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

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.