Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma
- Conditions
- Renal Cell CarcinomaUrinary Bladder Neoplasms
- Interventions
- Registration Number
- NCT02619253
- Lead Sponsor
- Nabil Adra
- Brief Summary
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)
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 52
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dose Finding Cohort Pembrolizumab Estimate the Recommended Phase 2 Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. 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). Dose Finding Cohort Vorinostat Estimate the Recommended Phase 2 Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. 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). Expansion Cohort Pembrolizumab 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. Expansion Cohort Vorinostat 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.
- Primary Outcome Measures
Name Time Method Objective Response Rate (Percentage of Patients With Complete Response or Partial Response) Up to 4.5 years Measured by RECIST v1.1 Complete response: Disappearance of all target lesions Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter The percentage of patients with objective response and its 95% confidence interval will be provided.
Progression Free Survival Up to 4.5 years Progression free survival was determined from start date of treatment to date of progression for patients who progressed or date of death for patients who died without progressing. The observations of patients remaining alive and progression free were censored at the date of last disease evaluation. The Kaplan-Meier method was used to determine the median and 95% confidence interval.
- Secondary Outcome Measures
Name Time Method Safety and Tolerablity: Number of Patients Who Experienced Grade 3 or 4 Adverse Events Up to 4.5 years Number of unique patients who had a treatment-related (possible, probable, or definite) adverse event with grade 3 or greater using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Number of Patients Experiencing a Dose Limiting Toxicity Up to 21 days Dose limiting toxicities (DLTs) are defined as Grade ≥ 3 hematological/non hematological toxicities attributable to vorinostat and/or pembrolizumab during the first 21 days of the combination treatment (days 1-21). If DLTs occur in 1 patient treated at the starting dose level a minimum of another 3 patients will be treated at this dose level. If a DLT occurs in more than 1 patient in the first 6 patients the study will be terminated. If a DLT occurs in \< 1/3 patients or ≤ 1/6 patients, 3 additional patients will be treated at the next dose level (level 2) with 200 mg vorinostat PO. If no DLTs occur at dose level 2, this dose level will be recommended for the expansion cohorts of the study.
Trial Locations
- Locations (4)
USC/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Indiana University Hospital
🇺🇸Indianapolis, Indiana, United States
Indiana University Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States