Phase I/II study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor entinostat in patients with metastatic renal cell carcinoma.

Abstract

TPS4687 Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I specific HDAC inhibitor, entinostat, has synergistic anti-tumor effect in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y et al Clinical Cancer Res 2007). Our group has also recently showed that low dose entinostat induces STAT3 acetylation, down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive function without affecting T effector cells (Shen Li et al PLoSONE 2012). Methods: Based on these preclinical evidences we have initiated a Phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic renal cell carcinoma. The primary objective of the study is to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria are clear cell histology, no prior treatments and being fit to receive high dose IL-2. The Phase I portion consists of two dose levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 (600,000 units/Kg every 8 hrs.) according to a 3+3 design. The sample size of 36 patients in the Phase II portion is powered to detect an increase in objective response rate from 20% to 40% as compared to historical data with high dose IL-2 alone. Correlative studies include assessment of CD4+, CD8+, CD4+/Foxp3, NK cells in tumor and blood samples by immunohistochemistry and FACS analysis, and tumor metabolism by FDG PET. We are also exploring the relationship between entinostat exposure with pharmacodynamic endpoints. To date dose level one has been completed without DLT. Enrollment to dose level two has begun in the Fall 2011. The results from this study may confirm the role of entinostat in enhancing the effect of IL-2 and may be translated into other combination strategies involving immunotherapies. The clinical trial and correlative studies are supported by the National Cancer Institute- R21CA137649.