Immunomodulation by HDAC inhibition: Results from a phase II study with entinostat and high-dose Interleukin 2 in renal cell carcinoma patients (CTEP#7870).

Abstract

500 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 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 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 dose of IL-2 (600,000 units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the Phase II dose level 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 entinostat was the Phase II recommended dose. No severe adverse events were observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were lymphopenia (50%), neutropenia (9%), and hypophosphatemia (6%). To date, we have enrolled 39 pts at dose level 2, and 35 have completed one cycle (84 days). Four pts were not evaluable. Twelve pts have achieved objective response (39%; 9 PR, 3 CR) with a median time to response of 81 days (55-96). The median PFS has not been reached with a median follow-up of 437 days (30-1428). Preliminary results show decreased Tregs and monocytic MDSCs following treatment and suggest an association of increased CD14+/CD86+ and CD14+HLADR+cells with objective response. Conclusions: The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells (R21CA137649; U01CA70095). Clinical trial information: NCT01038778.