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. 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.
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 and 200 mg).
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. Demonstrate adequate organ function. All screening labs should be performed within 10 days of treatment initiation. Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Subjects of childbearing potential should be willing to use 2 methods of contraception for the course of the study through 120 days after the last dose of study medication.
Acceptable methods of birth control include: abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections). NOTE: Females are considered of childbearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year). Male subjects without a previous vasectomy should agree to use an adequate method of contraception (i.e. Abstinence, condom with spermicidal foam/gel/film/cream) starting with the first dose of study therapy through 120 days after the last dose of study therapy. Subjects with urothelial carcinoma must have received a prior platinum-based regimen in the metastatic setting or have signed consent for this study within 12 months of receiving a platinum-based regimen in the perioperative setting (neoadjuvant or adjuvant). Subjects with a history of diabetes mellitus must have HgbA1c level of. Layout table for additonal information Responsible Party: Roberto Pili, Professor of Medicine, Robert Wallace Miller Professor of Oncology, Indiana University School of Medicine ClinicalTrials.gov Identifier: Other Study ID Numbers: IUSCC-0551 First Posted: December 2, 2015 Last Update Posted: January 31, 2019 Last Verified: January 2019 Layout table for additional information Studies a U.S.
FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Keywords provided by Roberto Pili, Indiana University School of Medicine.
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