Last updated on February 2019

Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma


Brief description of study

Primary objective: To assess the safety and tolerability of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma in order to select the recommended Phase 2 dose (RP2D).

Secondary objectives: (1) To evaluate the overall safety profile of pembrolizumab in combination with vorinostat; (2) To assess the anti-tumor activity (i.e. objective response rate, progression-free survival) of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma; (3) To characterize PD-L1/2, immune cell subsets, and miRs in tumor and/or blood.

Detailed Study Description

This is a Phase I/Ib, open-label, safety, and pharmacodynamics study of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma. This clinical study will be composed of a Dose Finding Phase and an Expansion Phase. The Dose Finding Phase will estimate the Recommended Phase II Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. The Dose Finding Phase will lead to the identification of an Expansion Test Dose for pembrolizumab in combination with vorinostat. The Expansion Test Dose will be the Recommended Phase II Dose (RP2D) (i.e. the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor). Patients will be treated with oral vorinostat every day for 14 days, and with pembrolizumab at the fixed dose of 200 mg IV. Each cycle is every 21 days. Two dose levels of vorinostat will be tested in 2-patient cohorts according to the 3 + 3 standard design (100 mg and 200 mg). 200 mg dose represents 50% of the recommended vorinostat dose as single agent.

For the Dose Finding Phase (Combination Phase), the starting dose level of vorinostat will be 100 mg by mouth (PO) every day for 14 days, with 7 days break. The first dose level will have a minimum of 3 patients treated (unless the first 2 patients experience dose-limiting toxicities (DLTs) before the 3rd patient is enrolled).

Once the RP2D is identified, the Dose Expansion Phase will be opened. During the Dose Expansion Phase, the study will have a run-in phase with sequential single-agents and then the combination phase. The reason for the run-in phase during dose expansion is to obtain data on the immunomodulatory effects of vorinostat separately from pembrolizumab. Thirty patients with prior treatments will be enrolled in two expansion cohorts: 15 anti-PD1 naive patients and 15 anti-PD1 resistant patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition).

Clinical Study Identifier: NCT02619253

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Recruitment Status: Open


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