Phase I study of entinostat and nivolumab with or without ipilimumab in advanced solid tumors (ETCTN-9844)

Purpose: Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8^þ effector:FoxP3^þ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ∓ ipilimumab in advanced solid tumors. Patients and Methods: Patients received an entinostat run-in (5 mg, weekly * 2) prior to the addition of ICIs. Dose escalation followed a modified 3þ3 design [dose level (DL)1/2: entinostat þ nivolumab; DL 3/4: entinostat þ nivolumab þ ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy. Results: Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n ¼ 7, 21%), anemia (n ¼ 9, 27%), and neutropenia (n ¼ 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone. Conclusions: The combination of entinostat with nivolumab ∓ ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.