Primary objective: To assess the early signals for anti-tumor activity (i.e. Objective response rate, progression-free survival) of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma. Secondary objectives: (1) To evaluate the overall safety profile of pembrolizumab in combination with vorinostat; (2) To assess the safety and tolerability of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma in order to select the recommended Phase 2 Dose (RP2D); (3) To characterize immune cell subsets, and miRs in tumor and/or blood. Condition or disease Intervention/treatment Phase Renal Cell Carcinoma Urinary Bladder Neoplasms Drug: Pembrolizumab Drug: Vorinostat Phase 1.

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This is a Phase I/Ib, open-label, safety, and pharmacodynamics study of pembrolizumab in combination with vorinostat in patients with advanced prostrate, 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 run-in phase may be waived at the investigator's discretion. The reason for the run-in phase during dose expansion is to obtain data on the immunomodulatory effects of vorinostat separately from pembrolizumab. Forty-five patients with prior treatments will be enrolled in three expansion cohorts: 15 anti-PD1 naive renal and urothelial patients 15 anti-PD1 resistant renal and urothelial patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-sensitive or castration-resistant prostate cancer. The prostate cohort has been added in an amendment during the Dose Expansion Phase, and therefore, will not be part of the Dose Finding Phase.

Once the Expansion Test Dose is identified, the Dose Expansion Phase will be opened and the combination will be tested in patients with advanced renal cell or urothelial cell carcinoma. Forty-five patients with prior treatments will be enrolled in three expansion cohorts: 15 anti-PD1 naive renal and urothelial patients, 15 anti-PD1 resistant renal and urothelial patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-sensitive or castration-resistant prostate cancer. Drug: Pembrolizumab. Subject Inclusion Criteria In order to be eligible for participation in this trial, the subject must: • Have one of the following diagnoses/conditions: • Renal cell carcinoma - previously treated and progressive disease, locally advanced or metastatic • Urothelial cell carcinoma - previously treated and progressive disease, locally advanced or metastatic • Prostate cell carcinoma - progressive disease, locally advanced or metastatic disease (enrolling only at IUSCC and its affiliates). Patients with hormone-sensitive disease where ADT in combination with either docetaxel or abiraterone is indicated will not be eligible (i.e.

Patients with high burden disease). • Be willing and able to provide written informed consent for the trial. • Be 18 years of age or older on day of signing informed consent. • Have measurable disease based on RECIST 1.1. For patients with solid malignancies or evaluable disease as assessed by bone scan and/or PET scan. Patients with advanced or metastatic prostate cancer can have either androgen-sensitive or castration-resistant disease. • Have a performance status of 0-2 on the ECOG Performance Scale.