Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870).

Abstract

<b>Purpose:</b> On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).<b>Experimental Design:</b> Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.<b>Results:</b> Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (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 Tregs were observed following treatment with entinostat, and lower numbers were associated with response (<i>P</i> = 0.03).<b>Conclusions:</b> This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. <i>Clin Cancer Res; 23(23); 7199-208. ©2017 AACR</i>.