List of studies


Study Results

  • SYMPLIFY - Observational study to assess a multi-cancer early detection test in individuals referred with signs and symptoms of cancer.

    • Research Summary

      Cancer is easier to treat if it is diagnosed early. The NHS has developed rapid referral pathways to allow cancers to be diagnosed earlier, but this requires us to run tests on a lot more people than turn out to have cancers. This creates worry for some people and may not be the most efficient use of NHS resources. A significant proportion of cancers are still diagnosed via other routes, often when it is too late to cure them. We know that the DNA from cancers can be detected in the blood early on and want to use this to detect cancers earlier than we do now. In this study we want to check the performance of one test, called a multi-cancer early detection (MCED) test. We will do this in people sent to one of 5 rapid referral pathways by their GP because they have symptoms that might be due to cancer. People taking part in the study will have their diagnostic test(s) in the normal way, but will also give a blood sample and permission for us to check their health records later to see if they were diagnosed with cancer and what appointments and other tests they had. At the end of the study, having tested the blood with the MCED test, we will understand more about how well it works in this group of people, and expect that this will help us to design another trial where we check how to use the test to decide who needs rapid referral to look for a possible cancer and what tests to use following a positive MCED result.

    • Inclusion Criteria:

      - Willing and able to give informed consent for participation in the study. - Male or Female, aged 18 years or above. - Referred to a RDC or a gynae, lung, upper GI or lower GI cancer 2WW pathway.

    • Exclusion Criteria:

      - has a history of invasive or haematological malignancy diagnosed within the previous 3 years - has undergone definitive treatment for invasive or haematological malignancy in the last 3 years (adjuvant hormone therapy is permissible in this context). - is taking cytotoxic or demethylating agents such as methotrexate - previous or current participation in another GRAIL study. “Participation” is defined as having signed consent and provided a blood sample.

    Read more Return to top ('Preview' button)
  • PROSECO - A UK multicentre prospective observational study evaluating COVID-19 vaccine immune responses in lymphoid cancer

    • Research Summary

      The UK government recently initiated population-wide COVID-19 vaccination in December 2020, on a priority basis. The clinical trial data on the clinical effectiveness and immunological responses elicited by these vaccines are primarily based on healthy individuals and exclude patients with active cancers or deficiencies of their immune systems. Patients with lymphoid cancer are significantly immunosuppressed, have increased mortality from COVID-19 and are less likely to develop a robust vaccine immune responses. This prospective observational study aims to evaluate the robustness and persistence of immune responses to vaccination, define factors associated with impaired immune responses and assess the incidence of COVID-19 infections in vaccinated individuals. To do this, we will collect peripheral blood from 680 patients with lymphoid cancers at 4 time points (pre-vaccination, and 4 weeks, 6 and 9 months following the first dose). The blood will be assessed in the laboratory for first, development of antibodies to SARS-CoV-2, the virus responsible for COVID-19 and second, development of T-cell immunological memory to SARS-CoV-2. Development of these antibodies and/or T-cell immunological memory would provide us with an indication of how effective COVID-19 vaccination is. Detailed clinical information will also be collated about their cancer and treatment. Upon study completion, we will be able to ascertain whether patients with lymphoid cancer can mount robust and sustained responses to COVID-19 vaccination, and have identified factors that might influence immunological response. This knowledge will allow us to modify our vaccination strategy or patient management to ensure optimal vaccine responses are achieved in this population, and thus protection from COVID-19.

    • Inclusion Criteria:

      1) Patients having a confirmed diagnosis of either: A) Hodgkin lymphoma B) Aggressive B-cell lymphoma (e.g. Burkitt's lymphoma, diffuse large B-cell lymphoma or de novo transformed follicular lymphoma, grade 3B follicular lymphoma) C) Indolent B-cell lymphoma (e.g. all grades of follicular lymphoma except grade 3b follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, chronic or small lymphocytic lymphoma, mantle cell lymphoma) D) Mature T/NK-cell malignancy (any subtype), 2) Patient must be > = 18 years. 3) Patients will have provided written Informed Consent.

    • Exclusion Criteria:

      1) Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent.

    Read more Return to top ('Preview' button)
  • Lung Health Checks in Wessex and Yorkshire: Integrated Biomarker Studies

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Defining the role and clinical need through care pathway analysis for GlycoScore: a new blood test for the detection, diagnosis and differentiation of patients with benign prostate hyperplasia and prostate cancer

    • Research Summary

      The diagnosis of prostate cancer relies on PSA blood tests (which are inaccurate and miss some aggressive tumours) and tissue biopsies (which are expensive and can be painful), meaning there is an urgent unmet clinical need to develop new tests to improve diagnosis. The GlycoScore blood test can detect prostate cancer which is likely to have with superior diagnostic accuracy (with unmatched performance compared to existing tests) and has the potential to transform how prostate cancer is diagnosed and prognosed. Dr Joy Allen is a co-applicant, leading the Newcastle MIC work packages to: 1) perform optimisation and validation of GlycoScore 2) undertake Care Pathway Analysis and early economic modelling to define the optimal clinical need, patient population(s) and potential role(s) where GlycoScore is most likely to be cost effective. Care pathway analysis involves qualitative research techniques, which is the focus for this IRAS application. The focus of the Care Pathway analysis will be to interview healthcare professionals to explore clinical opinion of the use of the GlycoScore test in practice, in both Primary and Secondary Care.

    • Inclusion Criteria:

      To be eligible for inclusion the participants must have relevant expertise and experience of the management and diagnosis of prostate cancer patients in the UK NHS. Additionally, the participants must be fluent English speakers, as the output of the evaluation will be developed from the recorded and transcribed interviews.

    • Exclusion Criteria:

      Clinicians with inadequate expertise in management and diagnosis of prostate cancer patients in the UK. Non-fluent English speakers.

    Read more Return to top ('Preview' button)
  • Development of an EORTC Patient-Reported Outcome (PRO) Questionnaire for Quality of Life (QOL) of children with cancer: Phase I & II

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Personalizing docetaxel dosing in advanced prostate cancer

    • Research Summary

      Patients with advanced prostate cancer are often treated with the chemotherapy drug docetaxel. The manufacturers of this drug suggest using the same amount of drug for everybody who needs it, however we know that because everyone is different, people end up with more or less of the drug circulating in their blood even after they have been given the same dose. A software program (a “Dosing Tool”) has been developed to provide information to doctors on how docetaxel will affect individual patients. The program may help doctors to make smarter decisions about exactly how much drug to give to different people. The purpose of the PARTNER study is to gather information from blood tests on patients being treated with docetaxel to help in the further development of the Dosing Tool. Some of these blood tests would have been taken anyway as part of patients’ routine treatment. Others are extra for this study. Apart from the additional blood tests everyone who enters the study is treated just as they would normally be if there weren’t taking part in the study at all. Using the information gathered from the study it is hoped that the Dosing Tool can eventually be approved for use across the UK and help ensure patients get the best possible outcomes when they are being treated with docetaxel for prostate cancer.

    • Inclusion Criteria:

      o Male, aged 18 years or above o Diagnosed with metastatic prostate cancer (hormone sensitive or castrate resistant) and has been histologically documented o Metastatic at disease onset or relapsed disease o A decision treatment has been made to start a course of docetaxel as part of their standard care treatment in accordance with the drug’s label and the treating clinician’s judgement o Patient has not received a previous cycle of docetaxel within 8 weeks of the date of enrolment o Life expectancy > 12 weeks o Participant is willing and able to give informed consent for participation in the study

    • Exclusion Criteria:

      o Patients with autoimmune disease receiving active treatments o Participant is unable to give informed consent

    Read more Return to top ('Preview' button)
  • CCP-Cancer UK: Clinical Characterisation Protocol for Severe Emerging Infections in the UK (CCP-UK) – a prospective companion study for patients with Cancer and COVID-19.

    • Research Summary

      Currently, there is extremely limited information regarding the risks posed by SARS-CoV-2 virus responsible for COVID19 to patients with cancer. This study aims to understand the presentation, management and outcomes of cancer patients with COVID19. The influence of cancer type and treatment will be explored as well as comparing cancer patients with non-cancer patients. This study will provide valuable information that would educate as well as help inform practice for future possible outbreaks. The information may also inform the development of guidelines with regard to the care and management of cancer patients with viruses such as COVID19 and similar infectious diseases. Cancer is immunosuppressive, the nature of the immunosuppression seems to be influenced by the microbiota, in addition pulmonary infections are also influenced by the host microbiota, therefore it is important to understand this impact in cancer patients. Analysis of samples from cancer patients with COVID19 offer the opportunity to learn more of these interactions The purpose of CCP-CANCER UK study is to obtain additional data from patients with cancer who were/are recruited into the Principal CCP-UK study which is the key national protocol for characterising COVID19 in the UK population. This study is designed to supplement, not replace, the Principal CCP-UK protocol. This study will be open to research sites who are currently participating in the Principal CCP-UK study. The CCP-Cancer UK study will run for two years. An additional specific cancer data set will be collected from participant's existing medical records. This cancer specific information when combined with the rich data set related to the COVID-19 episode (derived from CCP-UK) will enable a full understanding of COVID-19 in patients with cancer as well as enable a comparison with non-cancer patients.

    • Inclusion Criteria:

      Inclusion: Patients with proven COVID-19 and a diagnosis of cancer who are enrolled into any tier of the Principal CCP-UK protocol. Exclusion: None in addition to those specified in the principal CCP-UK study. *Exclusion criteria specified in CCP-UK Protocol; 1. Confirmed diagnosis of a pathogen unrelated to the objectives of this study and no indication or likelihood of co-infection with a relevant pathogen. 2. Refusal by participant, parent or appropriate representative.

    • Exclusion Criteria:

      None in addition to those specified in the Principal CCP-UK protocol: Exclusion criteria specified in CCP-UK Protocol; 1. Confirmed diagnosis of a pathogen unrelated to the objectives of this study and no indication or likelihood of co-infection with a relevant pathogen. 2. Refusal by participant, parent or appropriate representative.

    Read more Return to top ('Preview' button)
  • A Randomized, Double-Blind, Phase 3 Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Patients Newly Diagnosed with Higher-Risk Myelodysplastic Syndrome (Higher-Risk MDS)

    • Research Summary

      Myelodysplastic Syndrome (MDS) is a group of disorders that gradually affect the ability of a person's bone marrow (semi-liquid tissue present in many bones like backbones) to produce normal blood cells. Some people with MDS have a risk of the disease progressing to acute myeloid leukaemia (AML), and a risk of death from the disease itself. Symptoms of MDS include fatigue, shortness of breath, unusual paleness due to anemia (low red blood cell count), easy or unusual bruising, and red spots just beneath the skin caused by bleeding. The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no medicine), in participants with newly diagnosed higher-risk MDS. Venetoclax is an investigational medicine being developed for the treatment of MDS. The study consists of two treatment arms - In one arm, participants will receive venetoclax and AZA. In another arm, participants will receive AZA and placebo. Adult participants with newly diagnosed higher-risk MDS will be enrolled. Around 500 participants will be enrolled in approximately 200 sites worldwide. Participants in one arm will receive oral doses of venetoclax tablet and intravenous (infusion in the vein) or subcutaneous (given under the skin) AZA solution. Participants in another arm will receive oral doses of placebo tablet and intravenous or subcutaneous AZA solution. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

    • Inclusion Criteria:

      1. Adult male or female, at least 18 years old. 2. Diagnosis of MDS according to the 2016 WHO classification with presence of < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening. 3. Patient must have adequate liver functions as demonstrated by:  Serum alanine transaminase (ALT) < 3.0 × upper limit of normal [ULN];  Serum aspartate transaminase (AST) < 3.0 × ULN;  Serum total bilirubin ≤ 2.0 × ULN; (Patients with documented Gilbert's Syndrome may be allowed if total bilirubin > 2.0 × ULN following discussion with the TA MD) AND  Total white blood cell (WBC) count ≤ 10,000/μL; (Treatment with hydroxyurea is permitted to lower the WBC to reach this inclusion criterion. The WBC should be determined ≥ 24 hours after the last dose of hydroxyurea. The last dose of hydroxyurea should not be administered ≤ 3 days prior to the first dose of azacitidine.  Creatinine clearance ≥ 30 mL/min 4. Patient meets the following disease activity criteria:  Overall IPSS-R score > 3 (intermediate, high, or very high);  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;  Haematopoietic stem cell transplant (HSCT) eligible with no pre-arranged HSCT at the time of Study Day 1, or HSCT ineligible without plan for HSCT at the time of Study Day 1. 5. No prior therapy for MDS with any hypomethylating agent (for example, azacitidine, decitabine), chemotherapy or allogeneic stem cell transplantation.

    • Exclusion Criteria:

      1. Patient has previous diagnosis of:  Therapy-related MDS (t-MDS)  MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)  MDS/MPN including chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia (aCML), juvenile myelomonocytic leukaemia (JMML) and unclassifiable MDS/MPN. 2. Prior therapy for MDS with any hypomethylating agent (for example, azacitidine, decitabine), chemotherapy or allogeneic stem cell transplantation. 3. Patient has any chronic respiratory disease that requires continuous oxygen, history of clinically significant renal disease, cardiovascular, endocrinologic, hepatic, immunologic, metabolic, neurologic, psychiatric, or any other condition or known hypersensitivity to any study medications including excipients of azacitidine that in the opinion of the investigator would adversely affect participation in this study or interpretation of study results. 4. Patient has history of any active malignancy within the past 2 years prior to screening, with the exception of:  Adequately treated carcinoma in situ of the uterine cervix  Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin  Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy. 5. Patient has history of clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months. 6. Patient has conditions that could interfere with drug absorption including but not limited to short bowel syndrome. 7. Patient has history of clinically significant medical conditions or any other reason that the investigator determines would interfere with the patient's participation in this study or would make the patient an unsuitable candidate to receive study medicine. 8. Patient has history of an allergic reaction or significant sensitivity to constituents of the study medicine (and its excipients) and/or other products in the same class. 9. Patient has active, uncontrolled systemic infection. 10. Patient has positive test result(s) for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. 11. For all females of childbearing potential; lack of negative serum pregnancy test at the Screening Visit and lack of negative urine pregnancy test at baseline prior to the first dose of study medicine. 12. Female patients of childbearing potential who do not practice at least 1 protocol-specified method of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of venetoclax/placebo or 3 months after the last dose of azacitidine, whichever is later. 13. Female who is pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 30 days after the last dose of venetoclax/placebo or 3 months after the last dose of azacitidine, whichever is latest. 14. Male who is sexually active with female partner(s) of childbearing potential, who do not agree, from Study Day 1 through at least 30 days after the last dose of venetoclax/placebo or 3 months after the last dose of azacitidine, whichever is later, to practice the protocol-specified contraception. 15. Male who is considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of venetoclax/placebo or 3 months after the last dose of azacitidine, whichever is later. 16. Patient has prior therapy with a BH3 mimetic. 17. Patient has been treated with any investigational medicine within 30 days or 5 half lives of the drug (whichever is longer) prior to the first dose of study medicine or is currently enrolled in another clinical study or was previously enrolled in this study. 18. Patient has systemically used known strong or moderate cytochrome P450 (CYP)3A inducers within 7 days prior to first dose of study medicine through the end of the study. Patient has known medical conditions requiring chronic therapy of moderate CYP3A inducers. 19. Patient has received any live vaccine within 4 weeks prior to the first dose of study medicine , or expected need of live vaccination during study participation including at least 4 weeks after the last dose of study medicine. 20. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit (carambola) within 3 days before anticipated first dose of study medicine.

    Read more Return to top ('Preview' button)
  • Translational Renal Adjuvant MultiPle Arm Randomised Trial (TransRAMPART)

    • Research Summary

      Renal cell carcinoma is a type of kidney cancer that starts from the kidneys. It is the 8th most common cancer in the UK and an increase of new cases of 2% has been seen in the last twenty years. About half of the new cases of kidney cancer are among people aged 70 and above. Patients whose disease has not spread outside the kidneys typically have surgery to remove a part or all of their kidney (called a partial or radical nephrectomy). After surgery, patients are seen by their doctor with regular check-ups to look for signs of the cancer coming back or spreading to other parts of the body; this is generally called ‘active monitoring’ or ‘active surveillance’. Unfortunately, it is estimated that the cancer will return in 30-40% of the patients who have undergone surgery. Many clinical studies have been carried out to find if a new treatment after surgery might slow the cancer coming back or prevent it from coming back altogether. However, to date no treatment is available. RAMPART is a study looking at two new immunotherapy treatments (durvalumab and tremelimumab) that have shown a benefit in other cancer types. TransRAMPART is a translational research study being run within the RAMPART clinical trial. Translational research is carried out in the laboratory on biological samples that our patients provide. By biological samples we mean samples of tumour, blood and urine. In TransRAMPART study we will carry out research on these samples to gain a better understanding of kidney cancer and how people respond to treatment with the class of medication (immune checkpoint inhibitors) our patients will be taking in RAMPART.

    • Inclusion Criteria:

      The inclusion criteria are the same as the RAMPART study (as copied below). All RAMPART patients at TransRAMPART sites will be offered the opportunity to participate in this study. 1. Histologically proven RCC (all cell types of RCC are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); no evidence of residual macroscopic disease on post-operative CT scan after resection of RCC. Patients with treated bilateral synchronous RCCs are eligible. 2. At the start of recruitment patients with Leibovich score 3-11 will be eligible for randomisation. MRC CTU at UCL will monitor accrual and stop recruiting intermediate risk patients (Leibovich Score 3-5) after three years or when intermediate risk patients contribute 25% of the total accrual target, whichever is earlier. Recruitment of patients with Leibovich Score 6 11 will continue until the accrual target is reached. 3. Patients should have had surgery at least 28 days but no more than 91 days prior to their randomisation date. 4. Post-operative scans should be performed within 28 days prior to randomisation. 5. Patients with microscopically positive resection margins after radical nephrectomy at the nephrectomy bed, renal vein or inferior vena cava are eligible provided the post-operative CT scan shows no evidence of residual macroscopic disease. 6. WHO Performance Status 0 or 1. 7. Patient has archival FFPE pathology tissue available, and agrees to provide at least one sample (FFPE tumour block from nephrectomy, or a minimum of 10 unstained slides), as well as a baseline blood sample for future translational research. 8. Adequate normal organ and marrow function a. Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria). b. Absolute neutrophil count (ANC) > = 1.5 x 109/L (> = 1500 per mm3). c. Platelet count > = 100 x 109 (> = 100,000 per mm3). d. Bilirubin < = 1.5 x ULN (This will not apply to subjects with confirmed Gilbert’s syndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician). e. AST/ALT < = 2.5 x ULN. f. Calculated Creatinine Clearance level > 40mL/min by Cockcroft Gault formula (using actual body weight). 9. 12-lead ECG on which QTcF must be < 450 ms. In case of clinically significant ECG abnormalities, including a QTcF value > = 450 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. Patients are only eligible if a QTcF of < 450ms is confirmed 10. Subjects must be > = 18 years of age. 11. Written informed consent obtained from the patient. 12. Both men and women enrolled in this trial must be in agreement with trial policy on contraception during the treatment phase of the study and 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided. 13. Evidence of post-menopausal status or negative serum HCG pregnancy test for female pre menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age specific requirements apply: a. Women < 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy). b. Women > = 50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy induced menopause with last menses > 1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

    • Exclusion Criteria:

      The exclusion criteria are the same as the RAMPART study (as copied below). All RAMPART patients at TransRAMPART sites will be offered the opportunity to participate in this study. 1. Previous diagnosis of RCC. 2. Metastatic or macroscopic residual disease. 3. Patients with positive resection margins after partial nephrectomy. 4. Patients with a single pulmonary nodule > = 5mm diameter are not eligible unless the nodule has had a definite benign diagnosis. Patients with multiple small, less than 5 mm nodules may be eligible if nodules have been shown to be radiologically stable for at least 8 weeks. 5. Prior anticancer treatment (other than nephrectomy) for RCC. 6. Any unresolved toxicity NCI CTCAE Grade > = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria a. Patients with Grade > = 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician. 7. History of another primary malignancy except for: a) Malignancy treated with curative intent and with no known active disease > = 5 years before the first dose of IP and of low potential risk for recurrence. b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c) Adequately treated carcinoma in situ without evidence of disease. 8. History of leptomeningeal carcinomatosis. 9. Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow up period of an interventional study. 10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the start of treatment. Local surgery of isolated lesions for palliative intent is acceptable. 11. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 12. Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years may be included but only after consultation with the RAMPART Trial Management Team e. Patients with coeliac disease controlled by diet alone 13. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty. 14. History of allogeneic organ transplant. 15. Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection of any kind (patients who are exhibiting symptoms consistent with COVID-19, or who have tested positive, should not be randomised into the study until they are asymptomatic and at least 14 days after a positive test) b. Symptomatic congestive heart failure c. Uncontrolled hypertension d. Unstable angina pectoris e. Uncontrolled cardiac arrhythmia f. Active peptic ulcer disease or gastritis g. Active bleeding diatheses h. Psychiatric illness or social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. 16. Active infection including a. Tuberculosis b. Hepatitis B c. Hepatitis C d. Human immunodeficiency virus (positive HIV 1/2 antibodies). Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 17. Receipt of live attenuated vaccine within 30 days prior to the start of treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving investigational medicinal product and up to 30 days after the last dose of investigational medicinal product. 18. Pregnant or breastfeeding patients. 19. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 20. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients. 21. Previous investigational medicinal product assignment in the present study. 22. Clinically significant pneumonitis or fibrosis.

    Read more Return to top ('Preview' button)
  • A retrospective observational research study to describe the characteristics and real-world clinical outcomes of patients with locally advanced, unresectable Stage III non-small cell lung cancer receiving durvalumab in the United Kingdom.

    • Research Summary

      This is a retrospective observational research study to describe the characteristics and real-world clinical outcomes of patients with locally advanced, unresectable Stage III non-small cell lung cancer receiving durvalumab following platinum based chemoradiotherapy in the United Kingdom (the CODAK study). Data from this study will provide UK-specific real-world data on patients receiving durvalumab through the Early Access Programme (EAP) or post-reimbursement. The study will recruit approximately 250 patients, treated in 10 -12 UK secondary care hospitals, who were initiated on durvalumab between 1st September 2017 and 31st December 2019.

    • Inclusion Criteria:

      • Patient has documented diagnosis of locally advanced, unresectable Stage III NSCLC • Patient has received platinum-based CRT and received > = 1 dose of durvalumab • Patient was initiated on durvalumab (index event) between 1st September 2017 and 31st December 2019 via the EAP or non-EAP • Patient was aged > = 18 years at durvalumab initiation

    • Exclusion Criteria:

      • Patients who participated in the PACIFIC-R study • Participation in any clinical study with an investigational product at the time of durvalumab initiation or during the observational period

    Read more Return to top ('Preview' button)
  • Early iDEntification of Pancreatic cancer: a study to evaluate the utility of pancreatic exocrine insufficiency as a scrEening tool in high-risk iNdiviDuals

    • Research Summary

      Can breath and stool tests be used to detect inadequate pancreatic function in patients with pancreatic cancer? Pancreatic cancer is regarded as the most lethal cancer as most cases are diagnosed late and treatment options are often limited. There is some evidence that cancer can affect the organ’s function in the very early stages and this study hopes to take advantage of that. It will use breath and stool tests to determine if there is a difference between patients with early, operable pancreatic cancer and healthy controls without cancer. A third group, patients with chronic pancreatitis, will also be included as their restricted pancreatic function would form a good benchmark to determine how accurate the tests are in those with suspected altered function against those with established pancreatic disease. Cancer Research UK have funded this study, which will involve 25 participants with pancreatic cancer and 25 controls, as well as a small subset of those with chronic pancreatitis. They will arrive at the Clinical Research Facility in University Hospital Southampton whilst starved to undergo baseline blood tests (if pancreatic cancer) and then consume a breakfast meal with stable, non-radioactive labelled isotope present as a lipid (fat). The enzyme lipase is produced in the pancreas and aids digestion of fats and in normal pancreatic function should convert this lipid into carbon dioxide which is then excreted in the breath and detected. The enzyme elastase is also produced by the pancreas and is absent in pancreatic disease. This research hopes to establish if patients with pancreatic cancer have significantly different breath and stool profiles compared to healthy controls, and how different the are to those with chronic pancreatitis. This study hopes to run over a 12-month period. At the end of it, an inexpensive but reliable way of screening for pancreatic cancer may be established.

    • Inclusion Criteria:

      Male and female patients aged between 30-85 within the UHS catchment area for HPB surgery for pancreatic cancer – this includes patients across Hampshire, Dorset and the Isle of Wight.

    • Exclusion Criteria:

      • Patients with autoimmune or other chronic inflammatory conditions. • Healthy participants who previously had pancreatic disease e.g. acute pancreatitis which will be confirmed by their medical history (i.e. confirmation from their General practitioner-GP). • Participants who are pregnant. • Participants not willing to consent • Patients who are pyrexial on arrival to the CRF

    Read more Return to top ('Preview' button)
  • VALTIVE1: Validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors: Optimising the design of a subsequent randomised discontinuation trial

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase 1/2b, First-in-Human, Open-Label, Dose Escalation Study of Teclistamab, a Humanised BCMA x CD3 Bispecific Antibody, in Subjects with Relapsed or Refractory Multiple Myeloma.

    • Research Summary

      This is a Phase 2 Open-Label study to determine if the study drug is effective, safe and tolerable in a larger group of patients with relapsed or refractory multiple myeloma. A global study composed of three parts. The UK will be involved in Part 3 only. Parts 1 & 2 were designed to define a safe and tolerable dose and to determine the potential effectiveness of the study drug for Part 3. A total of 230 participants are to be enrolled, all participants will receive the study drug, teclistimab. Teclistamab is an antibody. Antibodies are proteins that attach to specific targets on cells or tissues to help the body fight cancer, infections and other diseases. Although there are treatments available for multiple myeloma, the disease is still incurable. This study is in patients where their disease is worsening or not responding to the current treatments (relapsed and refractory). The increasing number of patients with relapsed and refractory disease requires new therapies to address this unmet medical need. Potential participants will go through a screening phase of up to 28 days to determine their suitability for the study, with various health tests, including review of medical history, vital signs, electrocardiogram, blood samples, bone marrow samples, and imaging (X-Ray/CT). If eligible and the patient wants to participate then they will move into the treatment phase of the study. Each treatment cycle lasts 28 days and there are 4 doses of study drug at each cycle. Various health tests, including vital signs, review of side effects, blood samples, imaging (X-Ray/CT) depending on the study visit schedule. On completion of treatment participants go into a follow-up period, where long-term data on anti-cancer drugs and patient wellbeing. In total the participant will be on study for a maximum of two and a half years.

    • Inclusion Criteria:

      1. ≥ 18 years of age. 2. Documented diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) diagnostic criteria. 3. Measurable disease - Cohort A, Cohort B, and Cohort C: Multiple myeloma must be measurable by central laboratory assessment: • Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours; OR • Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio. Prior treatment • Cohort A: Patients must have 1) received ≥ 3 prior lines of therapy or be double refractory to a PI and IMiD and 2) previously received a PI, an IMiD, and an anti-CD38 antibody (refractory multiple myeloma as defined by IMWG consensus criteria). Note: Induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single line of therapy. - Undergone ≥ 1 complete cycle of treatment for each line of therapy, unless progressive disease was the best response to the line of therapy. - Must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG 2016 criteria on or within 12 months of last line of therapy. Also, patients with documented evidence of progressive disease (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible. • Cohort B: received ≥ 4 prior lines of therapy and whose disease is penta-drug refractory to an anti-CD38 monoclonal antibody, ≥ 2 PIs, ≥ 2 IMiDs. - Undergone at least 1 complete cycle of treatment for each line of therapy, unless progressive disease was the best response to the line of therapy. - Patient must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG 2016 criteria on or within 12 months of their last line of therapy. Also, patients with documented evidence of progressive disease within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible. • Cohort C: received prior treatment with CAR-T therapy directed against BCMA or an ADC directed against BCMA. - Patient must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG 2016 criteria. Also, subjects with documented evidence of progressive disease within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible. 4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. 5. Pre-treatment clinical laboratory values at Screening Phase: Haematology Haemoglobin > 8 g/dL (> 5 mmol/L) (without prior red blood cell [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted). Platelets < 75 × 109/L for patients in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count ≥ 50 x 109/L (without transfusion support in the 7 days prior to the laboratory test). Absolute Neutrophil Count (ANC) > 1.0 × 109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test). Chemistry AST and ALT ≤ 3.0 × upper limit of normal (ULN) Creatinine or Creatinine clearance Serum creatinine: ≤ 1.5 mg/dL OR Creatinine clearance: > 40 mL/min/1.73 m2 based upon Modified Diet in Renal Disease formula calculation. Total bilirubin ≤ 2.0 × ULN; except in patients with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 × ULN is required) Corrected serum calcium ≤ 14 mg/dL (≤ 3.5 mmol/L) or free ionized calcium < 6.5 mg/dL (< 1.6 mmol/L). 6. Women of childbearing potential must have a negative pregnancy test at screening and prior to the first dose of study drug using a highly sensitive pregnancy test. 7. Women of childbearing potential and fertile men who are sexually active must agree to use a highly effective method of contraception from the time of signing the ICF during the study and for 90 days after the last dose of study drug. Contraception must be consistent with local regulations regarding the use of birth control methods for participants participating in clinical trials. 8. Patient must sign an informed consent form indicating that he/she understands the purpose of and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the patient’s disease. 9. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.

    • Exclusion Criteria:

      1. Prior treatment with BCMA-targeted therapy, with the exception of Cohort C in Part 3. 2. Prior anti-tumor therapy, before the first dose of study drug: • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less. • Monoclonal antibody treatment for multiple myeloma within 21 days. • Cytotoxic therapy within 21 days. • Proteasome inhibitor therapy within 14 days. • Immunomodulatory agent therapy within 7 days. • Radiotherapy within 14 days. However, if focal radiation, the patient is eligible irrespective of the end date of radiotherapy. 3. Toxicities from previous anticancer therapies that have not resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy. 4. Received a cumulative dose of corticosteroids equivalent to ≥ 140 mg of prednisone within the 14-day period before the first dose of study drug (does not include pre-treatment medication). 5. Stem cell transplantation: • An allogeneic stem cell transplant within 6 months. Patients who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease. • Received an autologous stem cell transplant ≤ 12 weeks before the first dose of study drug. 6. Known active CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. 7. Plasma cell leukemia (> 2.0 × 109/L plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis. 8. Known to be seropositive for HIV or acquired immune deficiency syndrome. 9. Hepatitis B infection or at risk for hepatitis B virus reactivation as defined according to the American Society of Clinical Oncology guidelines. Active Hepatitis C infection as measured by positive hepatitis C virus (HCV)-RNA testing. 10. Pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation. 11. Known allergies, hypersensitivity, or intolerance to excipients of the study drug. 12. Any serious underlying medical condition, such as: • Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection. • Active autoimmune disease or a documented history of autoimmune disease. • Psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status. • Stroke or seizure within 6 months of signing ICF. • Any other issue that would impair the ability of the patient to receive or tolerate the planned treatment, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments. 13. Pregnant or breast-feeding, or planning to become pregnant while enrolled on study or within 90 days after the last dose of study drug. 14. Plans to father a child while enrolled on study or within 90 days after the last dose of study drug. 15. Major surgery within 2 weeks of the first dose, or not fully recovered from surgery, or surgery planned during the study or within 2 weeks after the last dose of study drug. 16. The following cardiac conditions: • New York Heart Association stage III or IV congestive heart failure • Myocardial infarction or coronary artery bypass graft (CABG) ≤ 6 months prior to enrollment • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration • History of severe non-ischemic cardiomyopathy • Impaired cardiac function (LVEF < 45%) as assessed by echocardiogram or multiple-gated acquisition scan (performed ≤ 8 weeks prior to enrollment). 17. Active malignancies (ie, progressing or requiring treatment change in the last 24 months). The only allowed exceptions are: • Non-muscle invasive bladder cancer. • Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured. • Non-invasive cervical cancer treated within the last 24 months that is considered completely cured. • Localized prostate cancer (N0M0): o With a Gleason score of 6, treated within the last 24 months or untreated and under surveillance. o With a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence. o Or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence. • Breast cancer: o Adequately treated lobular carcinoma in situ or ductal carcinoma in situ, o Or history of localized breast cancer and receiving anti-hormonal agents and considered to have a very low risk of recurrence.

    Read more Return to top ('Preview' button)
  • Phase I-II of the update of the EORTC Quality of Life Gastric module QLQ-STO22.

    • Research Summary

      The EORTC QLQ-STO22 (STO22) has been used internationally as a measure of the specific health-related quality of life (HRQoL) concerns of patients with gastric cancer (GC). The GC-specific module was developed in 2001 and although it one of the most well-established instruments for measuring the QOL of GC patients, there are some points worth considering which suggest a need to revisit the module and identify necessary modifications. Firstly, treatment strategy and drugs for systemic therapy have dramatically changed since the module was developed. The original STO22 measurement tool might not sufficiently cover the specific side-effects (such as skin rashes, peripheral neuropathy, mucositis) of these new and current regimens, which involve more intense and toxic chemotherapeutic agents Additionally, the surgical procedure for GC has shifted to a less invasive approach and thus the current version of the STO22 might not adequately cover post-surgical complications. An additional consideration relates to the absence of any contribution of specialists and patients from East Asian countries (Japan, Korea, China, Taiwan and Mongolia) in the development of the STO22. This is particularly important given that patient characteristics and treatment strategies are likely to be different in East Asian countries compared to Europe. The study will recruit 90 patients with GC and 15 HCPs across Europe and East Asia. Participants will be interviewed about their experiences of GC and asked to evaluate the current STO22. Study objectives include: 1) Assess the need for an updated STO22 questionnaire to accommodate changes to treatment modalities and include the perspective of patients and clinicians from East Asia; 2) Develop a provisional draft updated STO22 covering new treatment schedules and the experiences of patients with GC from East Asia thus positioning the STO22 more globally as a standard module to assess HRQOL of GC patients.

    • Inclusion Criteria:

      A) Age > = 18 years. B) Histologically proven as gastric adenocarcinoma with disease stages I-IV (UICC TNM 8th). C) Patients with a gastric or junction cancer whose epicentre is located within 2 cm of the oesophagogastric junction D) Patients receiving treatment (either currently or within the last 12 months) including a systemic treatment (chemotherapy, target agents, and immunotherapy), surgical resection, and radiotherapy or receiving supportive or palliative care. E) Patients who are willing and able to give fully informed consent to participate.

    • Exclusion Criteria:

      A) Patients under 18 years of age. B) Cancer survivors defined as people who have completed treatment with curative intent more than 12 months ago and are now cancer free. C) Patients enrolled in other quality of life studies which will affect the results of the current study.

    Read more Return to top ('Preview' button)
  • Patients’ preferences in the treatment of hormone-sensitive metastatic prostate cancer: a discrete choice experiment

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Precision medicine for liver tumours with quantitative magnetic resonance imaging and whole genome sequencing

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Retrospective, Multi-Centre, Observational Study of Outcomes and Toxicity of Panobinostat in combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma in a UK real world setting (PiMMS)

    • Research Summary

      This study will investigate the real-world outcomes for patients receiving Panobinostat for myeloma at hospitals in England. The primary objective is the evaluation of progression-free survival (PFS) of relapsed/refractory multiple myeloma (RRMM) patients receiving panobinostat in combination with bortezomib and dexamethasone following at least 2 prior regimens including bortezomib and an immunomodulatory agent. The study will also investigate other measures of response depth and length, toxicity and tolerability as measured by incidence and severity of adverse events and dose modifications in real world practice, and health economics measures, determined by number of outpatient, inpatient, and intensive care admissions and length of inpatient stay while on active treatment with Panobinostat. The study will comprise the retrospective collection of existing routine clinical data, with no additional input required from patients.

    • Inclusion Criteria:

      1. > = 18 years of age at the time of diagnosis with symptomatic myeloma. 2. Diagnosis of myeloma (according to IMWG diagnostic criteria) documented. 3. Received at least 2 prior lines of therapy before commencing panobinostat (note, at least 1 full cycle of chemotherapy, with or without a stem cell transplant or maintenance, constitutes a line of therapy). 4. Received at least 1 full cycle of panobinostat, bortezomib and dexamethasone between 01-Jan-2016 and 01-Jan-2018

    • Exclusion Criteria:

      1. Patient receiving panobinostat as part of clinical trial.

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

    • Research Summary

      -

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Impact of abemaciclib on patients’ roles and responsibilities (IMPACTOR)

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The impact of COVID-19 on patients with AML undergoing chemotherapy: an epidemiological study.

    • Research Summary

      The pandemic of COVID-19 has had significant implications globally. It is known that patients with underlying health conditions are more likely to develop severe COVID-19 but many patients, including patients with Acute Myeloid Leukaemia (AML), cannot wait for treatment for their disease. Unfortunately both AML and the standard intensive or non-intensive chemotherapy options make these patients more likely to pick up infections. This observational study will recruit 100 patients with AML who are receiving, or due to receive, treatment with chemotherapy. The main aims of this study are to record how many of these patients have had COVID-19 previously, have an active infection or go on to develop COVID-19 whilst receiving treatment for their AML. Other serious infections patients may experience will also be recorded. We will collect information on the treatments patients received and their outcome. Patients will be seen according to standard of care, there are no trial specific visits or assessments. The information collected will all be provided from the patient notes. Patients will be recruited over 6 months from selected NHS hospitals across the UK by their AML doctor or nurse. Data will be collected for 24 months from study entry and all patients will be followed up for survival until the end of the study. An optional sampling sub-study will collect samples from patient's consenting to the substudy, to analyse the immune response to infection, viral shedding, and the affect of the microbiome on Covid-19 infection.

    • Inclusion Criteria:

      • Patients with AML or MDS-EB2 planned for intensive (i.e. curative intent) or non-intensive chemotherapy • Patients with AML or MDS-EB2 receiving treatment at the start of the study period.* • Patients with known AML who present with relapse • Written informed consent for the study. * All stages of treatment are included (e.g. induction, consolidation, maintenance). Pre-existing conditions including myelodysplasia or myeloproliferative conditions are eligible. Patients with acute promyelocytic leukaemia (APML) are not eligible for this study. Intensive treatment includes regimens including Daunorubicin/Cytarabine, Fludarabine/Cytarabine/Idarubicin, intermediate/high dose Cytarabine, CPX-351, Gemtuzumab Ozogamacin, Midostaurin. Non-intensive treatments include Azacitidine, low dose Cytarabine, and Venetoclax based regimens.

    • Exclusion Criteria:

      • Age under 16 years • Patients undergoing allogeneic stem cell transplant at trial entry • Supportive care only (including hydroxycarbamide alone) - Patients with APML

    Read more Return to top ('Preview' button)
  • Pan Tumor Study for Long Term Follow-up of Cancer Survivors Who Have Participated in Trials Investigating Nivolumab

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PreOperative Endocrine Therapy for Individualised Care with Abemaciclib

    • Research Summary

      In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as endocrine therapy) for at least five years after surgery is very effective at reducing the risk of the cancer returning. However, for some women their cancer may eventually become resistant to these drugs. POETIC-A Registration part will identify those who have a higher risk of developing resistance to standard endocrine therapy (ET). 5000 - 6000 women diagnosed with early stage breast cancer and have not yet had surgery to remove the cancer will enter the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a type of ET, to treat the cancer for 2 weeks before surgery. A sample will be taken from the cancer during surgery and the study laboratory will measure a biological marker called Ki67. If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be less sensitive to endocrine therapy, and the study doctor will explore additional treatments after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage (2500 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or Group2: ET plus a new drug called abemacicilib. The first aim of the Treatment stage is to confirm whether abemaciclib given in combination with ET is more effective than giving ET alone in preventing the cancer coming back. The study laboratory will perform a second test on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib. Patients in Group 2 will receive ET plus abemacicilib for 2 years. Patients in both groups will have regular study visits during this period.

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase III trial of intensity-modulated proton beam therapy versus intensity modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Body composition and chemotherapy toxicity in women with early breast cancer (CANDO-3)

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Evaluation of the role of tongue base MucOsectomy and Step sErial Sectioning in the management of the unknown primary squamous cell cancer in the head and neck

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Phase 2 and 3: Understanding and improving community-based palliative care outside of normal working hours

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Mammographic Predictors of Cancer Recurrence after Breast Conservation and Adjuvant Endocrine Therapy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase 2, Double-Blind, Placebo Controlled Study of RV001V in Men with Biochemical Failure following Curatively Intended Therapy For Localized Prostate Cancer

    • Research Summary

      This study will evaluate the efficacy, safety and tolerability of RV001V, an investigational cancer vaccine against metastases from solid tumors. This vaccine will be evaluated in a phase 2,randomized, double blind,placebo controlled study in adult male with an earlier histologic diagnosis of prostatic adenocarcinoma and a biochemical recurrence after radical prostatectomy or definitive radiotherapy without distant metastasis and locoregional recurrence. The study will randomize approximately 180 patients to either RV001V or placebo treatment in a 1:1 manner. The objective of this Phase II study is to investigate whether a vaccination regimen with multiple subcutaneous (SC) administrations of RV001 Vaccine 0.1 mg/mL can reduce prostate-specific antigen (PSA) progression compared to the control group.

    • Inclusion Criteria:

      1. Men aged 18 and above with an earlier histologic diagnosis of prostatic adenocarcinoma. 2. Able to understand the study procedures and willing to provide IC. 3. Able and willing to comply with study requirements and complete all visits. 4. Biochemical recurrence (BCR) in compliance with the following 3 conditions: - after having finished last definitive treatment (including those who have received RP/RT followed by any modality of salvage therapy), - no distant metastasis by standard CT imaging with bone scintigraphy or a normal PET-CT and - no locoregional recurrence (including lymph nodes). Locoregional recurrence will be assessed by multi-parametric magnetic resonance imaging (MRI) in all patients treated with curative RT and should be confirmed with image guided prostatic gland biopsy in case of suspicious lesions. Any prostatic biopsy performed should be negative. 5. Prior definitive treatment with RP or RT. In case the patient was subjected to a RP, all the following will apply: a. PSA > = 0.2 ng/mL, b. PSA Doubling Time (PSADT)a > 3 months and < 12 months, c. History of Gleason 7 (4 + 3) or higher. Conversely, if the patient was treated with definitive RT and not prior RP, all the following will apply: a. PSA > nadira + 2 ng/mL, b. PSADTa > 3 months and < 12 months, c. History of Gleason score of 7 (4 + 3) or higher. 6. Eastern Cooperative Oncology Group (ECOG) performance status < = 2. 7. Laboratory values obtained < = 30 days prior to first vaccination a. Hemoglobin > = 5.6 mmol/L (0.72 g/L) b. Absolute granulocyte count > = 1.5 x 109 /L. c. Platelets > = 100 x 109 /L. d. Total bilirubin < = 1.5 x upper limit of normal (ULN). e. Creatinine < = 1.5 x ULN. f. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) < = 2.5 x ULN.

    • Exclusion Criteria:

      1.Patients who are receiving androgen-deprivation therapy (ADT) or considered a candidate for immediate ADT or are candidate to any local therapy according to applicable clinical guidelines or judged by the investigator. 2. Patients who have received prior ADT are not eligible with the exception of those that received ADT < = 36 months in duration and > = 9 months before randomization and administered only in the neoadjuvant/adjuvant setting. 3. Patient is planned for salvage therapy. 4. Castrate level of serum testosterone < 50 ng/dL at screening. 5. PSA > 10 ng/mL. 6. Small-cell, signet cell and neuroendocrine variants of adenocarcinomas. 7. An active malignancy likely to interfere with protocol treatment or FU. 8. Patients who have undergone major surgery or have had major bleeding within the last month prior to the first vaccination. 9. Prior treatment with any therapeutic cancer vaccine(s). 10. Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 11. History of alcohol or substance abuse within the last 5 years. 12. Patients receiving any investigational drug(s) or treatment within 30 days prior to inclusion in this trial. 13. History of significant autoimmune disease such as Inflammatory Bowel Disease, Systemic Lupus Erythematosus, Ankylosing Spondylitis, Scleroderma, Multiple Sclerosis. 14. Severe medical conditions, such as but not limited to severe asthma/chronic obstructive pulmonary disease (COPD), New York Heart Association (NYHA) grading 3 or above, poorly regulated insulin dependent diabetes, any significant organ damage as judged by theInvestigator. 15. Other medications, conditions or laboratory results that in the Investigator's opinion would contraindicate study participation for safety reasons or interfere with the interpretation of study results. 16. History of known allergy/hypersensitivity to any component of the study drug (such as Montanide ISA 51), or intolerance to SC injection. 17. Patients with a prior solid organ / stem cell transplantation. 18. Patients with known acquired immunodeficiency disorder (AIDS) or any inherited immunodeficiency disorder.

    Read more Return to top ('Preview' button)
  • Understanding patient experience of premalignant pancreatic cystic lesion surveillance prior to development of an intervention to improve current care.

    • Research Summary

      A pancreatic cyst is a fluid-filled sac found within the pancreas. Some pancreatic cysts contain cells that can turn into cancer over time. It is important to watch these cysts that are most often incidental and asymptomatic to see which ones pose a risk of becoming pancreatic cancer. Pancreatic cysts are watched under surveillance for many years. There are no national rules to recommend how to watch these cysts, making management plans difficult for hospitals. Although diagnosing pancreatic cysts could potentially help stop the development of pancreatic cancer, it also means there is more work required from both patients and clinicians. Currently management involves at least yearly scans for a number of years looking for any worrying change. Precancerous conditions create anxiety for patients, and it is important to consider patients’ experiences of living with this type diagnosis when developing any surveillance system that patients enter. This study will involve face-to-face interviews with approximately 30 patients under surveillance for pancreatic cystic lesions. To ensure the study captures representative experiences of different PCL pathways patients will be sampled by pathway. Recruitment will occur in 2 sites using different surveillance methods, patients will be invited at different time points within the surveillance pathway including: following diagnosis, following first surveillance test and following a longer period of surveillance. Interviews will be analysed using thematic analysis, to identify and analyse themes within the rich qualitative data. Results will be combined with the findings of preceding literature reviews to develop recommendations and potential interventions that could begin to improve care for patients who are diagnosed with and under surveillance for PCL.

    • Inclusion Criteria:

      1. Age > 18 years. 2. Diagnosis of PCL (IPMN (of the main duct or side branches), MCN or SPN). 3. Under imaging surveillance. 4. Understand and communicate in English. 5. Able and willing to provide informed consent.

    • Exclusion Criteria:

      1. Patients who have a pancreatic cystic disease that is not considered premalignant, such as: pancreatic pseudocysts and SCN (Serous cystic neoplasm) will not be included in this study (these patients do not have long term surveillance for the purpose of identifying malignant potential). 2. Patients who are having active treatment or surgery for PCLs will not be included as this study aims to understand the experience of surveillance. 3. Patients who have had surveillance imaging with the researcher (Ruth Reeve) will be excluded. 4. Cognitive concerns that may limit the individual’s ability to provide informed consent.

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A randomized multicenter clinical trial for patients with multi-organ, colorectal cancer metastases comparing the combination of chemotherapy and maximal tumor debulking versus chemotherapy alone.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Association between tumour amphiregulin, epiregulin and epidermal growth factor receptor (EGFR) expression and response to anti-EGFR agents in colorectal cancer

    • Research Summary

      EGFR is a protein found on the surface of some cancer cells that causes them to grow and divide. Cetuximab and panitumumab are drugs that switch off EGFR (anti-EGFR agents). They have been shown to help some patients with advanced colorectal cancer (aCRC). Unfortunately anti-EGFR drugs do not work for all aCRC patients, meaning many people experience unpleasant side effects without any benefit. The proteins amphiregulin and epiregulin (AREG/EREG) are known to work with the EGFR to cause cancer cells to grow and divide. We have previously shown that patients whose cancer cells produce high levels of AREG/EREG are more likely to respond to anti-EGFR agents than those that produce low levels but further work is needed before this test can be used in clinical practice. This study will recruit patients with aCRC in oncology centres in the north of England. We will collect data and stored tumour both from patients previously treated with anti-EGFR agents, and also patients newly starting treatment. We will test tumour AREG/EREG levels to see if they do identify the patients who respond to treatment. To make sure our test will be possible in routine practice, we will use a common method for identifying protein levels on cancer cells called immunohistochemistry. This is different from the slower and more expensive way we used in our previous work. We will also use digital pathology and artificial intelligence techniques to develop a quick and cost-effective way of performing the test and getting results to doctors and patients. We will be collecting anonymous medical information from participants’ records, including their response to treatment. To analyse AREG/EREG levels, we will use previously collected, stored tumour samples. Funding for this project has been provided jointly by Innovate UK and Roche and recruitment will run over a period of 32 months.

    • Inclusion Criteria:

      - Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced (either inoperable metastatic disease at diagnosis or inoperable recurrent disease) - Aged 18 or over at time treatment commenced - The patient has received or has consented to receive treatment with cetuximab or panitumumab

    • Exclusion Criteria:

      - Stage I, II or III colorectal adenocarcinoma - RAS mutant disease - Eligible for potentially curative surgery (prospective cohort) - Underwent cancer surgery subsequent to anti-EGFR therapy (retrospective cohort) - Unable to provide informed consent (NB consent will not be required for patients in the retrospective cohort who have passed away)

    Read more Return to top ('Preview' button)
  • SPRING - Seizure PRophylaxis IN Glioma

    • Research Summary

      The most common type of primary brain tumour is called a cerebral glioma; around 6000 new cases are reported in the UK each year. 20% of patients who are suspected to have this type of tumour will develop seizures which need to be treated with anti-epileptic drugs before surgery. Of the remaining patients who go on to have surgery 30-50% will develop seizures and need to take anti-epileptic drugs post-surgery or later on. People with a tumour that have had a seizure are given an anti-epileptic drug (AED). It is unclear if patients who have never had a seizure should be given an AED to prevent them occurring. Currently in the UK, some doctors prescribe AEDs to patients before surgery, whilst others do not. We need to find out whether an AED is needed, and at what dose, so that we can give up to date evidence based guidance to neuro-surgeons and patients and provide the best treatment for patients. This is a two arm study, patients will be randomly allocated on a 1:1 basis either Levetiracetam or no anti epileptic treatment.

    • Inclusion Criteria:

      1)Patients with suspected cerebral glioma on MRI 2)Capable of giving informed consent 3)Patients must be ≥ 16 years old 4)Patients must have a Karnofsky performance status ≥70 5)Patients must be able to safely swallow pills 6)Planned surgery for presumed glioma (biopsy or resection)

    • Exclusion Criteria:

      1)Pregnant 2)History of any type of seizure for at least 10 years prior to randomisation 3)Known Severe Chronic Kidney Disease (CKD4 - eGFR < 30ml/min) 4)Concomitant methotrexate 5)Concomitant AED (including use for other reasons (e.g. pain)) 6)Concomitant benzodiazepines 7)Hypersensitivity to levetiracetam

    Read more Return to top ('Preview' button)
  • A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Fulvestrant Versus Placebo + Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2−) Breast Cancer Following Recurrence or Progression On or After Treatment with an Aromatase Inhibitor (CAPItello-291)

    • Research Summary

      The purpose of this research study is to find out if a new medication called capivasertib given with fulvestrant (a standard of care medication) will work more effectively than fulvestrant alone in treating patients with locally advanced (inoperable) or metastatic hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2−) breast cancer. Capivasertib is not approved by any health authority, except for use in research studies. In women, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths worldwide. Although it can be treated, metastatic breast cancer remains incurable with a median survival of approximately 3 years and a 5-year survival rate of around 25%. Approximately 700 patients will take part in this research study, with 350 patients in each group. The study will last approximately 4 years. Procedures will include, but are not limited to, blood tests, physical examinations, vital signs, electrocardiogram (a test to measure heart activity), questionnaires and radiological or MRI scans to measure the tumour and assess the extent of the cancer. AstraZeneca AB and AstraZeneca K.K. are funding the research. The study is planned to run at 16 hospitals/cancer centres in the UK.

    • Inclusion Criteria:

      1. Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist at least 4 weeks prior to Cycle 1, Day 1 and must be willing to continue on it for the duration of the study. 2. Histologically confirmed HR+/HER2− breast cancer determined from the most recent tumour sample (primary or metastatic), as per the American Society of Clinical Oncology and College of American Pathologists guideline recommendations. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. 3. Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression; locally advanced disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible). 4. ECOG/WHO PS: 0-1. 5. Patients are to have received treatment with an AI containing regimen (single agent or in combination) and have: a) Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an AI, OR b) Radiological evidence of progression while on prior AI administered as a treatment line for locally advanced or metastatic breast cancer (this does not need to be the most recent therapy). 6. Patients must have measurable disease according to RECIST 1.1 and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. 7. FFPE tumour sample from primary/recurrent cancer for central testing.

    • Exclusion Criteria:

      1. Symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgement. 2. More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic disease. 3. More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for advanced breast cancer. 4. Prior treatment with any of the following: a) AKT, PI3K and mTOR inhibitors b) Fulvestrant, and other SERDs c) Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation d) Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort) or sensitive substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week prior to study treatment initiation. 5. Radiotherapy with a wide field of radiation up to 4 weeks before study treatment initiation (capivasertib/placebo) and/or radiotherapy with a limited field of radiation for palliation up to 2 weeks before study treatment initiation (capivasertib/placebo). 6. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment. 7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids up to 4 weeks before study treatment initiation. 8. Any of the following cardiac criteria: a) Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive ECGs b) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block) c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval d) Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥ 2 e) Uncontrolled hypotension – systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg f) Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive). 9. Clinically significant abnormalities of glucose metabolism as defined by any of the following: a) Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment b) HbA1c ≥ 8.0% (63.9 mmol/mol). 10. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH (if applicable). 11. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

    Read more Return to top ('Preview' button)
  • A RANDOMIZED PHASE II TRIAL ASSESSING TRIMODALITY THERAPY WITH OR WITHOUT ADJUVANT DURVALUMAB (MEDI4736) TO TREAT PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Multi-centre Observational study of maintenance Niraparib in Treatment of Ovarian CanceR: UK routine clinical practice experience

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Development of a module to supplement the EORTC Core instrument for the assessment of Health Related Quality of Life in Adolescents and Young Adults (AYAs) aged 14-39 years with cancer

    • Research Summary

      This study addresses the specific Health-related Quality of Life (HRQoL) concerns facing Adolescents and Young Adults (AYA) with cancer. Our previous research has found that there are issues specific to AYAs with cancer (aged 14-25) that are currently not covered by the European Organisation for Research and Treatment of Cancer core measure (EORTC QLQ C30). In our previous research, we defined AYAs as 14-25 years. Following the advice of international experts on AYA oncology, we have decided to extend our work to align it more closely to international definitions of AYAs which goes up to 39 years. This first phase of the research is largely exploratory, where we will extend our previous research and gain insight into the important issues for young adults with cancer aged 26-39 years. The second phase of the research will involve reviewing the 77 issues identified in our previous research with AYAs aged 14-25 and developing a list of questionnaire items. The third phase will involve pilot testing the AYA questionnaire with a larger group of patients aged 14-39 years recruited from the UK and across the world.

    • Inclusion Criteria:

      -Diagnosis of cancer -Treatment with curative intent or palliative / supportive care -Age 14-39 years -Comprehension of the language of the questionnaire -Willingness and ability to give informed consent

    • Exclusion Criteria:

      -Participation in the earlier phase of the study -Cancer survivors (i.e., participants who have completed treatment with curative intent and are now cancer free).

    Read more Return to top ('Preview' button)
  • Biomarker Study to Identify Subjects with Advanced Urothelial Cancer and Fibroblast Growth Factor Receptor Gene Aberrations

    • Research Summary

      This is a biomarker study to identify patients with Urothelial Cancer and selected Fibroblast Growth Factor Receptor (FGFR) gene mutations through molecular testing of their archival tumour tissue. Subjects with Urothelial Cancer who test positive for FGFR mutations may be screened for inclusion in Janssen-sponsored clinical studies testing the use of Erdafitinib.

    • Inclusion Criteria:

      1. Subjects over the age of 18 years. 2. Transitional cell carcinoma of the urothelium. Minor components (< 50% overall) of variant histology are acceptable. 3. Diagnosis of either: a. Metastatic or surgically unresectable UC (Stage IV), or; b. Localized surgically-resectable or resected UC with a T classification of T2 or above who are at high risk for progression to advanced disease as assessed by the investigator. 4. Available archival tissue sample for FGFR aberration analysis. The archived tissue must either be from 1) metastatic site, 2) localized UC specimen that includes muscle invasive disease (T2 or above). 5. Eastern Cooperative Oncology Group performance status of 0 to 2.

    • Exclusion Criteria:

      Not applicable.

    Read more Return to top ('Preview' button)
  • A Post-Authorisation Safety Study Patient Registry of patients with high-risk neuroblastoma being treated with the monoclonal antibody dinutuximab beta

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Investigation of novel plasma Human Papilloma Virus DNA assay for treatment response estimation in head and neck cancer.

    • Research Summary

      Approximately 2000 patients are diagnosed annually in the UK with oropharyngeal (throat) cancer caused by human papillomavirus (HPV) infection. The standard treatment is chemotherapy and radiotherapy followed by surgical removal of any cancer left behind. The surgery is undertaken based on results of a scan (18F-FDG PET-CT). However, approximately 20-30% of patients will receive unnecessary surgical intervention, as residual cancer is not confirmed on pathological examination post-surgery. Following surgery approximately 25% of patients will have immediate complications and all will suffer significant permanent side effects (pain, shoulder dysfunction, altered quality of life). Therefore a more reliable marker of true residual disease is required as a means of guiding management decisions. As HPV positive(+) oropharyngeal cancers release HPV-DNA into the blood stream its presence can serve as a detection marker of residual cancer after treatment. HPV-detect, an assay developed and tested in a single-centre, prospective pilot study at the Royal Marsden Hospital/Institute of Cancer Research, is a way to measure HPV-DNA levels using a blood test. Further validation of HPV-detect is now required in a prospective multi-centre study. The study is needed to establish its usefulness in patient care and evaluate its potential to predict the absence of residual disease and avoid unnecessary surgery. INOVATE is a multicentre study which aims to collect biological samples from 143 HPV+ and 48 HPV negative patients with oropharyngeal cancer. Patients will be asked to donate archival diagnostic tumour tissue samples and blood samples taken at specified time points up to 1 year following treatment. HPV-DNA levels will be measured using HPV-detect and the results correlated with the 18F-FDG PET-CT results at 12 weeks. In addition, barriers to adoption of the test and how to address these will be studied. A health economic analysis will study the cost benefits of implementing the test in the UK.

    • Inclusion Criteria:

      •Aged 18 years or above •Newly diagnosed patients with T1-T2/N1-3 or T3-T4/ N0-3 squamous cell carcinoma of the oropharynx. •Availability of tissue from one archival diagnostic tumour tissue block •Confirmed HPV status (p16InK4A IHC/ISH) •Patients must be candidates for and willing to undergo curative RT/CRT •Written informed consent.

    • Exclusion Criteria:

      -Previous or concurrent illness or situation, which in the investigator’s opinion would interfere with collection of the complete sample collection. -Any invasive malignancy within previous 5 years (other than non melanomatous skin carcinoma or cervical carcinoma in situ. -Clinical evidence of metastatic disease

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

    • Research Summary

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

    • Inclusion Criteria:

      Inclusion criteria for Randomisation 1 (R1): 1. Newly diagnosed as having multiple myeloma (MM) according to the updated International Myeloma Working Group (IMWG) diagnostic criteria 2014 (see Appendix 1 in protocol for criteria) requiring treatment. 2. Not eligible for stem cell transplant. 3. Aged at least 18 years. 4. Meet all of the following blood criteria within 14 days before R1: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L, or, in the case of heavy bone marrow infiltration (> = 50%) which in the opinion of the investigator is the cause of the thrombocytopenia and provided appropriate supportive measures and patient monitoring are in place, platelet count > = 30 x 10^9/L is permitted. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN. 5. Meet the pregnancy prevention requirements: Female participants who: a) Are not of childbearing potential (Appendix 8 in protocol), OR b) If they are of childbearing potential, agree to practice 2 effective methods of contraception (Appendix 8 in protocol), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a) Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Contraception for female and male participants must be in accordance with (and participants must consent to) the Celgene-approved Pregnancy Prevention Programme. If female and of childbearing potential (see Appendix 8 in protocol), they must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Pregnancy Prevention Programme. 6. Able to provide written informed consent. Inclusion criteria for Randomisation 2 (R2): 1. Randomised into the FiTNEss (Myeloma XIV) trial and received induction chemotherapy with ixazomib and lenalidomide continued for 12 cycles. 2. Achieved at least MR at the end of IRD induction according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol), with no evidence of progression prior to R2. 3. Meet all of the following blood criteria within 14 days before R2: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 10^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN.

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The ENABLE study: supported self-management in people living with cancer

    • Research Summary

      Supporting people to self-manage health-related problems improves quality of life and reduces health service use. However, most previous research has focussed on people having curative treatment, or people with long term conditions. There is little evidence to tell us the best way to support people to self-manage who are living with cancer that is treatable but not curable (TBNC). Advances in treatment mean more people are living longer with incurable cancer and it is important to look at new ways of supporting them. Aims: 1. Explore what self-management support means to patients living with cancer that is TBNC, their carers and health care professionals (HCPs). 2. Understand the roles undertaken by patients, carers and HCPs to support self-management of people living with TBNC cancer and how these change over time. 3. Identify resources and support needed/used by people to help them manage the impact of TBNC cancer and its treatment. 4. To identify what the goals of self-management should be from the viewpoint of patients, carers, HCPs and other stakeholders. Stages: Stage One: To investigate aims 1-3, we will interview around 30 patients with TBNC cancer and 30 carers, up to 3 times over the course of a year to see how perspectives change over time. Patients will be recruited to reflect a range of cancer types, treatment status, ages and gender to capture a range of experiences. Participants will be recruited from University Hospital Southampton NHS Foundation Trust and the Christie Hospital NHS Foundation Trust, Manchester. We plan to interview about 20 HCPs from a range of professions. Stage 2: To investigate aim 4, we will identify goals and priorities of care from interviews and explore consensus regarding these self-management outcomes of importance. We will ask patients, carers, HCPs and commissioners of care to rank priorities to develop an understanding of consensus or disagreement.

    • Inclusion Criteria:

      Patients: Purposive sampling will include reference to age, gender, intermediate or short term survival and treatment status. This will facilitate exploration of whether problems are experienced or managed differently through the illness trajectory. Patients with gastrointestinal, metastatic prostate and gynaecological cancer, and myeloma will be recruited. We will purposively sample and review the inclusion of other patient groups as data collection and analysis progresses. We will purposively sample participants, using deliberately inclusive criteria: 1. Adults > 16 years. No upper age limit. 2. People living with TBNC cancer, intermediate survival group (one-year survival over 50% less than 90%, five-year 20% to 80%) and short term survival group (‘poor health’ (fewer than 50% survive a year). 3. Capacity to give informed consent, judged by their healthcare team. Carers: Recruited patients will be asked to nominate the ‘person they get most support from’. (Patients who do not have a nominated carer will also participle in the study). Carers’ inclusion criteria 1. Adults > 16 years. No upper age limit. 2. An informal carer for a patient recruited to the study. Carers and patients will be interviewed separately to allow exploration of individual experiences and how these are constructed and maintained, however interviews can be joint at the participants request. We anticipate that most interviews will be conducted in the home setting, but alternatives will be offered if preferred. Health care professionals We will interview up to 20 HCPs once and characterize the roles undertaken by HCPs to understand how they can support effective SM, explore facilitators and barriers to the implementation of SMS and identify what SM outcomes are important to HCPs. We will purposefully sample from a range of HCPs including, nurses, oncologists, supportive care specialists, allied health professionals and community based clinicians such as GPs.

    • Exclusion Criteria:

      Patients: Exclusion criteria: 1. Patients who are likely to die within three months, as assessed by the clinical care team 2. Patients who do not have any treatment options available to them, as assessed by the clinical care team 3. Patients aged under 16 4. Patients who do not have the capacity to give informed consent.

    Read more Return to top ('Preview' button)
  • Molecular analysis of screen detected non-invasive breast cancer and atypical breast hyperplasias identified by the Sloane Project

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      Women with a previous history of invasive breast cancer

    Read more Return to top ('Preview' button)
  • Randomised phase II/III study of Rituximab and Ibrutinib (RI) versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as initial therapy for Waldenström's macroglobulinaemia

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • IP4- CHRONOS: Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer

    • Research Summary

      Men diagnosed with significant cancer confined to the prostate currently undergo radical therapy directed to the whole prostate (radiotherapy or prostatectomy). These provide good cancer control but can cause significant side effects. Focal Therapy involves targeting the cancer alone, whilst leaving healthy prostate gland alone. Case series have shown similar cancer control over 5 years with a much better side effect profile. However, there have been no randomised control trials (RCTs) comparing the success in cancer control and the quality of life in patients that undergo radical therapy vs those that undergo focal therapy. Further, there is a need to assess the use of additional therapies that may improve the cancer control outcomes following focal therapy. By having a trials platform with two RCTs (CHRONOS-A and CHRONOS-B) that reflect best patient and physician preferences/ equipoise, we aim to answer these questions. To improve acceptability, recruitment and compliance we have an embedded study aimed at reviewing clinician and patient perspectives and trial acceptability. CHRONOS-A will compare radical therapy to focal therapy, whilst CHRONOS-B will compare focal therapy alone to focal therapy with various therapies targeting the testosterone pathway that can shrink the cancer before it is treated. We think this might improve outcomes further for men that definitely want focal therapy.

    • Inclusion Criteria:

      1) Prostate cancer confirmed on biopsy of Gleason 6 or Gleason 7 overall 2) Serum PSA (prostate specific antigen) less than or equal to 20ng/ml 3) Stage < / = (radiological) T3aN0M0 or < / = (clinical rectal examination)T2N0M0 4) Minimum age of 18 years of age 5) Clinically fit enough to undergo all procedures listed in the trial that the patient has been been enrolled into

    • Exclusion Criteria:

      1) Previous prostate cancer treatment 2) Life expectancy less than 10 years 3) Unable to consent to participation in the trial 4) Previous or current use of current LHRH agonist or LHRH antagonist or anti-androgen use in CHRONOS-B 5) Less than 6 months of discontinuation of 5 alpha-reductase inhibitor use in CHRONOS-B

    Read more Return to top ('Preview' button)
  • A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects with Chronic Lymphocytic Leukemia

    • Research Summary

      Chronic lymphocytic leukaemia (CLL) is the most frequent form of adult leukaemia (Leukaemia is a cancer which starts in blood-forming tissue, usually the bone marrow. It leads to the over-production of abnormal white blood cells, the part of the immune system which defends the body against infection). This study will enrol participants with treatment-naïve (never undergone treatment) or relapsed (disease that reappears or grows again after a period of remission)/refractory (does not respond to treatment) CLL. Current standard therapy for CLL is chemoimmunotherapy (Chemotherapy uses different drugs to kill or slow the growth of cancer cells; immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer). Despite the potential for prolonged progression-free survival (PFS= the length of time during and after the treatment of a disease, that a patient lives with the disease but it does not get worse) chemoimmunotherapy is associated with significant short and long-term toxicities. Sponsor AstraZeneca is developing a new anticancer agent Acalabrutinib which is a selective, irreversible small molecule inhibitor of Bruton tyrosine kinase (BTK= a gene that provides instructions for making a protein called Bruton tyrosine kinase (BTK), which is essential for the development and maturation of B cells. B cells are specialised white blood cells that help protect the body against infection). This is a study to evaluate the safety and tolerability of Acalabrutinib mono therapy in participants with treatment-naive (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). There will be approximately 600 participants taking part in this study at about 170 study centres globally.

    • Inclusion Criteria:

      1. Men and women > = 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) 2. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018): a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing > = 1 B-cell marker (CD19, CD20, and CD23) and CD5 b. Prolymphocytes may comprise < 55% of blood lymphocytes c. Presence of > = 5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis) 3. Active disease as per at least 1 of the following IWCLL 2018 criteria a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia (haemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL) b. Massive (i.e., > = 6 cm below the left costal margin), progressive, or symptomatic splenomegaly c. Massive nodes (i.e., > = 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of < 30x109 /L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded. e. Autoimmune anaemia and/or thrombocytopenia that is poorly responsive to standard therapy f. B-symptoms documented in the participant’s chart with supportive objective measures, as appropriate, defined as > = 1 of the following disease-related symptoms or signs: o Unintentional weight loss > = 10% within the previous 6 months before screening o Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status > = 2; inability to work or perform usual activities) o Fevers higher than 100.5°F or 38.0°C for > = 2 weeks before screening without evidence of infection o Night sweats for > = 1 month before screening without evidence of infection 4. Must meet 1 of the following criteria: a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria: i. A score of > 6 on the Cumulative Illness Rating Scale (CIRS) ii. Creatinine clearance of 30 to 69 ml/min using the Cockcroft-Gault equation b. Have previously received therapy for CLL and have either refractory or relapsed CLL c. Have received prior BTKi therapy (i.e., defined as a participant who discontinued a BTKi for any reason except disease progression) for CLL 5. ECOG performance status of < = 2 6. Female participants of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilised male partner must use > = 1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Contraception measures and restrictions on sperm donation are not required for male subjects. 7. Fluorescence in situ hybridisation (FISH) within 60 days before or during screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis. 8. Each participants (or legally authorized representative if allowed per local regulations) must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorisation to use protected health information.

    • Exclusion Criteria:

      1. Participants who have had disease progression while on a BTKi for any malignant or non-malignant condition 2. Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the participant has been disease-free for > = 2 years 3. History of confirmed progressive multifocal leukoencephalopathy 4. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia’s formula (QTcF) > 480 msec at screening. Note: Participants with rate-controlled, asymptomatic atrial fibrillation are allowed to enrol in the study. 5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass 6. Evidence of active Richter's transformation. If Richter’s transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomography computed tomography (PET-CT) and/or biopsy according to guidelines 7. Central nervous system (CNS) involvement by CLL 8. Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with participants who are on ongoing anti-infective treatment and participants who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment a. Participants who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrolment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded. b. Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrolment. Those who are hepatitis C virus PCR positive will be excluded 9. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura defined as declining haemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone or equivalent for longer than 2 weeks) 10. History of stroke or intracranial haemorrhage within 6 months before the first dose of study treatment 11. History of bleeding diathesis (e.g., haemophilia or von Willebrand disease) 12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening 13. Major surgical procedure within 4 weeks before first dose of study treatment. Note: Participants who have had major surgery, must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment. 14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment in this study. 15. All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment 16. Absolute neutrophil count (ANC) < 0.50 x 109 /L or platelet count < 30 x 109 /L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion 17. Total bilirubin > 3.0x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase > 3.0x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a participant's total bilirubin is elevated secondary to Gilbert’s, the participant must have a documented unconjugated bilirubin being > 80% of the total bilirubin number. The investigator must also document that haemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin 18. Estimated creatinine clearance of < 30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement) Due to the size limit please see pages 23-25 of the protocol for the full exclusion criteria.

    Read more Return to top ('Preview' button)
  • A Phase 3, Randomized, Open-Label Study of Belantamab Mafodotin Administered in Combination with Bortezomib, Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone Alone in Participants with Newly Diagnosed Multiple Myeloma who are Ineligible for Autologous Stem Cell Transplantation

    • Research Summary

      Multiple myeloma (MM) is an incurable cancer of the blood plasma cells. Current treatment for fit MM patients is high-dose chemotherapy, with a stem cell transplant (ASCT) however, some patients, especially the elderly, are not able to have a transplant due to frailty or other illnesses. B-cell maturation antigen (BCMA) is a protein present on the surface of certain white blood cells (B-cells) and on tumour cells in patients with MM. Belantamab mafodotin, which is currently in development for the treatment of MM, is a type of antibody, which binds to BCMA and can kill tumour cells. In previous studies it has shown significant benefit with acceptable side effects which warrant further exploration. This study is for patients who are ineligible for ASCT. It consists of two parts, the Dose Selection part (Part 1) will evaluate the safety and tolerability of increasing doses of belantamab mafodotin in combination with bortezomib (Velcade), Lenalidomide (Revlimid), and dexamethasone (VRd). Part 1will determine the recommended dose for Part 2 (RP3D). Part 2 will evaluate the efficacy and safety of the RP3D of belantamab mafodotin plus VRd compared with VRd alone. Eligible participants for both parts will begin treatment after completing screening. Screening will involve imaging (x-ray, CT or MRI), blood samples, a bone marrow sample, vital signs, ECG, physical exam and an eye exam. Participants will receive belantamab mafodotin either as a single dose, or a split dose over 2 days, every 3 weeks via injection in a vein, reducing to every 4 weeks. A blood sample will be collected at every visit and participants will complete a number of questionnaires, have an ECG and eye exam. Participants will be treated until disease progression or unacceptable side effects. It is anticipated most participants will be in the study for an average of 44 months.

    • Inclusion Criteria:

      1. Participant must be over 18 years of age inclusive, at the time of signing the informed consent. 2. Diagnosis of multiple myeloma with a requirement for treatment as documented per International Myeloma Working Group (IMWG) criteria. Must have at least ONE aspect of measurable disease, defined as one of the following: a. Urine M-protein excretion > = 200 mg/24h, or b. Serum M-protein concentration > = 0.5 g/dL (> = 5.0 g/L), or c. Serum free light chain (FLC) assay: involved FLC level > = 10 mg/dL (> = 100 mg/L) and an abnormal serum free light chain ratio (< 0.26 or > 1.65). 3. Not a candidate for high-dose chemotherapy with ASCT due to presence of frailty and/or significant comorbid condition(s), such as cardiac, pulmonary or other major organ dysfunction that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation, as judged by the investigator. 4. ECOG status of 0-2 5. Adequate organ system functions 6. Male and/or female a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a woman of childbearing potential (WOCBP) OR • Due to lenalidomide being a thalidomide analogue with risk for embryo fetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, WOCBP participants will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment. Thereafter, WOCBP participants must use a contraceptive method that is highly effective (with a failure rate of < 1% per year) for a further 7 months. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second within 24 hours prior to prescribing lenalidomide therapy. b. Male Participants: Male participants are eligible to participate if they agree to the following from the time of first dose of study treatment until 5 months after the last dose of study treatment to allow for clearance of any altered sperm: • Refrain from donating sperm Plus either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR • Must agree to use contraception/barrier as detailed below: o Agree to use a male condom, even if they have undergone a successful vasectomy and female partner to use an additional highly effective contraception method with a failure rate of < 1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant. 7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

    • Exclusion Criteria:

      1. Smoldering multiple myeloma (SMM). 2. Prior systemic therapy for multiple myeloma, or SMM. An emergency course of steroids (defined as no greater than 40mg of dexamethasone, or equivalent per day for a maximum of 4 days (that is, a total of 160 mg) is permitted. 3. Patient is eligible for high dose chemotherapy with ASCT 4. Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by the NCI-CTCAE Version 5 5. Major surgery within four weeks prior to the first dose of study drug. 6. Presence of active renal condition (infection, requirement for dialysis or any other significant condition that could affect participant’s safety). 7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures. 8. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy. 9. Current active liver or biliary disease (except for Gilbert’s syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease as per investigator’s assessment). 10. Participants with previous or concurrent malignancies other than multiple myeloma are excluded. Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy that has been considered medically stable for at least 2 years. The participant must not be receiving active therapy, other than hormonal therapy for this disease. Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction. 11. Evidence of cardiovascular risk including any of the following: a. QTc interval > = 480 msec. b. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block. c. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening. d. Class III or IV heart failure as defined by the New York Heart Association functional classification system e. Uncontrolled hypertension. 12. Active infection requiring treatment. 13. Known HIV infection. 14. Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb), at screening or within 3 months prior to first dose of study treatment. 15. Positive hepatitis C antibody test result. 16. Current corneal epithelial disease except for mild punctate keratopathy 17. Intolerance or contraindications to anti-viral prophylaxis. 18. Unable to tolerate antithrombotic prophylaxis. 19. AL amyloidosis (light chain amyloidosis), active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening. 20. Exhibiting clinical signs of or has a known history of meningeal or central nervous system involvement by multiple myeloma. 21. Use of an investigational drug within 14 days or five half-lives (whichever is longer) preceding the first dose of study drug.

    Read more Return to top ('Preview' button)
  • Oxford Pre-cancerous Lymphoproliferative Disorders: Analysis and Interception study

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An open-label Phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy in patients with advanced haematological malignancies.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase 3, Randomized, Open Label Study to Compare Nivolumab plus Concurrent Chemoradiotherapy (CCRT) followed by Nivolumab plus Ipilimumab or Nivolumab plus CCRT Followed by Nivolumab vs CCRT followed by Durvalumab in Previously Untreated, Locally Advanced Non-small Cell Lung Cancer (LA NSCLC)

    • Research Summary

      The purpose of this study is to show that Nivolumab, or Nivolumab plus Ipilimumab, or Nivolumab plus Platinum-Doublet Chemotherapy improves progression free survival and/or overall survival compared with chemotherapy in patients with advanced lung cancer.

    • Inclusion Criteria:

      1) Participant and Target Disease Characteristics a) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 b) Histologically confirmed NSCLC, stage III unresectable, as per AJCC staging system, 8th edition0F1 i) Mediastinal lymph nodes that are merged or ≥2.0 cm (CT/MRI) in shortest axis with distinct margin are considered pathological. All other suspicious mediastinal lymph nodes including those that are enlarged (but < 2.0 cm in shortest axis) or FDG avid on PET/CT require further sampling for pathological confirmation if accessible by mediastinoscopy, thoracoscopy, or EBUS. Supraclavicular nodal involvement is acceptable given its upper border not extending above the upper border of the lateral end of the clavicle c) Newly diagnosed and treatment-naïve, with no prior local or systemic anticancer therapy given as primary therapy for locally advanced disease d) Measurable disease per RECIST 1.1 criteria e) All participants must have tissue submitted to a central laboratory during screening. Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or at least 15 unstained tumor tissue sections, obtained within 3 months prior to enrollment, with an associated pathology report, must be submitted to the core laboratory for inclusion. Biopsy should be excisional, incisional, punch biopsy, core needle or surgical specimen. Fine needle aspiration is unacceptable for submission. Biopsies of bone lesions that do not have a soft tissue component are also unacceptable for submission. The central laboratory must provide IRT with PD-L1 status prior to randomization. Local laboratory results for PD-L1 results may be acceptable on a case by case basis upon BMS approval. 2) Age and Reproductive Status a) Males and females, ≥18 years of age.

    • Exclusion Criteria:

      1) Medical Conditions a) Presence of resectable (regardless of stage) or metastatic disease (stage IV), including presence of CNS involvement. b) Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (eg, a condition associated with diarrhea or acute diverticulitis) c) Serious or uncontrolled medical disorders d) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast e) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll f) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease g) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways h) Presence of pleural/pericardial effusion on CT scan and/or X-ray, unless it is not cytologically positive nor exudative via pleuracentesis. Effusions that are too small to be tapped safely are acceptable i) Participants with EGFR mutation regardless of mutation type are excluded. Non-squamous tumor with unknown EGFR mutation status must be tested for EGFR mutation (PCR based test should be used). j) Known ALK translocation k) Clinical evidence of hearing loss l) ≥ Grade 2 peripheral neuropathy 2) Prior/Concomitant Therapy a) Prior thoracic radiotherapy. However, other prior radiotherapy is allowed and must be completed at least 30 days prior to study treatment with residual toxicities resolved prior to study enrollment. b) Pancoast tumor or other situations with surgery as part of management plan. c) Radiation plan does not comply with any of the following: i) Mean lung dose < 20 Gy and/or V20 < 35% ii) Mean oesophagus dose < 34Gy iii) Heart V45 < 35% or V30 < 30% 3) Physical and Laboratory Test Findings a) WBC < 2000/μL b) Neutrophils < 1500/μL c) Platelets < 100*103/μL d) Hemoglobin < 9.0 g/dL NOTE: May not transfuse within 14 days of randomization to meet eligibility criteria 3.a through 3.d.

    Read more Return to top ('Preview' button)
  • A randomised, double-blind, placebo-controlled phase III multi-centre study of azacitidine with or without MBG453 for the treatment of patients with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

    • Research Summary

      It is estimated that 15,000 to 20,000 new cases of Myelodysplastic Syndromes (MDS) are diagnosed annually in the USA (Klepin 2016). In Europe, the incidence rate of MDS is about 2 new cases per 100,000 each year (Visser et al 2012). The incidence of MDS is more frequent in male patients and increases with age, with a median age at diagnosis of about 70 years. Current treatment guidelines for MDS recommend modification of the disease with hematopoietic stem cell transplantation (HSCT, treatment with a curative intent), intensivechemotherapy or hypomethylating agents (HMAs; azacitidine and decitabine. Prognosis is poor and life expectancy is short with higher risk (intermediate, high, or very high) MDS, and Chronic Myelomonocytic Leukemia 2 (CMML-2) patients treated with the current standard of care based on hypomethylating agents. HMAs represent the standard of care for the vast majority of patients who cannot receive HSCT or cannot be treated with intensive chemotherapy. In MDS patients without major co-morbidities who are classified as higher risk, and who do not qualify for transplantation or intensive chemotherapy, HMAs are the first-line reference treatment. Azacitidine is the sole HMA which showed a prolongation of overall survival (OS) compared to conventional care regimens among patients with higher risk MDS. The anti-TIM-3 monoclonal antibody MBG453 is a novel immunotherapeutic agent with promising activity seen in AML and higher risk MDS. The purpose of the current study is to assess clinical effects of MBG453 in combination with azacitidine in adult subjects with higher risk MDS and CMML-2. This study will compare MBG453 plus azacitidine or placebo plus azacitidine. It is planned that the study will run at 5 sites in the UK, recruiting a total of 10 patients.

    • Inclusion Criteria:

      1. Signed informed consent must be obtained prior to participation in the study. 2. Age > = 18 years at the date of signing the informed consent form (ICF). 3. Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R):  Very high (> 6 points)  High (> 4.5 - < = 6 points)  Intermediate (> 3 - < = 4.5 points) OR Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with WBC < 13 x 109/L. 4. Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions. 5. Not eligible for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions. 6. Not eligible for hematopoietic stem-cell transplantation (HSCT) according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 8. Estimated Glomerular Filtration Rate (eGFR) > = 30 mL/min/1.73m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory). 9. AST and ALT < = 3 × upper limit of normal (ULN). 10. Total bilirubin < = 1.5 × ULN (except in the setting of isolated Gilbert syndrome, where subjects may only be included with direct bilirubin < = 1.5 x ULN). 11. Subject is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures.

    • Exclusion Criteria:

      1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is allowed except if the drug was administered within 4 months prior to randomisation. 2. Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomisation. 3. Investigational treatment received within 4 weeks prior to randomisation. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomisation is necessary to allow randomisation. 4. Current use or use within 14 days prior to randomisation of systemic steroid therapy (> 10mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment. 5. Live vaccine administered within 30 days prior to randomisation. 6. History of severe hypersensitivity reaction to any ingredients of the study treatments (azacitidine or MBG453) or their excipients, or to monoclonal antibodies. 7. Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) < = 3. 8. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia based on WHO 2016 classification (Arber et al 2016). 9. Diagnosis of primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016). 10. Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber et al 2016). 11. History of organ transplant or allogeneic stem cell transplant. 12. Subjects with prior malignancy, except: a) subjects with history of lower risk MDS treated by supportive care (e.g. growth factors, TGF'beta agents) or untreated are eligible. b) subjects with history of lower risk MDS who were treated adequately and failed lenalidomide are eligible. c) subjects with history of adequately treated malignancy for whom no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Subjects who are receiving adjuvant therapy such as hormone therapy are eligible. However, subjects who developed therapy related neoplasms are not eligible (see exclusion 10). 13. Active autoimmune disease requiring systemic therapy (e.g. 10 mg/day prednisone or equivalent or any immunosuppressive therapy). 14. Any concurrent severe and/or uncontrolled medical condition including significant cardiac or cardiac repolarization abnormalities. Subjects with active infection requiring parenteral antibacterial, antiviral or antifungal therapy which are controlled by adequate treatment are eligible. 15. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded. 16. HIV infection not controlled by standard therapy and/or with known history of opportunistic infection. 17. Any other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol. 18. Sexually active males unwilling to use a condom during intercourse while taking azacitidine and for 3 months after stopping this treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above, and female partners will be instructed to use highly effective contraception. 19. Subject is pregnant or breastfeeding. 20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 3 months after the last dose of azacitidine (or as per the respective local label, whichever is longer) and 150 days after the last dose of MBG453 or placebo.

    Read more Return to top ('Preview' button)
  • ATLANTA – Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Stratified Medicine Paediatrics: Genomic Characterisation of Relapsed Paediatric Cancers for Diagnostics and Stratified Therapy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      None

    Read more Return to top ('Preview' button)
  • Plasma analysis for response assessment and to direct the management of metastatic prostate cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An Open-Label, Multi-Centre Phase I/IIa Study Evaluating the Safety and Clinical Activity of Neoantigen Reactive T cells in Patients with Metastatic or Recurrent Melanoma (THETIS)

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PHOENIX Trial: A pre-surgical window of opportunity and post-surgical adjuvant biomarker study of DNA damage response inhibition and/or anti-PD-L1 immunotherapy in patients with neoadjuvant chemotherapy resistant residual triple negative breast cancer

    • Research Summary

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

    • Inclusion Criteria:

      INCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Signed Informed Consent Form (ICF) for Trial Registration; 2. Aged > = 18 years old; 3. Histologically confirmed invasive triple negative breast cancer (TNBC). TNBC defined as ER negative, PgR negative (ER and PgR negative as defined by Allred score 0/8, 1/8 or 2/8 or stain in < 1% of cancer cells) or PgR unavailable, and HER2 negative (immunohistochemistry 0/1+ or negative in situ hybridization) as determined by local laboratory and recorded in the patients notes; 4. Planned definitive surgical treatment after at least 6 cycles of neoadjuvant chemotherapy (NACT); 5. Radiographically measurable tumour mass assessable for new distinct radio-opaque marker insertion and repeated biopsies on the NACT mid-assessment standard of care imaging modality (MRI or US); or clinically thought to be > 5cm in diameter (T3); 6. Eastern Oncology Cooperative Group (ECOG) performance status 0-1; 7. Considered fit enough to have breast cancer surgery with curative intent; 8. Considered fit to complete at least 2 weeks of pre-operative trial treatment in the WOP; 9. Patients must be suitable for a mandatory pre-treatment baseline biopsy performed Day -1 or 1 of the window of opportunity (WOP) and a post-treatment biopsy performed on Day 14 of the WOP. Registered patients who are approached for Trial Entry will be required to consent to the pre- and post- WOP treatment biopsy. If it is deemed unsafe to proceed with biopsy upon Trial Entry the patient will not be eligible for Trial Registration. 10. Patients with clinical stage II disease or clinical suspicion of metastatic disease must have staging studies as per standard of care to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 11. Patients with stage III disease must have staging studies as per standard of care at any point after diagnosis but before Trial Registration, to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease), even if asymptomatic. 12. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed > 5 years prior to Trial Registration, and there is no evidence of recurrent disease; 13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before Trial Registration; 14. Patients must be: a) surgically sterile (i.e. if female have undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy; if male have undergone a bilateral orchidectomy); b) have a sterilised sole partner; or c) be post-menopausal; or d) must agree to practice total/true abstinence; or e) use two highly effective forms of contraception in combination during the period of trial treatment and be willing to do so for a period of at least 6 months following the end of trial treatment. Post-menopausal is defined in Protocol Section 6.3.1. INCLUSION CRITERIA FOR TRIAL ENTRY: 1. Signed Informed Consent Form (ICF) for Trial Entry; 2. Residual disease is confirmed as at least one viable disease focus > = 2cm on trial-specific dynamic contrast enhanced MRI scan performed 1 week following day 1 of the final cycle of NACT. 3. Recovery from all acute adverse events of prior NACT to baseline or NCI CTCAE Grade < = 1, except for alopecia. Patients with irreversible toxicity not reasonably expected to be exacerbated by trial treatment may be included only after consultation with the CI or Coordinating Investigator. 4. Patients must have adequate haematological, renal and hepatic function as defined in Protocol Section 9.1.1. 5. Women of childbearing potential must have a confirmed menstrual period and a negative urinary or serum pregnancy test prior to Trial Entry. This should be repeated as applicable to ensure a negative pregnancy test is performed within 3 days prior to commencing trial treatment (or on the day of planned trial treatment for Cohort C) 6. Confirmation that all Trial Registration inclusion criteria listed in Section 6.3.1 remain satisfied.

    • Exclusion Criteria:

      EXCLUSION CRITERIA FOR TRIAL REGISTRATION: 1. Definitive evidence of metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease); 2. Patients with bilateral tumours; 3. History of another primary malignancy within the last 5 years prior to Trial Registration, except for: a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; b. Adequately treated carcinoma in situ without evidence of disease; 4. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML; 5. Severe concurrent disease, infection or co-morbidity that, in the judgment of the local Investigator, would make the patient inappropriate for Trial Registration; 6. Resting ECG with QTc > 470msec for females and > 450 msec for men on 2 or more time points within a 24 hour period, factors which increase the risk of QTc prolongation or family history of long QT syndrome; 7. A diagnosis of ataxia telangiectasia; 8. Patients unable to swallow orally administered medication; 9. Patients receiving formal anti-coagulation treatment; 10. Patients with gastrointestinal disorder affecting absorption; 11. History of seizure or any condition that may predispose to seizure; 12. Other non-malignant systemic disease that would preclude trial treatment or would prevent required follow-up; 13. Pregnant or breast-feeding; 14. Prior exposure to ATR inhibitor (including AZD6738), PARP inhibitor (including olaparib), anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab); 15. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that in the investigators opinion would cause reasonable suspicion of a disease or condition, that contraindicates the use of trial treatment, that may increase the risk associated with trial participation, that may affect the interpretation of the results, or that would make this trial inappropriate for the patient; 16. Patients with a known hypersensitivity to the trial treatments or any excipients of the products; 17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT); 18. Active or prior documented autoimmune or inflammatory disorders (examples & exceptions are listed in Protocol Section 6.3.1). 19. Active infection including tuberculosis (TB), hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV) as described in Protocol Section 6.3.1. EXCLUSION CRITERIA FOR TRIAL ENTRY: 1. History of clinically significant or uncontrolled cardiovascular disease as described in Protocol Section 9.1.2; 2. History of loss of consciousness or transient ischemic attack within 12 months prior to Trial Entry; 3. Patients with Grade > = 2 neuropathy, as defined by NCI CTCAE v5.0 will be evaluated on a case-by-case basis after consultation with the CI or Coordinating Investigator; 4. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 2 weeks prior to Trial Entry. Patients must have recovered from any effects of any major surgery prior to commencing trial treatment. 5.Use of any investigational agent within 30 days prior to commencing trial treatment. 6. Concomitant use of known strong CYP3A inhibitors. 7. Concomitant use of known strong CYP3A inducers. The required washout period prior to commencing trial treatment is 5 weeks; 8. Whole blood transfusions in the last 4 months prior to commencing trial treatment (packed red blood cells and platelet transfusions are acceptable, with no blood transfusion or erythropoietin in the past 28 days prior to trial entry); 9. Current or prior use of immunosuppressive medication within 14 days prior to commencing trial treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisolone, or an equivalent corticosteroid. 10. Receipt of live attenuated vaccine within 30 days prior to commencing trial treatment. 11. Confirmation that none of the Trial Registration exclusion criteria listed in Section 6.3.2 are met.

    Read more Return to top ('Preview' button)
  • A Clinical Pharmacology Study to Investigate the Utility of Therapeutic Drug Monitoring in Challenging Childhood Cancer Patient Populations

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      a) Failure to meet the inclusion criteria

    Read more Return to top ('Preview' button)
  • IRONMAN: International Registry for Men with Advanced Prostate Cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström’s macroglobulinaemia

    • Research Summary

      Waldenström’s macroglobulinaemia (WM) is a rare type of slow growing lymphoma. It develops when a certain type or types of white blood cells, grow abnormally. There are a number of standard treatments that are currently used in treating WM. Though the cancer often responds to these current treatments, at some point the cancer usually returns. Therefore there is a need to find alternative treatments that are more effective, leading to lasting responses and improved quality of life. The PembroWM study will investigate whether the drugs rituximab (already used to treat WM) in addition to pembrolizumab (a type of immunotherapy designed to ‘re-awaken’ the immune system) will improve response to treatment. In this study, 42 adult (aged > = 18 years) patients with WM, whose disease has either come back or not responded to treatment, will be given pembrolizumab with rituximab. Treatment lasts for a maximum of 1 year with pembrolizumab given once every 3 weeks and rituximab a total of 7 times. Patients will be seen regularly during treatment and then yearly until the last patient entering the study completes their 2 year follow-up. The study will be conducted at NHS hospitals and is expected to last 4 years and 6 months.

    • Inclusion Criteria:

      1. Patients > = 18 years old 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 3. Presence of measurable disease, (defined as a serum IgM level of > 0.5g/L) and fulfils other World Health Organisation (WHO) diagnostic criteria for WM 4. Relapsed or refractory WM who have received > = 1 prior lines of therapy 5. Adequate renal function: estimated creatinine clearance > = 30ml/min as calculated using the Cockroft-Gault equation 6. Adequate liver function, including: o Bilirubin < = 1.5x the upper limit of normal (ULN), unless documented Gilbert’s syndrome o Aspartate or alanine transferase (AST or ALT) < = 2.5 x ULN 7. Adequate organ and bone marrow function: o Neutrophils > = 0.75x109/L o Platelets > = 50x109/L 8. Willing to comply with the contraceptive requirements of the trial 9. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP) 10. Written informed consent

    • Exclusion Criteria:

      1. Refractory to rituximab as defined by progression on/within 6 months of finishing a rituximab based regimen 2. Women who are pregnant or breastfeeding, or males expecting to conceive or father children at any point from the start of treatment until 4 months after the last administration of pembrolizumab 3. Clinically significant cardiac disease within 6 months prior to registration including unstable angina or myocardial infarction, uncontrolled congestive heart failure (NYHA class III-IV), and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. 4. History of significant cerebrovascular disease in last 6 months 5. Known central nervous system involvement of WM 6. Clinically significant active infection requiring antibiotic or antiretroviral therapy (including Hepatitis B, C or human immunodeficiency virus (HIV)) 7. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease 8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy 9. Active autoimmune disease apart from: o Type I diabetes or thyroid disease, controlled on medication o Skin conditions such as psoriasis, vitiligo or alopecia not requiring systemic treatment o Auto-immune thrombocytopenia, thought to be secondary to WM, provided that platelet count meet the criteria specified above, on daily doses of corticosteroid < = 10mg prednisolone or equivalent 10. Prior history of haemolytic anaemia (either warm or cold) 11. History of colitis 12. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis 13. Systemic anti-cancer therapy within 4 weeks prior to trial registration (except for BTK inhibitors, which may continue until cycle 1, day 1 of trial treatment) 14. Received a T cell depleting antibody (e.g. Campath) within 3 months prior to starting treatment 15. Received a live vaccine within 30 days prior to starting treatment 16. Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis 17. Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to starting treatment (unless prior agreed with the TMG) 18. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder) 19. Positive serology for Hepatitis B defined as a positive test for HepB surface antigen (HBsAg). Note: patients who are HepB core antibody (HBcAb) positive will only be eligible for the study if the HepB virus deoxyribonucleic acid (HBV DNA) test is negative and patients are willing to undergo monthly monitoring for HBV reactivation 20. Major surgery within 4 weeks prior to trial registration 21. Prior therapy with an anti-PD-1,anti-PD-L1 or CTLA4 monoclonal antibody 22. Prior allogeneic bone marrow transplantation 23. Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy or known HIV or acquired immunodeficiency syndrome (AIDS)-related illness 24. Current or prior use of immunosuppressive therapy within 7 days prior to start of treatment except the following: intranasal, inhaled, topical steroids or local steroid injections (eg. Intra-articular injections); systemic corticosteroids at physiologic doses (< 10mg/ day of prednisolone or equivalent) 25. Known or suspected hypersensitivity to components of pembrolizumab and/or rituximab (or other CD20 monoclonal antibody) 26. Current participation in any other clinical trial of an investigational medicinal product (CTIMP)

    Read more Return to top ('Preview' button)
  • A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or metastatic Melanoma

    • Research Summary

      The purpose of the study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug called NKTR-214, when combined with nivolumab versus nivolumab given alone in participants with previously untreated melanoma skin cancer that is either unable to be surgically removed or has spread

    • Inclusion Criteria:

      - Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 1. - Histologically confirmed Stage III (unresectable) or Stage IV melanoma, per the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition). - Treatment-naïve participants (no prior systemic anticancer therapy for unresectable or metastatic melanoma). - Measurable disease by RECIST 1.1. - Documented left ventricular ejection fraction (LVEF) > 45%.

    • Exclusion Criteria:

      - Active brain metastases or leptomeningeal metastases. - Uveal or ocular melanoma. - Participants with active, known, or suspected autoimmune disease. - Participants who take 2 or more antihypertensive medications for management of high blood pressure (including diuretics). - Known cardiac history.

    Read more Return to top ('Preview' button)
  • TACE-3: A two-arm multi-stage (TAMS) seamless phase II/III randomised trial of nivolumab in combination with TACE/TAE for patients with intermediate stage HCC

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared with Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    • Research Summary

      This is a Phase 3, randomised study of zanubrutinib versus ibrutinib, sponsored by BeiGene, Ltd. Approximately 400 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) will participate. CLL is the most common leukemia in the Western world. CLL is a treatable but essentially incurable disease. Inhibition of Bruton Tyrosine Kinase (BTK) has been shown to result in frequent and durable responses in patients with both previously untreated and relapsed CLL. Zanubrutinib (also known as BGB-3111) is a potent, specific, and irreversible BTK inhibitor with a favorable pharmacologic and pharmacokinetic (PK) profile. The primary objective of this study is to compare the efficacy of zanubrutinib versus ibrutinib (also an inhibitor of BTK) as measured by overall response rate, determined by independent central review. Once eligibility is confirmed, participants will be randomised in a 1:1 ratio to one of the following treatment arms: Arm A (Zanubrutinib 160 mg orally twice daily) or Arm B (Ibrutinib 420 mg orally once daily). Each participant is anticipated to be on the study approximately 50 months. There are three main phases to the study: screening, treatment and follow-up. Each study treatment cycle consists of 28 days. The following procedures may be carried out: measurement of height, weight, and vital signs (blood pressure, pulse, and temperature), complete physical examination, blood sample collection (including a pregnancy test for women of child bearing potential and tests for Hepatitis B and C) an echocardiogram, multigated acquisition, or gated heart pool scan (screening only) and specialised CT scans (or MRI scans). Bone marrow samples will be collected. Participants will also be asked to complete questionnaires and a diary.

    • Inclusion Criteria:

      Each patient eligible to participate in this study must meet ALL of the following criteria: 1. Age 18 years or older. 2. Confirmed diagnosis of CLL or SLL that meets the IWCLL criteria. 3. CLL/SLL requiring treatment as defined by at least 1 of the following criteria: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. b. Massive (≥ 6 cm below left costal margin), progressive, or symptomatic splenomegaly. c. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy. d. Progressive lymphocytosis with an increase of > 50% over a 2 month period or lymphocyte doubling time of < 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30 x 10 9/L (30,000/µL), lymphocyte doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection) should be excluded. e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy. f. Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs: i. Unintentional weight loss of ≥ 10% within the previous 6 months ii. Significant fatigue (ie, inability to work or perform usual activities) iii. Fevers > 100.5ºF or 38ºC for ≥ 2 weeks without other evidence of infection iv. Night sweats for > 1 month without evidence of infection. 4. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current guidelines or of an investigational regimen on a clinical trial. 5. Measurable disease by CT/magnetic resonance imaging (MRI). Measurable disease is defined as ≥ 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 7. Life expectancy ≥ 6 months. 8. Adequate bone marrow function as defined by: a. Absolute neutrophil count (ANC) ≥ 1000/mm3 (growth factor use is allowed), except for patients with bone marrow involvement in which case ANC must be ≥ 750/mm3. b. Platelet ≥ 75,000/mm3 (may be post-transfusion), except for patients with bone marrow involvement by CLL in which case the platelet count must be ≥ 50,000/mm3. 9. Patient must have adequate organ function defined as: a. Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease [MDRD] equation, or as measured by nuclear medicine scan or 24 hour urine collection). b. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal unless due to CLL/SLL. c. Serum total bilirubin < 3.0 × upper limit of normal (unless documented Gilbert’s syndrome). 10. Female patients of childbearing potential must practice highly effective methods (Section 5.1.2) of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib. 11. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other highly effective methods described in Section 5.1.2 during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib. 12. Ability to provide written informed consent and can understand and comply with the requirements of the study.

    • Exclusion Criteria:

      Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria: 1. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation). 2. Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening. b. Unstable angina within 3 months before screening. c. New York Heart Association class III or IV congestive heart failure. d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes). e. QTcF > 480 milliseconds based on Fridericia’s formula. f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening. 3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. 4. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention. 5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug. 6. Severe or debilitating pulmonary disease. 7. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 8. Active fungal, bacterial, and/or viral infection requiring systemic therapy. 9. Known central nervous system involvement by leukemia or lymphoma. 10. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs. 11. Known infection with HIV or serologic status reflecting active viral hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU), and if they are willing to undergo monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable. 12. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C. 13. Major surgery within 4 weeks of the first dose of study drug. 14. Prior treatment with a BTK inhibitor. 15. Last dose of prior therapy for CLL/SLL ≤ 14 days before randomization, with the following additional exclusion requirements: a. Treatment with monoclonal antibody-based therapy within 28 days of first dose of study drug. b. Treatment with chimeric antigen receptor T-cell therapy within 180 days of first dose of study drug. c. Treatment with Chinese herbal medicine with anticancer intent within 28 days of first dose of study drug. d. Chemotherapy or radiation treatment within 21 days of first dose of study drug or hematopoietic stem cell transplantation within 90 days of first dose of study drug. 16. Prior steroid use • For prior corticosteroid use of 10mg/day or less, regardless of reason or duration of treatment, must stop steroid no later than day prior to first dose. • For prior corticosteroid use of 10mg/day or more, regardless of reason or duration of treatment, must stop steroid 4 weeks prior to date of randomization. 17. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count, see inclusion criterion 8). 18. Pregnant or lactating women. 19. Vaccination with a live vaccine within 35 days prior to the first dose of study drug. 20. Ongoing alcohol or drug addiction. 21. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug. 22. Patient requires treatment with warfarin or other vitamin K antagonists. 23. Requires ongoing treatment with a strong CYP3A inhibitor or inducer. 24. Concurrent participation in another therapeutic clinical trial.

    Read more Return to top ('Preview' button)
  • SMALL: A Phase III, randomised, multi-centre trial addressing overtreatment of small screen-detected breast cancer by comparing standard surgery versus minimally invasive vacuum-assisted excision

    • Research Summary

      Multi-centre, randomised (1:2) phase III trial of surgery versus minimally invasive vacuum assisted excision of patients with small, biologically favourable screen-detected breast cancer, incorporating an 18 month internal pilot study with a QuinteT Recruitment Intervention (Information Study) to optimise recruitment

    • Inclusion Criteria:

      1) Female aged ≥ 47 years old with screen-detected breast cancer 2) ≤15mm maximum tumour diameter on mammogram and ultrasound 3) No associated malignant microcalcification outwith the lesion (calcification within the lesion is permitted) 4) Unifocal disease 5) Grade 1 disease on diagnostic core biopsy 6) ER strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in > 66% of tumour cell nuclei) 7) PR strongly positive (Allred score of 7 or 8, or equivalent, e.g. at least moderate positivity in > 66% of tumour cell nuclei) 8) HER2 negative (0 or 1+ by immunohistochemistry, or 2+ and negative by in situ hybridisation techniques (FISH or DISH) 9) Normal axillary ultrasound axillary, or equivocal ultrasound with benign fine needle aspiration cytology (FNAC) or core biopsy (CB) 10) Willing to be randomised 11) Able to provide written informed consent 12) Willing and able to undergo standard surgical treatment 13) Willing and able to undergo radiotherapy 14) Willing and able to take standard endocrine therapy 15) No previous diagnosis of ipsilateral breast cancer or DCIS (contralateral DCIS or invasive disease permitted if surgically treated ≥ 5 years previously and disease-free

    • Exclusion Criteria:

      1) Associated malignant microcalcification outwith the lesion 2) Bilateral breast cancer 3) Invasive lobular cancer 4) Grade 2 or grade 3 on core biopsy assessment 5) Not strongly ER or PR positive (Allred score of < 7, or equivalent, e.g. < 66% positivity of tumour cell nuclei) or HER2 positive tumour 6) Unable to provide informed consent 7) Any serious and/or unstable pre-existing medical, psychiatric or other condition that would prevent compliance with the trial or consent process 8) Unfit or unwilling to undergo standard surgical treatment 9) Contra-indications to standard adjuvant therapies (radiotherapy, endocrine therapy) 10) Previous ipsilateral invasive breast cancer or DCIS 11) Other invasive malignancy unless: Disease free for 5 years, or; Previous basal cell carcinoma, cervial carcinoma in-situ,, superficial bladder tumour 12) High risk group for developing breast cancer (as defined by NICE guidance)

    Read more Return to top ('Preview' button)
  • Exploring the ecology of upper gastrointestinal solid tumours from the genome to the microenvironment.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • MITHRIDATE: A phase III, randomised, open-label, Multicenter International Trial comparing ruxolitinib with either HydRoxycarbamIDe or interferon Alpha as first line ThErapy for high risk polycythemia vera

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An open label, multi-centre, phase I/IIa study evaluating the safety and clinical activity of neo-antigen reactive T cells in patients with advanced non-small cell lung cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PRECISION-Panc: Advancing personalised medicine treatment strategies for pancreatic cancer.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An open-label Phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination, in patients with advanced solid/metastatic tumours.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A PHASE II, RANDOMIZED, ACTIVE-CONTROLLED, MULTI-CENTER STUDY COMPARING THE EFFICACY AND SAFETY OF TARGETED THERAPY OR CANCER IMMUNOTHERAPY GUIDED BY GENOMIC PROFILING VERSUS PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH CANCER OF UNKNOWN PRIMARY SITE WHO HAVE RECEIVED THREE CYCLES OF PLATINUM DOUBLET CHEMOTHERAPY

    • Research Summary

      This study will compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in participants with poor-prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control after 3 cycles of first-line platinum based induction chemotherapy.

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A comparison of reduced dose total body irradiation (TBI) and cyclophosphamide with fludarabine and melphalan reduced intensity conditioning in adults with acute lymphoblastic leukaemia (ALL) in complete remission.

    • Research Summary

      The current national acute lymphoblastic leukaemia (ALL) trial in adults investigated whether a low (reduced) intensity chemotherapy regimen prior to transplant could improve the outcome of patients with ALL who are over 40 years of age. The results (60% 2 year survival) are very encouraging but patients who come to transplant with small amounts of ‘residual’ disease had less good outcomes. The goal of this trial is to see if a slightly stronger chemotherapy regimen (involving total body irradiation, (TBI)) can improve results by reducing the chance of the disease coming back (relapsing) without increasing the chance of not surviving the transplant. Up to 242 patients will be ‘randomised’ to the trial to receive either the established chemotherapy of fludarabine and melphalan or cyclophosphamide and TBI to compare the outcomes between the two treatment regimens. Other measures to reduce relapse will be the earlier use of donor white cell infusions and earlier stopping of immune suppressive drugs to enhance the immune effect of the transplanted cells (graft). Patients will be followed up for a minimum of 5 years. All patients on the next national ALL trial (UKALL XV) will be offered this trial but it will also be open to patients not on this study.

    • Inclusion Criteria:

      Patients with morphologically documented ALL who meet the following criteria; • Patients between the ages of 40-65 years. NB: Patients under the age of 40 who are considered unsuitable for a myeloablative transplant may enrol onto the trial following discussion with the CI via the Trials Office • Patients with ALL in first CR • Availability of a human leukocyte antigen (HLA) identical sibling or suitable matched unrelated donor (suitable matched defined as no greater than a single allele mismatch at HLA A, B, C or DRβ1). A single allele mismatch is permitted if there are adverse cytogenetics or MRD positivity at any timepoint • Patients considered suitable to undergo a RIC allogeneic SCT as clinically judged by the Local Investigator including:- o Adequate hepatic and renal function as determined by full blood count and biochemistry assessment o Resolution of any toxic effects of prior therapy (including radiotherapy, chemotherapy or surgical procedures). Patients with bone marrow suppression following therapy may enter the trial o Patients with abnormal cardiac and/or pulmonary function must be considered fit for allogeneic SCT including 8Gy of TBI at the time of randomisation. • Patients with an ECOG performance status 0,1 or 2 • Female of and male patients of reproductive potential(i.e. not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of admission for transplant conditioning therapy until 12 months after transplant • Patients have given written informed consent • Patients willing and able to comply with scheduled study visits and laboratory tests

    • Exclusion Criteria:

      • Patients with contraindications to receiving RIC allogeneic SCT • Female patients who are pregnant or breastfeeding. All women of childbearing potential (WOCBP) must have a negative pregnancy test before commencing treatment • Adults of reproductive potential not willing to use appropriate, effective, contraception during the specified period • Patients with renal or hepatic impairment as clinically judged by Local Investigator • Patients with active infection, HIV-positive or chronic active Hep-A or –C • Patients with concurrent active malignancy. Patients with a previous history of malignancy can be included if that malignancy is considered to be at a low risk of recurrence

    Read more Return to top ('Preview' button)
  • A Phase 3, Multicenter, Randomized, Open Label Study of Venetoclax and Dexamethasone Compared with Pomalidomide and Dexamethasone in Subjects with t(11;14)-Positive Relapsed or Refractory Multiple Myeloma

    • Research Summary

      A study designed to evaluate the safety and efficacy of venetoclax plus dexamethasone (VenDex) compared with pomalidomide plus dexamethasone (PomDex) in participants with t(11;14)-positive Relapsed or Refractory Multiple Myeloma.
      Subjects randomized to Arm 2 (PomDex) may elect, if eligible, to receive VenDex therapy after documented disease progression per International Myeloma Working Group (IMWG) criteria.

    • Inclusion Criteria:

      1. Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/ Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures. 2. Adult male or female, ≥ 18 years old. 3. Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug: • Absolute neutrophil count (ANC) ≥ 1000/µL; subject may use growth factor support to achieve ANC eligibility criteria; • Platelets: ≥ 50,000/mm3. For subjects with > 50% myeloma involvement in the marrow, a platelet count of ≥ 30,000 mm3 within 2 weeks prior to randomization is allowed. Subjects may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility; • Hemoglobin ≥ 8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria; • AST and ALT ≤ 3 × upper limit of normal (ULN); • Total bilirubin ≤ 1.5 × ULN (subjects with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN); • Creatinine clearance ≥ 30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula; • Serum calcium corrected for albumin ≤ 14.0 mg/dL (≤ 3.5 mmol/L). 4. Are willing or able to comply with procedures required in this protocol. 5. Are willing and able to receive antithrombotic prophylactic treatment. 6. Documented diagnosis of multiple myeloma based on standard IMWG criteria. 7. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 8. Subject has documented disease progression on or within 60 days of completion of their last therapy. 9. Subject has received at least 2 prior lines of therapy. • A line of therapy consists of at least 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens. 10. Subject must have received at least 2 consecutive cycles of lenalidomide and be refractory to lenalidomide as defined by one of the following: • Subject experienced PD on or within 60 days of completing treatment. • Subject exhibited PR or better but relapsed within 6 months after stopping treatment. 11. Subject must have received at least 2 consecutive cycles of a proteasome inhibitor (bortezomib, carfilzomib or ixazomib). 12. Subject has measurable disease at Screening, defined by at least 1 of the following: • Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L); OR • Urine M-protein ≥ 200 mg/24 hours; OR • Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL (100 mg/L), provided serum FLC ratio is abnormal. 13. Subject has MM positive for t(11;14) as determined by an analytically validated FISH assay per centralized laboratory testing. 14. A negative serum pregnancy test for all female subjects (except those of non-childbearing potential) within 10 to 14 days prior to initiating therapy and a negative urine pregnancy test within 24 hours for all female subjects (except those of non-childbearing potential) at baseline prior to the first dose of study drug. 15. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for women of childbearing potential practicing at least 2 protocol-specified methods of birth control that are effective from at least 30 days before starting study drugs through at least 30 days after the last dose of any study drug (refer to Section 5.2). 16. If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 through 30 days after the last dose of study drug, to practice the protocol-specified contraception.

    • Exclusion Criteria:

      1. No history of treatment with venetoclax or another BCL-2 inhibitor or pomalidomide. 2. No history of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years with the following exceptions: • Adequately treated in situ carcinoma of the cervix uteri or the breast; • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; • Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment; or • Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study. 3. No evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT). 4. No prior treatment with any of the following: a. • Allogeneic or syngeneic SCT within 16 weeks prior to randomization; or b. • Autologous SCT within 12 weeks prior to randomization. 5. No known meningeal involvement of multiple myeloma. 6. No history of clinically significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, pulmonary or hepatic disease within the last 6 months that, in the Investigator's opinion, would adversely affect the subject's participation in the study. 7. No history of known allergies, hypersensitivities, or intolerance to any of the study drug or excipients, or thalidomide derivatives. 8. None of the following conditions: • Nonsecretory multiple myeloma; • Active plasma cell leukemia i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential; • Waldenström's macroglobulinemia; • Primary amyloidosis; • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); • Known human immunodeficiency virus (HIV) infection; • Active hepatitis B or C infection based on screening blood testing; • Significant cardiovascular disease, including uncontrolled angina, arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure NYHA Class ≥ 3; • Major surgery within 4 weeks prior to first dose or planned during study participation; • Acute infections within 14 days prior to first dose requiring parenteral therapy (antibiotic, antifungal, or antiviral); • Uncontrolled diabetes or hypertension within 14 days prior to first dose; or • Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to first dose. 9. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the study and for at least 30 days after the last dose of study drug. 10. Male who is not considering fathering a child or donating sperm during the study and for at least 30 days after the last dose of study drug.

    Read more Return to top ('Preview' button)
  • A Phase 3 Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Subjects with Advanced Urothelial Cancer and Selected FGFR Gene Aberrations

    • Research Summary

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

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The Impact of the Oncotype DX® Breast Cancer Assay on Treatment Decisions in a UK Population of Patients with Estrogen Receptor-Positive Early Breast Cancer with 1-3 Positive Lymph Nodes, who are Potential Candidates for Chemotherapy, but for whom the Benefits of Chemotherapy are Uncertain

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Phase II Trial of Pembrolizumab and Radiotherapy in Cutaneous T cell lymphoma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An international phase III randomised study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Prospective Evaluation of the Management of Sporadic Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤ 2 cm

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PRIMUS 001 - An adaptive phase II study of FOLFOX-A (FOLFOX and nab-paclitaxel) versus AG (nab-paclitaxel and gemcitabine) in patients with metastatic pancreatic cancer, with integrated biomarker evaluation

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An International, Phase 2, Open-Label, Randomized Study of BGB-3111 Combined with Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma

    • Research Summary

      The purpose of the study is to evaluate the efficacy, safety and tolerability and of BGB-3111plus obinutuzumab versus obinutuzumab alone in subjects with relapsed/refractory non-Hodgkin follicular lymphoma.

      This is an open-label, randomized active control study of BGB-3111 plus obinutuzumab versus obinutuzumab alone in subjects with relapsed or refractory follicular lymphoma. Randomization is 2:1 and subjects will be stratified by the number of prior lines of therapy (2 - 3 vs > 3) and rituximab-refractory status. The study will evaluate the efficacy, as measured by overall response rate by independent review, safety and tolerability. Pharmacokinetic profile of BGB-3111 and obinutuzumab combination therapy will also be evaluated.

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • TrueNTH Global Registry- Prostate Cancer Outcomes

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The COMET Trial: Concordance between MRI and Pathology in the Diagnosis of Extranodal Tumour Deposits

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase Ia/Ib Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of RO7198457 as a Single Agent and in Combination with Atezolizumab in Patients with Locally Advanced or Metastatic Tumors.

    • Research Summary

      This is a Phase 1a/1b, open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, immune response, and pharmacokinetics of RO7198457 as a single agent and in combination with atezolizumab (MPDL3280A, an engineered anti-programmed death-ligand 1 [anti-PD-L1] antibody).

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Guiding Chordoma Treatment Through Molecular Profiling: A National Cohort Study

    • Research Summary

      Chordoma is a very rare, slow growing tumour that can occur anywhere from the base of the skull to the tip of the spine and affects 1 in 800,000 of the UK population. Currently very little is known about the condition. ‘Understanding Chordoma: A National Cohort Study’ is designed to better understand chordoma. Using samples of tissue and blood from patients we are investigating in great depth including genetic analysis why it develops in the way that it does why it grows, why some chordomas recur, what makes it spread, why certain people develop it and what makes some chordomas behave more aggressively than others. We will also investigate biomarkers (an identifier in the blood) that may allow earlier information on the risk of recurrence and metastatic disease than is currently available and provide a more accurate predictor of the behaviour of the disease (prognosis). Additionally, by comparing patient symptoms with findings from imaging (x-rays and scans) and tissue and blood analysis in the study aims at to evaluate current treatments with the aim of improving patient care. Some of the tissue samples may be collected for specific projects, however the consent provided by tissue donors permits long-term storage of samples to be used for future projects if the sample size allows for this. All donations to the projects are considered to be a gift for the benefit of other patients and future research.

    • Inclusion Criteria:

      All patients including children newly or previously diagnosed for chordoma plus all patients including children previously diagnosed with chordoma who are considered to be disease-free .

    • Exclusion Criteria:

      Private (non-NHS) patients Prisoners Patients unable to give informed consent Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection

    Read more Return to top ('Preview' button)
  • Phase 1/2 Dose-Escalation and Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CORT125281 with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

    • Research Summary

      This is an open-label, Phase 1/2a dose escalation study with an expansion phase to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy of CORT125281 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) to identify a recommended dose (RD) for Phase 2 studies.

      CORT125281 is a selective glucocorticoid receptor (GR) antagonist. In this study, CORT125281 will be administered orally in combination with enzalutamide to patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the regimen. The study consists of two phases: a dose-escalation phase and an expansion phase. The dose escalation phase is designed to determine DLTs, MTD/biologically active doses and the RD of CORT125281 plus enzalutamide in patients with mCRPC. Once the recommended dose has been determined, the following expansion cohorts will be enrolled and treated with CORT125281 plus enzalutamide at the recommended dose level.

      1. Patients who have progressed during treatment with abiraterone, and have received no other androgen receptor (AR)-blocking therapies

      2. Patients who have progressed during treatment with enzalutamide or other second-generation AR inhibitors.

      The effect of food on CORT125281 PK will be assessed in a portion of the patients enrolled in the Expansion Phase. The expansion cohorts will be enrolled in parallel.

      In each phase of the study, routine assessments of safety and tolerability will be performed using adverse event (AE) monitoring, measurement of vital signs, recording 12 lead electrocardiogram (ECG), physical examination and clinical laboratory safety tests, and samples will be collected to determine standard PK parameters for CORT125281, enzalutamide, and their major metabolites. PD, quality of life evaluations and preliminary evaluations of anti-tumor activity of CORT125281 with enzalutamide will be performed throughout the study.

    • Inclusion Criteria:

      Each patient must meet the following criteria to be enrolled in this study: 1. Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures, and provide written informed consent. 2. Males ≥ 18 years of age at time of signing consent. 3. Histologically confirmed metastatic adenocarcinoma of the prostate without histological neuroendocrine differentiation or small cell features. 4. Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy as follows: a. Cohort A: Patients must have progressed during treatment with abiraterone b. Cohort B: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide 160 mg QD. These patients will continue enzalutamide without interruption during the screening period (no wash-out period required). 5. Baseline tumor assessment performed within 28 days prior to the first dose of study treatment. 6. Prior surgical or chemical castration with serum testosterone < 1.7 nmol/L (50 ng/dL). If the method of castration is use of a luteinizing hormone-releasing hormone (LHRH) analogue, there must be a plan to maintain effective LHRH analogue treatment for the duration of the trial. 7. On stable doses of bisphosphonates or denosumab for 4 weeks prior to first dose of CORT125281 or enzalutamide without Grade 2 or greater toxicities. 8. Progressive disease by PSA or imaging after most recent prior therapy. PSA ≥ 1 ng/mL, if a confirmed rise in PSA is the only indication of progression. 9. Consent to provide mandatory paired tissue biopsies, obtained within 6 weeks prior to the first study dose of CORT125281 and/or enzalutamide and at Cycle 2 Day 1 (soft tissue biopsy is preferred, when possible). Optional: consent to provide additional on-study biopsy (1) obtained during procedure conducted as standard of care; or (2) at the time of disease progression. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 11. Adequate baseline organ function within 14 days of enrollment in the Lead-In Period: a. Absolute neutrophil count ≥ 1,500/μL, platelet count ≥100,000/μL, and hemoglobin ≥ 9 g/dL (NOTE: patients may not have received any growth factors or blood transfusions within 7 days prior to the hematologic laboratory values obtained during the Screening Period). b. Total bilirubin ≤ 1 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. Patients with a history of Gilbert’s syndrome may have bilirubin > 1.5 × ULN if there is no evidence of hepatobiliary obstruction or hepatic dysfunction. c. Creatinine ≤ ULN (Common Toxicity Criteria [CTC] Grade 0); if creatinine > ULN: creatinine clearance > 60 mL/min/1.73 m2 d. Albumin ≥ 3.0 g/dL (≥ 30 g/L). e. Activated partial thromboplastin time (aPTT) must be ≤1.5 × ULN and international normalized ratio (INR) < 1.5. Patients on anticoagulant therapy will have an appropriate aPTT and INR as determined by the Investigator. 12. If a patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control1 must be used during and for 100 days after completing treatment with CORT125281 or enzalutamide. A condom is required during and for 100 days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least 100 days after the final treatment administration. 13. Able to swallow and retain oral medication without uncontrolled nausea or emesis.

    • Exclusion Criteria:

      Patients who meet any of the following criteria will not be permitted entry to the study: 1. Received chemotherapy, radiotherapy, immunotherapy, or any investigational cancer therapies within 28 days prior to the first dose of enzalutamide and/or CORT125281, or treatment with such therapies is planned during protocol treatment. 2. More than two prior cytotoxic chemotherapy regimens for the treatment of mCRPC. 3. Dose Escalation Phase and Cohort A: Received prior therapy with enzalutamide. 4. Ongoing or anticipated therapy with hormone therapy (other than LHRH antagonist), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within 28 days prior to the first dose of enzalutamide and/or CORT125281. 5. Received palliative radiotherapy within 2 weeks prior to the first dose of enzalutamide and/or CORT125281. If palliative radiation therapy included the pelvis, a minimum of 4 weeks is required between palliative radiotherapy and the first dose of enzalutamide and/or CORT125281. 6. Contraindication or precaution for enzalutamide including history or risk factors for seizures; fructose intolerance; posterior reversible encephalopathy syndrome, or discontinuation of prior treatment with enzalutamide due to toxicity. 7. History of or current brain metastases. 8. Any clinically significant uncontrolled condition that may increase the risk to the study patient or that the Investigator considers places the patient at unacceptable risk, including but not limited to the following: a. Myocardial infarction or transient ischemic attack with 12 months of enrollment b. Acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within the past 6 months prior to enrollment, Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification. c. Recent history of or risk factors for torsades de pointes, including marked baseline prolongation of QT interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds (ms) using Fridericia's formula (QTcF) or need for concomitant medication associated with QT prolongation (refer to https://www.crediblemeds.org/). d. Uncontrolled hypertension: Sustained systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg; patients will be considered eligible if hypertension is treated and controlled during Screening. e. Active infection requiring IV anti-infective treatment. f. History of human immunodeficiency virus (HIV) or current chronic/active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), including: i. Patients with chronic or active hepatitis B as diagnosed by serologic tests are excluded from the study. In equivocal cases, hepatitis B or C polymerase chain reaction (PCR) may be performed and must be negative for enrollment. ii. Active autoimmune disease requiring systemic treatment. g. Alcohol or other substance abuse or cirrhosis. 9. Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity (e.g., saw palmetto, PC-SPES, PC-HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 28 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study. 10. Received systemic glucocorticoids within 28 days prior to the first dose of enzalutamide and/or CORT125281, or requirement for chronic or frequently used systemic glucocorticoids for medical conditions (e.g., rheumatoid arthritis, immunosuppression after organ transplantation). 11. Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 or with sensitive substrates of CYP3A4, CYP2C9 or CYP2C19. For patients currently receiving strong CYP2C8 inhibitors or strong CYP3A4 inducers, a minimum washout period of 21 days is required prior to initiating the first day of study treatment – Co-administration of enzalutamide with warfarin will not be exclusionary. If co-administration of warfarin cannot be avoided, conduct additional INR monitoring – Refer to Appendix C for examples of prohibited concomitant medications 12. Toxicities of prior therapies (except alopecia) that have not resolved to Common Terminology for Adverse Events (CTCAE) ≤ Grade 1. 13. Any other concurrent cancer or a history of another invasive malignancy within the last 3 years. 14. Concurrent enrollment on other Phase 1, 2, or 3 investigational treatment studies for the treatment of prostate cancer.

    Read more Return to top ('Preview' button)
  • Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • DANTE: A randomised phase III trial to evaluate the Duration of ANti-PD1 monoclonal antibody Treatment in patients with metastatic mElanoma

    • Research Summary

      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.

    • Inclusion Criteria:

      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:

      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.

    Read more Return to top ('Preview' button)
  • A Phase 1, Open-Label, Multicentre, Non-Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of AZD4573, a Potent and Selective CDK9 Inhibitor, in Subjects with Relapsed or Refractory Haematological Malignancies

    • Research Summary

      The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed or refractory haematological malignancies

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase II study of nivolumab monotherapy in patients with relapsed/refractory Hodgkin lymphoma, fit for autologous stem cell transplant, who fail to reach complete metabolic remission after first or second line salvage therapy

    • Research Summary

      The ANIMATE trial is testing a drug called Nivolumab in patients with Hodgkin lymphoma which has either relapsed after initial chemotherapy, or not responded well enough to initial chemotherapy. Usual treatment in this situation is 2-4 cycles of chemotherapy (‘salvage treatment’) followed by an autologous stem cell transplant (a transplant of the patient’s own cells). The cure rate after a transplant is high if there has been a very good response to salvage treatment. Response is assessed using PET-CT scans, where a small amount of radioactive glucose is injected and highlights areas where there is still active disease (a ‘positive’ PET scan). If the PET-CT scan is positive after salvage, more treatment is needed before transplant. Nivolumab is a drug which targets cancer cells and recruits the immune system to fight the cells. Nivolumab is approved for use in a number of cancers, including in Hodgkin lymphoma patients who have relapsed after stem cell transplant. This trial tests whether nivolumab is effective if used earlier, before stem cell transplantation. Patients will be registered to the trial during initial salvage treatment. After 2 cycles of combination chemotherapy (or 4 cycles if treated with brentuximab vedotin), patients will have a PET-CT scan, which will be reviewed by experts at St Thomas’ Hospital, London. If the scan is negative, patients will not receive trial treatment and will be followed up only. If the scan is positive, patients who are fit for treatment will receive 4-8 cycles of nivolumab, given every 2 weeks. Response will be checked by PET-CT after 4 cycles. Patients with a negative scan or progressive disease will stop treatment. Patients with a positive scan will have 4 more cycles before a final PET-CT scan. Patients on the trial will be followed up for at least 3 years.

    • Inclusion Criteria:

      Inclusion criteria for registration • Age 16 or over • Primary refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma in first relapse • About to receive, receiving or within 14 days of first 2 cycles of first or second line salvage therapy (4 cycles if receiving treatment with brentuximab vedotin) • Fit for autologous stem cell transplantation • Written informed consent • Willing to comply with the contraceptive requirements of the trial Inclusion criteria – trial treatment • Has received 2 cycles of first line or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • PET positive (Deauville score 4 or 5) after 2 cycles of first or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • Fit for further salvage chemotherapy • ECOG performance status 0-1 • Creatinine clearance > 30ml/min calculated by Cockroft-Gault formula • Bilirubin < 1.5 x ULN, ALT/AST < 2.5 x ULN • Adequate bone marrow function (Hb > 80g/l, Platelets > 50 x 10^9/l, neutrophils > 1.0 x 10^9/l

    • Exclusion Criteria:

      Exclusion criteria for registration • Nodular lymphocyte predominant Hodgkin lymphoma • Women who are pregnant or breastfeeding • History of colitis, inflammatory bowel disease or pneumonitis • Patients with autoimmune disorders excluding patients with vitiligo, diabetes mellitus type 1, hypo- and hyperthyroidism not requiring immunosuppressive therapy • Known history of hepatitis B or C infection • Known HIV infection • History of allergy (including severe/life threatening skin reaction) to monoclonal antibodies, anaphylaxis or uncontrolled allergy • Major surgery within 4 weeks prior to registration • Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within the past 6 months • Non-haematological malignancy within the past 3 years (some exceptions apply – listed in trial protocol) Exclusion criteria for trial treatment • Deauville score 1-3 after 2 cycles of first or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • Positive serology for hepatitis B or C (unless due to vaccination) • Active infection requiring systemic therapy • Ongoing immunosuppressive therapy, apart from inhaled, intranasal, topical corticosteroids or systemic corticosteroids at low doses (< = 10mg prednisolone or equivalent per day). • Chemo- or radiotherapy or corticosteroids at a dose of more than 10mg/day prednisolone or equivalent within 14 days prior to response PET-CT. NOTE: corticosteroids can be used AFTER a positive PET-CT scan for symptomatic disease but must be weaned to a dose of prednisolone < = 10mg/day or less (or equivalent) at least 7 days prior to starting nivolumab. • Treatment with any investigational agent within 28 days prior to planned start of nivolumab • Ongoing grade 2-4 non-haematological toxicities related to prior Hodgkin lymphoma treatments, with the exception of alopecia and grade 2 fatigue • Pregnant or breastfeeding women

    Read more Return to top ('Preview' button)
  • Tissue based immunometric analysis to guide personalised immunotherapy in solid malignancies

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The use of Microwave Ablation in the treatment of advanced melanoma with cutaneous metastases. An observational study using Emblation's microwave based treatment system SwiftTM

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PETReA: Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Methylphenidate versus placebo for fatigue in advanced cancer (MePFAC)

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Targeted therapy with or without dose intensified radiotherapy for oligo-progressive disease in oncogene-addicted lung tumours

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Rare Neoplasms of Gynaecological Origin

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Paediatric Hepatic International Tumour Trial

    • Research Summary

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

    • Inclusion Criteria:

      too long to import-copied to notes

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The Identification and characterisation of Inherited Predispositions to Colorectal Tumours (CORGI) 2

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer

    • Research Summary

      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:

      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 Criteria:

      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.

    Read more Return to top ('Preview' button)
  • A Phase 3 Randomized Study Comparing Nivolumab and Ipilimumab Combination vs Placebo in Participants with Localized Renal Cell Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse

    • Research Summary

      The purpose of this study is to determine whether the combination of nivolumab and ipilimumab is safe and effective for delaying or preventing recurrence of cancer in patients who have experienced the partial or entire removal of a kidney

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Post-operative avoidance of radiotherapy: biomarker selection of women categorised to be in a very low risk group by IHC4+C

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase I study of 131-1 mIBG followed by Nivolumab and Dinutuximab beta in children with relapsed/refractory neuroblastoma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • UK P3BEP - A randomised phase 3 trial of accelerated versus standard BEP chemotherapy for patients with intermediate and poor-risk metastatic germ cell tumours

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The SCOTTY Study - whole genome sequencing study of young colon cancer patients and their parents

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A cohort study to investigate body composition in women with breast cancer

    • Research Summary

      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.

    • Inclusion Criteria:

      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

    • Exclusion Criteria:

      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.

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Clinical and Biological factors associated with relapse and length of survival following relapse in UK neuroblastomas

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      N/A

    Read more Return to top ('Preview' button)
  • A randomised phase II trial of standard versus dose escalated radiotherapy in the treatment of pain in malignant pleural mesothelioma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • PLATO - PersonaLising Anal cancer radioTherapy dOse - Incorporating Anal Cancer Trials (ACT) ACT3, ACT4 and ACT5

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      See Main Inclusion Criteria

    Read more Return to top ('Preview' button)
  • Randomised, phase II/III, 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Case­-control study of individuals with increased risk of inherited women's cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Therapeutic HPV vaccine trial +/- anti-CD40 in HPV-driven squamous cell carcinoma.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A longitudinal observational study with phenotypic, functional and molecular analyses in real-world patients with mature lymphoid malignancies in the UK

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • LCH-­IV ­International Collaborative Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis

    • Research Summary

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

    • Inclusion Criteria:

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Stereotactic ablative radiotherapy for oligometastatic non-small cell lung cancer. A randomised phase III trial.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Phenotypic and Genotypic Characteristics of Paediatric Myelodysplastic Syndromes

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Tracking mutations in cell free tumour DNA to predict Relapse in eArly Colorectal Cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker to Stratify Management of Good and Poor Responders to Chemoradiotherapy: A Rectal Cancer Multicentre Randomised Control Trial

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV)-positive oropharyngeal cancer

    • Research Summary

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • BALLAD. A trial to evaluate the potential benefit of adjuvant chemotherapy for small bowel adenocarcinoma.

    • Research Summary

      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.

    • Inclusion Criteria:

      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.

    • Exclusion Criteria:

      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

    Read more Return to top ('Preview' button)
  • Response to Optimal Selection of neo-adjuvant Chemotherapy in Operable breast cancer: A randomised phase III, stratified biomarker trial of neo­adjuvant 5-Fluorouracil, Epirubicin and Cyclophosphamide vs Docetaxel and Cyclophosphamide chemotherapy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

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

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      Mixed hepatocellular tumours are excluded

    Read more Return to top ('Preview' button)
  • International Randomised Phase III Clinical Trial in Children with Acute Myeloid Leukaemia - Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination with Induction Chemotherapy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Refining Ovarian Cancer Test Accuracy Scores: A test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase III double-blind placebo-controlled randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours.

    • Research Summary

      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.

    • Inclusion Criteria:

      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

    • Exclusion Criteria:

      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.

    Read more Return to top ('Preview' button)
  • Short-course radiotherapy plus olaparib for newly diagnosed glioblastoma in patients unsuitable for radical chemoradiation: a randomised phase II clinical trial preceded by a lead-in phase I dose escalation study.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Adults with acute myeloid leukaemia or high-risk myelodysplastic syndrome

    • Research Summary

      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

    • Inclusion Criteria:

      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)

    • Exclusion Criteria:

      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

    Read more Return to top ('Preview' button)
  • SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Tissue analysis for stratifying therapy in proliferative lung diseases

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Improving radical treatment through MRI evaluation of pelvic sigmoid cancers (the IMPRESS trial)

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A phase I/II study of 177Lu-HH1 (Betalutin™) radioimmunotherapy for treatment of relapsed CD37+ non-Hodgkin lymphoma

    • Research Summary

      -

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • SERENADE: Screening for synchronous metastases in colorectal cancer using Hepatic Diffusion weighted MRI.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Multicenter Observational Prospective Study For The Identification Of Prognostic Factors In Patients With Mycosis Fungoides/Sezary Syndrome: Proposal For An International Prognostic Index For Cutaneous Lymphoma

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • National Lung Matrix Trial: Multi-­drug, genetic marker-directed, non­-comparative, multi-­centre, multi­-arm phase II trial in non-small cell lung cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Evaluating the effect of immune cells on the outcome of patients with mesothelioma

    • Research Summary

      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.

    • Inclusion Criteria:

      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

    • Exclusion Criteria:

      None identified (other than absence of consent)

    Read more Return to top ('Preview' button)
  • The ORANGE II PLUS Trial: An international multicentre randomised controlled trial of open versus laparoscopic hemihepatectomy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • A Trial for Older Patients with Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome

    • Research Summary

      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.

    • Inclusion Criteria:

      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

    • Exclusion Criteria:

      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.

    Read more Return to top ('Preview' button)
  • FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • An international randomised controlled trial to compare targeted intra-operative radiotherapy boost with conventional external beam radiotherapy boost after conservative breast surgery for women with early stage breast cancer and a high risk of local recurrence

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • The Cancer Research UK Stratified Medicine Programme: Pilot Study

    • Research Summary

      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

    • Inclusion Criteria:

      •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

    • Exclusion Criteria:

      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.

    Read more Return to top ('Preview' button)
  • A phase III multicentre trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Optimal Personalised Treatment of early breast cancer using Multiparameter Analysis

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Improving Population Outcomes for Renal Tumours of Childhood - applying P-Medicine tools to improve treatment decisions for Wilms tumour and other renal tumours of childhood and young adults: A SIOP Renal Tumours Study Group prospective clinical study

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Analysis of leukaemia associated antigen gene and protein expression in haematopoietic cells and their capacity to induce anti-tumour immune responses

    • Research Summary

      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.

    • Inclusion Criteria:

      • 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)

    • Exclusion Criteria:

      • Known positivity for HIV • Inability to obtain informed consent.

    Read more Return to top ('Preview' button)
  • A randomized trial for adults with newly diagnosed acute lymphoblastic leukaemia

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Investigation of the molecular and genetic mechanisms promoting oral cancer development and progression

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      N/A

    Read more Return to top ('Preview' button)
  • Colorectal Cancer Genetic Susceptibility Study 2

    • Research Summary

      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.

    • Inclusion Criteria:

      Mismatch repair gene mutation carriers (and tested relatives) will be identified in collaboration with the Regional Genetics Centre.

    • Exclusion Criteria:

      Unknown

    Read more Return to top ('Preview' button)
  • Oesophageal Cancer Clinical and Molecular Stratification Study (OCCAMS) - A Multicentre Study to Determine Predictive and Prognostic Biomarkers and Therapeutic Targets for Oesophageal and Junctional Adenocarcinoma including Whole Genome Sequencing.

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      Patients for palliative treatment

    Read more Return to top ('Preview' button)
  • Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy

    • Research Summary

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

    • Inclusion Criteria:

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

    • Exclusion Criteria:

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

    Read more Return to top ('Preview' button)
  • Identification and characterisation of prognostic factors in chronic B-cell lymphoproliferative disorders

    • Research Summary

    • Inclusion Criteria:

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

    • Exclusion Criteria:

      tbc

    Read more Return to top ('Preview' button)
  • Read more Return to top ('Preview' button)
  • Molecular and cytogenetic characterisation of peritoneal surface malignancies; Investigating the role of novel molecular markers and microRNAs in peritoneal malignancies

    • Research Summary

      The majority of patients with cancer die from the spread of cancer to other organs like the liver, lungs, bone or brain. In some cases, spread to other organs is still treatable however. Spread of cancer to the peritoneum is a particularly ominous finding and confers an exceptionally poor prognosis, historically implying a terminal phase of disease. While advances have been made in the management of patients with tumour spread to the peritoneum in recent times, the vast majority are incurable with a median life expectancy of 35 months. The current proposal aims to determine the basic molecular defects that characterize this mode of disease spread. Identification of the global and specific biological features that determine peritoneal spread of disease is central to understanding the properties of individual cancers, and would allow the construction of objective algorithms predictive of tumour behaviour to answer key questions like who will develop metastases or recurrence (and should therefore be offered aggressive further treatment); where they will spread to (to enable focused and cost−effective future surveillance); and how they might best be treated (thereby avoiding unnecessary treatments). Other applications from such a mechanistic understanding of these processes would be rational drug design complimented by tailoring of individual therapies to specific molecular signatures. A major emphasis of our work is therefore to bridge the gap from cutting edge molecular biology to real life improved patient management.

    • Inclusion Criteria:

      All patients over the age of 18 requiring surgery for peritoneal malignancy and Pseudomyxoma peritonei

    • Exclusion Criteria:

      Patients under the age of 18 Patients who are unwilling or unable to provide consent Patients whose cancer is unsuitable for surgery

    Read more Return to top ('Preview' button)

Accessibility tools

Return to header