A phase I/II study to evaluate the safety, pharmacodynamics, and efficacy of entinostat in combination with atezolizumab and bevacizumab in patients with renal cell carcinoma.

4526 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 enhance or resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we conducted a Phase I/II clinical study with the HDAC inhibitor entinostat in combination with the immune check point inhibitor atezolizumab and the VEGF inhibitor bevacizumab in RCC pts, either treatment naïve or previously treated with immune checkpoint inhibitors. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a Phase I/II clinical trial. This clinical study was composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. Due to unforeseen circumstances, enrollment was halted during Stage I of the Phase II portion. In the Phase I dose finding cohorts, according to the 3+3 standard design, pts received oral entinostat at 1 mg (dose level or dl1), 3 mg (dl 2), or 5 mg (dl 3) every 7 days, continuously, with atezolizumab at a dose of 1,200 mg/kg mg IV every three weeks in combination with bevacizumab at a dose of 15 mg/kg IV every 3 weeks. Phase II patients were split into two distinct cohorts: Cohort A (no prior treatments with PD-1 or PD-L1 inhibitors) and Cohort B (at least one prior treatment with a PD-1 or PD-L1 inhibitor for metastatic disease). Pts treated at dl3 were included in the Phase II efficacy analyses. Results: 31 pts (18 and 13 pts during Phase I and II, respectively) were enrolled. Phase I was completed with the following DLTs: hypertension (3) in dl1, encephalopathy and hyponatremia (dl2), pneumonitis and pruritis (dl3). Dl3 was established as the recommended phase II dose. The most common treatment-related toxicities were thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. A total of 21 grade≥3 events were observed. Nine pts achieved a partial response in Cohort A and one patient in Cohort B with an ORR 60% (CI 32.3-83.7) and 33.3% (28.2-56.4), respectively. According to Simon’s optimal two-stage design, the ORR met the Stage I primary objective. The median PFS was 13.7 months (CI 8.7-21.3) in Cohort A and 9.8 months (CI 1.3-NE) in Cohort B. We have collected blood samples to conduct several correlative studies on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and atezolizumab plus bevacizumab is relatively well tolerated and may be active in pts with ccRCC. Clinical trial information: NCT03024437 .