A phase II study to evaluate the safety, pharmacodynamics and efficacy of entinostat in combination with nivolumab plus ipilimumab in patients with renal cell carcinoma previously treated with nivolumab plus ipilimumab or nivolumab alone.

668 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we opened a Phase II clinical study with the HDAC inhibitor entinostat and the immune check point inhibitors nivolumab (nivo) and ipilimumab (ipi) in clear cell RCC pts previously treated with nivo + ipi or nivo alone. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a dose de-escalation, two stage, phase II clinical trial with a safety lead-in. Due to a funder decision, enrollment was halted after completion of accrual to the safety lead in group. Pts received oral entinostat at a dose of 5 mg (dose level 1) or 3 mg (dose level 2) every 7 days, continuously, with nivo at a dose of 3 mg/kg mg IV every three weeks in combination with ipi at a dose of 1 mg/kg every 3 weeks X 4 doses. Then, nivo 480 mg was continued every 4 weeks. Results: A total of 12 pts with prior nivo+ipi or nivo treatments was enrolled. Dose level 1 (5 pts enrolled) was completed with the following DLTs: thrombocytopenia, nausea and vomiting, pneumonitis. Seven pts were enrolled on dose level 2 which was established as the recommended phase II dose. The most common treatment-related toxicities were fatigue, hypophosphatemia, neutropenia and thrombocytopenia. All were transient. Most of the pts had 2 or more prior treatments. Four pts achieved a partial response, with 3 out 4 pts previously treated with nivo alone (ORR 33%; 95% CI 9.9-65.1). The median PFS was 11.1 months (CI 1.3-26.4). We collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and nivo+ ipi is relatively well tolerated and may be active in pts with RCC. Clinical trial information: NCT03552380 .