be the time it takes for patients to recover from the surgery. Other criteria that will be assessed include duration of hospital stay, complications, quality of life, cost of treatment and overall survival.
•Patients requiring left or right hemihepatectomy with or without the need for one additional hepatic wedge resection or metastasectomy •Able to understand the nature of the study and what will be required of them •Men and nonpregnant, nonlactating women aged over 18 •BMI between 18-35 •Patients in ASA IIIIII
•Inability to give written informed consent •Patients undergoing liver resection other than left or right hemihepatectomy with or without the need for one additional hepatic wedge resection or metastasectomy •Patients with hepatic lesion(s), located with insufficient margin from vascular or biliary structures to be operated laparoscopically. •Patients in ASA IVV •Repeat hepatectomy
Hepatobiliary Surgery Upper GI
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.
The main goal of this study is to show how the results of the Oncotype DX® test changes the decisions of physicians in the UK for women with ER-positive (ER+), early breast cancer (EBC) with 1-3 positive lymph nodes who are potential candidates for chemotherapy, but for whom the benefits of chemotherapy may be uncertain. This study will also assess how the results of the Oncotype DX assay affect the treatment preferences of the patient.
1. Patients must have undergone surgical treatment for breast cancer with adequate evaluation of lymph node status with a sentinel lymph node procedure or full axillary dissection, with positive involvement of 1-3 axillary lymph nodes as confirmed by histologic examination. 2. Patient must have adequate performance status (PS ECOG 0, 1) 3. Patient must be a candidate for treatment of their cancer with systemic chemotherapy in addition to hormonal therapy. 4. Patients should, in the treating physician’s judgment, represent the population for which the benefit of adding systemic chemotherapy to hormonal therapy is either unclear or may not be large enough to warrant the risk of undergoing chemotherapy. 5. Eligible Staging Criteria: - T1-3 N1, M0 (inclusive of N1mic) 6. Patient’s tumour must undergo central pathology review at Genomic Health Inc. (GHI) and must be found adequate for the Oncotype DX assay. 7. Patient’s tumour must be oestrogen-receptor positive (ER+, Allred score > 2) as per institutional guidelines and not have HER2 positive tumours by immunohistochemistry (IHC) or in situ hybridisation (ISH). 8. Patient must be over 18 years of age.
1. Patients have ER negative tumours (ER-, Allred score ≥ 2) 2. Patients have HER2 positive tumours (HER2+) as defined by IHC 3+ or HER2 gene amplified if tested by ISH 3. Patients have not had evaluation of lymph node involvement, have been deemed not to have lymph node involvement, or have only immunohistochemical confirmation (N0(i+)) of node involvement 4. Patients have a prior history of breast cancer in the same breast 5. Patients have been newly diagnosed with more than one operable primary breast tumour 6. Patients have multi-centric tumours (note: patients with multi-focal tumours may be included) 7. Patients have known metastatic breast cancer 8. Patients have < 2mm invasive tumour as assessed by local pathologist 9. Patients have received any kind of neo-adjuvant treatment 10. Patients have poor performance status (ECOG 2, 3, 4) and/or other clinical factors that would render the patient a non-viable candidate for adjuvant chemotherapy 11. Patients with a current medical condition such as psychiatric illness that would interfere with their ability to consent and participate in this study 12. Male patients with breast cancer
Patients aged 18-59 at date of diagnosis, who have had a diagnosis of adenocarcinoma of the colon or rectum within the last five years. Patient must have a family history of bowel cancer (parent/sibling/child also diagnosed).
Patients will be excluded if they do not meet the inclusion criteria.
Colorectal Cancer Genetics
Cancers that occur at the junction between the oesophagus (gullet) and the stomach are called gastro oesophageal junction (GOJ) adenocarcinomas. They are 6 times more common than they were 30 years ago and have a very poor outcome (only 1 in 5 patients will survive five years). We have previously developed a new way of determining how advanced a patient’s GOJ adenocarcinoma is (what we call staging) using both the physical features determined by the radiology tests and the molecular features of the cancer. This system works significantly better than the existing way we stage these cancers. However this new system was developed using patients who had already had their surgery. We now want to test it on patients at the beginning of their treatment- or what we term prospectively. The patient’s management will not differ from current practice but as well as looking at the features used for staging at the moment we will also record our new system in parallel. We will also test samples of the cancer, which are already routinely taken, for the molecular changes we think will predict survival. After this patients will undergo the standard treatment at each of the centres involved. It will then be possible to determine both how practical our new system is and how good it is at predicting survival. We will be running this prospective trial in multiple hospitals across the country to ensure that our system is broadly applicable. If we can prove that our revised staging system, using both the physical features of the tumour and the molecular changes, can accurately predict outcome this will allow us to give far better information to our patients about their chance of a cure but also it will also allow treatments to be targeted at those who will benefit the most.
The inclusion criteria is any patient with tissue proven diagnosis of adenocarcinoma of the oesophagus, stomach and gastro-oesophageal junction including those undergoing endoscopic therapy (endoscopic mucosal resection +/- radiofrequency ablation or stent insertion in palliative patients ) or surgery (oesophagectomy or extended total gastrectomy). This includes patients with intramucosal cancer and advanced disease.
Patients for palliative treatment
Gastroenterology Upper GI Upper GI Surgery
At present, there are no means of predicting if patients' symptoms are due to bowel cancer. When patients present to their GP with bowel symptoms that need investigating, they will be referred for a colonoscopy. We are conducting a study that aims to determine whether the Faecal Immunochemical Test (FIT) can be used in the future as an effective tool to identify patients at risk of bowel cancer. In 2005, NICE introduced guidelines where patients with certain symptoms that are associated with a high probability of bowel cancer are referred under the two week rule to secondary care for investigations. These patients must be seen within two weeks of referral and if a cancer is diagnosed, patients must be treated within 62 days of referral. The vast majority of patients referred undergo an endoscopic examination either a colonoscopy (to view the whole colon) or a flexible sigmoidoscopy (to view the left side of the colon) to confirm whether a patient has an underlying cancer or not. However, only 10-15% of these referrals have underlying bowel cancer or significant pathology such as precancerous polyps. The remaining patients do not have significant pathology. In 2015, NICE expanded the criteria significantly in order to increase the pick up rates of bowel cancer from these two week referrals. This means that a large number of patients unnecessarily undergo endoscopic examination with the associated risk of bowel perforation, sedation and the procedure itself. This also strains the cash-strapped resources of the NHS. The FIT test is a simple one-off stool test that patients can do at home and has shown promise in predicting bowel cancer in both the screening (Moss et al 2016) and symptomatic (MacDonald et al 2015, Auge et al 2015, Mowat et al 2015, Cubiella et al 2015) patient settings.
Referred for colonoscopy under 2 week rule for suspected colorectal cancer Informed consent
Unable to give informed consent Stool sample taken during bowel preparation Unable to take adequate stool sample Unable to complete bowel preparation Unable to tolerate complete colonoscopic examination
Colorectal Cancer Colorectal Surgery
Non-Hodgkin’s Lymphoma (NHL) is the fifth commonest malignant disease in adolescents and young adults. It is a spectrum of malignant tumours of lymphocytes and lymph glands. Each different type of NHL requires a different treatment to achieve cure. NHL occurs in both children and adults, though the relative incidence of the different types changes with age. Cancer registry data show consistently lower survival for NHL patients aged 15 to 24 years compared to younger children. It is unknown whether this is a consequence of the different chemotherapy regimens used by paediatric and adult oncologists, or a change in disease biology during adolescence. There is no information available to address these questions. There is no record of how many young adults are treated on individual chemotherapy regimens and few enter clinical trials. Even the exact incidence of each NHL type is uncertain as new knowledge of tumour biology has changed the way NHL has been classified over the past decade. In cancer registries, which use older classifications, more than 40% are recorded as NHL without stating which type. This epidemiological study will collect diagnosis, treatment and outcome data on every 15 to 29 year old with NHL, diagnosed during a 3 year period in England, Scotland and Wales. The aim is to establish the incidence of each NHL type, document the treatments being used and record remission and cure rates. We will also make an inventory of whether there is spare lymphoma tissue, taken originally for diagnosis, which can be made available for future biological study of young adult NHL. The development of young adult cancer services in the UK puts us in a unique position to understand NHL in this age group. The new information from this study will provide a more rational basis for treatment recommendations, for future clinical trial design, and ultimately lead to improvements in patient cure and survival.
All patients within the target age (15-29) with a new diagnosis of Non-Hodgkin's Lymphoma, diagnosed in England, Wales and Scotland.
There is currently no standard treatment beyond first-line etoposide/platinum-based chemotherapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma. Therefore the treatment of patients whose disease progresses on or after this first-line treatment is an area of unmet need. Combination regimens such as irinotecan/5-flourouracil/folinic acid are a second-line treatment option currently used in Europe and world-wide for this subset of patients. However, there is currently no trial evidence supporting this treatment regimen in these patients. Results of the NAPOLI-1 phase III trial of liposomal irinotecan in the treatment of patients with metastatic pancreatic adenocarcinoma after gemcitabine-based therapy reported improved survival for those patients who received a combination of liposomal irinotecan with 5-FU/folinic acid compared to those patients who received 5-FU/folinic acid alone. Liposomal irinotecan has been found to show an improved distribution into tumour tissue in comparison to irinotecan, and this may have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma. Docetaxel is standardly used as a second-line treatment option in patients with small cell lung cancer who have progressed on primary etoposide-platinum combination therapy. Therefore this drug could also have clinical benefit in patients with extra-pulmonary neuroendocrine carcinoma as the biology of the disease is similar to small cell lung cancer. The overall aim of the NET-02 trial is to select a treatment for continuation to a Phase III trial. The intention of the trial is to determine whether liposomal irinotecan/5-fluorouracil/folinic acid and docetaxel are sufficiently active in this population of patients. If both treatments are found to be efficacious, selection criteria will be applied to select a treatment to take forward. 102 eligible participants will be randomised to receive either liposomal irinotecan/5-fluorouracil/folinic acid given every 14 days, or docetaxel given every 21 days. Participants will be treated for a minimum of 6 months or until discontinuation of treatment as per protocol.
1. Age > = 18 years and life expectancy > 3 months. 2. Diagnosed with poorly differentiated (as defined by the World Health Organisation in 2010, Ki 67 > 20%) extra-pulmonary neuroendocrine carcinoma (NEC grade 3). (Carcinoma of unknown primary is allowed if lung primary has been excluded). 3. Prior treatment with first-line platinum-based chemotherapy for NEC in the advanced setting and > = 28 days from Day 1 of the previous treatment cycle. 4. Documented radiological evidence of disease progression OR discontinuation of first-line platinum-based chemotherapy due to intolerance. 5. Measurable disease according to RECIST 1.1 (Appendix 1). 6. Eastern Co-operative Oncology Group (ECOG) performance status < = 2 (see Appendix 2). 7. Adequate renal function with serum creatinine < = 1.5 times upper limit of normal (ULN) and creatinine clearance > = 50ml/min according to Cockroft-Gault or Wright formula (see Appendix 3). 8. Adequate haematological function: Hb > = 90g/L, WBC > = 3.0 x 109/L, ANC > = 1.5 x 109/L, platelet count > = 100 x 109/L. 9. Adequate liver function: serum total bilirubin 1.5 x ULN (biliary drainage is allowed for biliary obstruction) and ALT and/or AST 2.5 x ULN in the absence of liver metastases, or 5 x ULN in the presence of liver metastases. 10. A negative pregnancy test is required at registration in women of childbearing potential . 11. Men* and women** of reproductive potential must agree to use a highly effective form of contraception*** during the study and for 6 months following the last dose of trial treatment. In addition, male participants should use a condom during study participation and for 6 months following the last dose of trial treatment. 12. Patients must be able to provide written informed consent. 13. Patients must be able and willing to comply with the terms of the protocol. * Women of reproductive potential are defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. ** Men of reproductive potential are defined as post-pubescent and not permanently sterile by vasectomy or bilateral orchidectomy. *** Highly effective contraception is defined as one of the following: combined (oestrogen and progesterone-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
1. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients. 2. Use (including self-medication) within one week of randomisation and for the duration of the study of any of the following: St. John’s wort, grapefruit, Seville oranges, medicines known to inhibit UGT1A1 and medicines known to inhibit or induce either CYP3A4 or CYP3A5 (see Appendix 8 of protocol for list*). 3. Previous treatment (for neuroendocrine carcinoma) with any of the components of combination chemotherapy regimens detailed in this study (nal-IRI or 5-FU or irinotecan or topoisomerase inhibitors or taxane-based therapy). 4. Incomplete recovery from previous therapy in the opinion of the investigator (surgery/adjuvant therapy/radiotherapy/chemotherapy in advanced setting), including ongoing peripheral neuropathy of > CTCAE grade 2 from previous platinum-based therapy. 5. First line treatment administered within 4 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to treatment start in this study. 6. Concurrent palliative radiotherapy involving target lesions used for this study (< 28 days from discontinuation of radiotherapy). Radiotherapy for non-target lesions is allowed if other target lesions are available outside the involved field. 7. Patients must not have a history of other malignant diseases (within the previous 3 years, and there must be no evidence of recurrence), other than: • Extra-pulmonary neuroendocrine carcinoma. • Non-melanoma skin cancer where treatment consisted of resection only or radiotherapy. • Ductal carcinoma in situ (DCIS) where treatment consisted of resection only. • Cervical carcinoma in situ where treatment consisted of resection only. • Superficial bladder carcinoma where treatment consisted of resection only. 8. Documented brain metastases, unless adequately treated (surgery or radiotherapy only), with no evidence of progression and neurologically stable off anticonvulsants and steroids. 9. Clinically significant gastrointestinal disorder (in the opinion of the treating clinician) including hepatic disorders, bleeding, inflammation, obstruction, or diarrhoea > CTCAE grade 1 (at time of study entry). 10. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion. 11. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure**. 12. Severe bone marrow failure or bone marrow depression after radiotherapy or treatment with other antineoplastic agents (defined as haematological values of haemoglobin or white blood cells or neutrophils or platelets not meeting inclusion criteria). 13. Known active hepatitis B virus, hepatitis C virus or HIV infection. 14. Active chronic inflammatory bowel disease. 15. Breastfeeding women. 16. Evidence of severe or uncontrolled systemic diseases which, in the view of the treating clinician, makes it undesirable for the patient to participate in the trial. 17. Evidence of significant clinical disorder or laboratory finding which, in the opinion of the treating clinician, makes it undesirable for the patient to participate in the trial. 18. Medical or psychiatric conditions that impair the ability to give informed consent. 19. Any other serious uncontrolled medical conditions (in the opinion of the treating clinician). * For patients receiving any of these medications, use of an alternative agent is recommended. ** It is recommended that subjects should have a systolic blood pressure of either less than 150 mmHG, and/or a diastolic blood pressure of less than 100 mmHg at rest (average of 3 consecutive readings 3-5 minutes apart). Anti-hypertensive drugs may be used to achieve these values.
Prostate cancer is the most common cause of cancer in men. Prostate cancer that has spread to other parts of the body (metastatic) is incurable and is often fatal. New drugs called immune checkpoint inhibitors work with the patient’s own immune system to fight the cancer. These drugs look promising in other cancers but have not been as successful in prostate cancer. However, we and others have done research which showed that it may be possible to pick out people more likely to respond to these types of drugs by looking at certain features of the cancer tissue. If the cancer tissue contains a lot of DNA mutations, show deficiencies in its ability to repair DNA, or if we see a lot of cells from the immune system in the tissue, we say it has a positive immunogenic signature (ImS +ve) and we think it is more likely to respond to treatment with immune checkpoint inhibitor drugs. We plan to enrol patients with metastatic prostate cancer. Patients with ImS +ve cancer could go on to have treatment with a combination of two immune checkpoint inhibitors, nivolumab (Nivo) and ipilimumab (Ipi). About 1 in 4 prostate cancer patients will have ImS +ve disease. We plan to test around 175 men for the ImS to identify 35 with ImS +ve cancer who will go on to have the study treatment. The main aim is to see if these men do better on treatment with Nivo and Ipi than we would expect if they were having routine treatment. Both drugs are given intravenously in the hospital every 3-4 weeks. Treatment lasts for up to a year and patients will be followed up for up to 5 years after registration in the main study. The study will recruit patients from around 15 sites in the UK. We expect recruitment to start in the fourth quarter of 2017 and it will take about 18 months to recruitment.
Inclusion criteria for Pre-Screening (Assessment of ImS): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Patient has archival prostate cancer tissue available or has disease amenable to biopsy and is willing to undergo a new biopsy for assessment of ImS. Disease amenable to biopsy is: o Soft tissue lesion meeting RECIST criteria that in the opinion of clinician and interventional radiologist is safe to biopsy, or o Bone lesion that is deemed suitable to biopsy by a suitably trained clinician. • Men > = 18 years. • Adequate venous access for administration of treatment and collection blood samples for exploratory biological samples. • Life expectancy of > 6 months. • Has had or is having > = 1 line of systemic treatment for CRPC, or is currently having first line systemic treatment for mCRPC. • Reasonable expectation that the patient does currently, or will within the next year, fulfil all eligibility criteria for trial treatment Inclusion Criteria for Main Study (Treatment): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Immunogenic signature positive disease within 1 year of registration to Pre-screening part of trial • Patients with disease amenable to biopsy must be willing to have a new biopsy (if new biopsy was not required for assessment of ImS). • WHO performance status of 0-1. • Adequate haematological status. • Adequate liver and renal function. • Has had 1 line of systemic treatment for CRPC. • Documented prostate cancer progression within 6 months prior to screening for the Main Study • Ongoing androgen deprivation with serum testosterone < 1.73 nmol/L.
Exclusion criteria for Assessment of ImS: • Any history of autoimmune disease, with the exception of patients with a history of autoimmune-related hyperthyroidism or hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone • Patients with prior allogeneic stem cell or solid organ transplantation • Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field is permitted). • Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity • Patients with the following risk factors for bowel perforation: o History of acute diverticulitis or intra-abdominal abcess in the last 3 years o History of GI obstruction or abdominal carcinomatosis • History of grade > = 2 peripheral neuropathy. • Prior treatment with Sipuleucel-T, immune checkpoint targeting agents or other novel immune-oncology agents • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina. • Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stable insulin regimen are eligible. • Patients with uncontrolled adrenal insufficiency. • Known active hepatitis B or C infection. • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Exclusion criteria for treatment: All exclusion criteria to exclude patients from Assessment of ImS apply • Patients with risk factors for bowel perforation. • Patients must not have had systemic corticosteroid therapy (> 10mg daily prednisone equivalent) for 14 days prior to study entry, or concomitant use of other immunosuppressive medications. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. • Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
The Primary objective is to compare two Level-1 evidence based approaches to adenocarcinoma of the oesophagus and oesophago-gastric junction. The MAGIC study included a minority of patients with oesophageal and junctional tumours and staging and QA modalities did not encompass current standards. The CROSS trial was not specific to adenocarcinoma, and compared a multimodal regimen to surgery alone.
1. Histologically-verified adenocarcinoma of the oesophagus or oesophagogastric junction based on OGD. 2. CT- 18FDG-PET in all patients and EUS, if feasible 3. Staging laparoscopy will be performed for tumours of the abdominal oesophagus, junction and proximal stomach i.e. AEG II and AEG III (at the investigator's discretion) 4. Pre-treatment stage cT2-3, N0-3, M0 5. No prior abdominal or thoracic radiotherapy 6. Male/female patients aged > 18 years 7. ECOG Performance Status 0, 1 or 2 8. ASA Grading I-II 9. Adequate cardiac function. For all patients an ejection fraction > 50% is required. If patients have a known history of significant cardiac disease (e.g. known ischaemic heart disease, cardiomyopathy) an ejection fraction > 50% and cardiac clearance by a consultant cardiologist for major surgery and cancer therapies is required. Where necessary, the Chief Investigator should be consulted to discuss the patient's eligibility. 10. Adequate respiratory function. Patients should have pulmonary function tests completed with FEV1 > 1.5L 11. Adequate bone marrow function: absolute neutrophil count (ANC) > 1.5x109/l; white blood cell count > 3x109/l; platelets > 100x109/l; haemoglobin (Hb) > 9g/dl (can be post-transfusion). 12. Adequate renal function: glomerular filtration rate > 60ml/minute calculated using the Cockcroft-Gault Formula 13. Adequate liver function: serum bilirubin < 1.5x ULN; AST < 2.5x ULN and ALP < 3x ULN (ULN as per institutional standard) 14. Written informed consent must be obtained from the patient before any study-specific procedures are performed. 15. Women of child-bearing potential and male subjects must agree to use an effective barrier method of contraception for up to 6 months following discontinuation of therapy. Effective barrier method of contraception is defined as any medically recommended (or combination of methods) as per standard of care. 16. Women of child-bearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to treatment.
1. Tumours of squamous histology. 2. Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma. 3. Any prior chemotherapy for gastrointestinal cancer. 4. Prior abdominal or thoracic radiation. 5. Patients who are unfit for surgery or cancer treatments based on cardiac disease. 6. Patients with acute systemic infections. 7. Patients who are receiving treatment with sirivudine or its chemical related analogues such as brivudine, which is contraindicated with capecitabine administration. 8. Clinical COPD with significant obstructive airways disease classified by FEV1 < 1.5 L or PaO2 less than 9kPa on room air. 9. Known peripheral neuropathy >Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible). 10. Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection. 11. Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). 12. Women who are pregnant or breastfeeding.
This study proposes to investigate a range of clinically significant co-morbidities which develop in female Hodgkin Lymphoma survivors treated in childhood and young adulthood. Hodgkin Lymphoma is one of the most common malignancies in young adults and has seen significant improvement in survival over recent decades resulting in an increasing number of long term Hodgkin Lymphoma survivors. However, the high dose chemotherapy and radiotherapy treatments used are known to be toxic to patients and can greatly increase long-term risks of side effects such as second primary cancers, cardiovascular disease, and other adverse events. Relatively little has been published about the full range of longterm treatmentrelated effects that impact on life quality and health status in Hodgkin Lymphoma patients. There is also a lack of information on the effects of more modern treatments, intended to reduce long-term toxicity, and a lack of consensus about how to tailor long-term follow-up to best diagnose and manage late-effects. This study will collect and analyse treatment and co-morbidity information on women treated for Hodgkin Lymphoma across England and Wales at ages ≤35 years during 1956-2010. We will expand an existing national cohort study of 5,000 women treated for Hodgkin Lymphoma, the largest of its kind in the world, which has undertaken research to inform the risks of developing breast cancer after Hodgkin Lymphoma treatments. The cohort would be doubled in size to include young female Hodgkin Lymphoma patients who have been treated with a much wider range of treatments and more recently diagnosed patients. We aim to improve understanding of late-effects of different types of treatment, of longer follow-up periods and to greatly expand the range of long-term effects which have been reported on. By doing so we aim to contribute to the development of risk profiles to help inform treatment choices and personalised follow-up and screening schedules for Hodgkin Lymphoma patients.
Women diagnosed with Hodgkin Lymphoma and treated before the age of 36 years. Treated for Hodgkin Lymphoma before 2010. Treated in England and Wales.
Male. Treated outside UK. Resident outside UK. Treated for Hodgkin Lymphoma (for the first time) over the age of 35 years.
The trial consists of a series of parallel multi-centre single arm Phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers. The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive design is adopted to achieve this objective. The trial is primarily an enrichment putative biomarker design, including patients who are positive for at least on of the actionable targets included in the trial. Patients who are positive for just one putative biomarker will receive the experimental targeted drug specific for that putative biomarker. Putative biomarkers within each drug cohort have been chosen such that in the majority of cases it is not expected that patients will be positive for two or more putative biomarkers within the same drug. In the rare situation that patients are positive for two or more putative biomarkers relevant across different drugs, treatment will be allocated in accordance with the following strategy: - All amplifications and rearrangements will be treated with targeted agent appropriate to them irrespective of concomitant mutations. This will yield crucial predictive biomarker information. - For concomitant mutations decisions will be made by the Chief Investigator on a case-by-case basis and based on close consideration of pathway preference and likely dominance of one signal pathway over another together with any pre-clinical efficacy studies that address the activity of the drugs in the presence of concomitant mutations.
• Patients must have completed all standard of care therapy that the treating oncologist thinks is appropriate. As a minimum patients must have failed one or more lines of treatment (either radiological documentation of disease progression or due to toxicity). • Patients who have progressed after surgical resection and adjuvant therapy will be eligible for entry without the need for the administration of first line metastatic therapy, if they have progressed within 6 months of completing their adjuvant treatment. • Patients will also be eligible without the necessity for first line regimen if they have relapsed within 6 months of completion of definitive chemoradiation. • Consented and provided an adequate specimen to adequately characterise the molecular genotype of the tumour in the molecular pre-screening according to the molecular exclusion rules (see section 6.4 for definition of an adequate sample). • Histological or cytologically confirmed NSCLC stage III (not suitable for radical radiotherapy or surgery) or stage IV. This includes patients who may have abnormal histology, but IHC strongly support either squamous cell carcinoma (p63 positivity) or adenocarcinoma (Thyroid transcription factor 1 [TTF1] positivity). If a physician and pathologist are convinced after multi-disciplinary review that the patient has stage III or IV NSCLC but where all the IHC is negative and the morphology does not distinguish a specific sub-type, these patients will be eligible for non-histology specific cohorts. • CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1 (see Appendix 1). • Adequate haematological function within 7 days of treatment. o Haemoglobin ≥ 90 g/L. o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. o Platelets ≥ 100 x 109/L. • Adequate hepatic function within 7 days of treatment in patients with no liver metastasis (see arm specific entry criteria for adequate hepatic function in patients with liver metastases). o Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN). o Alanine transferase (ALT) ≤ 2.5 x ULN. o Aspartate transferase (AST) ≤ 2.5 x ULN. • Adequate renal function within 7 days of treatment. o Creatinine clearance (CLcr) > 50 ml/min (measured or calculated by Cockcroft and Gault equation – see Appendix 4). • Age ≥ 18 years. • Females must agree to use adequate contraceptive measures (as defined in Section 6.3), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. o Women aged under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution. • Provision of signed and dated, written informed consent prior to any study specific
• Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment. • Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption. • Any psychological, familial, sociological or geographical condition hampering protocol compliance. • Concurrent malignancies or invasive cancers diagnosed within past 3 years except for adequately treated basal cell carcinoma of the skin and in situ carcinoma of the uterine cervix. • Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. • Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration (see CTCAE - Appendix 3). • Patients who have previous symptomatic brain metastases or spinal cord compression are excluded unless they have had adequate treatment, no evidence of progression or symptoms, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • Patients with asymptomatic brain metastases picked up at screening CT scan are not excluded providing that in the view of the investigator they do not require immediate radiotherapy or surgical intervention, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment. • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. • Pregnant or breast-feeding women.
The main purpose of this study is : To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction To compare mitoxantrone (anthracenedione) & cytarabine with liposomal daunorubicin (anthracycline) & cytarabine as induction therapy. To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy. To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard risk patients. To compare the toxicity and effectiveness of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.
Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation): • A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary) • Age < 18 years • No prior chemotherapy or biological therapy for AML other than that permitted in the protocol • Normal cardiac function (fractional shortening ≥28% or ejection fraction ≥55%) • Fit for protocol chemotherapy • Documented negative pregnancy test for female patients of childbearing potential • Patient agrees to use effective contraception (patients of childbearing potential) • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study: • Patients meets the inclusion criteria for trial entry • Age ≥12 months for the major dose finding study • Age ≥ 12 weeks and < 12 months for the minor dose finding study • Karnofsky or Lansky performance score of ≥50 • Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2 • Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert’s syndrome or similar disorder • ALT or AST ≤10 x ULN for age • Written informed consent from the patient or parent/legal guardian Inclusion criteria for participation in R3: • Patient meets the inclusion criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial • Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories, see national MyeChild 01 Laboratory Manual): 1) Patients with good risk cytogenetics/molecular genetics and a MRD level < 0.1% by flow after course 2, or a decrease in transcript levels of > 3 logs after course 2 for those with an informative molecular marker but without an informative marker of sufficient sensitivity for flow MRD monitoring Or 2)Patients with intermediate risk cytogenetics/molecular genetics with a MRD level < 0.1% by flow after course 1 and course 2, or a decrease in transcript levels of > 3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring • Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in R4: • Patient meets the eligibility criteria for trial entry • Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial • Patient is in CR or CRi defined as < 5% blasts confirmed by flow cytometry//molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4. • Patient meets one of the following criteria and is a candidate for haemopoeitic stem cell transplant (HSCT) as per the protocol: 1) High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi) 2) Intermediate risk cytogenetics with MRD > 0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of > 0.1% may be used 3) Good risk cytogenetics with flow MRD > 0.1% confirmed by a decrease in molecular MRD of < 3 logs or rising transcript levels after course 3 despite treatment intensification (FLAIda) and after discussion with the Clinical Coordinators Availability of a 910/10 human leukocyte antigen (HLA) matched family or unrelated donor or 58/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1 • Written informed consent from the patient or parent/legal guardian
Exclusion criteria for all randomisations • Acute promyelocytic leukaemia (APL) • Myeloid leukaemia of Down Syndrome (ML DS) • Blast crisis of chronic myeloid leukaemia • Relapsed or refractory AML • Bone marrow failure syndromes • Prior anthracycline exposure which would inhibit the delivery of study anthracyclines • Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML • Pregnant or lactating females
Children's Cancer and Leukaemia Haematological Oncology Teenage and Young Adult's Cancer
Background: Multiple myeloma (MM) is a blood cancer with approximately 4500 new cases in the UK each year. Treatment for MM has changed in the last decade with the arrival of new drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). These new drugs have been shown to improve response rate and duration of response in second-line treatment (second treatment for patients whose MM has deteriorated since their first treatment). The Myeloma X study showed that an autologous stem cell transplant (ASCT) (using the patient’s own stem cells) as part of second-line treatment prolongs progression free survival (PFS) following chemotherapy containing a proteasome inhibitor (known as re-induction therapy). Consequently, the number of second ASCTs performed in the UK has risen and is now recommended (for suitable patients) by the International Myeloma Working Group. However, the Myeloma X study showed that depth and duration of response in second-line ASCT, was less than that of first-line ASCT. Hence, this study will investigate whether depth and duration of response can be improved by the addition of a proteasome inhibitor called ixazomib to melphalan conditioning, consolidation and maintenance treatment. Aims: This trial aims to determine and compare: a) The depth of response between standard melphalan conditioning and augmented (adding ixazomib) melphalan conditioning at second ASCT. b) The impact of adding consolidation and maintenance treatment versus no further treatment, on progression free survival. Methods: This is a phase III, randomised, controlled, multi-centre, open-label trial with a single intervention registration stage and two randomisations. The first randomisation will be between augmented ASCT and standard ASCT. The primary end-point is to assess improvement in depth of response. The second randomisation will be between consolidation and maintenance treatment versus no further treatment. The primary end-point being to assess the duration of response as determined by PFS.
1.Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) previously treated with ASCT). 2.First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy. 3.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3). 4.Aged at least 18 years. 5.Participants must have the following blood results within 14 days before registration: a.Absolute neutrophil count (ANC) ≥1x109/L b.Platelet count ≥75x109/L. If the participant has ≥50% bone marrow infiltration a platelet count of ≥50x109/L is allowed. Platelet transfusions are not allowed within 3 days before registration in order to meet these values. 6.Adequate renal function within 14 days before registration: a.Creatinine clearance ≥30ml/min (calculated according to Cockcroft-Gault equation or other locally approved formula) 7.Adequate hepatobiliary function within 14 days before registration: a.Total bilirubin < 2 x upper limit of normal (ULN) b .ALT < 2 x ULN 8.Adequate pulmonary function within 14 days before registration: a.Adequate respiratory functional reserve (delineated by KCO/DLCO (carbon monoxide diffusion in the lung) of ≥50%). No evidence of a history of pulmonary disease. If a significant history, then a review by a respiratory medicine physician is required. 9.Adequate cardiac function within 12 weeks before registration: a.Left ventricular ejection fraction (LVEF) ≥40%. Note: repeat confirmation of cardiac function is needed if treatment is given between this assessment and registration. 10.Female participants who: a.Are not of childbearing potential (Appendix 8), OR b.If they are of childbearing potential (Appendix 8), agree to practice 2 effective methods of contraception (Appendix 8), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a.Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b.Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Contraception for female and male participants must be in accordance with (and consent to) the Celgene-approved Thalidomide Pregnancy Prevention Programme. 11.If female and of childbearing potential (see Appendix 8), must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Thalidomide Pregnancy Prevention Programme. 12.Patients agree not to receive other clinical trials treatment, including investigational medicinal products (IMPs) not included in this trial, within 30 days of trial registration and throughout the duration of the trial, until disease progression. 13.Able to provide written informed consent.
1.Received prior second line therapy for their relapsed disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone (up to a maximum of 200mg is allowed but not within 30 days prior to registration). Radiotherapy sufficient to alleviate or control pain of local invasion is permitted, but must not be within 14 days before registration. Patients who have received hemi-body radiation or similar since relapse will not be eligible. 2.≥Grade 2 peripheral neuropathy within 14 days before registration. 3.Known HIV or Hepatitis B/C seropositivity. 4.Known resistance, intolerance or sensitivity to any component of the planned therapies. 5.Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 6.Previous or concurrent malignancies at other sites (excluding completely resected non-melanoma skin cancer or carcinoma in situ of any type, such as cervical cancer). 7.Pregnant, lactating or breast feeding female participants. 8.Failure to have fully recovered (i.e. less than or equal to Grade 1 toxicity) from the reversible effects of prior chemotherapy. 9.Major surgery within 14 days before registration. 10.Central nervous system involvement with myeloma. 11.Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration. 12.Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 13.Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 14.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing. 15.Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.
Haematological Oncology Haematology
The new treatment being tested in this study is called Selinexor - this is a type of Selective Inhibitor of Nuclear Export (SINE) drug, which is taken orally. This will be given with cyclophosphamide and prednisolone to see if this combination is effective at treating patients with relapsed and refractory multiple myeloma (RRMM). This study is part of the Myeloma UK Clinical Trial Network portfolio of prioritised multiple myeloma clinical studies. There will be up to 60 participants who will take part in this trial from hospitals throughout the UK. The aim of this trial is to compare two different combinations of drugs used to treat multiple myeloma that has relapsed after two or more treatment lines of anti-myeloma therapy. Cyclophosphamide and prednisolone are both very commonly used in the treatment of multiple myeloma, and will often be given with a third drug (e.g. thalidomide, lenalidomide or bortezomib). However, there are currently few treatments available to patients who have not responded well (are refractory) to their previous treatment or who need further treatment because their myeloma has come back. This study is designed to compare a new combination of Selinexor, cyclophosphamide and prednisolone, with cyclophosphamide and prednisolone alone followed by SCP at disease progression.
1. Able to give informed consent and willing to follow study protocol assessments 2. Aged 18 years or over 3. Participants with confirmed myeloma based on International Myeloma Working Group (IMWG) criteria Rajkumar et al. (2014) 4. Measurable disease with at least one of the following: - Paraprotein > = 5g/L - Serum free light chains > = 100mg/L with abnormal ratio for light chain only myeloma - Bence Jones protein > = 200mg/L 5. Participants with relapsed or relapsed refractory myeloma who have received > = 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide, and now require further treatment 6. Patients for which cyclophosphamide and prednisone alone would be a suitable treatment 7. Eastern Cooperative Oncology Group (ECOG) performance status of < = 2 8. Female participants of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative urine pregnancy test at screening. Male participants must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment 9. Required laboratory values within 14 days prior to randomisation: - Platelet count > = 50x109/L. Platelet count of 30-50 is acceptable if bone marrow aspirate or trephine shows tumour replacement of > 50%. Platelet support is permitted within 14 days prior to randomisation, although platelet transfusions to help participants meet eligibility criteria are not allowed within 72 hours prior to the blood sample to confirm protocol eligibility - Absolute neutrophil count > = 1.0 x 109/L. Growth factor support is not permitted within 14 days prior to randomisation - Haemoglobin > = 90 g/L. Blood support is permitted - Alanine transaminase (ALT) and / or aspartate transaminase (AST) < = 3 x upper limit of normal - Creatinine clearance > = 30 ml/min (using Cockcroft Gault formula) - Bilirubin < = 1.5 x upper limit of normal
Participants meeting any of the following exclusion criteria are not eligible to take part in this trial: 1. The following participants will be excluded: - those with non-measurable disease - those with a solitary bone or solitary extramedullary plasmacytoma - plasma cell leukaemia 2. Participants with a history of malignancy (other than myeloma) within 5 years before the date of randomisation (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator, with concurrence with the Chief Investigator, is considered cured with minimal risk of recurrence within 5 years) 3. Participants with a known or underlying uncontrolled concurrent illness that, in the investigator’s opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study, including, but not limited to the following: - acute or chronic graft versus host disease, - uncontrolled hypertension, - symptomatic congestive heart failure, - unstable angina pectoris, - myocardial infarction within past 6 months, - uncontrolled cardiac arrhythmia, - active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis - psychiatric or social conditions that may interfere with participant compliance, - uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral - or any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study 4. Participants who have previously received Selinexor. 5. Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment. (NB: Prednisone up to a dose of 175 mg per week may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease are also permitted). 6. Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures or conditions that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s) 7. Female participants who are lactating or have a positive pregnancy test at screening 8. Known allergy or intolerance to any of the study medications, their analogues, or excipients in the various formulations of any agent 9. Major surgery within 14 days prior to randomisation 10. Radiotherapy within 7 days prior to randomisation for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation 11. Chemotherapy or immunotherapy or any other anticancer therapy within 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1 (except steroids in the doses outlined above) 12. Myeloma involving the Central Nervous System
Multiple myeloma is a disorder of plasma cells in the bone marrow. It is the second most common haematologic cancer in the EU, causing about 21,000 deaths in the EU in 2008. Approximately 20% of patients with myeloma have an extremely poor prognosis with a survival of less than 3 years and these patients are characterised as having high risk (HR) disease. There have been no significant improvements in outcome over the last decade for patients with HR disease. However recent data has demonstrated the efficacy of the combination of multiple novel agents in high risk disease. The aim of this phase II study is to assess whether future trials in this setting are feasible, and to determine risk status for participants with myeloma, in order to recruit high risk participants into MUK nine B. Participants who are found to be high risk and who are eligible will be provided with information on MUK nine B. Participants who are found not to be high risk will be treated according to NICE standard treatment (which may include other clinical trials). Patients will be followed up and data and biological samples will be centrally collected according to the schedule of MUK nine A to generate a knowledge resource about real-world treatment outcomes in newly diagnosed myeloma in the UK. The study includes approx 560 adult participants undergoing bone marrow investigation due to suspected symptomatic multiple myeloma or participants with biopsy confirmed symptomatic multiple myeloma, willing to undergo a further study bone marrow aspirate for molecular profiling. Participants will be recruited from approximately 30 approved NHS Hospitals throughout the UK.
• Undergoing bone marrow investigation due to suspected symptomatic multiple myeloma or Participants with biopsy-confirmed symptomatic multiple myeloma, willing to undergo a further study bone marrow biopsy for molecular profiling. • Aged 18 years or over • Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion) • ECOG (Eastern Cooperative Oncology Group) < = 2
Solitary bone/solitary extramedullary plasmacytoma Primary diagonosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstroms Disease Received therapy for myeloma other than local radiotherapy, therapeutic plasma exchange or dexamethasone up to a maximum of 160mg. (Radiotherapy sufficient to alleviate or control pain or local invasion is permitted). • Unfit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion) • Prior or concurrent invasive malignancies except the following: o Adequately treated basal cell or squamous cell skin cancer o Incidental finding of low grade (Gleason 3+3 or less) prostate cancer o Any cancer from which the subject has been disease free for at least 3 years. • Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including: o NYHA functional classification III or IV congestive heart failure o Uncontrolled angina, hypertension or arrhythmia o Myocardial infarction in the past 6 months • Grade 2 or greater peripheral neuropathy • Participants with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy • Unwilling to participate in a clinical trial, in principle.
Multiple myeloma is a disorder of plasma cells which accumulate in the bone marrow. It is the second most common haematologic cancer in the EU, causing about 21,000 deaths in the EU in 2008. Approximately 20% of patients with myeloma have an extremely poor survival of less than 3 years and these patients are characterised as having high risk (HR) disease. There have been no improvements in outcome over the last decade for patients with HR disease. However recent data has shown that combination of multiple novel agents is potentially better and therefore in this phase II trial we wish to evaluate whether we can improve the outcomes for high risk patients by using multiple biological agents during treatment over a number of stages. The primary objective of this trial is to look at whether a combination of four novel agents bortezomib (Velcade), lenalidomide (Revlamid) dexamethasone & Daratumumab(darzalex) with cyclophosphamide is active in a high risk patients, to take forward into a phase III trial compared to standard treatment. Approximately 560 participants with myeloma will need to be registered for screening at diagnosis in order to include 95 high risk participants in the MUK nine b:Optimum Protocol.
Target participants: • Confirmation of High Risk status from ICR following bone marrow and blood sample processed through the screening protocol. • Previously untreated participants, although participants may have received up to 2 cycles of CTD (Cyclophosphamide, thalidomide, dexamethasone), CVD (Cyclophosphamide, velcade, dexamethasone), CRD (cyclophosphamide, revlamid, dexamethasone) or VTD (velcade, thalidomide, dexamethasone) pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUK nine a Protocol.(In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted). • Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment: - Paraprotein > = 5g/L or > = 0.5 g/L for IgD subtypes. - Serum free kappa or lambda light chains > = 100 mg/L with abnormal ratio (for light chain only myeloma). - Urinary Bence Jones protein > = 200 mg/L. • Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance. • Aged 18 years or over. • Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion). • ECOG Performance Status (Eastern Cooperative Oncology Group) < = 2. • The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this: • Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe. • Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy • Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for 4 months after discontinuation from this trial • All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial. - Calculated creatinine clearance > = 30mL/min (using Cockcroft-Gault formula). - ALT and/or AST < = 2.5 times upper limit of normal (ULN). - Bilirubin < = 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin < = 2.0 times ULN - Platelet count > = 75 x 109/L. (> = 50 x 109/L if myeloma involvement in the bone marrow is > 50%). Platelet support is permitted. - Absolute neutrophil count (ANC) > = 1.0 x 109/L. Growth factor support is permitted. - Haemoglobin > = 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines. - Corrected serum calcium < = 3.5 mmol/L. Eligibility criteria for ASCT • Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight. • Received a minimum of 4, unless CR has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd - cyclophosphamide, bortezomib, lenalidomide, daratumumab, dexamethasone) cycles. • Achieved a response of SD or better. Eligibility Criteria for Consolidation Part 1 (VRDd - bortezomib, lenalidomide, daratumumab, dexamethasone) • Undergone autologous transplant with HDM-V (high dose melphalan-bortezomib) conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted. Eligibility Criteria for Consolidation Part 2 (VRD - bortezomib, lenalidomide, daratumumab) • Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted. Eligibility Criteria for Maintenance (RD - lenalidomide, daratumumab) • Received 12 cycles of Consolidation Part 2 (VRD). • Neutrophils > = 1.0 x 109/L. Growth factor support is permitted. • Platelet count > = 75 x 109/L. Platelet support is permitted.
Exclusion Criteria • Participants that have progressive disease • Solitary bone/solitary extramedullary plasmacytoma. • Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom’s Disease. Medical history and Concurrent disease: • Prior or concurrent invasive malignancies except the following: o Adequately treated basal cell or squamous cell skin cancer. o Incidental finding of low grade (Gleason 3+3 or less) prostate cancer. o Any cancer from which the subject has been disease free for at least 3 years. • Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous (e.g uncontrolled diabetes or uncontrolled coronary artery disease). o Any clinically significant cardiac disease, including: o myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV. o uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade > = 2) or clinically significant ECG (Electrocardiogram) abnormalities. o screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec. • Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second < 60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening. • Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C. • Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products. • Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone. • Previous treatment with daratumumab or any other anti-CD38 therapies. • Participants with contraindication to thromboprophylaxis. • Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0). • Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). • Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study. • Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. • Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial, 4 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial, within 4 months after the last dose of trial treatment. • Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery. • Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study.
18 and over
The aim of this prospective non-interventional registry is to establish an accepted standard of care for melanoma patients with minimal sentinel node (SN) tumour burden. Currently, if a melanoma patient has a positive (or metastatic) SN, this patient will be offered a Completion Lymph Node Dissection (CLND). This is a surgery which aims to remove all lymph nodes from the same area as the SN. However, if the positive SN is only minimally involved, some centres do not normally offer a CLND. In fact, the CLND does not increase survival for patients with a minimal SN tumour burden, but it can give doctors some information that may help them to make treatment decisions. This surgical operation may have significant side effects for the patient. In addition, only approximately 20% of patients with a positive SN have further lymph node metastases in the same area. This means that about 4 patients out of 5 will not benefit from a CLND. As a result, there is an urgent need to identify which SN positive patients could be safely spared from a CLND. Evidence shows that breast cancer patients with minimal SN tumour burden can be safely managed with observation only, and without a CLND. There is some evidence that the same situation exists in melanoma as well. The purpose of this registry is to confirm this. The results of this registry will support the aim of discovering whether melanoma patients with minimal SN tumour burden should undergo a complete lymph node dissection (CLND) or not. In addition, translational research on the tumour tissue will be carried out if participants consent to use of their tissue for such purposes. This is optional; participants will be able to refuse permission to use their tumour tissue and still participate in the main study.
♦ Histological evidence of primary cutaneous melanoma ♦ Metastases solely confined within the SN: - in the sub-capsular space (with no parenchymal infiltration) and with a maximum diameter of the largest metastasis not greater than 0.4 mm or - regardless of the site, any sub-micrometastasis with a maximum diameter not greater than 0.1 mm If there is more than 1 metastatic SN, the patient will be still eligible provided that all involved SN have minimal tumor burden, regardless of the amount of positive SNs and the basin of interest ♦ Absence of clinically apparent metastatic disease at the time of or before undergoing a SN procedure ♦ No previous SN procedure for locally recurrent melanoma or uncertain malignant disease, such as atypical Spitz tumor/naevi ♦ Age ≥18 years ♦ No history of a previous melanoma (preceding the melanoma which prompted the SN biopsy) ♦ No history of any other malignancy within the past 5 years, except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and in situ cervical cancer ♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial ♦ Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations
See Main Inclusion Criteria
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
Children's Cancer and Leukaemia
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
The aims of the study are: 1.) To provide diagnostic and follow-up bone marrow samples and complete follow-up clinical data from patients suspected to have a myeloid disorder to clinician scientists 2.) To create a population register to inform the results of laboratory studies
Patients: i) Patients with an abnormal blood count requiring investigation by blood and bone marrow sample. OR ii) Patients known to have a blood disorder who are having a bone marrow sample taken as part of the assessment of that disorder. OR iii) Patients under follow-up with an established diagnosis of MDS/CMML who do NOT require a bone marrow biopsy but can be followed clinically for registry purposes. Control subjects (Nuffield Orthopaedic Centre, Oxford only centre doing this at present. This is not expected of other collaborating centres): Patients having elective orthopaedic surgery who have a normal blood count .
Patients i) Age < 18. Controls i) Age < 18. ii) On treatment likely to impair bone marrow function iii)History of having had treatment likely to have impaired bone marrow function
Sometimes women have more than one breast cancer in the same breast at the same time. These women are usually offered a mastectomy (removal of that breast) and breast reconstruction. It may be possible to treat these patients by removing each cancer using breast-saving surgery (lumpectomies), used for women with only one breast cancer. Databases show that women who had lumpectomies did well, but they may have been healthier before the surgery than those who had a mastectomy. We need to be sure that lumpectomy is effective, safe, and acceptable for this patient group before making it universally available. We will run a small study to evaluate whether a sufficient number of eligible patients can be identified and are willing to accept randomisation of the interventions in question. Recruitment and compliance rates of which will inform the feasibility and design of a larger trial. This will comprise a multi-centre randomised controlled trial in women with Multiple Ipsilateral Breast cancer (MIBC) requiring surgery. Participants will receive either Therapeutic Mammoplasty (TM) following excision of each cancer focus or mastectomy (+/- reconstruction). Patients will be randomised (1:1) into either intervention or control group. Therapeutic mammoplasty is an operation to remove breast cancer(s) whilst also significantly reducing the size of the breast. Therapeutic mammoplasty can be used to remove more than one cancer in the breast using separate lumpectomies. Both skin and breast tissue are removed, leaving scars similar to those seen after a standard breast reduction. Each patient is followed up for 12 months post treatment with a total of 50 patients recruited. Timings of the follow-up visits are aligned with standard of care practice for this patient population with quality of life questionnaires and clinical photographs completed before and after surgery. Twenty women will also be invited to an optional semi-structured interview at twelve months.
1. > 40 years with MIBC, with the largest clinical cancer measuring 30mm as part of multifocal or multicentric “disease sites”. 30mm may include the size of a single cancer and its surrounding small satellite cancers. Clinically diagnosed (ultrasound and biopsy) either axillary lymph node negative or positive where axillary treatment depends on local policy. 2. Minimum of two invasive foci of breast cancer as defined within a “disease site”. 3. Suitable for TM (best practice) using one large lumpectomy (multifocal) or any number of “distant” lumpectomies (multicentric) to excise “disease sites”. 4. Fit for adjuvant therapy as per pre-operative evaluations (ECG, Chest X-ray, blood biochemistry). 5. Willing and able to provide written informed consent
1. Neo-adjuvant therapy 2. Women considered high risk by local centre or known to have BRCA1/2 gene mutation 3. Ductal Carcinoma in situ (DCIS) only, and extensive DCIS 4. Bilateral breast cancers 5. Previous breast cancer (invasive or DCIS in either breast) 6. Pregnancy as confirmed on blood tests or ultrasound examination. 7. Metastatic disease. 8. Any previous type of breast radiotherapy 9. Significant other clinical risk factors and co-morbidities at the discretion of the treating clinicians. 10. Previous or concomitant malignancy except adequately treated: non-melanomatous skin cancer; in situ carcinoma of the cervix and in situ melanoma
Breast Cancer Breast Surgery
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
Mantle Cell Lymphoma (MCL) is a type of non-Hodgkin's lymphoma; a cancer of the lymphocytes (white blood cells) that occurs when the growth of these cells is out of control. MCL is a relatively rare, usually aggressive cancer for which there is currently no known cure. Many patients are treated as soon as they are diagnosed because they generally have a poor prognosis. However, our experience tells us that there is a sub-set of patients that have a less aggressive form of the disease. They can remain asymptomatic, sometimes for years. These patients need not be treated with systemic chemotherapy straight away and ‘watching and waiting’ does not affect the outcome at all. There are currently no tests that can tell us which patients have indolent behaving disease at diagnosis. Knowing this will be really helpful in finding the best way to treat people with this disease in the future. The only way that we can really be sure which type of MCL a patient has, is to observe what happens to them over the next few years. We will collect baseline blood and saliva samples, diagnostic biopsy material and clinical information from patients who are newly diagnosed with MCL. These samples will be stored in a Biobank. After this, patients will not directly be involved as the information we need to collect can be found in the medical notes. We aim to recruit 300 participants over 3 years. Once the study is completed, we will know which patients have indolent MCL and which patients have aggressive MCL. We will then study the stored samples to try to identify and understand the differences between indolent and aggressive forms of MCL.
aged 16 and over newly diagnosed mantle cell lymphoma able to give consent
Received systemic treatment for mantle cell lymphoma (localised radiotherapy is acceptable)
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
This study is being set up in order to permit prospective molecular typing of samples of non Hodgkin lymphoma from surplus material obtained at routine biopsies. It is intended to facilitate identification of patients for whom molecular targeted therapies may be available. The results of molecular typing will be returned to the clinical team caring for the patient, in order to make them aware of specific abnormalities which would make specific targeted therapy an option within a clinical trial.
A diagnosis of diffuse large B-cell lymphoma or follicular lymphoma in an adult patient.
Drugs that stimulate the immune system to attack tumours are revolutionising treatment for some cancers. Results in oesophageal cancer have not been as exciting as in lung or skin cancer, so the drugs have not replaced existing treatments like chemotherapy and radiotherapy. We don't yet know if giving them with the usual treatments will help. The trial will give a first look at the potential to add durvalumab, a new drug that activates the immune system, to current standard treatments for oesophageal cancer. First we will check that durvalumab can be given safely with chemotherapy in patients with oesophageal cancer that has spread. If this is safe we will then test durvalumab with chemotherapy or chemoradiotherapy given before surgery to patients with potentially curable disease. Depending on how the first part of the trial goes we may also check if we can add a second immunotherapy drug, called tremelimumab, to chemotherapy for inoperable oesophageal cancer. As well as looking at how safe and effective this is we will study the effect of treatment on patients' tumours. The study will run in 2 academic centres in the UK, and is sponsored by the Ludwig Institute for Cancer Research, supported by the University of Oxford. Astrazeneca is providing the durvalumab and tremelimumab for the trial. Patients being treated in the trial will have the usual treatment, lasting 2 to 6 months, but with the new drug(s) added. Durvalumab may also be given after the usual treatment has finished, for up to 6 months.
1. Histological diagnosis of oesophageal or gastrooesophageal cancer - Cohorts A and B - metastatic/locally advanced cancer - Cohorts C and D - deemed suitable for surgery with curative intent 2. Recovered from prior therapy (Grade 1 persistent AEs acceptable) 3. Anticipated lifespan greater than 4 months 4. ECOG performance status of 0 or 1 5. At the time of day 1 of the study, subjects with brain metastases must be asymptomatic and show evidence that their CNS disease is not progressing 6. Adequate normal organ and marrow function as defined in detail in the protocol 7. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 8. Age ≥18 years 9. Have been informed of other treatment options 10. Willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits, examinations, biopsies and follow up
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study. 2. Participation in another clinical study with an investigational product during the last 6 weeks 3. Prior or concurrent systemic anti-cancer therapy 4. Mean QT interval corrected for heart rate (QTc) ≥470 ms 5. Current or prior use of immunosuppressive medication within 28 days 6. Active or prior documented autoimmune disease within the past 2 years 7. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 8. History of allogeneic organ transplant 9. Uncontrolled intercurrent illness 10. Known history of previous clinical diagnosis of tuberculosis 11. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab 12. Prior exposure to tremelimumab / durvalumab or checkpoint inhibitors 13. History of severe allergic reactions to any unknown allergens or any components of the study drugs. 14. Known dihydropyrimidine dehydrogenase (DPD) deficiency 15. Treatment with sorivudine or its chemically related analogues, such as brivudine 16. Peripheral sensitive neuropathy with functional impairment prior to first course 17. History of sarcoidosis syndrome. 18. Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may be available. 19. Known immunodeficiency or active HIV. 20. History of pneumonitis or interstitial lung disease. 21. Major surgical procedure (as defined by the investigator) within 30 days prior to Day 1 or still recovering from prior surgery. 22. Women who are breast feeding or pregnant 23. Any condition that, in the clinical judgment of the treating physician, is likely to interfere with evaluation of study treatment, interpretation of subject safety or study results, prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk. 24. Subjects should not donate blood while participating in this study
LI (less intensive)-1 will evaluate several relevent therapeutic questions in Acute Myeloid Leukemia (AML) as defined by the WHO and High-Risk Myelodysplastic Syndrome. The trial is primarily designed for patients ver 60 years for whom conventional chemotherapy is not considered suitable. The trial is part of a continuous program of developement aimed at improving the outcomes of treatment in this patient population.
1. One of the forms of AML (except APL) 2. Over 60 years of age (usually) 3. Informed consent taken. 4. AC220 intervention only, additional cardiac criteria must be met and electrolyte levels corrected pre-treatment.
1. Less than 60 years of age (usually). 2. Previously received cytotoxic chemo for AML treatment. 3. In blast transformation of CML. 4. Concurrent active malignncy under treatment. 5. Pregnant or lactating. 6. APL. 7. Known HIV positive. 8. Bilirubin ≥ 1.5xULN, unless with Gilbert's syndrome. 9. AST ≥ 2.5 x ULN 10. Alk phos ≥ 2.5 x ULN 11. Serum creatinine ≥ 2.0mg/dL 12. History of MI, unstable angina CVA/ITA within 6 months 13. AC220-only cardiac exclusions.
The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year feasibility phase, in women confirmed by Central Histopathology Review to have low risk DCIS. Comprehensive site training will be complimented by a patient friendly DVD designed to ensure consistent and appropriate use of terminology. Patients will be randomised between standard surgery and active monitoring with annual mammography. Follow-up will be for a minimum of 10 years.
1) Female, aged ≥ 46 years 2) Screendetected or incidental microcalcification (unilateral or bilateral) 3) Histologically confirmed diagnosis of non-high grade DCIS confirmed by local pathologist on either small volume core biopsy and/or Vacuum Assisted Core Biopsy (VACB) or on open diagnostic surgical biopsy (without clear margins) 4) DCIS diagnosed ≤90 days before registration 5) Able to give informed consent and comply with the trial schedule and completion of Patient Reported Outcome questionnaires 6) Patient fit to undergo surgery 7) Written informed consent obtained
1) Previous or current diagnosis of invasive cancer or ipsilateral DCIS (previous surgically treated contralateral DCIS is permitted) 2) A mass lesion clinically on mammogram or on ultrasound scan (if performed) at the site of the microcalcification before biopsy 3) Any serious and/or unstable preexisting medical, psychiatric, or other condition that would prevent compliance with the trial or consent process 4) Recent onset ipsilateral bloodstained nipple discharge, unless cytology and/or Ultrasound Scan (USS) confirmed concomitant duct ectasia 5) High risk group for developing breast cancer (as defined in current NICE guidelines for familial breast cancer, or due to prior exposure to mantle field radiotherapy)
Breast Cancer Breast Surgery
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).
Children's Cancer and Leukaemia Haematological Oncology Haematology Teenage and Young Adult's Cancer
Total thryroidectomy(surgery to remove the thyroid gland) followed by Radioactive Iodine Ablation is the standard treatment for patients presenting with intermediate or high risk well differentiated thyroid cancer. Radioiodine (RAI) is mainly used to eliminate any residual normal thyroid tissue. In a subgroup of patients characterised as having low risk of recurrence there is debate as to whether ablation represents overtreatment. RAI causes many side effects including increased risk of a second primary cancer. IoN will answer the question of whether RAI is necessary for low risk differentiated thyroid cancer patients who already have been offered the other two important modalities of treatment i.e. Total Thyroidectomy and optimal TSH (Thyroid Stimulating Hormone) suppression. Patients who have undergone a total thyroidectomy will be randomised (allocated randomly) into one of two groups by a computer program. One group will receive ablation at an activity of 1.1 GBq (Giga Becquerels), the other will not receive ablation. There will be an equal number of patients in both groups. The study is being funded by Cancer Research UK and has a phase II component to assess whether recruitment is feasible before moving to a phase III study. 570 patients will be recruited for the study.
• R0 total thyroidectomy (Rx at the discretion of the MDT) completed within 6 months prior to randomisation (for 2 stage TTs, only the second stage must have been carried out within the 6 month time frame) • Negative pregnancy test in women of child bearing potential • Aged 16 or over • WHO performance status 0 – 2, self-caring • Histological confirmation of differentiated thyroid carcinoma (MDT decision for inclusion based on overall clinic-pathological assessment): • Papillary thyroid cancer o Non aggressive histological features (small foci of aggressive histology allowed at the discretion of the MDT) o pT1a(m): all individual foci ≤1cm o pT1b and pT1b(m): > 1-2cm o pT2 and pT2(m): > 2-4cm o pT3 and pT3(m): > 4cm o pT3 R0: any size with minimal extrathyroidal extension recommended by the MDT o pN0 o pN1a o pNX • Follicular thyroid cancer/Hürthle cell cancer, minimally invasive with capsular invasion only (or up to four foci of possible invasion of intra-capsular vessels at the discretion of the MDT) o pT1b: > 1-4cm intrathyroidal o pT3 R0: up to 4cm only with minimal extrathyroidal extension recommended by the MDT • Histological material available for Central Review (see section 8.6) • Willing to use contraception for the duration of the trial until 6 months post radioiodine treatment (for females) or 4 months post treatment (for males) (see section 5.5.3), if allocated to the ablation group. NB: Multifocal tumours (≥2 foci) of all histological types should be designated with “(m)”, and the size of the largest focus determines the classification (as described in the TNM 7th edition). For example, if there are two foci, one 0.8cm and the other 3cm, the classification is based on the 3cm focus; i.e. pT2(m).
• pT1a - Papillary and Follicular carcinoma which is unifocal and ≤1cm in size • < 4cm Encapsulated Follicular Variant of Papillary Thyroid Cancer (EFVPTC) with no capsular invasion • Anaplastic or medullary carcinoma • R1 or R2 thyroidectomy • Patients with: o pN1b o M1 • Aggressive Papillary thyroid cancer with any of the following features: o Widely invasive o Poorly differentiated o Anaplastic o Tall cell o Columnar cell o Diffuse sclerosing variants • Follicular thyroid cancer/Hürthle cell cancer with any of the following features: o Anaplastic o Widely invasive o Poorly differentiated o Tumours greater than 4cm • Incomplete resection or lobectomy • pT4 or macroscopic and microscopic tumour invasion of loco-regional tissues or structures • Pregnant women or women who are breast feeding • Patients who have had CT performed with iv contrast less than 2 months before ablation • Previous treatment for thyroid cancer (except surgery) • Previous malignancies with limited life expectancy or likely to interfere with the patient’s ability to be able to comply with treatment and/or follow-up for at least 5 years • The following GI conditions: dysphagia, oesophageal stricture, active gastritis, gastric erosions, peptic ulcer, suspected reduced gastrointestinal motility • MDT decision against ablation or suitability for trial in light of severe co-morbid condition/s including: o Unstable angina o Recent myocardial infarction or cerebrovascular accident (CVA) o Severe labile hypertension o Any patient who cannot comply with radiation protection including: patients with learning difficulties patients with dementia patients with a tracheostomy that require nursing care patients requiring frequent nursing/ medical supervision
Head and Neck Cancer
Pancreatic Cancer (PC) is the 11th most common cancer in the UK with approximately 7,600 new cases annually. Due to it's aggressive nature PC has one of the worse prognoses of any cancer with a 5-year survival rate of only 3%, and a median survival of less than 6 months. PC is characterised by aggressive local tumour growth, early metastasis, a limited response to chemo- and radiotherapy, and an intense fibrotic reaction resulting in a very poor prognosis. Despite advances in the understanding of underlying mechanisms in PC little progress has been made in the prevention, early diagnosis and clinical treatment of patients with PC. To significantly improve the outcome from this devastating disease it is imperative that we gain a better understanding of the molecular and cellular mechanisms involved in order to propel the way for more effective treatments. The aim of this study is to increase the understanding of the mechanisms promoting the development and progression of pancreatic cancer. The areas where the research will be principally concentrated are: 1. Investigating the mechanism(s) regulating tumour cell invasion 2. Investigating the interplay between tumour cells and supporting, non malignant cells of the tumour stroma (fibroblasts, endothelial cells and inflammatory cells) 3. Identification of biological mechanisms and markers that are predictive of malignant transformation and aggressive malignant disease, which may represent novel therapeutic targets.
1. All patients undergoing surgical resection of the pancreas 2. A pre-treatment EUS biopsy may also be collected if patients undergo this procedure
Children (age less than 16). The reason to exclude children is that pancreatic cancer is extremely rare in this age group
The objective of the study is to carry out international field testing of the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Anal Cancer Health-related Quality of Life (HRQoL) Questionnaire Module (the EORTC QLQ-ANL27). The questionnaire was designed to include all relevant and important HRQoL issues specific to patients with anal cancer treated with chemoradiotherapy (CRT). The questionnaire was developed according to EORTC Module development guidelines over three phases: Phase 1 involved the generation of HRQoL issues relevant to patients undergoing CRT for primary or recurrent (locoregional) anal cancer. Issues were identified from a literature review and interviews with patients and health care professionals. In Phase 2 these issues formed questions which were then pilot tested and reviewed in Phase 3 by a separate group of anal cancer patients. The final version of the questionnaire, the EORTC QLQ-ANL27 is designed to supplement the EORTC QLQ (core questionnaire applicable to patients across cancer types). The EORTC QLQ-ANL27 now requires testing with a larger number of patients across different cultures in order to determine its measurement properties and acceptability and this is the focus of the current study. Patients with anal cancer who have not previously been involved in Phases 1-3 will be interviewed and asked to complete the questionnaire alongside the EORTC QLQ-C30. They will then complete a de-briefing questionnaire asking them to share their thoughts on the questionnaire in terms of whether anything is missing from the questionnaires and whether any of the questions were confusing, difficult to answer, or upsetting. In the debriefing interview, patients will also be asked how long it took to complete the QLQ-ANL27 and whether they needed any help completing it. Some participants will be asked to complete the questionnaire on two occasions to check for consistency or changes in responses.
Participants will be recruited if they are aged 16 years or above with a confirmed diagnosis of primary or recurrent (locoregional) anal cancer. Participants must be aware of their diagnosis and have been or currently treated with chemoradiotherapy. Only participants able and willing to give informed consent will be included. Participants will be included if they have not previously been involved in earlier phases (1 and 3) of the study.
Participants will not be invited to take part if they have a diagnosis of rectal adenocarcinoma and if they have not been treated with both chemotherapy and radiotherapy. Participants who have already been involved in this study and who do not have an adequate understanding of English in order to complete the questionnaires will not be eligible to be involved.
To investigate in a randomised trial whether additional short-course chemotherapy given on a weekly schedule immediately before standard chemoradiation leads to an improvement in overall survival in patients with locally advanced cervical cancer.
A patient with all the following characteristics may be included in the study: • Histologically confirmed FIGO stage Ib2-IVa squamous, adeno or adenosquamous carcinoma of the cervix (except FIGO IIIA). Patients with histologically confirmed FIGO stage IB1 and positive lymph nodes are also eligible. • Deemed suitable and fit for radical chemoradiation • Medically fit to receive carboplatin and paclitaxel • ECOG performance status 0 – 1 see Appendix II • No evidence of active TB • Aged 18 and over • Adequate renal function, defined as a GFR ≥ 60 ml/min calculated using the Wright equation (or ≥ 50 ml/min for radioisotope GFR assessment) • Adequate liver function, as defined by ALT or AST < 2.5 ULN and bilirubin < 1.25 ULN • Adequate bone marrow function as defined by ANC ≥1.5 x 109/L, platelets ≥ 100 x 109/L • Using adequate contraception precautions if relevant • A documented negative HIV test (patients recruited from high risk countries or who have moved within the past 10 years from high risk countries) • A documented negative pregnancy test (if applicable) • Capable of providing written or witnessed informed consent Patients with positive nodes (either histologically/PET positive ≥15 mm on CT/MRI) at or below the level of the aortic bifurcation may be included in the study provided none of the exclusion criteria apply.
A patient with any of the following characteristics is excluded from the study: • Previous pelvic malignancy (regardless of interval since diagnosis) • Previous malignancy not affecting the pelvis (except basal cell carcinoma of the skin) where disease free interval is less than 10 years • Positive lymph nodes (imaging or histological) above the aortic bifurcation* • Hydronephrosis which has not undergone ureteric stenting or nephrostomy except where the affected kidney is non-functioning • Evidence of distant metastasis i.e. any non-nodal metastasis beyond the pelvis • Previous pelvic radiotherapy • Prior diagnosis of Crohn’s disease or Ulcerative colitis • Uncontrolled cardiac disease (defined as cardiac function which would preclude hydration during cisplatin administration and any contraindication to paclitaxel) • Pregnant or lactating * i.e. PET any size, CT/MRI ≥ 15mm
Gynaecological Cancers Radiotherapy
This study aims to understand how high quality care can be provided for people with dementia undergoing outpatient cancer treatment (radiotherapy, chemotherapy or other anti-cancer treatment). The study uses ethnography, where a researcher conducts fieldwork to better understand a group of people. Fieldwork will take place over 12 months in the outpatient departments of University Hospital Southampton NHS Foundation Trust. It will include observations, interviews and review of patient notes. The people who will be invited to take part are: - People with dementia having cancer treatment; - Friends or family supporting people with dementia having cancer treatment; - Staff involved in the care of people with dementia having cancer treatment. All those who take part in the study will be asked to give consent. The study includes: - Observation. Up to 30 hours of observation will take place in the general clinic areas as well as during doctor appointments and when treatment is being given. The researcher will take detailed notes. - Interviews. Up to 40 interviews will be carried out with patients, carers and staff. Interviews will be digitally recorded. - Patient notes. Researchers will look at patient notes to add to information from observation and interviews. They will look at the notes to find out about diagnosis, treatment and support offered to patients. These methods will help the researchers form a picture of the outpatient setting including how people act (behaviour), the surroundings and conditions (environment), and the way treatment and support is organised (processes). This will show how healthcare organisations might best provide cancer treatment for people with dementia that is person-centred (focused on the needs of the person) and of a high quality.
Patient participants: - Adult, aged over 18; - Confirmed diagnosis of any cancer; - Undergoing or due to undergo cancer treatment (radiotherapy, or chemotherapy or other SACT delivered via any route e.g. oral, intravenous, subcutaneous, intrathecal) OR have finished these treatments within the last 6 months; - Treatment administered in ambulatory care setting: hospital treatment centre, outreach clinic or home environment; - Diagnosis of dementia of any type (Alzheimer’s, Lewy body, vascular, fronto-temporal), documented in patient case notes; - Capacity to decide to take part in the study; OR after capacity assessed, enhancements made, consultations carried out, decision made to include participant (following British Psychological Society Practical Guide, Dobson 2008) Non-patient participants: - Adult, aged over 18; - Informal carer of patient participant (relative/spouse/friend/neighbour); OR healthcare professional/ NHS staff involved in care & management of patient participant or other patients with dementia having cancer treatment.
Patient participants: - Acute or critical illness; - Inability to communicate choices and preferences either verbally or non-verbally; - No confirmed diagnosis of dementia; - Cognitive impairment as a result of aetiology not related to dementia, such as brain injury, delirium, learning disability or brain metastases.
Psychosocial Oncology and Survivorship Supportive and Palliative Care
Metastatic melanoma has a very poor prognosis: median overall survival is 8 months untreated and around 2 years even with optimal systemic therapies. A gene called BRAF is abnormal in about half of melanomas and biological agents targeting the BRAF pathway have been shown to extend life. They are now routinely available in NHS clinical practice. Giving BRAF and MEK inhibitor drugs together offers the best anti-cancer treatment for these patients. However, treatment is limited by side-effects (often affecting the skin) and secondary resistance (which means the cancer regrows usually after about a year). Laboratory experiments and case reports suggest intermittent dosing of these chronic orally administered drugs makes BRAF pathway inhibitors work for longer, extending life and reducing side effects. In the INTERIM trial, we will test whether less treatment than usual is acceptable to patients and doctors and, potentially, more beneficial. We also aim to develop better tools to monitor skin side-effects. We will recruit 150 patients with advanced BRAF mutant melanoma. All patients will receive BRAF+MEK inhibitor treatment with standard dabrafenib+tremetinib, either taken continuously every day, or with planned treatment breaks in each 28 day cycle. Comparing these 2 groups will determine if it is feasible to recruit patients and deliver intermittent therapy, any impact on patient quality of life, and an initial estimate of how long the drugs work.
• Signed informed consent • Age > = 18 years old • Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable or metastatic melanoma • Measurable disease by RECIST • ECOG performance status 0-2 • Minimum life expectancy 12 weeks • Adequate bone marrow, renal and liver function • Received no prior BRAF or MEK inhibitor therapy for metastatic disease • Willing and able to comply with the scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other study procedures • Archival tumour tissue sample available • Women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout treatment
• Concomitant immunotherapy being administered to treat advanced melanoma • Other invasive malignancies diagnosed within the last year which are not in complete remission, or for which additional therapy is required • Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial • Women who are pregnant, plan to become pregnant or are lactating during the trial period • Other investigational anti-cancer drugs • Use of strong inducers and inhibitors of CYP3A or CYP2C8
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).
Children's Cancer and Leukaemia
Male carrier of a known pathogenic BRCA1 or BRCA2 mutation OR MSH2, MSH6, MLH1 mutation Male who has tested negative for a known pathogenic BRCA1, BRCA2, MSH2, MSH6 or MLH1 mutation present within their family Age 40-69 years WHO performance status 0-2 No previous history of prostate cancer Informed written consent must be sought according to ICH/EU GCP, and national/local regulations before subject registration.
Previous cancer with a terminal prognosis of less than five years. Previous prostate cancer
Genetics Prostate Cancer Surgical Urology
Every year more than 40.000 people in the UK are diagnosed with colorectal cancer, of which about two thirds are localised in the colon. Survival and local recurrence rates are improving at a great rate for rectal cancer but much less so for colon cancers. More than half of colon cancers arise in the left side of the colon and the greatest proportion in the pelvis (sigmoid colon). If patients with a high risk of poor outcome and local recurrence can be identified preoperatively, they can be treated with neoadjuvant treatment to improve their outcome. In rectal cancer this has already been succesfully applied using MRI and has lead to a reduction of pelvic recurrence from 40% to 5-10% (MERCURY Trial). To identify high risk patients, accurate preoperative imaging is needed. We propose that if MRI rather than CT (the current standard of care) is used for staging sigmoid cancer in the same way that has been used for rectal cancer, we will be able to select more patients that would benefit from dedicated surgical road mapping and treatment before surgery. The IMPRESS Trial is a randomized clinical trial that will compare the standard of care for colon cancer (preoperative CT followed by treatment discussion by Multidisciplinary Team) with an interventional arm (combination of preoperative CT and MRI followed by routine treatment discussion by MDT).
- 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
Colorectal Cancer Other
In recent years, many diseases have been found to be affected by how the immune system works and in particular cancer. There are now new treatments, which target the relevant biological mechanisms; these can be used on their own or together with existing treatments. Promising results have been seen in patients with several different types of malignancies and several drugs are now approved for use in clinic with many more in clinical trials. So far only a relatively small proportion of patients with cancer benefit from immunotherapy; the risk of significant toxicity is real and to-date unpredictable for each individual. This is because we still do not fully understand how immunotherapy works and how to choose the right treatment for the right person. The purpose of this project is to improve our knowledge of how the immune system functions in people with malignancies; we would also like to work out what effect any treatments they may receive has on the way their immune system fights cancer. We plan to do this by collecting tissue and blood samples from patients before and after they receive anti-cancer treatment and conducting in depth comprehensive analysis of the immune response – at the genetic, functional and morphologic levels – and cross-reference with clinical outcome data. The ultimate aim is to predict which patients are most likely to benefit from particular drugs and least likely to experience side-effects; further more we would use the information gained to guide us choose which new immunotherapy drugs are worth combining with existing treatments to investigate in future larger scale clinical trials or use in personalised medicine approaches.
1. Suspected or confirmed diagnosis of a solid malignancy 2. Aged 18 or over. 3. Ability to understand the study requirements and provide written informed consent. 4. Either of: a. Scheduled to undergo diagnostic procedure – surgical/endoscopical or image guided biopsy b. Scheduled to have elective curative or palliative resection of primary tumour or metastatic deposit c. Patient with a histologically proven diagnosis willing to undergo additional research procedures necessary to acquire fresh tumour samples and/or provide excess material from previously obtained biopsies. 5. Willing to provide additional blood samples.
1. Underlying medical conditions that in the opinion of the investigator would pose a contraindication to procedures necessary for tissue sampling. 2. Confirmation of non-cancer diagnosis. 3. Withdrawal of consent
Supportive and Palliative Care
Primary mediastinal Large B-cell lymphoma (PMBL), accounts for less than 5% of non-Hodgkin’s lymphoma's (NHL) occurring predominantly in females with a median age at presentation in the third or fourth decades. It is estimated that of the 12,000 newly diagnosed NHL cases per annum, 500 will be PMBL. Current practice is to give intensive chemotherapy sometimes with the addition of mediastinal radiotherapy (RT). Uncertainty exists however, as to whether consolidation radiotherapy following immunochemotherapy is necessary and given the late effects of such treatment whether PET scanning can be used to discriminate between patients who require radiation from those who do not. Functional imaging with PET scanning has been shown to distinguish between residual masses which contain active lymphoma and those where the lymphoma has been eliminated. Although used to determine treatment options in many other lymphomas, whether it can be used similarly in PMBL has yet to be determined. This trial aims to answer this question by recruiting 752 newly diagnosed patients with PMBL who are due to receive a standard chemotherapy regimen which contains rituximab. Patients will be recruited from 21 countries internationally (including 14 sites in the UK). Patients will receive an initial PET/CT scan before they commence their chemotherapy. Following chemotherapy they will receive a further PET/CT scan. Patients whose PET scans are negative will be randomised to receive either consolidation radiotherapy or observation. Patients with a positive PET or who achieve a partial response will not be randomised but referred back to their clinician for further treatment. The primary endpoint is progression free survival at two years. Randomised patients will be followed up for 10 years to assess overall survival and safety. Those not randomised will be followed up to ascertain their response to the treatment given by the investigator, disease progression and overall survival.
Previously untreated primary mediastinal diffuse large Bcell lymphoma, CD20 positive. Patients must have histological confirmation of the diagnosis (it is recommended that the immunohistochemical panel includes: CD45, CD20, CD30, CD15, CD10, BCL6, BCL2, MUM1), and in addition have a dominant mass within the anterior mediastinum. No evidence of extranodal disease outside the chest including spleen and bone marrow Age at least 18 years. Fit to receive chemotherapy and radiotherapy with curative intent. Patients will be eligible if the treatment phase consisting in a Rituximab combined with any anthracycline-containing chemotherapy regimen without consolidation with autologous stem cell support (e.g., 6 cycles of CHOP14-21, DA-EPOCH, Mega-CHOP or 12 weeks of VACOP-B or MACOP-B). At least 6 courses of Rituximab should be administered Able and willing to give informed consent, and to undergo staging including PET scanning Willingness to comply with an appropriate contraceptive method in women of childbearing potential or men. Histological diagnostic material available for review.
History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of the cervix within the last 5 years. Evidence of clinically significant cardiac disease at diagnosis, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry. Cardiac impairment due to local extension of lymphoma will not be an exclusion criterion in the absence of other cardiac disease. Known HIV-positive serology. Pregnant or lactating women. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Neuroblastoma is the commonest solid tumour of childhood. The majority of cases are high risk disease, and the survival of these patients is only around 30% at five years. Radiotherapy to the primary tumour site is standard practice. It improves local control and may improve survival. However the radiation tolerance of adjacent critical normal structures can limit the dose of radiotherapy that can be delivered. A recently developed way of delivering radiotherapy - Intensity Modulated Arc Radiotherapy (IMAT) offers a potential way to overcome some of the limitations through much better shaping of the volume treated to a high dose, and better avoidance of organs at risk (OAR) of damage This study aims to see if, and to what extent, dose escalation is safely possible in children with abdominal neuroblastoma using both IMAT and conventional radiotherapy techniques. This is an unblinded, multicentre randomised UK trial. 50 patients, aged 18 months or older at diagnosis with high risk abdominal neuroblastoma who require radical radiotherapy will be randomised to receive either the 'intended' standard dose (21Gy) or an 'intended' experimental dose (36Gy). Pre-treatment dosimetry will use established normal tissue constraints to ensure that over-treatment of OAR does not occur and that they are not damaged. This may mean that in some patients the full 36Gy dose is not given, and a lower *actual* dose is therefore the compromise outcome. Radiotherapy plans will be prepared for each patient using both conventional and IMAT techniques and the plan judged to have the best balance between target volume coverage to the randomised dose allocation, and sparing of OAR will be chosen for delivery. Having defined an increased dose which can safely be delivered to the majority (80%) of patients, a randomised phase III trial powered to detect superiority of the increased dose over the standard will be planned.
• Any patient with high-risk neuroblastoma of the abdominal or pelvic regions who requires radical radiotherapy • Fit to receive radical radiotherapy • Aged > = 18 months at diagnosis • Informed consent from patient, parent or guardian • Documented negative pregnancy test for female patients of child bearing potential. • Patient agrees to use effective contraception during treatment period (patients of child bearing age).
• Pregnant patient
Children's Cancer and Leukaemia
Ovarian carcinoma is the fifth commonest cause of cancer death in women in the UK. Platinum-based chemotherapy remains the cornerstone of treatment. Despite advances in treatment, about 80% of women with advanced ovarian cancer have a recurrence that is ultimately fatal. Patients who relapse > 6 months after completing first-line platinum-based chemotherapy are retreated with further platinum-based chemotherapy regimens. The median survival after first relapse is about 40 months. Two novel biological agents, cediranib targeting blood vessel growth, and olaparib targeting DNA repair processes, have individually led to an improvements in ovarian cancer control. A combination of these drugs has also demonstrated greater activity than either of them alone. The aim of the ICON9 trial is to improve progression free and overall survival by adding maintenance therapy (treatment used to slow the growth or return of cancer after initial treatment) with cediranib and olaparib in patients who have relapsed > 6 months after completing platinum-based chemotherapy. We also seek to determine the effects of treatment on the quality of life, and to find cancer markers which may help identify which treatments patients are most likely to benefit from. Patients who have responded to a minimum of 4 cycles of platinum based chemotherapy will be randomised for maintenance treatment with either olaparib and cediranib or olaparib alone. The maintenance regimen may be continued even if the disease has worsened, as indicated by CT scan, if the clinician believes the patient is still deriving benefit. Trial treatment must be discontinued if further cancer treatment is started. ICON9 will be undertaken internationally in approximately 70 sites. The target accrual is 618 patients. The trial is funded by Cancer Research UK and AstraZeneca. It is sponsored by University College London and coordinated by the CR UK & UCL Cancer Trials Centre.
1. Histologically proven diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with second-line platinum-based chemotherapy. Patients may be included post-surgery for relapsed disease if undertaken more than 6 months after progression from first-line therapy. 2. Patients must have had CT or MRI proven relapsed disease (measureable by RECIST 1.1 or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse. 3. Patients showing response to chemotherapy mid-treatment (post 3 or 4 cycles), either by GCIG CA125 criteria or ‘partial response’ on CT/MRI scan, or no evidence of progression having undergone surgical debulking, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/or somatic). 4. Completed a minimum of 4 cycles (and maximum of 6 cycles) of platinum-based chemotherapy for first relapse (2nd line treatment) with at least a partial response on imaging (CT or MRI) by RECIST 1.1 if measureable disease, or CA125 response by GCIG criteria if non-measurable disease. No CT/MRI or CA125 evidence of progression after surgical debulking and chemotherapy (above). 5. Prior front-line maintenance therapy with bevacizumab is permitted. 6. ECOG performance status 0-1. 7. Adequate bone marrow function, liver and renal function. 8. Availability of archival diagnostic tumour sample or tumour samples at relapse if patient has undergone further biopsy or surgical debulking. 9. Adequately controlled blood pressure (systolic blood pressure [SBP] < = 140 mmHg; diastolic blood pressure [DBP] < = 90mmHg) on maximum of 3 antihypertensive medications.
1. Non-epithelial ovarian cancer, carcinosarcoma and mucinous carcinomas, ovarian clear-cell carcinoma. 2. Cerebrovascular accident (including transient ischemic attacks) within last 12 months. 3. Gastrointestinal impairment that could affect ability to take, or absorb oral medicines including sub-acute or complete bowel obstruction. 4. Symptomatic or clinically significant inflammatory bowel disease (Crohn’s disease or ulcerative colitis. 5. Evidence of severe or uncontrolled cardiac disease. 6. Evidence of active bleeding or bleeding diathesis.
Solitary bone plasmacytoma (SBP) is a form of blood cancer, in which abnormal plasma cells collect at a single location in the skeleton. The standard treatment is radiotherapy, however around two-thirds of patients either relapse or go on to develop a more widespread version of the disease called myeloma. Scientists now think these patients relapse because they already have very low levels of disease present in their bone marrow when their plasmacytoma is diagnosed. Using blood and bone marrow tests, they think they are able to identify patients who are most likely to relapse. The IDRIS study will investigate whether progression can be delayed or prevented by giving these patients further treatment with lenalidomide and dexamethasone after radiotherapy. 140 patients with newly-diagnosed SBP will be registered into the trial after radiotherapy. A bone marrow sample will be reviewed to check for 'high risk' features predictive of relapse. Patients with 'high risk' features will be randomised to have either lenalidomide and dexamethasone (group A1) or no further treatment (group A2). Patients with no 'high risk' features (group B) will also have no further treatment. Lenalidomide and dexamethasone treatment consists of up to 9 cycles of treatment, each lasting 4 weeks. Both drugs are taken at home, by mouth, and patients will be seen at their outpatient clinic every four weeks until treatment is finished. Patients on all arms will be followed up for at least 5 years. They will be seen every 3 months until 2 years post radiotherapy, every 6 months in years 3-5 and annually thereafter.
INCLUSION CRITERIA FOR REGISTRATION: - Patients with newly-diagnosed SBP - SBP treated with local radiotherapy with curative intent (see appendix 2). - Radiotherapy completed within 28 days of registration - Age ≥18 years - ECOG performance status 0-2 - Written informed consent - Willing to comply with the requirements of the Celgene pregnancy prevention programme INCLUSION CRITERIA FOR RANDOMISATION: - Phenotypically aberrant plasma cells in a BM aspirate taken from a site outside the radiotherapy field and/or - Abnormal serum free light chain ratio at diagnosis (or at time of registration if SFLC not measured prior to radiotherapy)
- Multifocal plasmacytoma, solitary extramedullary plasmacytoma or myeloma - ≥10% bone marrow plasma cells - Clinical suspicion of failure to respond to radiotherapy - Receiving or intention to treat with systemic corticosteroid therapy (e.g. dexamethasone or prednisolone) unless otherwise agreed by the TMG - Severe hepatic impairment (bilirubin > 2xULN or AST/ALT > 2xULN) - Creatinine clearance < 30 mL/min - Pregnant or lactating women - Non-haematological malignancy within the past 3 years (exceptions apply – see section 6.2.2) - Patients at a high risk of venous thromboembolism due to: -Treatment with erythropoietic stimulating agents (e.g. erythropoietin, epoetin alpha, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta) -Other risk factors not listed above and unable to receive thromboprophylaxis - Patients with untreated osteoporosis - Patients with uncontrolled diabetes - Patients with a known history of glaucoma - Any other medical or psychiatric condition likely to interfere with study participation - Receiving treatment with an experimental drug or experimental medical device. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study. Any experimental drug treatments must be stopped at least 4 weeks before planned start of lenalidomide and dexamethasone. - Evidence of current or past hepatitis B infection. Patient should test negative for both surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) EXCLUSION CRITERIA FOR RANDOMISATION: - Creatinine clearance < 30 mL/min
ICON8 Standard first line chemotherapy for ovarian cancer is a combination of two drugs: carboplatin and paclitaxel, given once every 3 weeks for 18 weeks. However, giving these agents weekly may be more effective; this is called dose-fractionated chemotherapy. In the original ICON8 study, two dose-fractionated chemotherapy regimens were compared with standard carboplatin-paclitaxel. The ICON8 study completed recruitment in November 2014. The main outcome measures of ICON8 are whether dose-fractionated chemotherapy extends the time until ovarian cancer relapses and whether women who receive it live longer. Secondary outcome measures are comparative toxicity, impact on quality of life and cost-effectiveness. Two interim-analyses are planned: the first looking at feasibility and safety of the dose-fractionated regimens; and the second at their activity. ICON8B Recent studies have suggested that outcomes for women with advanced disease can be improved by adding a third drug called bevacizumab to three-weekly carboplatin-paclitaxel. Bevacizumab, and weekly dose dense paclitaxel have markedly different economic implications for healthcare providers, and place distinct burdens on patients with respect to treatment-related toxicity and duration of therapy. Hence there is an urgent need to compare these treatment approaches in a randomised trial. In ICON8B standard 3-weekly carboplatin-paclitaxel and bevacizumab will be compared to dose fractionated chemotherapy with or without bevacizumab in a randomised controlled trial. The main outcome measures are to determine whether dose-fractionated chemotherapy with bevacizumab extends the time until ovarian cancer relapses and whether women who receive it live longer. Secondary outcome measures are comparative toxicity, impact on quality of life and cost-effectiveness. One interim analysis is planned to establish the safety of neo-adjuvant bevacizumab in delayed primary surgery patients.
ICON8 1. Females aged 18 years and above 2. Signed informed consent and ability to comply with the protocol 3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis): • Epithelial ovarian carcinoma • Primary peritoneal carcinoma of Müllerian histological type • Fallopian tube carcinoma • Ovarian carcinocarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary) 4. FIGO stage IC or above, which may be based on clinical and radiological assessment in patients who have not undergone immediate primary surgery 5. Confirmed high-risk histological subtype for patients with FIGO stage IC/IIA disease, namely • High grade serous carcinoma • Clear cell carcinoma • Other histological subtype considered poorly differentiated/grade 3 6. ECOG Performance Status (PS) 02 7. Life expectancy > 12 weeks 8. Adequate bone marrow function • Absolute Neutrophil Count > 1.5 x 10^9/l • Platelets (Plt) > 100 x 10^9/l • Haemoglobin (Hb) > 9g/dl (can be post transfusion) 9. Adequate liver function (within 28 days prior to randomisation) • Serum bilirubin ≤ 1.5 x ULN • Serum transaminases ≤ 3 x ULN in the absence of parenchymal liver metastases or ≤ 5 x ULN in the presence of parenchymal liver metastases 10. Adequate renal function as defined by GFR (Glomerular Filtration Rate) ≥ 30ml/min 11. Able to start chemotherapy within 8 weeks of after immediate primary surgery (where applicable) ICON8B 1.Females aged 18 years 2.Signed informed consent and ability to comply with the protocol 3.Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis): •Epithelial ovarian carcinoma •Primary peritoneal carcinoma of Müllerian histological type •Fallopian tube carcinoma •Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary). 4.High-risk disease defined as •FIGO (2013) Stage IIIA1(ii), IIIA2 with positive retroperitoneal lymph nodes > 10mm in diameter, IIIB or IIIC disease i.With > 1cm residual disease following IPS or ii.Planned to undergo primary chemotherapy with or without DPS •FIGO Stage IV disease i.With any volume of residual disease following IPS or ii.Planned to undergo primary chemotherapy with or without DPS. NB. The FIGO 2013 staging system should be used for women entering ICON8B. Stage may be based on clinical and radiological assessment in patients who have not undergone IPS. 5.ECOG Performance Status (PS) 0-2 6.Life expectancy > 12 weeks 7.Adequate bone marrow function: •Absolute Neutrophil Count (ANC) 1.5 x 109/l •Platelets (Plt) 100 x 109/l •Haemoglobin (Hb) 9g/dl (can be post transfusion). 8.Adequate liver function: •Serum bilirubin (BR) 1.5 x ULN •Serum transaminases 3 x ULN in the absence of parenchymal liver metastases or ≤5 x ULN in the presence of parenchymal liver metastases. 9.Adequate renal function as defined by: •Directly measured GFR (Glomerular Filtration Rate) ≥ 30 ml/min, or •Calculated creatinine clearance ≥ 60 ml/min. NB. If the calculated creatinine clearance is < 60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation. 10.Adequate coagulation profile: •International normalised ratio (INR) ≤1.5 •Activated prothrombin time (APTT) ≤1.5xULN. 11. Able to start chemotherapy within 8 weeks after IPS (where applicable).
ICON8 1. Non-epithelial ovarian cancer 2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology 3. Borderline tumours (tumours of low malignant potential) 4. Prior systemic anticancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy) 5. Previous malignancies within 5 years prior to randomisation apart from: adequately treated carcinoma insitu of the cervix, breast ductal carcinoma insitu, nonmelanomatous skin cancer; or previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion 6. Preexisting sensory or motor neuropathy grade ≥2 7. Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at highrisk of treatment-related complications or prevent compliance with the trial protocol 8. Planned intraperitoneal cytotoxic chemotherapy 9. Planned maintenance treatment with systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression. 10. Any previous radiotherapy to the abdomen or pelvis 11. Sexually active women of childbearing potential not willing to use adequate contraception (eg. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards 12. Pregnant or lactating women 13. Treatment with any other investigational agent prior to protocol defined progression 14. Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor) 15. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible ICON8B 1.Non-epithelial ovarian cancer 2.Peritoneal cancer that is not of Müllerian origin, including mucinous histology 3.Borderline tumours (i.e. tumours of low malignant potential) 4.Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy) 5.Previous malignancies within 5 years prior to randomisation apart from: a.adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or b.previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion. 6.Pre-existing sensory or motor neuropathy CTCAE grade ≥2 7.Proteinuria at baseline: •> 1gm protein/24h by a 24-hour urine collection. NB. Proteinuria should be initially assessed by urine dipstick. If urine protein is ≥2+ on urine dipstick, a 24-hour urine protein collection must be performed. 8.Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including: a.Cerebrovascular disease, including transient ischaemic attacks (TIAs), cerebrovascular accident (CVA; i.e. stroke) and intracranial bleeds (i.e. intra-cerebral haemorrhage, sub-arachnoid haemorrhage or sub-dural haemorrhage) within 6 months before trial entry b.Cardiovascular disease as follows: i.Uncontrolled hypertension, defined as sustained BP> 150/100mmHg while receiving anti-hypertensive medication NB. Patients with a BP> 150/100 mmHg prior to randomisation should be commenced on a calcium-channel blocker or other anti-hypertensive agent; or in the case of patients already on anti-hypertensives, medical therapy should be optimised. The BP should then be re-checked a few days later, if BP is controlled to ≤150/100mmHg the patient may be entered into the trial ii.Myocardial infarction or unstable angina within 6 months prior to randomization iii.New York Heart Association (NYHA) grade ≥2 congestive heart failure iv.Poorly controlled cardiac arrhythmia despite medication NB. Patients with rate-controlled atrial fibrillation are eligible v.Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision c.History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication) d.Recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis) e.Previous gastrointestinal perforation. 9.Chronic daily use of high-dose aspirin, > 325mg/day, within 10 days prior to study entry 10.Surgery (including open biopsy) or significant traumatic injury within 28 days prior to anticipated date of first dose of bevacizumab NB. If IPS was performed within 28 days of planned start of treatment, patients are eligible but bevacizumab must be omitted from cycle 1. 11.Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1 12.Active ulcer or bone fracture 13.Anticipated to require extensive dental work during protocol treatment 14.Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at high-risk of treatment-related complications or prevent compliance with the trial protocol 15.Clinical symptoms or radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive recto-sigmoid involvement on imaging related to ovarian cancer 16.Evidence of intra-abdominal free air not explained by paracentesis or recent surgical procedure 17.Symptomatic abdominal fistulae 18.History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible 19.Sexually active women of childbearing potential not willing to use adequate contraception (e.g. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards 20.Pregnant or lactating women who are currently breastfeeding 21.Known hypersensitivity to carboplatin, paclitaxel, bevacizumab or their excipients (including cremophor) 22.Planned intraperitoneal cytotoxic chemotherapy 23.Planned treatment with any other systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression 24.Any previous radiotherapy to the abdomen or pelvis 25.Treatment with any other investigational agent prior to protocol defined progression.
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.
Head and Neck Cancer Head and Neck/Oncology Oral and Maxillofacial Surgery
HORIZONS is a cohort study to explore recovery of health and well-being in adults diagnosed with cancer. Experiences and outcomes of cancer treatment and care are changing. A growing number of people are experiencing cancer not as a life-limiting disease, but as a life-changing and long-term condition. There is a growing imperative to understand the changing landscape of cancer and its consequences: as we do so, we will be better able to inform the design and delivery of cost effective interventions that make possible supported self-management, as well as service organization and delivery. The key research questions are: What impact does cancer and its treatment have on the lives of people diagnosed with cancer in the short, medium and long term? What are the health outcomes, experiences and self-management activities over the life-course across different cancer types and who and what influence these? HORIZONS is a series of prospective cohort studies of adults treated for non-metastatic cancer to capture their health outcomes and experiences from before they begin active treatment and regularly over their life-course. Our initial cancer cohorts will be breast cancer (diagnosed under age 50), non-Hodgkin lymphoma, and gynaecological cancers (ovarian, cervical, uterine). We will start recruitment with three pilot sites in NHS Trusts before rolling out full recruitment to approximately 50 NHS secondary care Trusts. Questionnaires will be completed before treatment (baseline), and followed up at regular intervals. We will maintain and develop HORIZONS as a national and international resource to explore consequences of different cancer diagnoses and treatments from the individual perspective across the life-course
To be included, patients must: • Have a new diagnosis of one of the selected cancer types or • Have new/second primary cancer at a site previously treated for cancer • Have no distant metastases • Be awaiting primary curative intent treatment (or soon after diagnosis for those not undergoing immediate treatment) • Be ≥16 years old • Be able to complete questionnaires in English (use of an interpreter may support reduced consent and allow collection of medical details) • Be able to provide written, informed consent Have the ability to complete questionnaires
Disease is recurrence/progression (either locally advanced or metastatic) at an existing cancer site They are having treatment for a potentially curative recurrence of disease e.g. locally advanced disease (i.e. they have been previously treated for the same cancer) They have metastatic disease from a cancer at another site (Previous diagnosis of cancer at any other site would not be grounds for exclusion unless disease was metastatic)
Psychosocial Oncology and Survivorship
Head & Neck 5000 is a large observational study of people with head and neck cancer from across the United Kingdom. The overall aim of the Head & Neck 5000 Follow-up Study is to describe the social, lifestyle and clinical outcomes in people with head and neck cancer and relate these to information gained from the original Head & Neck 5000 study. In order to achieve this, participants who have taken part in Head & Neck 5000 for at least three years will be sent an invitation to complete the Follow-up Study questionnaire. Data will be collected from the medical notes and through linkage to national databases for all participants who consented to this.
1. Participants recruited to the original Head & Neck 5000 cohort 2. Participants who have been in the Head & Neck 5000 study for a minimum of 3 years
1. Participants who did not consent to be approached regarding further research 2. Participants withdrawn from the H&N5000 study 3. Participants who are now considered to meet the criteria for mental incapacity or vulnerability set out in the Mental Capacity Act 2005
Head and Neck Cancer Head and Neck Surgery
Treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR (epidermal growth factor) mutations or ALK (anaplastic lymphoma kinase) rearrangements has developed significantly with tyrosine kinase inhibitor (TKI) therapies. Higher response rates and progression free survival (PFS) are seen compared to comparator chemotherapy; however disease progression will ultimately occur in all patients due to acquired resistance to TKI. A proportion of patients progress initially at a limited number of sites (< = 3), termed oligo progressive disease (OPD). Optimal management of these patients is uncertain and further systemic options are limited in the UK. Stereotactic body radiotherapy (SBRT) delivers high dose radiation to small, well-defined tumour targets whilst limiting doses received to surrounding tissue. The benefit of SBRT treatment prior to change in systemic treatment is an important question to be addressed. HALT aims to assess whether SBRT treatment to OPD sites increases time patients benefit from TKI therapy until further disease progression. HALT is a phase II, randomised multi-centre study with integrated seamless continuation to phase III trial following acceptable safety and feasibility assessment. HALT aims to recruit 110 patients with mutation positive advanced NSCLC with OPD following initial response to TKI. Patients will continue on background TKI and will be randomisation (2:1) to receive SBRT or not. Patients will be seen 8 weeks post randomisation, then 3 monthly in line with routine care. Tumour imaging and toxicity assessment will be 3 monthly until disease progression. Quality of Life will be assessed at baseline, 8 weeks and at the first 3 month visit. Research bloods will be collected a baseline, after the first SBRT fraction (treatment group), 8 weeks and 3 monthly until change in systemic therapy. PFS defined as time from randomisation to ‘poly’-progression (> 3 progressing lesions) or death will be the primary endpoint.
1. Male or female, > = 16 years of age 2. Established histological diagnosis of advanced NSCLC, not suitable for radical treatment, with defined actionable mutation receiving targeted TKI therapy 3. Clinical and/or radiologically confirmed response to TKI therapy (assessed locally usually 2-3 months post commencing TKI) 4. Confirmed OPD defined as < = 3 extracranial sites of progressive disease. All sites must be visible, imaging defined targets and suitable for treatment with SBRT. 5. Adequate baseline organ function to allow SBRT to all relevant targets 6. Predicted life expectancy > = 6 months 7. Karnofsky Index > = 60% or ECOG 0-2 8. Provision of written informed consent
1. > 3 extracranial sites of progressive disease 2. Progressing or newly diagnosed brain metastases not amenable to radical surgery or SRS. Treated brain metastases which have remained clinically and radiologically stable for ≥ 6 months are permissible. 3. Prior radiotherapy near the oligoprogressive lesion precluding ablative SBRT 4. Co-morbidities considered clinically to preclude safe use of SBRT e.g. IPF in patients with an oligoprogressive lung lesion, inflammatory bowel disease in patients with an oligoprogressive pelvic lymph node 5. Any psychological, sociological or geographical issue potentially hampering compliance with the study 6. Pregnancy
Human papillomaviruses (HPV) causes about 5% of cancer worldwide. High-risk subtypes cause cervical, anogenital and head and neck cancer. Conventional treatments for these cancers include surgery, radiotherapy and chemotherapy: each of these has significant side effects, and new treatment modalities are clearly required. Immunotherapy offers the option of long term disease control by activating the patient’s own immune system to destroy the cancer. This study aims to combine a vaccine (specific for HPV) and an antibody (to stimulate the patient’simmune system), to generate an immune response against HPV. HARE-40 is a phase I/II vaccine and immunostimulatory antibody dose escalation study with two different parts: Part1 comprises three arms in which we will test the HPV mRNA vaccine as monotherapy. Part 2 comprises three arms in which we will test the HPV mRNA vaccine in combination with anti-CD40 IS Ab. Initially, we will undertake a multi-centre phase I, open label study in patients with previous HPV16+ HNSCC without current clinical evidence of disease (Arm 1A) and in patients with HPV16+ advanced disease (Arm 1B). Once a safe and tolerable dose has been established the trial will be opened to patients in the neoadjvant setting following ethical and regulatory review and approval. We will further seek approval for part 2 of the trial which will be added to the protocol via substantial amendment. The HPV16 antigen‐specific immune response will be evaluated before and after treatment in circulating blood and, where possible, in tumour and skin biopsies.
Arm 1A: • Previous HPV16+ head and neck squamous cell carcinoma. • At least 12 months after completion of treatment. • Within 5 years of treatment completion. • Currently no clinical evidence of disease. • ECOG performance status 0 or 1. • Able to provide written informed consent. Arm 1B: • HPV16+ head and neck, cervical, anogenital and penile carcinoma patients with recurrent disease. • Intention to treat is palliative. • Patient willing to have repeated tumour biopsies and re-biopsy deemed safe and feasible clinically. • Tissue samples available confirming HPV16+ disease to send to Central Laboratory.
• Patients unable to consent. • Any patient who has been previously vaccinated in any Arm of the trial. • < 18 years • Systemic steroids (prednisolone > 10 mg/day or equivalent) or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. Replacement steroids for adrenal insufficiency/failure are allowed. • Major surgery in the preceding three to four weeks, which the patient has not yet recovered from. • Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection. • Patients with clinically relevant autoimmune disease will be excluded. • Patient with a history of anaphylactic reactions or severe allergies are excluded. • Patients with any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease. • Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study.Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing. • Patients who have a positive pregnancy test or who are breast feeding. • Fertile males or females who are unable or unwilling to use an effective method of birth control (eg. condom with spermicide, diaphragm with spermicide, birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until end of treatment +28 days (day 113). • Elevated Liver Function Tests – ALT > 3.0 x ULN, AST > 3.0 x ULN, Bilirubin > 3.0 x ULN. • Arm 1B patients with the presence of liver metastasis only: Elevated Liver Function Tests – ALT > 5.0 x ULN, AST > 5.0 x ULN, ALP > 5.0 x ULN. Patients who are likely to have rapid disease progression may not be good candidates for the trial. In such cases, please discuss with the Chief Investigator. • Any other investigational drug within 28 days or 5 half-lives depending on what gives the longer range before the first treatment of this study.
General Surgery Gynaecological Cancers Head and Neck Cancer Head and Neck/Oncology Skin Cancer
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.
Breast Cancer Genetics Gynaecological Cancers
The protocol describe a generic three step process to develop and validate a tumour specific or domain specific quality of life questionnaire. Phase I involves a literature search and patient interviews to identify relevant issues. Phase II generates items/questions from the issues. Phase III involves pilot testing the items in a larger patient sample. As the study is conducted on behalf of the EORTC Quality of Life Group cross cultural acceptability is key and at all phases patients from at least 3 European countries are recruited. A final step is field study to validate the measure but that is not covered by this protocol. Amendments will be submitted detailing the specific tumour or domain to be tested as the process is independent of the topic of the questionnaire.
All patients will be aged 18 or over. For disease questionnares patients will all have a confirmed diagnosis of the specific cancer (e.g. thyroid). For domain specific questionnaires (e.g. communication) all patients will have a confirmed diagnosis of cancer, but a range of sites will be sampled. For each questionnaire a grid will be prepared for stage of disease x treatment. Exact details of the eligibility criteria will be specified in the protocols which will be submitted as an amendment.
Patients under 18 will be excluded. Patients unable to speak or read English will be excluded. (As this is an international study the questionnaires will be simultaneously developed in other languages in other countries.)
Psychosocial Oncology and Survivorship
FOCUS4 is an umbrella, or platform, for testing novel agents in biomarker-defined subpopulations of first-line advanced disease colorectal cancer patients who are not considered candidates for potentially curative surgery. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type. See Trial Schema in the Trial Protocol. • The backbone of the platform is 16 weeks of treatment with any standard first line colorectal cancer treatment, after which, as is frequently standard practice in the UK and Europe, there is a programmed treatment break for responding and stable patients. During that break, either new agent(s) or placebo is administered. The primary outcome measure for assessing the activity of the new treatment is progression free survival in the interval (time to death or progression requiring resumption of chemotherapy). • At present, four coherent biomarker-stratified groups can be identified and trials will be established in each of these cohorts as follows: - BRAF mutant - PIK3CA mutation or complete loss of PTEN on IHC - KRAS or NRAS mutant - All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS) - Unclassified biomarker results • For each of these subgroups, a relevant novel agent or combination is to be tested in an adaptive double blind randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity (the principles are derived from the Multi-Arm, Multi-Stage (MAMS) design). FOCUS4 will open with one molecularly stratified trial (FOCUS4-D) testing AZD8931 (a HER 1,2 3 inhibitor) against placebo in patients stratified into the All wild-type cohort. In addition, a non-stratified trial (FOCUS4-N) will be open for patients whose biomarker results are unclassified or who are unable or unwilling to participate in the molecular trial available to them.
Registration Inclusion Criteria (please refer to the protocol for eligibility for randomisation) 1. Male/female patients at least 18 years old 2. Formalin fixed paraffin embedded (FFPE) tumour block taken prior to the commencement of standard chemotherapy and available for biomarker analysis 3. Histologically confirmed adenocarcinoma of the colon/rectum 4. Inoperable metastatic or locoregional disease (synchronous or metachronous) 5. WHO performance status 0, 1 or 2 6. Unidimensionally measurable disease RECIST 1.1 classification 7. Have had an electronically accessible CT scan performed within 4 weeks prior to start of standard chemotherapy 8. Platelet count < 400 x 109/L prior to start of standard chemotherapy 9. For women of childbearing potential, a negative pregnancy test and acceptable contraceptive precautions 10. Effective contraception for male patients if the risk of conception exists 11. Consent for screening of an archival FFPE tumour block for biomarker analysis (PIS1 & CF1) 13. Patients should have sufficient capacity for informed consent and provided signed informed consent
Registration Exclusion (please refer to the protocol for eligibility for randomisation) 1. Previous systemic palliative chemotherapy using a different regimen for established advanced or metastatic disease 2. Adjuvant chemotherapy given in the last 6 months 3. Patients with brain metastases 4. Pregnant and lactating women
Assess the safety and tolerability of combination treatment with defactinib (VS-6063) and pembrolizumab - Determine the recommended doses of the two agents to be used in combination - Preliminary assessment of clinical anti-tumour activity as assessed by imaging - Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on the cell types making up the tumour, by evaluation of tissue samples for changes in immune cell infiltrate on treatment - Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on FAK signalling (defactinib is a FAK inhibitor), by evaluation of phosphorylated FAK
All parts of study 1. Informed, written consent 2. Male or female, aged 18 years or older at the time consent is given 3. ECOG performance status 0 or 1, with no deterioration over the previous 2 weeks 4. Life expectancy of at least 3 months 5. Measurable disease according to irRECIST criteria, with at least one measurable lesion that has objectively progressed since (or on) any previous therapy 6. Adequate bone marrow, liver and renal function on blood investigations within 7 days prior to treatment initiation: a. Creatinine ≤ 1.5 x ULN OR GFR ≥ 60 mls/min for patients with creatinine levels > 1.5 x ULN. (using the standard methodology at the investigating centre - i.e Cockcroft-Gault, Wright, MDRD or CKD-EPI formulae, EDTA clearance or 24 urine collection) b. Total bilirubin ≤ 1.5 x ULN c. Alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x ULN (if both measured, both must meet criteria) d. White blood cell count ≥ 3.0 x 109/L e. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L f. Platelets ≥ 100 x 109/L g. Haemoglobin ≥ 90 g/L h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN, UNLESS patient is receiving anticoagulation therapy, in which case INR or PT must be within the intended therapeutic range. 7. Patients must have been offered all appropriate standard-of-care treatments (or all those indicated before anti-PD- 1/PD-L1 therapy, if licensed) 8. Patients must agree to use adequate contraceptive measures for the course of the study through 120 days after the last dose of study medication 9. Women of child-bearing potential must have a negative pregnancy test within 72 hours prior to start of dosing 10. Consent to supply any available archival tissue Dose escalation (Phase I) 11. Pathological diagnosis of any advanced solid tumour type, with confirmation that a tissue sample (core biopsy or resected specimen) is available Pancreatic expansion (Phase IIa) 12. Pathological diagnosis of pancreatic ductal adenocarcinoma, with confirmation that a tissue sample (core biopsy or resected specimen) is available NSCLC expansion (Phase IIa) 13. Pathological diagnosis of non-small cell lung cancer (NSCLC) 14. Lesion suitable for repeat biopsy 15. Baseline biopsy containing tumour material during eligibility 16. Consent for paired biopsies on study Mesothelioma expansion (Phase IIa) 17. Pathological diagnosis of mesothelioma 18. Lesion suitable for repeat biopsy 19. Baseline biopsy containing tumour material during eligibility 20. Consent for paired biopsies on study
All parts of study 1. An additional invasive cancer in the last 5 years (other than treated and controlled localised non-melanoma skin cancer or cervical carcinoma-in-situ, or indolent prostate cancer that has been stable for > 1 year) 2. Any central nervous system metastases unless treated and asymptomatic, as well as stable on imaging and not requiring steroids in the preceding 4 weeks 3. Any interventional studies, systemic cancer therapies or monoclonal antibodies in the preceding 4 weeks (6 weeks for mitomycin C and nitrosureas) 4. Any live vaccines in the preceding 4 weeks 5. Systemic immunosuppressive agents in the preceding 2 weeks. Immunosuppressive agents include steroids NHS R&D Form IRAS Version 5.4.2 17 200488/1095978/14/206 such as prednisolone (doses ≥ 15 mg daily) or dexamethasone (doses ≥ 2 mg daily) Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment. 6. Diagnosis of immunodeficiency 7. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment 8. Known interstitial lung disease or active, non-infectious pneumonitis 9. Known history of Tuberculosis (TB), Human Immunodeficiency Virus (HIV) or active Hepatitis B or C 10. Other severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, recent myocardial infarction, organ failure or active infection) 11. Baseline (non-laboratory) toxicities greater than grade 1 (CTCAE v4.03) despite optimal supportive therapy, including fatigue, anorexia, nausea or diarrhoea, but with the exception of alopecia 12. Pregnancy or lactation 13. Limited ability to swallow or absorb oral medications 14. Hypersensitivity to defactinib (VS-6063), pembrolizumab or excipients (including L-histidine, L-histidine hydrochloride monohydrate, sucrose or polysorbate 80) 15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
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.
A case: control study design in which the cases will be patients with known Barrett’s Oesophagus (BE) and controls individuals with reflux or indigestion (dyspepsia) symptoms referred for endoscopy. Four centres with expertise in Barrett’s oesophagus will recruit patients. All participants will swallow the Cytosponge device prior to having an endoscopy. The Cytosponge will be processed for a number of different biomarkers. The results will be compared with the endoscopy findings.
Any patient clinically fit for an endoscopy with Barrett’s oesophagus (for the cases) and (or) with upper GI symptoms of reflux or dyspepsia as an indication for endoscopy. Individuals must be able to provide informed consent.
Individuals with a diagnosis of an oro-pharynx, oesophageal or gastro-oesophageal tumour, or symptoms of dysphagia,
All UK patients who participated in the TARGIT-A Trial were initially treated for early breast cancer between 2000-2012. A total of 3451 patients from 33 hospitals in 11 countries participated in the trial and a comparison was made between traditional radiotherapy given over several weeks (external beam radiotherapy, EBRT) with TARGeted Intraoperative radioTherapy (TARGIT-IORT) as a single dose given during the operation to remove the breast cancer. The trial was funded by the Health Technology Assessment (HTA) programme of the Department of Health, UK and sponsored by University College London. The results from this trial have been published in major medical journals and have already started changing the way breast cancer in treated around the world; please see www.targit.org.uk for more details. We would like to continue to collect data about the health status of all patients to enable us to learn about longer term differences in the effects of these treatments on health. An analysis of this information could improve treatment for patients with breast cancer. For this, HTA have granted us further funding.
All patients who participated in the TARGIT-A trial.
1. Any patient who has withdrawn consent for further follow-up, or died. 2. Any patient who is unable to give formal written consent.
Mantle cell lymphoma is a rare but aggressive form of non hodgkins' lymphoma that typically affects older patients. For younger, fitter patients the most effective treatment is considered to be stem cell transplantation. For older patients, this is not an option and they are generally offered a combination of chemotherapy and rituximab. The purpose of this study is to compare the effect on progression-free survival of treatment with ibrutinib given in combination with rituximab (IR) against treatment with standard chemotherapy given in combination with rituximab. Participants will receive treatment for 24 weeks, followed by a 2 year maintenance period. They will then be followed up until disease progression or the end of the study, whichever comes first. We are also interested in the cost of delivering these two types of treatments, the quality of life they give patients and the side effects they cause. This is a multicentre, open label, integrated phase II/III randomised controlled study in untreated patients with mantle cell lymphoma who are over the age of 60 and are therefore considered unsuitable for stem cell transplant. There will be an interim analysis after 77 evaluable participants have completed 24 weeks of treatment with IR in order to establish that the overall response rate with IR is high enough to justify continuing to a phase III study. We will recruit 400 patients from as many hospitals and cancer centres in the United Kingdom as have the capacity to open the study. ENRICH is funded by Cancer Research UK and the ibrutinib is supplied and distributed free of charge by Janssen. Janssen have also provided funds for a sub study to explore the value of minimal residual disease flow cytometry in mantle cell lymphoma.
• Male/female patients 60 years and over • Pathologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t (11:14)(q13;q32) and/or overexpress cyclin D1 • Stage IIIV disease, measurable by imaging and requiring treatment in the opinion of the treating clinician • No previous treatment for MCL (other than localised radiotherapy or 7 day pulse of steroids for symptom control) • Performance status ECOG 02 • Absolute neutrophil count > 1.0x10*9/L or platelets > 100x10*9 /L independent of growth factor support or unless related to lymphoma • AST and/or ALT < 3xULN • Total bilirubin ≤1.5xULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin • Calculated creatinine clearance > 30mL/min • Able to give voluntary written informed consent
• Patients considered fit enough to undergo autologous or allogeneic stem cell transplant as treatment for MCL • Known serological positivity for HBV, HCV, HIV • Major surgery within two weeks prior to Day 1 of Cycle 1 • Diagnosed with or treated for any other malignancy than MCL within 2 years prior to Day 1 of Cycle 1 (except BCC, SCC or any in situ malignancy) • Active systemic infection requiring treatment • Male subjects with female partners of childbearing potential who are unwilling to use appropriate contraception methods whilst on study treatment • Women who are pregnant or breastfeeding • Serious medical or psychiatric illness likely to interfere with participation in this clinical study • Concurrent treatment with another investigational agent
A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to their liver (metastases) develop disease recurrence and die from their disease. A previous small study (the EMT study) suggested a possible survival benefit in patients who took naturally-occurring ‘omega-3’ EPA (a fish oil supplement) before their liver surgery. The EMT2 study is a larger study which will recruit 448 men and women with liver metastases from bowel cancer. Trial participants will receive either EPA-triglyceride (purified from fish oil) or placebo (dummy capsules). EMT2 will investigate whether patients who take this supplement before liver surgery and for up to four years after surgery, remain free of recurrence for longer than those who take placebo. Participants will receive five capsules per day of either EPA or placebo and the allocation will be generated at random by a computer. This is a double blinded trial which means that neither the participant nor the clinician will know which treatment the participant is receiving during the trial. Trial treatment will start at least two weeks prior to liver surgery and will continue for at least two, and up to four years, after surgery. The trial will be open for at least two years after the last participant enters the trial so the length of treatment will depend on when the participant joins the trial. The trial visit schedule closely mirrors the standard follow-up visits which are part of standard care. Participants are seen at least two weeks before liver surgery, at liver surgery and then at six-monthly intervals thereafter for a minimum of two years and a maximum of four years. Depending on when the participant last attended clinic at the time the trial closes, a trial-specific appointment at the end of the trial may be required.
• Aged ≥18 years • Able to provide written informed consent • Histological diagnosis of colorectal cancer with evidence of liver metastases • Planned liver resection surgery for colorectal cancer liver metastasis with curative intent, including repeat ‘re-do’ colorectal cancer liver metastasis liver surgery (a second independent resection for a separate colorectal cancer liver recurrence) • Intention to receive ≥2 weeks treatment with IMP prior to colorectal cancer liver metastasis surgery
• Incurable extra-hepatic metastases • Current (in the last 2 months) or planned regular (> 3 doses per week) use of O3FA-containing supplements, including fish oil and cod-liver oil supplements • Fish/seafood allergy • < 2 weeks before planned CRCLM surgery • Inability to comply with trial treatment and follow-up schedule • Known bleeding tendency/condition (e.g. von Willebrand disease) • A previous malignancy within the last 5 years other than: - colorectal cancer - non-melanoma skin cancer where treatment consisted of resection only or radiotherapy - ductal carcinoma in situ (DCIS) where treatment consisted of resection only - cervical carcinoma in situ where treatment consisted of resection only - superficial bladder carcinoma where treatment consisted of resection only • A previous malignancy where the patient has been disease-free for ≤5 years • Pregnant or breastfeeding women or women of childbearing potential not willing to use effective contraceptive measures. Women of childbearing potential are defined as fertile, following menarche and until becoming post- menopausal unless permanently sterile. • Men defined as fertile (post-pubescent and not permanently sterile by bilateral orchidectomy) and not willing to use effective contraceptive measures if appropriate.
Colorectal Cancer Hepatobiliary Surgery
Patients with a persistent high white cell count with or without swollen glands/ lymph nodes are often diagnosed with cancers of the lymphatic system. However a significant proportion of these patients are not assignable to a specific category based on current technology. This can have an adverse impact on their treatment as the optimal treatment in these unclassifiable cases is not clear. Moreover, these patients are often excluded from entry into clinical trials and so cannot access new drugs. In many cases of lymphatic cancer received by the Royal Marsden, a specific category cannot be assigned using current technology. Recently, new genetic technologies have identified a number of key mutations associated with lymphatic cancers. We propose to introduce these new genetic tests to improve categorisation of these disorders in order to improve patient outcomes by increasing opportunities for entry into clinical trials as well as identifying new therapeutic targets. It is estimated that the number of indolent B-Cell Lymphoproliferative Disease (B-LPD) cases that are assigned a definitive category using current technology is 30%. Our plan therefore is to systematically study unclassifiable groups of B-LPD by creating a well defined immunomorphology work flow for their identification. Samples thus identified will be screened using an Next Generation Sequencing (NGS) panel which is able to detect well established, B-LPD associated genetic aberrations including IgH translocations and genetic mutations. Based on the numbers above, we are looking to screen at least 120 samples over 2 years with the hypothesis that mutation screening will increase the number of cases with a definitive diagnosis or detectable mutation by at least 15%,
Indolent, mature clonal B-cell malignancy that is not assignable to a specific WHO category by current technology.
Non-clonal B-cell proliferation. High grade and/or immature clonal B-cell malignancy. Bone marrow samples with less than 20% infiltration will be excluded Patient unable to provide consent for tumour and germ line samples.
Almost 60% of all patients diagnosed with breast cancer (48000 annually in the UK) undergo breast conserving surgery (BCS. Surgical removal of the cancer aims to reduce the risk of local recurrence and patient mortality. In order to minimise the amount of tissue removed, excision up to the cancer free area (margins) is undertaken. Further surgery, following initial breast cancer surgery, is required in 25% 30% of patients because of disease found at the edges of the tissue removed.Reducing the need for further operations benefits patients (by reducing the number of operations required, improving cosmetic outcome and minimising anxiety) and the NHS (by realising economic benefits).MarginProbe, a disposable probe which measures the margins of tissue removed during breast cancer surgery, allows the surgeon to remove further tissue during the same surgical procedure to clear any involved margins, minimising subsequent reoperations. Four hundred and sixty patients in 6 specialist Breast Units will be randomly allocated after BCS (and specimen radiology), by telephone randomisation, to either: -MarginProbe assessment of the surgical specimen with reexcision of margins if required; -Standard BCS (clinical and radiological clear margins) whereby the wound will be closed and the surgery completed (standard UK practice).
Women aged 18-90 years with DCIS or Invasive Breast cancer containing DCIS diagnosed histopathologically. Histologically diagnosed DCIS or invasive lobular cancer in core biopsy (B5a or B5b). Tumour size 1.5cm 4cm and undergoing breast cancer surgery. Written informed consent.
Unsuitable for BCS on basis of tumour size (< 1.5cm or > 4cm) or stage. Radiotherapy contraindicated. No histopathological evidence of DCIS or invasive lobular cancer. Neoadjuvant chemotherapy.
Breast Cancer Other
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)
Prostate cancer PCa (PCa) is the most common male cancer and second most common cause of male cancer death. Currently most men are diagnosed with PCa as a result of a blood test called the PSA (Prostate Specific Antigen). Men, who present to their GPs with symptoms due to benign (non-cancerous) enlargement or simply requesting a PCa check, are offered a PSA test. However, the PSA test is not consistently accurate: the PSA level can be high and the man may not have PCa or likewise, to a lesser degree, the PSA can be normal and the man may harbour significant cancer. There is therefore an urgent need to identify a test which is more accurate than PSA, a test that can identify men with significant PCa who need an MRI and prostate biopsy, but can also exclude men who don't have significant PCa, ensuring these men do not undergo unnecessary testing or anxiety. We have completed a number of pilot studies and have shown that EN2 protein is expressed by cancer cells and actively secreted into the urine of men with PCa. We have shown urinary EN2 has high specificity and sensitivity as a diagnostic marker. A specific level of urinary EN2 was able to distinguish between PCa that was significant (needed immediate treatment) versus insignificant (could be monitored) on the basis of tumour volume. The aim of this study is to evaluate urinary EN2 as a diagnostic biomarker in the setting of conventional urological practice. In addition, we will determine whether specific levels of EN2 in this setting correlate with radiological and pathological findings and aid in defining patients suitable for active surveillance versus those requiring immediate treatment.
Men over 18 referred from the GP to a urology clinic, who have elevated PSA levels between 4-20ng/ml
An active urine infection as confirmed by urine dipstick testing or midstream urine microscopy Men with PSA 20, men already diagnosed with prostate cancer, men with a prior or concurrent malignancy (apart from basal cell carcinoma of the skin) and men who cannot give informed consent.
This study is for women with ovarian cancer that has come back following treatment, and is resistant to platinum chemotherapy. Weekly paclitaxel chemotherapy is standard for these women, but there is a need to provide more effective treatments. TAK228 is an unlicensed oral drug that blocks the PI3K/AKT/mTOR pathway, which is important to the survival and spread of cancer cells. When TAK228 is combined with paclitaxel in the laboratory, the anti-cancer effect of both is increased. The DICE trial will show whether using TAK228 in combination with weekly paclitaxel is more effective at treating the patient population than weekly paclitaxel alone. DICE will also look for ‘biomarkers’ that measure the activity of the cancer and the effects of treatment. This may help us understand which women might benefit from receiving TAK228 and weekly paclitaxel in future. DICE is a randomised study recruiting 126 women over 3 years from hospitals in the UK and Germany. Eligible patients will have tissue based diagnosis of advanced/recurrent ovarian cancer (clear cell, endometrioid or high grade serous or carcinosarcoma), have had chemotherapy before, and be platinum-resistant (the cancer has returned/grown significantly during or within 6 months of platinum-containing chemotherapy). Randomisation will be to one of 2 groups (63 women in each). Treatment is divided into 4 week 'cycles': Group 1: weekly paclitaxel for 3 weeks followed by 1 week rest each cycle Group 2: weekly paclitaxel (see Group 1) plus TAK228 for 12 days each cycle Women will stop treatment when the cancer grows significantly, there are unacceptable side effects, or the investigator and/or patient decides to stop. Women will be followed up until 6 months after the last patient stops study treatment, or up to 18 months after the last patient is randomised, whichever is sooner.
1. Able to understand and willing to sign informed consent form prior to initiation of any study procedures 2. Females > = 18 years of age 3. Pathological diagnosis of ovarian, fallopian tube or primary peritoneal cancer, of clear cell, endometrioid or high grade serous subtype or carcinosarcoma. Local tumour board/MDT histological review is required and in mixed tumours more than 50% endometrioid, clear cell or high grade serous elements are required to define the predominant histology 4. Platinum-resistant (recurrence within 6 months of platinum treatment), or platinum refractory disease (recurrence during platinum treatment), patients having received at least one prior line of chemotherapy. Carboplatin and weekly paclitaxel are permitted as first line therapy 5. Measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by CT or MRI 6. Fresh tumour biopsy during screening is compulsory if judged technically feasible by radiologist 7. Patients with a history of brain metastasis are eligible as long as all the following criteria are met: brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study treatment, and no ongoing requirement for dexamethasone or anti‐epileptic drugs 8. Available blocks for (IHC) and tissue microarray (TMA) or, if no block is available, 20 ordinary unstained slides (5µm sections) will be acceptable 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0‐2 10. Adequate organ and bone marrow function 11. Patients who: a. Are postmenopausal for > 1 year before the screening visit OR b. Are surgically sterile OR c. If of childbearing potential, patient agrees to practice one of the following from informed consent to 90 days after the last dose of study treatment (or longer, as mandated by local labelling [e.g. Summary of Product Characteristics]): i. Practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time OR ii. Practice true abstinence where this is in line with the preferred and usual lifestyle of the patient 12. For women of child‐bearing potential, negative blood serum pregnancy test within 14 days prior to the first study treatment 13. Able to swallow oral medication
1. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, mTORC1/2 inhibitors or mTORC1 inhibitors 2. Prior weekly single agent paclitaxel 3. Known allergy to paclitaxel and/or any excipients of investigational medicinal products; 4. Treatment with strong inhibitor/s and/or inducer/s of cytochrome P450 (CYP) 3A4 or CYP2C8 within 7 days of study treatment 5. Central nervous system (CNS) metastasis, for patients who have brain metastases, they will be eligible if their brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and no ongoing requirement for dexamethasone or anti‐epileptic drugs 6. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient’s participation in the study 7. Known human immunodeficiency virus infection 8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection 9. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol 10. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study treatment, or previously diagnosed with another malignancy and evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection 11. Breast feeding or pregnant 12. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK228. In addition, patients with enteric small bowel stomata are also excluded 13. German sites only: Unable to be regularly followed up for any reason (geographic, familiar, social, psychological, housed in an institution e.g. prison because of a court agreement or administrative order) 14. German sites only: Subjects that are dependent on the sponsor (and/or contracted body e.g. CRO) or investigational site as well as on the investigator 15. Treatment with any investigational products, chemotherapy or radiotherapy within 28 days, or major surgery within 21 days of study treatment 16. History of any of the following within the last 6 months before administration of the first dose of study treatment: a. Ischemic myocardial event, including angina requiring therapy and artery revascularisation procedures b. Ischemic cerebrovascular event, including transient ischemic attack and artery revascularisation procedures c. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) d. Placement of a pacemaker for control of rhythm e. New York Heart Association (NYHA) Class III or IV heart failure f. Pulmonary embolism 17. Significant active cardiovascular or pulmonary disease including: a. Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before first dose of study treatment is allowed. b. Pulmonary hypertension c. Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air d. Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement e. Medically significant (symptomatic) bradycardia f. History of arrhythmia requiring an implantable cardiac defibrillator g. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes) 18. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study treatment 19. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study treatment 20. Poorly controlled diabetes mellitus defined as glycosylated haemoglobin (HbA1c) > 7%;
Patient reported outcomes such as quality of life (QoL) are increasingly used both in clinical trials and routine clinical care. The European Organisation for Research into Treatment of Cancer (EORTC) ‘QLQ-C30’ is an internationally used questionnaire to assess general QoL and is considered suitable for use in patients with all cancer types. This core questionnaire can be supplemented by modules specific to cancer type and in 2013 the QLQ-GINET21 questionnaire module was developed with the aim to be suitable for patients with all types of gastrointestinal Neuroendocrine tumours(NETs). WHO: Significant differences, however, exist between NETs from gut and pancreatic origin (pNET) with a variety of distinct hormonal syndromes affecting some patients with pNET. Patients with pNET can experience specific disease symptoms, receive different treatments and hence experience different treatment side effects. NET specialist clinicians now consider that the GINET21 module should be re-developed for patients with pNET and in particular for those patients with hormonal syndromes. WHERE: This international, multi-centre study will take place in clinical centres in Europe (UK, Germany, Italy, Spain and Poland) and is expected to be conducted over two years. HOW: This is an observational study using questionnaires and covers Phase 1 and 3 of EORTC module development. All pNET patients will receive full written information and time to consider consent to participate. In Phase 1 patients have an in depth interview with a specialist NET ‘clinician/health professional’ to complete the QLQ-C30 and then review and comment on a list of possible pNET module questions and to suggest relevant issues missing from the list. In Phase 3 different pNET patients would consent to an interview with a specialist NET ‘clinician/health professional’ to complete QLQ-C30 and then pre-test a provisional list of module questions and give a response score for each question, together with rating of relevance and importance. Afterwards patients comment on the completeness and acceptability of the module questions.
Diagnosis of Neuroendocrine Tumour of Pancreatic origin (Functioning or non-functioning) confirmed histologically and fulfil all of the following criteria: - With primary or metastatic disease and not surgically cured - Able to understand the language of the questionnaires - Aged 18 years or above - Mentally and physically fit to complete an interview - Absence of any psychological, physical or other condition potentially hampering compliance with the study protocol - Capable of understanding the study patient information sheet and providing written informed consent in accordance with ICH GCP and national/local regulations and procedures
Diagnosis of Neuroendocrine Tumour of Pancreatic origin (Functioning or non-functioning) confirmed histologically - But fulfil Any of the following criteria: - Prior curative surgery for pNET with no current disease - Assisted in the Phase 1 or Phase 3 interviews for the development of the original QLQ-GINET21 module - Under 18 years of age - Unable to understand the language of the questionnaires - Patients who are unable to self-complete QoL questionnaires or participate in a structured oral interview where the QoL questionnaires are administered by a researcher or clinician - Presence of a psychological, physical or other condition which would make it difficult for them to comply with the protocol - Unable or unwilling to give written informed consent - Participating in other QoL investigations that might interfere with this study - Have another concurrent cancer, other than localised skin cancer.
Metastatic melanoma has a poor prognosis if untreated. Recently, two types of drugs which activate the immune system have been shown to extend survival. The most active are those which target a molecule known as PD1. Two anti-PD1 drugs, pembrolizumab and nivolumab, are licensed to treat metastatic melanoma and are becoming the initial treatment of choice, in the UK and worldwide. Pembrolizumab and nivolumab are given as intravenous infusions every 2 or 3 weeks for as long as there is benefit. Anti-PD1 drugs are given continuously because that is how they were given in trials, but there is no biological evidence for this. Up to 40% of patients remain on treatment after 1-2 years. The drugs seem to make most difference within the first year of treatment. There is no evidence that continuing treatment beyond 1 year brings any benefit. It is possible that shorter durations may be equally effective, with fewer side-effects. Continuing treatment exposes patients to potentially severe immune-related side-effects. Also, the burden of continuous treatment is significant, as patients must attend clinic before each treatment for safety checks. There is evidence that some patients continue to respond even after treatment has stopped. This study will assess whether treatment with anti-PD1 drugs can be stopped after 1 year. Consenting patients will, after 12 months of treatment, be randomly allocated to stop treatment, or to continue for as long as there is benefit (the current standard). All patients will be closely monitored for response and to assess and manage side-effects. The main goal is to compare how long patients in the two groups live without melanoma re-growing. If the trial shows that anti-PD1 drugs can be given for a shorter time compared with standard recommendations, without compromising their effectiveness and safety, these findings will change clinical practice worldwide.
Eligibility for REGISTRATION • Histologically or cytologically confirmed unresectable stage III or stage IV (metastatic) melanoma, including cutaneous and non-cutaneous melanoma • Aged > = 18 years • Planned or currently receiving (< 12 months) treatment with first-line pembrolizumab or nivolumab • Written informed consent for registration Inclusion criteria for RANDOMISATION • Registered in DANTE • Progression-free by RECIST v1.1 criteria at 12 months (+/- 4 weeks) from the start of pembrolizumab or nivolumab • 12 months (+/- 4 weeks) from start of pembrolizumab or nivolumab • Eastern co-operative oncology group (ECOG) performance status 0-2 • Considered fit by the treating clinician to continue to receive ongoing treatment with pembrolizumab or nivolumab • Written informed consent for randomisation
Exclusion criteria for RANDOMISATION • Severe co-morbidities, including severe auto-immune disease or pneumonitis • Active infection requiring systemic therapy • Known history of HIV, hepatitis B or C • Other malignancy within past 5 years, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers • Pregnant, breast-feeding or patients with reproductive potential (female and male) unwilling to use adequate contraception while receiving anti-PD1 therapy and for 6 months after the last dose. Women of reproductive potential are defined as: following menarche and until becoming post-menopausal, unless permanently sterile. Men of reproductive potential are defined as: post-pubescent and not sterile by vasectomy or bilateral orchidectomy. • Prior systemic treatment for advanced melanoma, including ipilimumab and combination ipilimumab and nivolumab, other than BRAF and MEK inhibitors and the current treatment for advanced melanoma. Prior adjuvant or neo-adjuvant therapy is allowed as long as it was completed at least 12 months prior to starting anti-PD1 therapy. • Treated brain metastases with MRI evidence of progression and/or requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisolone equivalents) • Untreated brain metastases that are symptomatic and/or require local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
Ovarian cancer (OC) is the most lethal gynaecological cancer. 1 in 52 women will be diagnosed with the disease in their lifetime and survival from the disease is highly dependent on the stage at diagnosis. At stage 1, 90% of women will survive their cancer for 5 years or more after diagnosis. At stage 3 this figure drops to 20% and then to just 5% at stage 4. Due to the non-specific nature of symptoms (bloating, abdominal discomfort) most affected women (70%) are diagnosed at advanced stage 3 or 4. The current blood test CA-125 is poor and only identifies 50% of Stage 1 ovarian cancers. Therefore, novel diagnostic tools to detect ovarian cancer are urgently needed. This study is examining new biomarkers based on steroid hormones. Hypothesis: Steroid hormone metabolites are of diagnostic value in detecting ovarian cancer. Aim: to explore the steroid metabolome in ovarian cancer compared to benign tumours and normal ovary through the following research questions: Q1. Does the steroid pathway differ in OC subtypes and benign tumours? Q2. Is there a steroid profile in urine that can identify OC subtypes or benign tumours? Q3. Can we equate gene expression with activity in the steroid pathway? Hormones have been implicated in ovarian cancer progression but their true role remains unexplained. We plan to use new technology such as mass spectrometry to search for hormone metabolites that can spot the disease early. To do so we will recruit patients with ovarian tumours (benign and malignant), obtain samples from them (urine, tissue and blood) and analyse them for steroid and other novel markers. As research progresses, novel markers hitherto unknown may also be tested. We will also be studying the genes expressed in OC to understand how changes in steroid hormone production may take place.
Women over the age of 18 years with capacity to give informed consent and from the following patient groups: 1. Patients having elective surgery for their ovaries to be removed(oophorectomy)for malignancy or benign related conditions. 2. Patients diagnosed with ovarian cancer and having surgery after a period of neo-adjuvant chemotherapy. 3. Patients having elective surgery (oophorectomy) for benign unrelated conditions.
1.Age < 18 years. 2.Patients who do not understand verbal or written English 3.Patients lacking capacity to consent
The CRUK Stratified Medicine Programme has now progressed to Part 2 (SMP2) after demonstrating in the pilot, Part 1, that the study was feasible in the UK. SMP2 has a sole focus on advanced non small cell lung cancer and is designed to facilitate molecular profiling for enrolment in the National Lung Matrix trial of patients with locally advanced or late stage metastatic lung cancer (Stage IIIA, IIIB or IV primary carcinoma of the lung). The programme aims to profile patient’s tumour samples to identify aberrations that make them eligible for the Matrix trial. In order to recruit patients to the trial the programme aims to successfully profile 2000 tumour samples per year across several centres in the UK. We will seek patient consent for: 1. Referral of surplus diagnostic tumour biopsies to genetic testing laboratories (technology hubs) in the UK for analysis of patterns of genetic change in the tumours. 2. Collection of a sample of blood for the extraction of normal germline nucleic acid, for the purposes of comparison to the paired tumour. 3. Collection of routine clinical data on demographics, initial and subsequent diagnostics, treatment and outcomes 4. The linkage of this information in a pseudonymised database for further analyses by the partners in the programme and researchers. 5. The communication of the results of molecular testing to the oncology team at the referral site
•Adenocarcinoma (all subtypes, IASLC classification recommended) •Squamous cell carcinoma •Other non-squamous non-small cell primary lung carcinoma subtypes, including large cell carcinoma providing neuroendocrine differentiation has been excluded using immunohistochemistry Tumour samples may be from the following types: •Bronchoscopic, percutaneous or surgical biopsies from primary tumour, lymph node or other metastases including visceral, cerebral and bone (see below for decalcification requirements) •Paraffin-embedded cell blocks from endoscopic bronchial ultrasound fine needle aspiration/biopsy (EBUS FNA/B) samples from tumour/lymph nodes or malignant effusions •Late stage (IIIA and above) lung resections •DNA remaining after local molecular testing (e.g. for EGFR or ALK) may be acceptable for analysis. Any centre intending to submit extracted DNA should in the first instance discuss this with the lead scientist at the relevant SMP2 molecular genetics laboratory (i.e. Birmingham, Cardiff or Royal Marsden/ICR). Each patient must have a matching blood sample. Capable of giving informed consent, and such consent recorded. Over the age of 18
Under the age of 18. Incapable of giving informed consent. The following are not eligible for the CRUK Stratified Medicine programme: •Non-epithelial malignancies •Small cell carcinoma •Typical or atypical carcinoid and tumourlets •Large cell neuroendocrine carcinoma •Malignant mesothelioma •Malignant tumour of another primary site metastatic to the lung e.g. metastatic colorectal carcinoma •Samples should not be from a patient known to have bloodborne or transmissible infection such as HIV, viral hepatitis (with a detectable viral load) or tuberculosis.
Lung Cancer Skin Cancer
The CYTOFLOC trial will obtain preliminary data on the acceptance rate, effectiveness and completion rate of a minimally invasive technique called Cytosponge that collects cells from the gullet (oesophagus), which can then be potentially used for identification of disease recurrence. Cytosponge is a capsule-sized device which contains an expandable, spherical mesh which is attached to a string. The capsule dissolves in the stomach after swallowing, releasing the sponge which is then retrieved by gently pulling the string after five minutes. As the sponge is pulled out it collects the cells from the lining of the oesophagus. The Cytosponge samples the entire oesophagus and therefore is more likely to pick up any abnormal cells than a biopsy, because Cytosponge will pick up abnormal cells even from areas not visualised on endoscopy (video examination of the gullet and stomach). Participants have the option to consent to their surplus tissue remaining after routine biopsies being used in further research analysis. These samples include: - baseline diagnostic biopsies - endoscopic/surgery biopsies testing for residual cancer near the time of CYTOSPONGE testing (post chemo-radiotherapy) Participants also have the option of providing a research blood sample for further analysis. If we can show that Cytosponge is a safe, feasible and acceptable screening tool for detection of residual or recurrent cancer following treatment with Chemoradiotherapy (CRT) for oesophageal cancer, we plan to run larger clinical trials in the future. In such studies we will study the effectiveness of Cytosponge as surveillance strategy after CRT, by using the test on multiple occasions over a period of time.
1. Male or female, Age >/= 16 years who a. have undergone pre-operative CRT as treatment for oesophageal cancer and are due to undergo oesophagectomy or b. have undergone definitive CRT as treatment for oesophageal cancer 2. 4-16 weeks post completion of CRT 3. Dysphagia score 0-2 (Mellow Scale) 4. Able to swallow tablets 5. Physiologically fit for endoscopy 6. Written (signed and dated) informed consent 7. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations.
1. Known to have oesophageal varices or stricture requiring dilatation of the oesophagus 2. Unable to temporarily discontinue anticoagulation therapy/medication prior to their procedure 3. Oesophageal stent 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.
The UK has the highest incidence of mesothelioma. The incidence has risen by 497% since the late 1970’s and is increasing worldwide due to continued mining and use of asbestos. For patients with mesothelioma who have relapsed after taking pemetrexed and cisplatin, there is currently no standard treatment, making this an urgent unmet need. Recent trials in this area have not found an effective treatment that improves overall survival. Following a debate in the House of Lords, a national survey assessing the research priorities in mesothelioma found that ‘exploiting the potential of immunotherapy’ was a top priority. This trial was designed in response to that survey. It uses the immunotherapy agent nivolumab which blocks programmed cell death 1 (PD-1) receptor on activated T-cells (a type of white blood cell forming part of the immune system). Early research has found a dependency of mesothelioma on the PD-1 checkpoint. By attaching to PD-1, nivolumab blocks its action (checkpoint inhibition), preventing it from turning off the T-cell, and therefore allowing the immune system to work. PD-1 checkpoint inhibition has revolutionised the treatment of melanoma and it is hoped to be as effective in mesothelioma. This trial is a randomised, double blind placebo controlled trial of patients with mesothelioma who are third relapse following a platinum based chemotherapy treatment. Patients will be randomised in a 2:1 ratio (nivolumab: placebo). 332 patients will be recruited from 25 UK centres over a four-year period with the last patient having a minimum of 6 months follow up. All patients will be on treatment for 12 months unless they progress or withdrawal prior to this. Clinic visits will occur every 12 weeks, mirroring standard care. Data following progression will be obtained from the NHS Information Centre.
1) Histological confirmation of mesothelioma 2) Prior treatment with at least two lines of platinum based chemotherapy 3) ECOG Performance Status 0-1 4) Evidence of disease progression (which is radiologically assessable through RECIST) on CT scan within 28 days of trial treatment 5) Age 18 and above 6) Screening laboratory values within protocol specified ranges 7) Willing to use adequate contraception methods where applicable 8) Willing to provide blood and tissue samples relating to mesothelioma 9) Expected survival of at least 12 weeks
Patients meeting the following criteria will be excluded: 1) Untreated, symptomatic CNS metastases 2) Carcinomatous meningitis 3) Active, known or suspected auto-immune disease 4) Those requiring systemic treatment with corticosteroids or immunosuppressive medications within 14 days of planned first dose 5) Other active malignancy requiring treatment 6) Serious or uncontrolled medical disorder or active infection which would impact on the trial or affect their involvement 7) Prior treatment with anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibody 8) History of testing positive for HIV or AIDS or a positive test for Hepatitis indicating acute or chronic infection 9) History of allergy or sensitivity to monoclonal antibodies 10) Women who are pregnant or breastfeeding
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
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.
Colorectal Cancer Genetics
There is a critical clinical need to develop tests that can better identify and predict future risk of relapse (cancer returning) in patients with primary triple negative breast cancer (TNBC), to allow further treatment to be tailored to prevent or delay relapse. DNA from cancer cells also called circulating tumour DNA (ctDNA), can be detected in the blood of cancer patients, and can be used to track progress of disease. Detection of ctDNA requires highly sensitive assays as only a small amount of cancer DNA is present in the blood. Due to technological advances personalised assays for ctDNA monitoring can be designed. ctDNA blood tests allow for highly sensitive and specific serial sampling to be performed during treatment. Poor outcomes in TNBC patients are compounded by a lack of suitable targeted drugs. Immunotherapy is showing great promise in cancer treatment and pembrolizumab is a promising novel immune therapy in the treatment for TNBC, with evidence of activity in initial studies in metastatic TNBC patients. This study will recruit patients who have completed, standard therapy for primary, potentially curable, TNBC. Patients will be asked to provide serial blood samples for blinded ctDNA screening. Randomisation to pembrolizumab treatment or observation will be triggered if a ctDNA test is positive, indicating that the patient still has residual cancer and is at very high risk of future relapse. The main aims are to assess whether ctDNA screening can be used to predict which patients are at highest risk of relapse, and identify patients that have microscopic or minimal residual disease (MRD), that is not visible on imaging. Then, in patients that have MRD detected, to assess the potential effectiveness of adjuvant treatment with pembrolizumab, assessed as the ability to result in a sustained clearance of ctDNA, as a surrogate marker of effectiveness.
Inclusion criteria for all patients: 1.Signed Informed Consent Form for Registration 2.Male or female patients ages 16 years or older 3.ECOG performance status 0 or 1 4.Histologically proven primary triple negative breast cancer as defined as oestrogen receptor (ER) negative, progesterone receptor (PgR) negative (if available, otherwise PgR unknown), (as defined by Allred score 0/8 or 2/8 or stain in < 1% of cancer cells) and HER2 negative (immunohistochemistry 0/1+ or negative by in situ hybridization) as determined by local laboratory 5. Provision of tissue from two archival tumour tissue samples (either from diagnostic biopsy, and/or primary surgery, or where available residual disease post-neoadjvuant chemotherapy). If only one tumour sample is available, the site should inform the ICR-CTSU who will discuss eligibility with the Chief Investigator or if unavailable the designated TMG member. Patients who have tumours previously sequenced outside the c-TRAK TN trial must provide one archival tumour tissue sample and the report that confirms the mutations detected (see section 14.1.1) 6. Patients with moderate or high risk early stage triple negative breast cancer according to the following risk of relapse criteria: High risk criteria: a. Neoadjuvant chemotherapy – residual invasive cancer in the axillary nodes after chemotherapy, defined as at least microscopic residual disease (> 0.2mm) by histology, OR OSNA macroscopic, OR OSNA microscopic with residual invasive cancer in the breast b. Adjuvant chemotherapy – tumour size > 50mm and node positive AND/OR > = 4 nodes positive regardless of primary tumour size Moderate risk criteria: a. Neoadjuvant chemotherapy – residual invasive cancer in the breast and axillary lymph node negative after chemotherapy b. Adjuvant chemotherapy – tumour size > 20mm AND/OR involved axillary macroscopic lymph node defined as > = 2mm by histology or OSNA macroscopic Note: Patients who have received both neoadjuvant chemotherapy and further adjuvant chemotherapy must fulfill the adjuvant chemotherapy risk criteria to be eligible on either clinical staging prior to neoadjuvant chemotherapy or pathological staging at surgery. 7. Patients registered according to following criteria for timing of registration Neoadjuvant chemotherapy: Patients must be registered within 3 months of surgery or within 4 weeks of completing adjuvant radiotherapy if indicated, whichever occurs later. Patients may be registered before or during radiotherapy and should be registered as early as possible Adjuvant chemotherapy: Patients must be registered within 3 months of the last cycle of adjuvant chemotherapy, or within 4 weeks of completing adjuvant radiotherapy, whichever occurs later. Patients may register during adjuvant chemotherapy or radiotherapy and should be registered as early as possible 8. Provision of blood samples for germline DNA analysis and exploratory ctDNA analysis 9. Patients with bilateral tumours can be included if both are triple negative and if two archival tissues samples can be provided per tumour 10. Patients must have had surgery achieving clear margins (as per local guidelines) 11. Female and male patients of reproductive potential must be willing to use an adequate method of contraception, for the first year of the trial and if randomised to pembrolizumab, for the duration of treatment through to 120 days after the last dose of pembrolizumab (see appendix 2). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient 12. Patients must be willing to have frequent blood tests (every 3 months for 2 years in ctDNA screening and 3 weekly if subsequently allocated pembrolizumab) and receive a 12 month course of pembrolizumab if randomised to pembrolizumab treatment on ctDNA detection 13. No evidence of distant metastatic disease on staging scans conducted at any time since initial diagnosis Additional inclusion criteria for patients randomised to pembrolizumab treatment: 1. Signed Informed Consent Form for pembrolizumab treatment 2. Adequate organ function as defined by bone marrow function, renal function and coagulation laboratory values as per protocol 3. Women of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 4. Patients willing to receive a 12 month course of pembrolizumab and have frequent blood tests (every 3 weeks during treatment and every three months for a year following completion of pembrolizmuab treatment)
Exclusion criteria for all patients: 1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than surgery, locoregional adjuvant radiotherapy, standard adjuvant chemotherapy, or a bisphosphonate/denosumab. 2. Prior treatment with a PDL1, PD1, or other immunomodulatory therapy. 3. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for basal cell carcinoma of the skin or cervical carcinoma in situ 4. Patients previously entered into a therapeutic trial during or after neoadjuvant chemotherapy where experimental therapy is continued post-surgery. Patients involved in clinical trials involving experimental drugs prior to primary standard treatment (i.e. window of opportunity trials) can be considered for entry into c-TRAK TN. 5. Treatment with an unlicensed or investigational product within 4 weeks of trial entry. 6. Active autoimmune disease requiring systemic therapy in the last two years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of such systemic treatment. 7. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab. 8. Known history of active TB (Tuberculosis Bacillus). 9. Known history of Human Immunodeficiency Virus (HIV). 10. Known active Hepatitis B or Hepatitis C. 11. Known history of, or any evidence of active, non-infectious pneumonitis. 12. Active infection requiring systemic therapy. 13. Females who are pregnant or breastfeeding. 14. Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written informed consent. Additional exclusion criteria for patients randomised to pembrolizumab treatment: 1. Any concurrent or planned anti-cancer treatment (e.g. adjuvant chemotherapy) since completing standard therapy for early stage triple negative breast cancer other than locoregional adjuvant radiotherapy or standard adjuvant chemotherapy, or a permitted bisphosphonate/denosumab. 2. Diagnosis of an additional cancer since enrolment in the trial other than basal cell carcinoma of the skin or cervical carcinoma in situ 3. Prior chemotherapy, targeted small molecule therapy or radiation therapy within 4 weeks of first administration of pembrolizumab. 4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to first administration of pembrolizumab treatment. 5. Has not recovered (< = Grade 1 or at patient’s baseline) from adverse events due to a previously administered therapy. Note: Patients with < = grade 2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the trial. If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the surgery prior to randomisation. 6. Treatment with an unlicensed or investigational product within 4 weeks of first administration of pembrolizumab treatment 7. Active autoimmune disease requiring systemic therapy in the last two years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of such systemic treatment. 8. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first administration of pembrolizumab treatment. 9. Known history of active TB (Tuberculosis Bacillus). 10. Known history of HIV (Human Immunodeficiency Virus). 11. Known active Hepatitis B or Hepatitis C. 12. Known history of, or any evidence of active, non-infectious pneumonitis. 13. Active infection requiring systemic therapy. 14. Received a live vaccine within 30 days of planned start of pembrolizumab. (Seasonal flu vaccines are generally inactivated and are permitted; however intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines and are not permitted.) 15. Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written informed consent. 16. Females who are pregnant or breastfeeding.
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).
Children's Cancer and Leukaemia
Bone marrow transplantation is a highly efficacious treatment for leukaemia but is often complicated by graft-versus-host disease (GvHD), which accounts for the main toxicity of the procedure. During the last few years we have developed a hugely successfully national programme to treat severe refractory cases of GvHD with Mesenchymal Stromal Cells (MSC). In order to maximise the effects of this treatment we need to better understand how MSC work. We have recently discovered that MSC injected into GvHD recipients are killed by host immune cells. The dying MSC are fundamental to produce the control of GvHD. For this reason, here we propose to fully characterize the host killer cells in GvHD patients. The data will provide information to select the patients who are more likely to respond to MSC. We will also learn which drugs may interfere with the killer cells and ultimately perfect MSC therapies.
-Ability to give informed consent -Patients with GvHD after allogeneic Haematopoietic Stem Cell Transplantation or Donor Lymphocyte Infusion (irrespective of the donor, conditioning regimen, source of stem cells or underlying condition). Only a clinical diagnosis will be sufficient to be included, provided the exclusion of potential alternative aetiologies -Patients will be eligible irrespective of the type of treatment used (steroids or other second-line therapies) -Patients must receive MSC as GvHD treatment -Patients and MSC donors must have signed an informed consent form.
-Inability to give informed consent -Active and uncontrolled infection. Patients with documented uncontrolled EBV, CMV or fungal infection. Pyrexia of unknown origin or documented bacteraemia is permitted. -Evidence of relapsed or progressive malignant disease at the time of enrollment in the study -Patients in poor clinical conditions with life expectancy of less than 30 days
Breast cancer remains the commonest cancer in women worldwide. Obesity is associated with an increased risk of post-menopausal breast cancer and poorer prognosis in both pre- and post-menopausal women. With the obesity rate in British women predicted to increase to 43% by 2030, there is a need to investigate the role of this risk factor in breast cancer. However, it is recognised that body mass index (BMI), calculated from height and weight, is a simplistic way of measuring body habitus. To date, no techniques in routine clinical use give any valuable measure of a patient’s true muscle mass or body fat (body composition). This study will assess the use of a novel method to provide valid and clinically acceptable measures of body composition in women receiving treatment for breast cancer. Bioelectrical impedance spectroscopy (BIS) provides detailed information on body composition from a brief non-invasive procedure. The SECA BIS analyser has been extensively validated in non-cancer patients. We will validate this technology against a traditional method of body composition measurement (deuterium water dilution) in a group of early breast cancer patients. BIS measurements of body composition in women presenting with and without breast cancer will be compared to identify potential factors predictive of risk or prognosis. Changes in body composition will be monitored whilst patients progress through different treatments. Questionnaire information on lifestyle will allow detailed characterisation of the study cohort. Blood and surplus tissue specimens will be stored for future biochemical analyses. All study patients will receive conventional treatment for primary breast cancer. This pilot study will establish recruitment feasibility and provide data for power calculations ahead of a future definitive study investigating body composition and clinical outcome in breast cancer. This project will also establish a firstclass biological resource for future research projects.
Patients: First diagnosis of invasive breast carcinoma (stage I and II) prior to definitive treatment, female, aged 47-73 years, no evidence of metastatic disease, able to complete written records in English, post-menopausal Controls: Attendance at UHS breast clinic with no diagnosis of invasive breast carcinoma, female, aged 47-73 years, able to complete written records in English, postmenopausal
For both groups: Women who refuse their consent, previous invasive malignancy (with the exception of non-melanomatous skin cancer), Ductal carcinoma in situ (controls only), lobular carcinoma in situ (controls only), conditions preventing physical participation in the study, plans for neo-adjuvant chemotherapy or hormone therapy, no plans for surgical treatment, premenopausal.
The molecule CD32b is thought to be present on many B-cells including the malignant B-cells in some types of lymphoma and leukaemia. The study drug, BI-1206, is an anti-CD32b monoclonal antibody which attaches to CD32b on the surface of B-cells and is thought to act by recruiting host immune cells toward the tumour leading to cancer cell death as well as enhancing the anti-cancer effect of other anti-CD20 antibodies such as rituximab by stopping them being absorbed by cells. The proposed study is a first in man clinical trial of the drug called BI-1206 on its own and then also in combination with an anti-CD20 antibody (such as rituximab) which is commonly used to treat lymphoma and some types of leukaemia. The four main aims of this trial are to find out: - The maximum dose of BI-1206 that can be given safely to patients (to a maximum dose of 800mg) on it's own and in combination with an anti-CD20 antibody, rituximab. - More about the potential side effects of BI-1206 and how they can be managed. - What happens to BI-1206 inside the body. - The effect of BI-1206 treatment (with or without rituximab) on tumour size and survival. Approximately 81 patients with relapsed or refractory CD32b positive B-cell lymphoma or leukaemia will be entered into this study. This will include approximately 19 recruited for the BI-1206 dose escalation phase (Part A), up to 12 (likely 6) for a combination dose escalation and up to a further 50 patients recruited to two dose expansion cohorts; one of BI-1206 alone and one of BI-1206 plus rituximab (Part B). The final number will depend on the number of dose escalations required to reach the MTD.
1. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up 2. B-cell lymphoma or chronic lymphocytic leukaemia proven by histology or flow cytometry, relapsed or refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient. Patients should have received at least one line of conventional previous therapy which must have included a rituximab based regimen. 3. CD32b positive malignancy as demonstrated centrally by immunohistochemistry or flow cytometry prior to study entry. Available tissue or blood must have been taken within six months of study entry. 4. Life expectancy of at least 12 weeks 5. World Health Organisation (WHO) performance status of 0-2 6. Haematological and biochemical indices within the ranges shown below. Haemoglobin (Hb) ≥9.0 g/dL (red cell support is permissible) Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (or > 0.5 x 10^9/L if due to lymphoma), granulocyte - colony stimulating factor (G-CSF) support is not permissible at screening Platelet count ≥50 x 10^9/L (or ≥30 x 10^9/L if due to malignant involvement of bone marrow) Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert’s syndrome in which case up to 3 x ULN is permissible. Or: Alanine amino-transferase (ALT) and /or aspartate amino-transferase (AST) ≤ 2.5 x (ULN) unless raised due to malignant hepatic involvement in which case up to 5 x ULN is permissible Either: Calculated creatinine clearance (Cockcroft Gault)≥30 mL/min (uncorrected value) Or: Isotope clearance measurement ≥30 mL/min (corrected) 7. 18 years or over 8. B-cell lymphoma patients only: patient has at least one measurable lesion by CT scan (defined as greater than 1.5 cm in one axis) or in the case of Waldenström's macroglobulinemia, disease must be assessable by the criteria stated in the protocol. 9. Patients recruited to Part B, Arm 2 (combination arm) only: CD20 positive malignancy as demonstrated by immunohistochemistry or flow cytometry prior to study entry. Analysis must have been performed within 6 months of study entry.
1. Allogenic bone marrow transplant within 12 months prior to the first dose of BI-1206 or presence of chronic graft versus host disease. 2. Patients with clinically active leptomeningeal or central nervous system lymphoma/leukaemia. 3. Patients with transformed lymphoma from a pre-existing indolent lymphoma. 4. Patients with a previous history of transformation, but on this disease episode have a biopsy proven indolent recurrence may be included. Patients with proven or suspected Richter transformation are not eligible. 5. Doses of prednisolone > 10 mg daily (or equipotent doses of other coritcosteroids) are not permitted whilst on the study other than as pre-medication. During the screening period, doses of up to 20 mg per day may be given but the dose must be reduced to 10 mg/day by Cycle 1 Day 1 (or Day -7 in the CLL combination expansion). 6. Known or suspected hypersensitivity to study drugs. 7. Cardiac or renal amyloid light-chain (AL) amyloidosis. 8. Radiotherapy, endocrine therapy, immunotherapy, chemotherapy or investigational medicinal products during the previous 4 weeks before treatment. 9. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the Centre for Drug Development (CDD) should not exclude the patient. 10. 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 forms of contraception (one highly effective form plus a barrier method) as defined in the protocol are considered eligible. 11. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception as defined in the protocol. Men with pregnant or lactating partners must also be willing to ensure that their partner uses an effective method of contraception for the same duration (as defined in the protocol) to prevent exposure to the foetus or neonate. 12. Major thoracic or abdominal surgery from which the patient has not yet recovered. 13. At high medical risk because of non-malignant systemic disease including infection. 14. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV). 15. Patients with an active, known or suspected autoimmune disease (not including CLL auto-immune disease). Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to participate. 15. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association), prior history of cardiac ischaemia or prior history of cardiac arrhythmia. 16. Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or any other reason (Part B combination arm only). 17. Active, ongoing infection. 18. Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial. 19. Is a participant or plans to participate in another interventional clinical study, whilst taking part in this Phase I/IIa study of BI-1206. Participation in an observational study would be acceptable. 20. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for three years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
Biomede is an international, multicenter, randomised, open-label, adaptive, phase II trial of treatment for Diffuse Intrinsic Pontine Glioma (DIPG). This trial mandates a biopsy of the tumour to obtain the biological profile of the tumour. The allocation of treatment in each patient will be based on the specific biological tumour profile. Recruitment target is 80 patients in the UK, 250 in the EU with DIPG over 4 years. The initial agents to be studied based on biomarkers profile are; Dasatinib, Erlotinib and Everolimus as single agents combined with standard radiotherapy.
Eligibility criteria for the BIOMEDE study (pre-screening for the randomised subtrials) - Diagnosis of DIPG (clinical and radiological, or histological in case the biopsy was performed before study entry) - DIPG at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy - NB : Metastatic disease allowed. Patient with metastatic disease are eligible for the study (including the randomised trial if diagnosis of DIPG confirmed). In this situation, radiotherapy will have to start within three weeks after the biopsy while targerted treatment will start at the end of the irradiation - Age > 6 months and < 25 years. For children below the age of 3 years, inclusion in the study and medical decisions should be discussed with the coordinating investigator. - Eligible for a biopsy, or biopsy performed for diagnostic purpose and material available for the biomarker assessment - Eligible for cerebral radiotherapy - Patient covered by an health insurance if national requirement - Written informed consent given by patient and/or parents/legal representative for biomarkers assessment and registration in the study. Common eligibility criteria for the BIOMEDE randomised subtrials - Eligibility criteria for the study (see above) - Confirmed histological diagnosis of diffuse intrinsic pontine glioma (grade II, III, IV WHO), confirmed by central pathology review (including the assessment of the loss of H3K27me3 by immunohistochemistry or the presence of a mutation in the histone H3 variant genes). Patients without classical clinical and radiological diagnostic criteria who fulfil the histological and biological criteria of DIPG are eligible for the trial. Pilocytic astrocytoma and ganglioliomas are not eligible. - Life expectancy > 12 weeks after the start of study treatment - Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take the neurologic deficit per se into account. NB: Children and young adults with a worse performance status due to glioma-related motor paresis can be included. - Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/l - Total bilirubin < 1,5 x ULN, AST and ALT< 2,5 x ULN - Serum creatinine < 1,5 X ULN for age. If serum creatinine > 1,5 ULN, creatinine clearance must be > 70 ml/min/1,73 m² (EDTA radioisotope GFR or 24 hours urines collection) - Normal coagulation tests: prothrombin rate (prothrombin time = PT), TCA (PTT), fibrinogen - No current organ toxicity > grade 2 according to the NCI-CTCAE version 4.0 especially cardiovascular, pulmonary or renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment, interstitial lung disease, pulmonary arterial hypertension).In case of known or possible cardiac disease, a cardiological advice will be required prior to the inclusion in the randomized trial as a preexisting cardiopathy represents a contra-indication to dasatinib. - Effective and appropriate contraception for patients (male and female) of reproductive potential during their entire participation in the study and during 6 months after the end of treatment. Effective contraception are defined in CTFG Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials” - Negative pregnancy test (serum beta-HCG) evaluated in the last week in females of reproductive potential - Written informed consent given by patient and/or parents/legal representative for treatment and randomization Eligibility criteria for the subtrials Eligibility criteria for the different subtrials will be mainly based on biomarkers assessment as detailed in the table above. In addition, contra-indication and precautions for use to specific drugs will be considered.
Non eligibility criteria for the study - Massive intratumour bleeding - Any other concomitant anti-cancer treatment not foreseen by this protocol - Any other cancer during the last 5 years - Uncontrolled intercurrent illness or active infection - Any other co-morbid condition that in the investigator’s opinion would impair study participation - Unable for medical follow-up (geographic, social or mental reasons) - Patient not fulfilling one of the previous eligibility criteria. - Patient previously treated with irradiation on the brainstem for another neoplasm - Patient with congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. - Patient not covered by a social security agreement accepted in the treating country if national requirement. - Pregnant or breast feeding women - NB: A patient with known hypersensitivity for one the drug or its excipients could still participate to the study and receive one of the other drug(s)
Brain Cancer Children's Cancer and Leukaemia Neurosurgery Teenage and Young Adult's Cancer
To assess the efficacy (in terms of Disease free survival which is defined as time from randomisation to recurrence, development of a new primary or death from any cause) of observation against 24 weeks of adjuvant post-operative chemotherapy in resected stage I-III small bowel adenocarcinoma and to assess the efficacy of 24 weeks of adjuvant post-operative fluoropyrimidine monotherapy versus fluoropyrimidine plus Oxaliplatin combination chemotherapy.
1. R0 resected stage I, II or III small bowel adenocarcinoma 2. No evidence of residual or metastatic disease at laparotomy and on CT/MRI imaging of chest, abdomen and pelvis. 3. Patients must be registered and randomised within 12 weeks of surgery and commence chemotherapy within 14 weeks of surgery 4. ECOG Performance Status of 0 or 1 5. Absolute neutrophil count of ≥ 1.5 x10(9)/l 6. Platelet count ≥ 100 x 10 (9)/l 7. Haemoglobin ≥ 90 g/l (previous transfusion is allowed) 8. AST and ALT ≤ 2.5 x upper limit of normal (ULN). (At least one of ALT or AST MUST be performed) 9. Creatinine clearance > 50 ml/min (calculated by Cockcroft Gault or Wright equation) or measured by EDTA 10. Serum bilirubin ≤ 1.5 x ULN 11. Signed and dated informed consent indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment. 12. Age ≥ 16 years 13. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
1. Non-adenocarcinoma histology of small bowel tumour which includes but is not confined to lymphoma, GIST, carcinoid or other neuroendocrine tumour, squamous carcinoma, melanoma or sarcoma. 2. Previous neo-adjuvant chemo(radio)therapy for small bowel adenocarcinoma 3. Clinically significant cardiovascular disease (i.e. active or < 12 months since cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association [NYHA] grade II or greater, congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension) 4. Pregnancy/lactation or of child bearing potential and not using medically approved contraception. (Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential) 5. Previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease free interval of at least 3 years and treatment was with curative intent 6. Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency 7. Known untreated coeliac disease (may be enrolled if diet controlled), untreated chronic inflammatory bowel disease or other cause of malabsorption or intestinal obstruction 8. Grade ≥ 2 peripheral neuropathy 9. Administration of any investigational drug within 28 days or 5 half lives, whichever is longer, prior to receiving the first dose of trial treatment
The AVAIL-T trial is a trial to find out how effective avelumab is at treating patients with primary T-cell lymphoma that is refractory to or has relapsed following initial treatment. Up to 35 people will be taking part in the AVAIL-T trial at hospitals across the United Kingdom. All patients on the trial will be recruited over 2 years and receive 8 cycles of avelumab treatment. Avelumab is an anti-PD-L1 antibody that will be given as an infusion once every 2 weeks in cycles lasting 28 days. The trial will look at the response to aveulumab, by measuring the change in the tumour size using CT scans, and seeing how long that response is maintained. It will also look at toxicity, overall survival, and progression free survival. In addition the trial will analyse blood samples and samples of the lymphoma to understand better how the cancer behaves. This may guide us in developing better treatments in the future.
• Male or female patients aged > = 16 years • Life expectancy > 12 weeks • ECOG performance status < = 2 • Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified (PTCL NOS) , angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy associated T-cell lymphoma (EATL), extranodal NK/T- cell lymphoma (ENKL), transformed mycosis fungoides (LCT MF), and subcutaneous panniculitis and T cell lymphoma * For all relapsed and refractory patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 3 months of registration • Failed at least 1 prior therapy (but no upper limit of prior regimens) • Adequate haematological function defined by at registration: o absolute neutrophil count (ANC) > = 1.0 × 109/L, (unsupported) o platelet count > = 75 × 10 9/L, (unsupported) o haemoglobin > = 90 g/L (may have been transfused) • Adequate hepatic function and no evidence of hepatic involvement by T-cell lymphoma as defined by: o total bilirubin level < = 1.5 × the upper limit of normal (ULN) range (patients with elevated bilirubin due to Gilbert’s syndrome are eligible) o AST and ALT levels ≤ 1.5 × ULN for all patients and o no clinical suspicion of hepatic involvement by T-cell lymphoma and o no liver abnormalities on imaging studies that might be due to T-cell lymphoma • Adequate renal function defined by an estimated creatinine clearance > = 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) • CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in cranio-caudal length attributable to relapsed/non responding lymphoma • Negative serum pregnancy test at screening for women of childbearing potential. • Highly effective contraception for both male and female patients if the risk of conception exists. (Note: women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required from consent, throughout and for at least 60 days after avelumab treatment. • Ability to give informed consent
Patients are not eligible for the trial if they fulfill any of the following exclusion criteria: • All patients with active CNS involvement of lymphoma • Prior organ transplantation, including allogeneic stem cell transplantation • Significant acute or chronic infections including, among others: o Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), o Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) • Current use of immunosuppressive medication, EXCEPT for the following: o intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); Systemic corticosteroids at a maximum dose of 1 mg/kg of prednisone or equivalent during screening (to be stopped by day 1 of trial treatment); Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). • Active autoimmune disease that might deteriorat e when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible • Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade > = 3) • Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade < = 2 or other Grade < = 2 not constituting a safety risk based on investigator’s judgment are acceptable • Pregnancy or lactation • Known alcohol or drug abuse • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to registration), myocardial infarction (< 6 months prior to registration), unstable angina, congestive heart failure (> = New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. • Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study • Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (e.g. the flu vaccine) • Active infection requiring systemic therapy • Major surgery within 4 weeks of trial entry • Patients and partners of childbearing potential not willing to use two methods of effective contraception during and for 60 days after therapy
The primary objectives of this trial are to compare progression-free survival (PFS, the time from starting the trial to the point at which the cancer starts to grow again or the patient dies, whichever comes first) in patients within different biomarker-defined subgroups (the treatment/placebo offered within each arm of the trial will be defined by specific molecular features of that individual patients tumour). Initially, patient urothelial tumour samples will be tested for Androgen Receptor (AR). Patients whose tumour is negative for AR will be offered the arm of the trial offering a drug called cabozantinib or placebo. The primary outcome will be PFS for patients for patients receiving each therapy. Further therapeutic arms (with additional options for treatment and molecular tumour testing) will be added in future throughout the trial.
Inclusion criteria for ATLANTIS are as follows: 1 - Previously diagnosed stage IV urothelial cancer (UC) (T4b, Nany, Many; Tany, N1-3, M0; Tany, Nany, M1). Histologically confirmed urothelial cancer. This includes cancers of the urinary bladder, ureter, renal pelvis or urethra with transitional and/or squamous histology. A component of either or both of these histologies is adequate for entry. 2 - Able to commence the trial treatment within 10 weeks of completing chemotherapy. 3 - Adequate tissue for biomarker testing. Testing will occur centrally. 4 - Patients must have received between 4 and 8 cycles of first line chemotherapy for Metastatic/advanced UC to be eligible. Previous adjuvant or neoadjuvant chemotherapy does not count as a line of therapy. 5 - Adequate organ function as defined in drug specific appendices. 6 - ECOG performance status 0-2. 7 - Age ≥ 16 years. 8 -Female patients of childbearing potential must agree to comply with effective contraceptive measures, have been using adequate contraception since the last menses, will use adequate contraception during the trial, and have a negative pregnancy test within one week of trial entry. 9 -Male patients with partners of child-bearing potential must agree to take measures not to father children by using one form of highly effective contraception, effective at the first administration of IMP and throughout the trial. 10 - Written informed consent prior to admission to this trial. 11 -Meets all inclusion criteria for the relevant component subgroup listed in the appendices for each specific IMP.
Exclusion creiteria for ATLANTIS are as follows: 1 - Progression during first-line chemotherapy for metastatic disease. This should be based on a radiological comparison between the pre-chemotherapy CT and end of treatment CT (local review). Patients may be permitted to enter the trial if their end of chemotherapy scans shows response or stable disease (local assessment using RECIST 1.1) when compared to their latest pre-chemotherapy scan, even if there is progression when compared to a nadir scan performed during chemotherapy. These patients should be discussed with the trial team. 2 - Do not currently require second line chemotherapy in the opinion of the investigator. 3 - More than one line of chemotherapy for metastatic or locally advanced disease (where the regimen is changed during first-line treatment without evidence of progression (for example the patient changes from cisplatin to carboplatin due to toxicity) this will constitute a single line of chemotherapy). Prior adjuvant / neoadjuvant chemotherapy is permitted in addition. 4 - Patients receiving radical/curative surgery or radiotherapy at the end of first line treatment (palliative radiotherapy is allowed). 5 - Patients receiving less than 4 or more than 8 cycles of chemotherapy before randomisation and initiation of trial intervention (excluding any chemotherapy given as neo-adjuvant / adjuvant). 6 - Treatment with any other investigational agent within 28 days prior to first dose of trial medication within ATLANTIS. 7 - Less than 3 or more than 10 weeks since the last infusion of first-line chemotherapy for advanced/metastatic UC at time of initiation of trial interventions. 8 - History of another malignancy in the last 2 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated / biochemically stable, organ confined prostate cancer not requiring on-going androgen deprivation therapy). 9 - 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). 10 - Positive pregnancy test for females. 11 - Inadequate organ function as defined in drug specific appendices. 12 - Ongoing therapy with prohibited medication which cannot be discontinued prior to starting trial specific intervention (as defined in drug specific appendices). 13 - Major surgery or any radiotherapy within 4 weeks prior to trial entry (palliative radiotherapy within > 2 weeks is permitted). 14 - Significant comorbidity or serious intercurrent medical or psychiatric illness, including serious active infection which, in the opinion of the investigator would make it inappropriate for the patient to enter the trial. 15 - Women who are breast feeding. 16 - Meets any of the exclusion criteria listed in the relevant component subgroup specific appendix.
Diffuse large B-Cell lymphoma is the most common subtype of non-hodgkins lymphoma, accounting for around 40% of the diagnoses. Current treatment uses a combination immunochemotherapy resulting in a cure in around 60-70% of patients who are treated within a clinical trial setting. It is recognised however that the outcomes found in clinical trials are generally better than those in the general population, which in this condition, although increases have been seen, has survival rates just under 60%. This difference is possibly due to the under-representation of the elderly in clinical trials who generally have poorer outcomes due to numerous comorbidities and the effects of chemotherapy toxicity on their health. Second-line strategies for such patients only provide an event free survival rate of 20% at 3 years, however this is only in those who are fit enough to receive the high dose therapy and who relapse within 12 months of primary treatment. For those patients who aren’t able to have these treatments the outcome is quite poor (survival less than 6 months). It has proven challenging to find effective treatment strategies for this group. As the incidence of DLBCL is rising and around 40% occur in those over 70, it is necessary that an effective treatment be found. Recent studies using a combination of rituximab, with oxaliplatin and gemcitabine (GemOx) in this population achieved a 44% complete response rate after 4 cycles of treatment and a 5 year progression free survival rate of 13%. This study intends to build on this success by using the R-GemOx in combination with a new antibody, atezolizumab in the hope that this will improve outcomes. Participants will be randomised on a 3:1 ratio to receive the R-GemOx with atezolizumab in comparison to R-GemOx only.
1) Histologically proven CD20 +ve diffuse large B-cell lymphoma 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) for gene expression profiling and central pathology review. 2) Refractory to, or relapsed following, first-line or second-line treatments with rituximab concurrently with anthracycline or anthracenedione-based chemotherapy (etoposide or gemcitabine allowed if comorbid). Refractory disease must fulfil one of the following: a) 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. b) Continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) is recommended but not mandatory. c) Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommended but not mandatory. 3) Not eligible for high-dose therapy with peripheral blood progenitor cell rescue at Investigator discretion as a result of: (a) Age (b) Co-morbidity (c) Previous HDT. Rationale to be clearly documented on eCRF and medical notes. 4) Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumour sites. 5) CT/PET scan showing at least: • 2 or more clearly demarcated lesions/nodes with a long axis > 1.5cm and short axis > = 1.0cm OR • 1 clearly demarcated lesion/node with a long axis > 2.0cm and short axis > = 1.0cm. 6) Resolution of toxicities from previous therapy to a grade that in the opinion of the investigator does not contraindicate study participation. 7) Patients aged 16 years or over. 8) Willingness to participate in appropriate pregnancy prevention measures. • Female patients who are fertile and of childbearing potential must have a negative serum or urine pregnancy test during screening (within 7 days prior to the start of trial treatment) and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of rituximab are considered eligible. Unless they are surgically sterile or > = 2 years after the onset of menopause. • Male patients with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of rituximab are considered eligible. Male subjects must also refrain from donating sperm during this period. Unless they are surgically sterile. • Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate 9) Written informed consent using current version of Protocol, Patient Information Sheet and Informed Consent Form. 10) ECOG performance status < = 3
1) Received any of the following treatments within two weeks prior to start of study therapy (unless otherwise stated): • Anti-cancer cytotoxics (excluding corticosteroids) • Radiotherapy unless it is to a limited field at to control life/organ-threatening symptoms. 2)DLBCL that is refractory to or relapsed within 3 months of a gemcitabine regimen for DLBCL 3) Major surgery within 4 weeks of registration. 4) Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half-lives or 4 weeks prior to registration. 5) History of stroke or intracranial haemorrhage within 6 months prior to registration. 6) Pre-existing peripheral neuropathy grade > 2. 7) Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV), a current LVEF of < 40% 8) Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study 9) Known lymphoma involvement of the CNS. 10) Known or suspected hypersensitivity to study treatments that in the opinion of the investigator contraindicates their participation. Patients with known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis or idiopathic pneumonitis, or evidence of active pneumonitis will be excluded from study participation. 11) Known HIV positivity; positive serology for Hep B (defined as positivity for Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (anti-HBc)) or C; chronic or current infectious disease (except evidence of prior vaccination). 12) Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 2 weeks of the start of Cycle 1. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-y) release assay. 13) 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. 14) Screening laboratory values: • platelets < 75x109/L (unless due to lymphoma involvement of the bone marrow) • neutrophils < 1.0x109/L (unless due to lymphoma involvement of the bone marrow) • creatinine > 2.0 times upper normal limit (unless due to lymphoma or unless creatinine clearance > 60mL/min (calculated using Cockcroft and Gault equation)) • total bilirubin > 1.5 times upper normal limit (unless due to lymphoma or a known history of Gilbert’s disease, no higher than > 3 times upper normal limit) • ALT/AST > 2.5 times upper normal limit (unless due to lymphoma, no higher than > 5 times upper normal limit) • alkaline phosphatase > 2.5 times upper normal limit (unless due to lymphoma, no higher than > 5 times upper normal limit) 15) Subjects known or suspected of being unable to comply with the study protocol. 16) Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening. 17) 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 patients with controlled Type I diabetes mellitus on a stable dose of insulin). Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: - Rash must cover < 10% of body surface area - Disease is well controlled at baseline and requires only low-potency topical corticosteroids - No occurance of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months 18) Patients who have previously undergone allogeneic transplantation. 19) Vaccination with a live vaccine within 28 days of study treatment or anticipation of need for such a vaccine during the course of the study and up to 5 months after the last dose of atezolizumab. 20) History of severe allergic anaphylactic reactions to chimeric, human or humanised antibodies, or fusion proteins. 21) Known hypersensitivity to CHO cell products or any component of the IMP
The study is designed as a prospective international (including also non-European institutions) multicentre cohort study, which will be coordinated by the Pancreatic Surgery Unit of San Raffaele Scientific Institute (Lead Study Centre) under the auspices of the European Neuroendocrine Tumor Society (ENETS) . The study duration is 6 years, patients will be recruited for 5 years from December 2016 to December 2021, with a follow up of 1 year at least (end of the study: December 2022) . After 2 years of recruitment an interim analysis will be performed in December 2018. San Raffaele Scientific Institute will be the lead centre from where the international study will be managed and coordinated. Participating study centres will identify, recruit patients and will send pseudoanonimised data of patients to the lead centre, which is responsible for statistical analysis, storing and controlling data. The research database will be managed and analysed by the Lead Study centre research team. Study participation is voluntary, there will be no reimbursement for patients.
-Age > 18 years -Individuals with asymptomatic sporadic NF-PNEN < = 2 cm -Diagnosis has to be proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging technique (CT or MR) that is positive at 68Gallium DOTATOC-PET scan or Octreoscan. -Patients who undergo surgery for NF-PNEN< 2cm within 12 months. In these cases, diagnosis has to be proven by histological confirmation of NF-PNEN -Able to consent.
Exclusion Criteria -NF-PNEN > 2 cm of maximum diameter -Presence of genetic syndrome (MEN1, VHL, NF) -Presence of symptoms (specific symptoms suspicious of a clinical syndrome related to hypersecretion of bioactive compounds) or unspecific symptoms
Other Upper GI
This study involves patients diagnosed with an unusual form of melanoma known as neurotropic melanoma. When this type of melanoma is diagnosed on the head or neck, the traditional treatment is surgery. This disease may have a high rate of local recurrence after surgery. If so, having radiation therapy soon after surgery could reduce the risk of the melanoma from returning but there have been no randomised trials to study this. Therefore, the purpose of this trial is to investigate if having radiation therapy soon after surgery on the head and neck is better at preventing the melanoma returning than just having surgery alone.nitial post-operative radiation therapy compared to initial observation after surgery for neurotropic melanoma. The main purpose of this study is to compare the rates of local recurrence in each arm of the trial. A total of 100 patients will be recruited across Australia, New Zealand and in other countries. The study involves half of the participants (‘Arm A’) having a 4 week course of radiation to the area of surgery. The other half of the participants (‘Arm B’) will have ongoing assessments (‘observation’) and can receive radiation if the melanoma returns (‘recurrence’). Patients randomised to receive radiation (‘Arm A’) treatment needs to commence within 3 months of the operation or when healing has occurred. They will usually need to visit the radiation department 5 days a week (not on weekends) for 20 treatments in total. To participate in this study patients will need to be available to see your doctor regularly for at least 5 years (every 3 months for the first 2 years, then 6 monthly) to check for any signs of melanoma return and to monitor any long term side effects experienced.
This study involves patients diagnosed with an unusual form of melanoma known as neurotropic melanoma. When this type of melanoma is diagnosed on the head or neck, the traditional treatment is surgery. This disease may have a high rate of local recurrence after surgery. If so, having radiation therapy soon after surgery could reduce the risk of the melanoma from returning but there have been no randomised trials to study this. Therefore, the purpose of this trial is to investigate if having radiation therapy soon after surgery on the head and neck is better at preventing the melanoma returning than just having surgery alone.nitial post-operative radiation therapy compared to initial observation after surgery for neurotropic melanoma. The main purpose of this study is to compare the rates of local recurrence in each arm of the trial. A total of 100 patients will be recruited across Australia, New Zealand and in other countries. The study involves half of the participants (‘Arm A’) having a 4 week course of radiation to the area of surgery. The other half of the participants (‘Arm B’) will have ongoing assessments (‘observation’) and can receive radiation if the melanoma returns (‘recurrence’). Patients randomised to receive radiation (‘Arm A’) treatment needs to commence within 3 months of the operation or when healing has occurred. They will usually need to visit the radiation department 5 days a week (not on weekends) for 20 treatments in total. To participate in this study patients will need to be available to see your doctor regularly for at least 5 years (every 3 months for the first 2 years, then 6 monthly) to check for any signs of melanoma return and to monitor any long term side effects experienced. Patients may be included in the trial only if they meet all of the following criteria: - Tumour located above the clavicle and below the jaw or occiput (neck primary) or above the jaw/occiput (head primary) - Complete macroscopic resection (minimum 1cm surgical excision margin) of all known invasive disease with 5mm microscopic margin - Histologically confirmed neurotropic primary melanoma NHS R&D Form IRAS Version 5.2.19 o Neurotropism is identified pathologically by the presence of melanoma cells around nerve sheaths (perineural invasion) or within nerves (intraneural invasion). o Occasionally, the tumour itself may form neuroid structures (termed „neural transformation‟; this is also regarded as neurotropism) o “Normal”-looking nerves that appear to be “entrapped” within the tumour should not be regarded as neurotropism - A 5mm histopathological margin on invasive disease is recommended (irrespective if whether the tumour is involving a nerve), unless constrained by an anatomical boundary. - No previous surgery for melanoma (other than complete macroscopic resection as stated above) (i.e. Not recurrent disease) - No evidence of in-transit, nodal or distant metastases as determined by clinical examination, sentinel node biopsy, elective nodal dissection, or any form of imaging. - Aged 18 years or older - Has provided written informed consent for participation in this trial - ECOG performance status score of 2 or less Life expectancy greater than 6 months - Patients capable of childbearing are using adequate contraception - Available for follow up
Patients who fulfil any of the following criteria are not eligible for admission to trial: - Intercurrent illness that will interfere with the radiation therapy such as immunosuppression due to medication or medical condition. - Clinical and/or MRI evidence of a named cranial or cervical nerve involvement by tumour - Inability to localise surgical bed on any form of imaging and/or surgical margins (cm) not known - Previous radical radiation therapy to the head and neck, excluding superficial radiation therapy to cutaneous SCC or basal cell carcinoma, which is not within or overlapping the tumour bed. - High risk for poor compliance with therapy or follow-up as assessed by investigator - Patients with in-transit, nodal or distant metastases - Patients with prior cancers, except: those diagnosed ≥ 5 years ago with no evidence of disease relapse and clinical expectation of relapse of less than 5%; prior successfully treated Level 1 cutaneous melanomas ≥ 2 years ago; or non-melanoma skin cancer; or carcinoma in situ of the cervix. - Albinism. - Participation in other clinical trials with the same primary endpoint. - Women who are pregnant or lactating.
Ageing Head and Neck Cancer Skin Cancer
In AML19 we will ask a number of specific questions. • Is the use of a fractionated Mylotarg (GO) ( 2 doses of 3 mg/m2 used in the ALFA) superior to a single Mylotarg dose (3mg/m2 used in AML15 and 17) when combined with either DA or FLAG-Ida induction chemotherapy • Does FLAG-Ida /GO induction (best of AML15) improve survival compared to DA (60mg/ m2 x 3) /GO induction • Does the addition of 1 or 2 courses of HDAC consolidation to 2 courses of FLAG-Ida induction improve survival? • In patients who do not have a FLT3 mutation does the addition of Ganetespib (using the same dose schedule as AML18) to post course 1 chemotherapy improve survival in patients with good or standard risk AML? • In high risk patients or those patients with known poor risk cytogenetics at diagnosis is CPX-351 used at the dose schedule established in the Phase 2 study superior to FLAG-Ida
Patients are eligible for the AML19 trial if: • They have one of the forms of acute myeloid leukaemia as defined by the WHO Classification (Appendix A) — this can be any type of de novo or secondary AML or high risk Myelodysplastic Syndrome (defined as > 10% bone marrow blasts) • Patients with acute promyelocytic leukaemia (APL) are eligible and should be entered into the randomisations specifically for APL (see Section 9). • They are considered suitable for intensive chemotherapy. • They should normally be 18 years up to the age of 60, but patients over this age are eligible if intensive therapy is considered a suitable option. • The Serum creatinine should be ≤ 1.5 × ULN (upper limit of normal) • Patients eligible for the Mylotarg randomisation must have Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤2.5 ×ULN and bilirubin ≤2.×ULN (Note: Patients who do not comply with the liver inclusion criteria are eligible to enter the trial but will be excluded from the Mylotarg randomisation) • A negative pregnancy test within 2 weeks prior to trial entry in WOCBP to be repeated throughout the trial prior to each course of protocol treatment • Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Similarly women must agree to highly effective contraceptive measures (See Appendix J). This applies to APL and AML patients. In both males and females these measures must be in place for at least 30 days after the last administration of all IMPs. • They have given written informed consent APL Patients: • They have provided signed written informed consent (PIS 3) • They have a morphological diagnosis of APL (if cytogenetic or molecular diagnosis is not confirmed patients will transfer to the non-APL treatments) • They should be over 18 years. • They have WHO performance status 0-2 • Their Serum total bilirubin is < 2.0 mg/dL (≤51 µmol/L) • Their Serum creatinine is < 3.0 mg/dL (< 260 µmol/L)
Patients are not eligible for the AML arms of the AML19 trial if: • They have previously received cytotoxic chemotherapy for AML. [Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy is not an exclusion.] • They have received demethylation therapy for AML or high risk MDS defined as marrow blasts > 10%. Patients treated for lower risk MDS who progress to AML are eligible. • They are in blast transformation of chronic myeloid leukaemia (CML). • They have a concurrent active malignancy requiring treatment. • They are pregnant or lactating. • The physician and patient consider that intensive therapy is not an appropriate treatment option. • Known infection with Human Immunodeficiency Virus (HIV). • Patients with AST or ALT more than 2.5 times the local upper limit of normal or Bilirubin more than twice upper limit of normal, are not eligible for the Mylotarg randomisations. For Ganetespib randomisation there are specific cardiac exclusions: • A myocardial infarction within 12 months • Uncontrolled angina within 6 months • Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA) performed either within 1 month prior to study screening or during screening results in a left ventricular ejection fraction (LVEF) that is ≥ 45% (or institutional lower limit of normal value). • Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes [TdP]) or any history of arrhythmia will be discussed with the Clinical Coordinator/Safety Physician prior to patient’s entry into the study. • Prolonged QTcF interval on pre-entry ECG (≥450 ms) • Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker • Heart rate < 50/minute on pre-entry ECG • Uncontrolled hypertension • Obligate need for a cardiac pacemaker • Complete left bundle branch block • Unstable Atrial fibrillation APL Patients: • They are aged < 18 • They have an active malignancy requiring treatment at time of study entry • There is a lack of subsequent diagnostic confirmation of PML-RARA fusion at molecular level • Known infection with Human Immunodeficiency Virus (HIV). • Significant arrhythmias, ECG abnormalities or neuropathy are apparent • Severe uncontrolled pulmonary or cardiac disease is apparent. • They are pregnant or lactating
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.
Lung cancer is the most common cause of cancer mortality in the UK. NSCLC accounts for approximately 85% of all lung cancers and a third of the patients present with stage III disease. Most patients present with inoperable disease and therefore radiotherapy plays a major role in treatment. However, the majority of patients are not suitable for the gold standard treatment (concurrent chemo-radiotherapy) due to performance status and comorbidities. Consequently novel strategies integrating radiotherapy advances and radiobiological knowledge need to be evaluated in patients treated with sequential chemo-radiotherapy. The UK strategy has been to develop separate dose escalation protocols for accelerated radiotherapy schedules (CHART-ED , IDEAL-CRT, I-START and Isotoxic IMRT. This study will compare these schedules with a UK standard sequential chemo-radiotherapy schedule of 55Gy in 20 fractions over 4 weeks. As it would be impossible to test all schedules in phase III study the aim is to use a combined randomized phase II screening / ‘pick the winner’ approach to identify the best schedule to take into a randomised Phase III study against conventionally fractionated radiotherapy. Suitable patients will have histologically / cytologically confirmed, stage III NSCLC and are able to undergo chemoradiotherapy treatment. The study will recruit 360 patients; 120 patients on the standard arm and 60 on each experimental arm. Patients will complete 3 cycles of a platinum based chemotherapy before being randomised on study to one of the radiotherapy schedules.
1. Histologically or cytologically confirmed stage III NSCLC. 2. Performance status (PS) – ECOG 0-2. Patients with PS 2 can only be included if the local investigator deems the general condition is explained by disease or the primary chemotherapy treatment. 3. Inoperable disease, unsuitable for concurrent chemoradiation, in the opinion of the treating Oncologist. 4. Patients who have had a partial response or stable disease on CT assessment after 2 cycles of platinum based chemotherapy. 5. Measurable disease as defined by RECIST criteria Version 1.1. 6. Willing and able to give written informed consent. 7. Aged 16 or over. 8. Adequate PFT results: FEV1 and/or KCO ≥ 40% of predicted
1. Previous or current malignant disease likely to interfere with the protocol treatment or comparisons. 2. Medically unstable (unstable diabetes, uncontrolled arterial hypertension, infection, hypercalcaemia, ischaemic heart disease). 3. Connective tissue disorders (Scleroderma, Systemic Lupus Erythematosus). 4. Clinically significant interstitial lung disease. 5. History of physical or psychiatric disorder that would prevent informed consent and compliance with protocol. 6. Pregnant or lactating women. 7. Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial protocol and follow up schedule.
AML 18 is the replacement trial for AML16 intensive. The UK sees approximately 2000 new cases of AML being diagnosed each year in adults aged over 60 years. This 1600 patient trial is primarily designed for patients over the age of 60 who are considered fit enough for an intensive chemotherapy approach and will aim to test the effects of adding new treatment agents to commonly used chemotherapy combinations in order to improve patient survival and treatment regimes. The AML18 Trial is available to any patient who has primary or secondary AML as defined by the WHO Classification (excluding Acute Promyelocytic Leukaemia), or high risk Myelodysplastic Syndrome (i.e. > 10% marrow blasts) over the age of 60. It is a randomised controlled Phase II/III trial using a factorial design for maximum efficiency to evaluate two induction options followed by treatment with a small molecule post course 1 and dose intensification for suitable patients. There are four randomisation comparisons within the trial: The first randomisation will compare standard the chemotherapy schedule Daunorubicin/AraC (DA) combined with 1 or 2 doses of Mylotarg in course 1. Following recovery from course 1 patients who fail to achieve CR or are MRD positive by centralised flow cytometry will be randomised to one of three options, either DA chemotherapy, DA chemotherapy plus Cladribine or Flag Ida for up to 2 courses of therapy. Patients who achieve CR after course 1 will be randomised to 1 or 2 further courses of DA chemotherapy. Patients who have known adverse risk cytogenetics at diagnosis may enter a phase 2 evaluation of the combination of Vosaroxin plus Decitabine, for up to 5 courses. At course 2 all patients will also enter a randomisation to receive AC220 versus no AC220 with or without maintenance. Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable HLA matched donor is available The study has been set up by the Centre for Trials Research in Cardiff.
1)They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML – or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB2). 2)They should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the AML19 trial. 3)They have given written informed consent. 4)Serum creatinine ≤ 1.5 × ULN (upper limit of normal) 5)Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics 6)Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Similarly women must agree to adequate contraceptive measures. Contraceptive measures must be in place for 3 months following completion of Decitabine and 6 months after the last administration of Cladribine. 7)ECOG Performance Status of 0-2
Patients are not eligible for the AML18 trial if: They have previously received cytotoxic chemotherapy for AML [Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion] They are in blast transformation of chronic myeloid leukaemia (CML) They have a concurrent active malignancy excluding basal cell carcinoma They are pregnant or lactating They have Acute Promyelocytic Leukaemia Known infection with human immunodeficiency virus (HIV) Patients with AST or ALT more than 2.5 times the local upper limit of normal, or bilirubin more than 1.5 upper limit of normal, are not eligible for the Mylotarg randomisation or Vosaroxin/Decitabine registration. For the Vosaroxin/Decitabine Entry Left ventricular ejection fraction (LVEF) < 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)] History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry Hemodialysis or peritoneal dialysis required. In addition patients are not eligible for the AC220 randomisation if they have: Cardiovascular System Exclusion Criteria: Known serious cardiac illness or medical conditions, including but not limited to: I. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker II. Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted. III. Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix for the list of such medications) IV. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker V. Complete left bundle branch block (LBBB) VI. History of long QT Syndrome or a family member with this condition VII. Serum potassium, magnesium, and calcium levels not outside the laboratory’s reference range VIII. QTc > 450 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient’s QTc measurements. QTcF (Fridericia’s formula) is preferred. Please see the trial website for QTcF calculator.
Biliary tract tumours are relatively rare, accounting for 0.7% of malignant tumours in adults, with approximately 1200 new cases registered each year in England and Wales. The 1-year and 5-year survival is poor at 22% and 9% respectively (Cancer Survival Trends in England and Wales 1971 – 1995). Approximately 15-20% of cases are suitable for surgical resection but the outlook remains poor with survival at 5 years approximately 15% (Cancer Survival Trends in England and Wales 1971 – 1995. Most tumours are advanced at presentation and are unsuitable for surgical resection. The ACTICCA-1 trial will investigate the role of adjuvant chemotherapy with Cisplatin and Gemcitabine compared to surveillance. This study will determine whether the Cisplatin and Gemcitabine regimen which is effective in advanced disease will show a benefit in the adjuvant setting. This is an international, multicentre, prospective, randomised controlled trial comparing adjuvant treatment with Cisplatin and Gemcitabine with no adjuvant treatment in patients who have undergone a complete macroscopic resection of biliary tract cancer. Patients will be followed up for a period of 5 years, primarily assessing disease free survival and overall survival at 2 and 5 years respectively. Quality of Life sub studies are planned to be investigated within the trial also. The results of this study will be used to further define the optimum management for patients who undergo a complete resection of their biliary tract cancer. This result could have the potential to change the current practice for treating these patients.
Eligibility criteria for enrolment phase 1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic biliary tract cancer, or muscle invasive gallbladder cancer) scheduled for radical surgical therapy 2. Written informed consent 3. No prior chemotherapy for biliary tract cancer 4. No previous malignancy within 3 years or concomitant malignancy, except: nonmelanomatous skin cancer or adequately treated in situ cervical cancer 5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 9. No pregnancy or lactation Eligibility criteria for treatment phase (before randomisation) 1. Histologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic biliary tract cancer or muscle invasive gallbladder cancer) after radical surgical therapy with macroscopically complete resection (mixed hepatocellular tumours are excluded) 2. Macroscopically complete resection (R0/1) within 6 (16) weeks before scheduled start of chemotherapy 3. ECOG 01 4. Age > 18 years 5. Adequate haematologic function: ANC ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin ≥9 g/dl or ≥5.59 mmol/L 6. Adequate liver function as measured by serum transaminases (AST and ALT) ≤5 x ULN and bilirubin ≤3 x ULN 7. Adequate renal function, i.e. serum creatinine ≤1.5 x ULN, glomerular filtration rate ≥ 60 mL/min (MDRD) 8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy 9. No concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 30 days prior to randomisation 10. Negative serum pregnancy test within 7 days of starting study treatment in premenopausal women and women < 1 year after the onset of menopause (Note: a negative test has to be reconfirmed by a urine test, should the 7day window be exceeded) 11. Written informed consent 12. No prior chemotherapy for biliary tract cancer 13. No previous malignancy within 3 years or concomitant malignancy, except: nonmelanomatous skin cancer or adequately treated in situ cervical cancer 14. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 15. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informedconsent 16. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 17. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 18. No pregnancy or lactation
Mixed hepatocellular tumours are excluded
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.
Breast Cancer Colorectal Cancer Prostate Cancer
A prospective, phase III, two-arm, open-label clinical study to evaluate the efficacy and safety of Acelarin (NUC-1031) vs. gemcitabine in patients with metastatic pancreatic carcinoma. Objectives: To evaluate the efficacy and safety of Acelarin compared with gemcitabine in patients with metastatic pancreatic carcinoma. Exploratory objectives are to discover possible biomarkers to predict additional benefit of Acelarin over gemcitabine for subsequent validation. Study arms: Arm 1: Acelarin: 825 mg/m2 administered intravenously on days 1, 8 and 15 of a 28 day cycle. Arm 2: Gemcitabine 1000mg/m2 administered intravenously on days 1, 8 and 15 of a 28 day cycle. Randomisation will be stratified by ECOG performance status (PS) (0/1 vs 2). The planned treatment duration per patient will be until progression of disease, unacceptable toxicity or withdrawal of consent. Participation in the study will be until withdrawal of consent or death. Patients who stop treatment before having developed progressive disease (PD) will be assessed every 12 weeks for response until PD occurs. Patients will receive screening CT scan and ECG. Lung function test at baseline and end of treatment. CT scan every 12 weeks after screening until PD as per RECIST 1.1 Optional additional biopsy for translational biomarker analysis. Optional translational blood sample taken at baseline, day 1 of each cycle and end of treatment.
a) Age ≥ 18 years. b) Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the pancreas.* c) Metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected pancreatic cancer can be included. d) Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment. e) Unidimensionally measurable disease. f) ECOG performance status 0, 1 or 2 where treatment with combination chemotherapy is not deemed appropriate or is declined by the patient. g) Platelets ≥100 x 109/l; neutrophils ≥ 1.5 x 109/l at entry. h) Documented life expectancy > 3 months. i) Informed written consent. *Patients will be approached for consenting to provide either an additional core of tissue material for biomarker discovery at the sametime as a diagnostic biopsy or in those patients that have already had a diagnostic biopsy to undergo a second biopsy after randomisation into the trial. Neither of these biopsies is compulsory. Patients who don't wish to have extra tissue taken for Biomarker discovery will be approached for consent to released surplus tissue from the original diagnostic specimen if this exists.
a) Laboratory results: • Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR). • Haemoglobin < 10G/dl • Creatinine clearance < 30 mL/minute (calculated by CockcroftGault formula) • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or alkaline phosphatase (ALP) > 2.5 x ULN or > 5x ULN if judged by the investigator to be related to liver metastases. b) Medical or psychiatric conditions compromising informed consent. c) Intracerebral metastases or meningeal carcinomatosis. d) Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. e) Pregnancy or breast feeding. f) Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed > 12 months previously. g) Radiotherapy within the last 4 weeks prior to start of study treatment. h) Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer. i) Hypersensitivity to gemcitabine or any of the excipients of gemcitabine or Acelarin (NUC1031). j) All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be from the list below, the other must be a condom1 or abstaining from sexual intercourse, until six months after treatment has ended: o Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: either oral, intravaginal or transdermal. o Progesterone-only hormonal contraception associated with inhibition of ovulation: either oral, injectable or implantable. o Intrauterine device (IUD) o Intrauterine hormonereleasing system (IUS) o Bilateral tubal occlusion o Vasectomised partner2 o Sexual abstinence3 1Male or female condom with or without spermicide is not an acceptable method of contraception alone. 2 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomised partner has received medical assessment of the surgical success. 3 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
The overall aim of the feasibility component of the trial is to determine if it is feasible to deliver SBRT in a multicentre trial setting in a rare disease. In particular, will clinicians recruit to the trial and will sufficient patients accept randomisation. If the feasibility component proves successful, the trial would continue into the full phase II trial. The overall aim of the phase II trial is to evaluate the efficacy of 6 of cycles of CisGem chemotherapy followed by SBRT compared to 8 cycles of CisGem.
1. A histopathological / cytological diagnosis of locally advanced, nonresectable biliary tract carcinoma (intra or extrahepatic), or ampullary carcinoma 2. Not suitable for radical surgery, or medically unfit for surgery as decided by a hepatobiliary MDT 3. Tumour visible on crosssectional imaging 4. Measurable disease (according to RECIST criteria v1.1) 5. Tumour must be ≤6 cm in the longest dimension 6. Adequate biliary drainage 7. WHO PS 0 or 1 8. Adequate haematological function: • Haemoglobin ≥ 100 g/L (the use of transfusion to achieve desired Hb is acceptable) • White blood cell count (WBC) ≥ 3.0 x 109/L • Absolute neutrophil count (ANC) ≥1.5 x 109/L • Platelet count ≥ 100 x 109/L 9. Adequate liver function: • Total bilirubin ≤1.5 x ULN (except for patients with known documented cases of Gilbert’s syndrome) • ALT and/or AST ≤ 2.5 x ULN • ALP ≤ 5 x ULN • Albumin > 250 g/L 10. Adequate renal function: • Serum urea < 1.5 x ULN • Serum creatinine < 1.5 x ULN • GFR ≥ 45 mL/min using a validated creatinine clearance calculation (e.g. CockroftGault or Wright formula). If the calculated creatinine clearance is less than 45 mL/min, GFR should be assessed using an isotopic clearance method to confirm GFR ≥ 45 mL/min 11. Life expectancy > 12 weeks 12. 16 years of age or over 13. Patients may have had prior chemotherapy as long as patient meets all other inclusion/exclusion criteria. 14. Patient must have given written informed consent
1. Metastatic disease 2. Direct tumour extension in the duodenum, stomach, small bowel or large bowel. 3. Previous abdominal radiotherapy or previous selective internal radiotherapy such as hepatic arterial Yttrium therapy 4. Previous hypersensitivity to platinum salts 5. Any evidence of severe or uncontrolled systemic diseases which, in the view of the investigator, makes it undesirable for the patient to participate in the trial (including diabetes with established sensory peripheral neuropathy, unstable or uncompensated respiratory, cardiac, hepatic or renal disease) 6. History of prior malignancy that could interfere with the response evaluation (exceptions include insitu carcinoma of the cervix treated by conebiopsy/resection, nonmetastatic basal and/or squamous cell carcinomas of the skin, or any early stage (stage I) malignancy adequately resected for cure greater than 5 years previously) 7. Other concomitant anticancer therapy (except steroids) 8. Any psychiatric or other disorder likely to impact on informed consent. 9. Women who are pregnant or lactating NB. Whilst not excluded, patients with significant hearing impairment must be made aware of potential ototoxicity and may choose not to be included. If included, it is recommended that audiograms be carried out at baseline and prior cycle 2 of CisGem
Diffuse large B-cell lymphoma (DLCBL) is the commonest of the non-Hodgkin's lymphomas. Whilst the majority of patients will respond well to conventional immunochemotherapy (R-CHOP), a significant number of patients will either fail to respond to initial therapy or relapse after completion of therapy. Bruton's tyrosine kinase (BTK) is an enzyme dysregulated in numerous B-cell malignancies, including DLCBL. Acalabrutinib is an orally active BTK-inhibitor. It is hypothesised that the addition of acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLCBL. The proposed study is a phase Ib/II clinical trial to determine a suitable tolerated dose and efficacy of acalabrutinib in combination with standard R-CHOP immunochemotherapy to treat patients with DLBCL. The main aims of this clinical study are to find out: -The maximum dose of acalabrutinib that can safely be given to patients -More about the potential side effects of acalabrutinib and how they can be managed -The effect the combination of R-CHOP and acalabrutinib has on DLBCL Approximately 6-24 patients with DLBCL will be entered into the dose-escalation phase, and a further 15 patients will be recruited to a dose expansion cohort. The final number will depend on the number of dose escalations required.
1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a central laboratory for gene expression profiling and pathology review 2. Measurable disease of at least 15mm 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node diameter > 10cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease are not 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 (umolL)] 8. Serum bilirubin < 35μmol/L and transaminases < 2.5x 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 55% 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. However newly diagnosed patients with DLBCL who are found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible 2. Diagnosis of primary mediastinal lymphoma 3. Diagnosis of primary Central Nervous System lymphoma. 4. History of stroke or intracranial haemorrhage in preceding 6 months 5. History of bleeding diathesis (eg. haemophilia, von Willebrand disease) 6. Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg. phenprocoumon) within 7 days of first dose of acalabrutinib. However patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible 7. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2 inhibitor (eg. ABT-199) 8. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer 9. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to short-acting H2-receptor antagonists or antacids are eligible for enrolment into this study. 10. Uncontrolled systemic infection 11. Major surgery in the preceding 4 weeks of first dose of study drug. 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 12. 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, or corrected QT interval (QTc) > 480 msec at screening. 13. 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. - Positive test results for hepatitis C virus (HCV) antibody serology will not be eligible. 14. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7 14. Breastfeeding or pregnant 15. Men who are sexually active and can potentially father children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7 16. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug. 17. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent 18. 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. Note: these cases must be discussed with SCTU 19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass 20. Any immunotherapy within 4 weeks of 1st dose of the study 21. Concurrent participation in another therapeutic clinical trial
This study is being carried out to see if Avelumab is effective in treating patients with high risk triple negative breast cancer (TNBC). Breast cancer is the most common malignancy in women and is the leading cause of cancer related death in European women. The term TNBC is used to define tumours that do not express oestrogen receptors, progesterone receptors and HER2 receptors. TNBC comprises < 20% of breast cancers, and remains the subtype with poorest outcome. There is a significant need to develop new therapies for this group of patients. Immunotherapy is emerging as a promising strategy for anti-cancer treatments, where the immune system helps the body fight against tumour cells. Avelumab is designed to stop a protein called PDL1 (programmed death-ligand 1) being expressed on the cancer. PDL1 helps to camouflage the cancer, preventing the body’s immune system from identifying the cancer and fighting it. Avelumab works against PDL1, allowing the immune system to recognise the tumour cells as foreign bodies and attack them. The main purpose of this study is to see if Avelumab is an effective treatment for TNBC. The study is for patients who have received the standard treatments of surgery and chemotherapy treatment, and who have features that maybe associated with a higher risk of recurrence. Also included is a biomarker component to find out which patients tumours have certain molecular traits that may derive more benefit from this treatment. The study will determine whether 1-year administration of the Avelumab improves survival in patients at risk of recurrence. The study will recruit 335 patients, aged 18+, with high risk TNBC. Consenting eligible patients will be randomly placed into one of two groups. One group will receive Avelumab, and the other group will receive no treatment and will be under observation (as per normal clinical care).
-Male/female aged> 18 years -Signed informed consent -ECOG performance status 0/1 -Non-metastatic histologically confirmed primary invasive breast carcinoma -Normal organ & marrow function -Highly effective contraception for male & female subjects (from 28 days prior to trial treatment to at least 60 days after stopping trial treatment) - FFPE block containing tumor tissue or at least 7 unstained tumor slides Specific Stratum A: -TNBC: hormone receptor (ER< 10% & PgR< 10%) & HER2 negative (IHC0/1+ or ISH non-amplified). If discordance between pre-operative core-biopsy & surgical sample, receptor assessment on surgical sample has to be considered for inclusion criteria evaluation -Completed treatment with curative intent including surgery & adjuvant chemotherapy -Adequately excised: have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy. Margins of resected specimen should be free of invasive tumor & ductal carcinoma in situ (CIS). In the case of breast-conserving surgery patients with margins positive for lobular CIS are eligible without additional resection. Patients who undergo mastectomy or with a microscopic positive deep margin are eligible, provided have received radiotherapy on chest wall -Had axillary lymph node (LN) dissection for evaluation of pathologic nodal status. Must meet 1 of: a. if 4 or more metastatic LN, any pT b. if 1 to 3 metastatic LN, pT> 2cm c. if no metastatic LN, pT> 5cm -Had adjuvant chemotherapy after surgery. Adjuvant treatment should have included at least 3courses of an anthracycline agent & 3courses of a taxane agent. Patients who cannot complete all planned treatment cycles for any reason are considered high risk & therefore are eligible for the study. Patients who received dose-dense regimens & those who received carboplatin as part of the adjuvant treatment are eligible -No more than 10weeks may elapse between the completion adjuvant chemotherapy&randomization Specific Stratum B: -TNBC: hormone receptor negative (ER < 10% & PgR < 10%) & HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology laboratory. Both the diagnostic core-biopsy performed prior to neoadjuvant chemotherapy & the residual disease assessed on the surgical specimen should show TN receptor status. Discordant TN status will not be eligible -Patients must have completed treatment with curative intent including: neoadjuvant chemotherapy & surgery -Adequately excised: patients should have undergone adequate tumor excision after preoperative chemotherapy, which means surgical removal of all clinically evident disease in the breast & LN’s a. Must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy. Margins of resected specimen should be free of invasive tumor & ductal CIS. In the case of breast-conserving surgery patients with margins positive for lobular CIS are eligible without additional resection. Patients who undergo mastectomy, patients with a microscopic positive deep margin are eligible, provided have received radiotherapy on chest wall b. LN surgery: -Axillary dissection without sentinel node evaluation is permitted after preoperative therapy -If positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy(SNB) performed prior to preoperative therapy, additional surgical evaluation of the axilla following preoperative therapy is required -If SNB performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy -Sentinel node after preoperative therapy is allowed if no evidence of axillary node involvement was documented by ultrasonography at diagnosis. If SNB after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required. If SNB performed after preoperative therapy is positive, additional surgical evaluation of the axilla is recommended -Pathologic evidence of residual invasive carcinoma in the breast &/or axillary LN’s on the surgical specimen obtained after preoperative therapy (ypT1micN0, ypT1micN0i+, ypT0N0i+ will be excluded) -Clinical stage at presentation: T1–4,N0–3,M0 (T1a/bN0 tumors will not be eligible) -Completed neoadjuvant chemotherapy before surgery. Neoadjuvant treatment should have included at least 3 courses of an anthracycline agent & 3 courses of a taxane agent. Patients who cannot complete all planned cycles are considered high risk & therefore are eligible. Patients who received dose-dense regimens & those who received carboplatin as part of the adjuvant treatment are eligible -No more than 10 weeks may elapse between the surgery & randomization. If positive margins after first intervention requiring additional resection, interval of 10 weeks will be calculated from date of last surgery
1. Metastatic breast cancer. 2. Synchronous bilateral breast cancer, unless both tumors confirmed triple negative disease. 3. History of non-breast malignancies within the 5 years prior to study entry, except for the following: Carcinoma in situ (CIS) of the cervix, CIS of the colon, Basal cell and squamous cell carcinomas of skin. 4. Prior organ transplantation, including allogeneic stem-cell transplantation. 5. Prior or concomitant treatment with any other investigational agents. 6. Prior therapy with any antibody / drug targeting T-cell coregulatory proteins (immune checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4). 7. Concurrent anticancer treatment (e.g. cytoreductive therapy, immune therapy, cytokine therapy except for erythropoietin). If indicated, radiotherapy to the operated breast/chest wall/locoregional lymph nodes is admitted 8. Concomitant treatment with all herbal (alternative) remedies with immunostimulating properties (for example, mistletoe extract) or known to potentially interfere with major organ function (e.g. hypericin) 9. Major surgery for any reason, within 4 weeks of randomization and / or if the subject has not fully recovered from the surgery within 4 weeks of randomization 10. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before initiation of the trial treatment (with the exception of subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to < = 10 mg prednisone daily) 11. Significant acute or chronic infections including, among others: a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) 12. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses < = 10 mg or equivalent prednisone per day c. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 13. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 14. Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be < = 10 mg per day of equivalent prednisone 15. Known severe hypersensitivity reactions to monoclonal antibodies (Grade > = 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) 16. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident /stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (New York Heart Association Classification Class > = II), or serious uncontrolled cardiac arrhythmia requiring medication 17. All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment 18. Any psychiatric condition that would prohibit the understanding or rendering of informed consent 19. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines) 20. Known alcohol or drug abuse 21. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (however, alopecia, grade 2 neuropathy and any other grade 2 not constituting a safety risk based on investigator’s judgement are acceptable) 22. Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods Criteria specific for Stratum A : 1. Patients in any of the following stage categories are not eligible: - 1 to 3 metastatic axillary lymph nodes and pT< 2cm; - 0 metastatic axillary lymph nodes and pT< 5cm. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed within 10 years Criteria specific for Stratum B : 1. No invasive residual disease in the breast and axilla at pathological examination after neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded 2. History of any prior (ipsi- and/or contralateral) invasive breas
The study vaccine, AST-VAC2, will target the hTERT protein and help the immune system attack cancer cells. The vaccine is made by taking embryonic stem cells that have been obtained ethically from a single donor and developed in the laboratory to become dendritic cells. Dendritic cells occur naturally in the body as part of the immune system however these dendritic cells have a special role in finding proteins in the body which are associated with cancer and it is hoped that the vaccine will train the immune system to recognise these proteins and attack the cancer. Some cancers have more of a certain type of protein called hTERT and it has been shown that targeting hTERT can lead to destruction of cancer cells by the immune system. Human Leukocyte Antigen (HLA) is another type of protein. If a HLA test shows that a patient is positive for a specific HLA protein, this may mean that there is a better chance of the vaccine attacking the cancer (AST-VAC2 can only work with some types of HLA). The study is a first in man clinical trial and is in two parts. Part 1 will ensure that the vaccine can be given safely and if there are any initial signs of how it works in the body. Part 2 will continue looking at the safety but also how the vaccine works in a group of patients without measurable cancer. Approximately 24 patients with non-small cell lung cancer (NSCLC) will be treated with AST-VAC2. This includes 12 patients in Part 1 of the study (patients with advanced disease) and 12 patients in the Part 2 of the study (after surgical treatment). Alongside patients who receive the vaccine, the study will also ask approximately 24 patients, who will not be eligible to receive the vaccine because of their HLA test result, to be part of an observation group. This group of patients will continue to receive standard care. The study will then compare the vaccine treated group with the observation group. The three main aims are to find out: • If the dose can be given safely. • Potential side effects and how they can be managed. • What happens to AST-VAC2 inside the body (looking for effects in blood, skin or tumour).
1. a) Safety cohort (Arms A & B): Patients with advanced NSCLC (metastatic or locally advanced), for which no conventional therapy is appropriate or is declined by the patient – - Able to and likely to be well enough to receive six vaccinations i.e. judged by the Investigator to not require alternate treatment for the duration of the vaccination schedule and period to off trial visit. - Has had sufficient wash out periods from previous treatments as follows: i) four weeks for chemotherapy ii) six weeks for investigational medicinal products (IMPs) iii) eight weeks for immunotherapy (shorter intervals may be acceptable based on half-life of treatment. Eligibility will be confirmed by the Sponsor and CI). - Measurable disease - Biopsiable disease is preferable however patients without biopsiable disease can still be considered for the study. b) Expansion cohort (Arms C & D): NSCLC patients in the adjuvant setting, currently disease free, for which no conventional therapy is appropriate or is declined by the patient - - Able to and likely to be well enough to receive six vaccinations i.e. judged by the Investigator to not require alternate treatment for the duration of the vaccination schedule and period to off trial visit. 2. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up. 3. Confirmed HLA*A2:01 positive genotype (Treatment arms A and C only). 4. Life expectancy of at least 12 weeks. 5. World Health Organisation performance status of 0-2. 6. Haematological and biochemical indices within the ranges shown below. These measurements must be performed prior to the patient receiving the first AST-VAC2 vaccination. - Haemoglobin: > = 9.0 g/dL - Absolute neutrophil count: > = 1.5 x 10^9/L - Platelet count: > = 100 x 10^9/L - Lymphocyte count: > 1.0 x 10^9/L - Bilirubin: < = 1.5 x upper limit of normal - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and alkaline phosphatase (ALP) : < = 3.0 x ULN - Creatinine: > 30 mL/min 7. 18 years or over at the time consent is given.
1. Radiotherapy (except for palliative reasons) during the previous four weeks before treatment. 2. Ongoing toxic manifestations of previous treatments greater than CTCAE Grade 1. Exceptions to this are alopecia or certain Grade 2 toxicities, which in the opinion of the Investigator and the Sponsor should not exclude the patient. 3. Systemic steroids or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. 4. Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) [oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence*, effective from the first administration of AST-VAC2 throughout the trial and for six months afterwards are considered eligible (treatment arms only). 5. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception [condom plus spermicide] or to sexual abstinence* effective from the first administration of AST-VAC2, throughout the trial and for six months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate (treatment arms only). * Abstinence is only considered to be an acceptable method of contraception 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. 6. Major thoracic or abdominal surgery from which the patient has not yet recovered. 7. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. 8. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV). 9. Evidence of any ongoing active autoimmune disease. 10. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), prior history of cardiac ischaemia or prior history of cardiac arrhythmia. 11. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I trial of AST-VAC2. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator and Medical Advisor would be acceptable. - Control arm patients: If a patient in either of the control arms consequently wishes to consent to another treatment trial/withdraw from the trial for other reasons, prior to the end of their follow up period, then their follow up information as per (protocol) Section 7.4, will be recorded in the electronic case report form (eCRF) and the patient will be withdrawn from the trial. 12. Any vaccination given within four weeks before the first AST-VAC2 vaccination. 13. Any planned prophylactic vaccination from trial entry until completion of the AST-VAC2 vaccinations. 14. Any condition which might interfere with the patient’s ability to generate an immune response. 15. Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.