Testing the Addition of Tazemetostat to the Immunotherapy Drug, Pembrolizumab (MK-3475), in Advanced Urothelial Carcinoma

Official Title

A Pilot Study of Tazemetostat and Pembrolizumab (MK-3475) in Advanced Urothelial Carcinoma

Summary:

This phase I/II trial studies the side effects and best dose of tazemetostat and how well it works when given together with pembrolizumab in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes or other places in the body (locally advanced/metastatic). Tazemetostat may stop the growth of tumour cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumour cells to grow and spread. Giving tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat.

Trial Description

Primary Outcome:

• Objective response rate (ORR)

Secondary Outcome:

• Incidence of adverse events

PRIMARY OBJECTIVE: I. To conduct a safety lead-in phase that identifies the safe recommended phase II dose for combination tazemetostat and pembrolizumab (MK-3475). SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of pembrolizumab (MK-3475) in combination with tazemetostat. II. To evaluate the objective disease response rate of combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B). III. To evaluate the progression free survival to combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B). IV. To evaluate immune-related response using tumour response by immune-related Response Evaluation Criteria in Solid Tumours (irRECIST) in combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B) based on irRECIST criteria. CORRELATIVE OBJECTIVES:
I. To determine if EZH2 and H3K27me3 chromatin methylation determines disease response to EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline tissue samples. II. To determine if mutations in genes associated with histone methylation determine disease response to EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline tissue samples. III. To identify the immune response (T cell phenotypes), T-cell clonality with comparison to T-cell infiltrating lymphocytes and neoantigen profile of responsive and resistant urothelial carcinoma treated with combination anti-PD1 and EZH2i by analyzing blood and tissue samples throughout the study. OUTLINE:

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year.

View this trial on ClinicalTrials.gov