A Phase I/ IB , Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and Efficacy of Pembrolizumab in Combination With Vorinostat in Patients With Advanced Prostate, Renal or Urothelial Carcinoma
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: ABSTRACT Background Immunosuppressive factors such as regulatory T cells and myeloid‐derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD‐1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial (UC), renal (RCC) and prostate (PCA) carcinoma. Methods The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and 1 week OFF) and a fixed dose of pembrolizumab (200 mg IV every 21 days). Patients (pts) were assigned to three cohorts: Cohort A (previously treated, anti‐PD1/PD‐L1 naïve UC and RCC), Cohort B (previously treated, anti‐PD1/PD‐L1 resistant UC and RCC pts), and Cohort C (PCA pts). Results Dose levels 1 and 2 were completed without DLTs. We have enrolled 44 pts. (36 evaluable) in the dose expansion cohorts, and the most common resolved grade 3/4 toxicities were diarrhea, hypophosphatemia, acute kidney injury, anemia, and hypothyroidism. For Cohort A (13 pts), B (11 pts), and C (12 pts) the objective response rate was 8%, 0%, and 17%, and the median progression‐free survival was 2.9, 3.5, and 3.5 months, respectively. Four partial responses were observed, and two PCA pts. had a complete biochemical response with undetectable PSA. Persistent lower levels of peripheral CD11+, CD14+ HLA‐DR− monocytic MDSCs were associated with clinical benefit. Conclusion The combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint‐resistant UC/RCC pts. and immune checkpoint‐naïve PCA pts. Trial Registration: NCT02619253
Source: Cancer Medicine
DOI: 10.1002/cam4.70725
Institutions: University at Buffalo, State University of New York, University of Southern California, USC Norris Comprehensive Cancer Center, Indiana University Health, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University Indianapolis, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,700
OpenAlex ID: W4408921826