Phase 1 Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)
Mené sur 33 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée de l'entinostat (un inhibiteur de HDAC) en combinaison avec le nivolumab, et dispensé avec ou sans ipilimumab
Purpose: Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector: FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase (HDAC) inhibitor entinostat with nivolumab {plus minus} ipilimumab in advanced solid tumors. Experimental Design: Patients received an entinostat run-in (5 mg, weekly x 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design (Dose level [DL]1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + 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 anti-tumor activity, change in tumor CD8/FoxP3 ratio pre- and post-therapy. Results: Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AEs) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n=7, 21%), anemia (n=9, 27%), and neutropenia (n=4, 12%). The RP2D was 3mg entinostat weekly, 3mg/kg q2 weeks nivolumab, and 1mg/kg q6 weeks ipilimumab (max 4 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, nivolumab {plus minus} ipilimumab was safe and tolerable with expected rates of irAEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.