Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)

  • Roussos Torres E
  • Rafie C
  • Wang C
  • et al.
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Abstract

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.

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APA

Roussos Torres, E. T., Rafie, C., Wang, C., Lim, D., Brufsky, A., LoRusso, P., … Connolly, R. M. (2021). Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844). Clinical Cancer Research. https://doi.org/10.1158/1078-0432.ccr-20-5017

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