Pembrolizumab in Muscle Invasive/Metastatic Bladder Cancer

NCT02560636 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: CCR 4255
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Invasive Bladder Cancer

Keywords

Muscle Invasive; Metastatic; Advanced

Outcome Measures

Primary Outcomes (2)

• Establishing the maximum tolerated dose (MTD)

  Establishing the maximum tolerated dose (MTD) that can be safely combined with hypofractionated radiotherapy to the bladder in the absence of dose limiting toxicity (DLT) by assessing adverse events in the patient population.

  up to 36 months

• Measurement of the rates of toxicity

  Adverse events will be graded and assessed by CTCAEv4.

  6 weeks after the last fraction of radiotherapy has been administered

Secondary Outcomes (3)

• Measurement of the percentage of patients experiencing late grade 2+ and 3+ toxicity

  6 weeks and one day following the completion of radiotherapy until the 28 days after the patients last dose of Pembrolizumab

• Measuring rates of tumour response to treatment.

  3 months after completion of radiotherapy

• Measurement of progression free and overall survival rate

  Long term survival followup (reported at 2 years)

Other Outcomes (3)

• Measurement of progression-free survival in patients with no PD-1/PDL-1 expression vs high levels of PD-1/PDL-1 in their tumour

  36 months

• Report the proportion of patients free of grade 2 or higher toxicity

  3 and 6 months postradiotherapy completion

• Report the proportion of patients with complete or partial response in non-irradiated metastases

  3 and 6 months

Study Arms (5)

Dose level 1a

EXPERIMENTAL

Radiotherapy: 24Gy in 6f Pembrolizumab: 100mg

Drug: Pembrolizumab; Radiation: Radiotherapy

Dose level 1b

EXPERIMENTAL

Radiotherapy: 24Gy in 6f Pembrolizumab: 200mg

Drug: Pembrolizumab; Radiation: Radiotherapy

Dose level 2a

EXPERIMENTAL

Radiotherapy: 24Gy in 4f Pembrolizumab: 100mg

Drug: Pembrolizumab; Radiation: Radiotherapy

Dose level 2b

EXPERIMENTAL

Radiotherapy: 24Gy in 4f Pembrolizumab: 200mg

Drug: Pembrolizumab; Radiation: Radiotherapy

Dose level 3a

EXPERIMENTAL

Radiotherapy: 30Gy in 5f Pembrolizumab: 200mg

Drug: Pembrolizumab; Radiation: Radiotherapy

Interventions

Pembrolizumab DRUG

Pembrolizumab - Trial Treatment

Also known as: MK-3475/pembrolizumab (KEYTRUDA®)

Dose level 1a; Dose level 1b; Dose level 2a; Dose level 2b; Dose level 3a

Radiotherapy RADIATION

Radiotherapy

Dose level 1a; Dose level 1b; Dose level 2a; Dose level 2b; Dose level 3a

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed invasive bladder.carcinoma (T2-4,N0-3,M0-1).
• Be willing and able to provide written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Have measurable disease based on RECIST 1.1. , or, in group A, disease assessable by cystoscopic assessment.
• Have consented to analysis of tissue from an archival tissue sample
• Have a performance status of 0-1 on the ECOG Performance Scale.
• Planned for hypofractionated radiotherapy
• Demonstrate adequate organ function as defined in table 2 (please see protocol) all screening blood tests should be performed within 10 days of confirmation of eligibility.
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to confirmation of study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy if their partner has childbearing potential (as defined by not being surgically sterilized or have not been free from menses for \> 1 year).

You may not qualify if:

• 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.
• Note: Subjects with ≤ Grade 2 neuropathy or chemotherapy induced alopecia/nail changes are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting 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.

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• Royal Marsden NHS Foundation Trust: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

NIHR Biomedical Research Centre at RM and ICR (https://www.cancerbrc.org/)

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Tree AC, Jones K, Hafeez S, Sharabiani MTA, Harrington KJ, Lalondrelle S, Ahmed M, Huddart RA. Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer. Int J Radiat Oncol Biol Phys. 2018 Aug 1;101(5):1168-1171. doi: 10.1016/j.ijrobp.2018.04.070. Epub 2018 May 4.

  PMID: 30012528 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

pembrolizumab; Radiotherapy

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Professor Robert Huddart

  Royal Marsden NHS Foundation Trust

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2015
• First Posted: September 25, 2015
• Study Start: June 6, 2016
• Primary Completion: January 15, 2025
• Study Completion (Estimated): July 30, 2028
• Last Updated: January 6, 2026

Record last verified: 2025-12

Locations

GB (1)