Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)
Year: 2021
Type: article
Study design: Clinical Trial
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 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 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 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 = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 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.
Source: Clinical Cancer Research
Authors: Evanthia T. Roussos Torres, Christine Rafie, Chenguang Wang, David Lim, Adam Brufsky, Patricia LoRusso, Joseph Paul Eder, Vincent Chung, Melinda Downs, Molly Geare, Richard Piekarz, Howard Streicher, Leslie Anforth, Michelle A. Rudek, Qingfeng Zhu, Sepideh Besharati, Ashley Cimino-Mathews, Robert A. Anders, Vered Stearns, Elizabeth M. Jaffee, Roisin M. Connolly
Institutions: University of Southern California, Johns Hopkins University, Johns Hopkins Medicine, USC Norris Comprehensive Cancer Center, Sidney Kimmel Comprehensive Cancer Center, University of Miami, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Yale Cancer Center, City Of Hope National Medical Center, City of Hope, National Cancer Institute, National Institutes of Health, National Institutes of Health Clinical Center, University College Cork
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Bristol-Myers Squibb, Commonwealth Foundation, Johns Hopkins University, Tower Cancer Research Foundation, National Comprehensive Cancer Network, Syndax Pharmaceuticals, National Institutes of Health, Sidney Kimmel Comprehensive Cancer Center, National Cancer Institute, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1044130170, G1165598027, G1200945081, G1529121756, G1610190245, UPLC with Tandem MS for Sensitive Quantitative Analysis of Small Molecules, G2897488819, G3081895925, G3318661017, G3565137481, G3628273783, G465951118, G5350495373, G5603718298, G6110132416, Institute for Clinical and Translational Research, G644256362, G6743030886, G741073515, G7832261492, Johns Hopkins Institute for Clinical and Translational Research, G890239628, G9000009208, G9000041231, G9000066787, G9000069200, G9000073008, G9000100011, G9000166659, Yale Clinical and Translational Science Award, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W3171824834