Status and phase
Conditions
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About
PLUMMB is an phase I trial to investigate the safety, tolerability and effectiveness of an immunotherapy drug called Pembrolizumab used in combination with radiotherapy. The study will also investigate two different doses of pembrolizumab, starting at 100mg (through an intravenous drip) and increasing to 200mg for the next cohort of patients, if the first dose is well tolerated. The patients suitable for this study will be: Group A those with locally advanced bladder cancer or Group B patients whose cancer has spread from the bladder (metastatic bladder cancer).
Treatment in the PLUMMB trial will start with a pembrolizumab 2 weeks prior to starting a course of 4 - 6 weeks radiotherapy. Treatment with pembrolizumab will then be given every three weeks. Patients in Group A will then continue to take pembrolizumab for up to a year unless they have disease progression or unacceptable side effects in the meantime. Patients in Group B will continue taking pembrolizumab for as long as needed until they have disease progression or unacceptable side effects.
Patients will be seen every 3 weeks during treatment and every 3-6 months thereafter. CT scans will be done every 3 months during treatment and as per usual care (usually 6 monthly) after the treatment has finished. Patients in Group A will also have a cystoscopy (camera test) to look into the bladder 3 months after they finish radiotherapy. This is standard care and would be the same for patients not on a research study.
Full description
Risk and burden for patients
Patients in this study have cancer that often proves hard to control with standard care. The early phase nature of this study means that the intervention may not have any benefit for patients who take part in the study. However, they will still receive the standard treatment of radiotherapy. Throughout the study, any patients who have significant side effects from the trial drug will be withdrawn from the trial and will still be eligible to receive standard care. The study itself carries a number of potential burdens:
Phase 1 trial of Pembrolizumab: Patients will be carefully monitored for toxicity throughout the trial. A phase I trial has already been conducted to determine the maximum tolerated dose (MTD) of pembrolizumab in bladder cancer. To date no MTD has been defined and the maximum dose tested showed acceptable toxicity and positive effects on reducing tumour size. This study will assess two dose levels of pembrolizumab: 100mg and 200mg and differing radiotherapy doses (24-30Gy in 4-6f). Dose escalation will only occur if the current cohort have shown no signs of unacceptable toxicity at 6 weeks after completing radiotherapy.
Recruitment
Participants will be offered information about this study by their clinical teams if they are considered to meet the entry criteria and express interest in taking part in an experimental study. It will be made clear that the study is experimental in nature and that there will not necessarily be a therapeutic benefit from taking part in the study. It will also be made clear that, should patients decide not to take part their future care will not be affected. Patients will be given sufficient time and information to make an informed decision about entering the trial, and not less than 24 hours; all patients entering the trial will give written informed consent. Inclusion and exclusion criteria for this study are standard for a phase 1 trial of a new oncology drug.
Confidentiality
Patients will be linked to a unique identifier the code for which will be held on a password protected database held only by the study team. Blood samples, tumour sample processing and other data analysis will take place at the laboratories of Royal Marsden and Institute of Cancer Research in London or Sutton. Sample processing will take place using the study number only. No other patient identifiable information will be available on study samples. Investigators will have access to patient identifiable information on password protected NHS hospital notes and databases only.
Conflict of Interest
Patients may be recruited to the study by those involved in their prior clinical care. The investigators do not expect conflict of interest between research and healthcare duties for a number of reasons: patients must give their full informed consent before entering the study, specifically regarding the unknown efficacy of the study drug and the intensive nature of the study. Those patients who do not continue in the study will maintain a relationship with the clinical team if required for symptom control. At the end of the study, patients will be able to access the results if they wish, through the Royal Marsden Website or contact the study team directly.
Use of tissue samples in future research
If participants give their consent, any leftover blood or tissue samples which are not required for this study will be stored for future unspecified research in line with the human tissue act regulations. Access and use of samples for research purposes will require appropriate ethical approval. Future researchers will not be able to identify individual patients from their biobank data, demographic and clinical information will be available.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Exclusion criteria
The subject must be excluded from participating in the trial if the subject:
Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
Previous pelvic radiotherapy, history of inflammatory bowel disease or other conditions that would in the opinion of the investigator would preclude the safe administration of pelvic radiotherapy.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>dose equivalent to 10mg of Prednisolone/day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent or therapy.
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, localized prostate cancer (≤T2 ≤ Gl3+4) or in situ cervical cancer that has undergone potentially curative therapy. Patients may have received treatment for previous urothelial malignancy.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
Has an 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 steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
Has an active infection requiring systemic therapy.
Has a 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.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
Has a known history of Human Immunodeficiency Virus (HIV).
Has known clinical history of Hepatitis B or Hepatitis C .
Has received a live vaccine within 30 days prior to the first dose of trial treatment.
Primary purpose
Allocation
Interventional model
Masking
34 participants in 5 patient groups
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Central trial contact
Sijy Pillai
Data sourced from clinicaltrials.gov
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