Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).
Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each course was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival.
47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%-53%), the median progression-free survival was 13.8 months (95% CI 6.0-18.8), and the median overall survival was 65.3 months (95% CI 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03).
This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Sep 22 [Epub ahead of print]
Roberto Pili, David I Quinn, Hans Hammers, J Paul Monk, Saby George, Tanya Dorff, Thomas Olencki, Li Shen, Ashley R Orillion, Dominick Lamonica, Roberto A Salas Fragomeni, Zsolt Szabo, Alan D Hutson, Adrienne Groman, Susan M Perkins, Richard L Piekarz, Michael A Carducci
Oncology, Indiana University ., Norris Comprehensive Cancer Center, University of Southern California., UT Southwestern., Division of Medical Oncology, Internal Medicine, The Ohio State University and The James Comprehensive Cancer Center., Cell Stress Biology, Roswell Park Cancer Institute., Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center., Medical Oncology, Ohio State University., Center for Immunotherapy, Roswell Park Cancer Institute., Oncology Translational Research, Janssen., Genitourinary Program, Roswell Park Cancer Institute., Johns Hopkins University., Biostatistics, Roswell Park Cancer Institute., School of Medicine, Indiana University Simon Cancer Center., Medical Oncology Branch, National Cancer Institute., School of Medicine, Johns Hopkins University.