Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that the class I selective HDAC inhibitor entinostat has synergistic antitumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of Tregs. Thus, we have conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic clear cell renal cell carcinoma.

Methods: The primary objectives were to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria were clear cell histology, no prior treatments, and being fit to receive high dose IL-2. 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 every 8 hrs, up to 14 doses). Each cycle was 85 days. To test our hypothesis, the fixed sample size for the phase II was 36 with a type I/II error of 10%. If 11 or more of the pts have a response, the hypothesis that the response rate is ? 20% is rejected.

Results: Dose levels 1 and 2 were completed without DLTs and 5 mg was the recommended phase II dose for entinostat. The most common transient grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%). We have enrolled a total of 47 pts (44 at dose level 2), and 37 have completed one cycle (84 days) treatment. Four pts were not evaluable and were replaced. To date, the objective response is 35% (10 PR, 3 CR), the median progression-free survival is 16.1 months (6.2,27.8) and the median overall survival is 65.3 months (52.6,65.3). Decreased Tregs have been observed following treatment and lower numbers were associated with response. Analysis of monocityc MDSCs and activated antigen presenting cells will be also reported.

Conclusions: The results from this clinical trial suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells, and represent the first example of how epigenetic agents may be rationally combined with immunotherapies. (R21CA137649; U01CA70095)

Citation Format: Roberto Pili, David I. Quinn, Hans J. Hammers, J. Paul Monk, Saby George, Tanya B. Dorff, Thomas Olencki, Li Shen, Dominick Lamonica, Alan Hutson, Adrienne Groman, Susan M. Perkins, Richard Piekarz, Michael Carducci. Results from a phase I/II study with the HDAC inhibitor entinostat in combination with high-dose interleukin-2 in renal cell carcinoma patients (CTEP#7870). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT015.