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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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.




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.

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