A double-blind, randomized, placebo-controlled phase II study of the steroidal aromatase inhibitor exemestane with and without the isoform selective histone deacetylase inhibitor (HDACi) entinostat in metastatic breast cancer (MBC).

Abstract

TPS128 Background: Anti-estrogentherapies, including aromatase inhibitors, are effective in the treatment of MBC patients who are estrogen receptor (ER) positive, but acquired resistance to these agents eventually develops in virtually all patients, leading to disease progression. Decreased ER expression levels and increase in growth factor signaling both contribute to resistance to aromatase inhibitors (Brodie et al 2009 J Steroid Biochem Mol Biol). Preclinically, HDACi reverse ER expression silencing (reviewed in Stearns et al 2007 Cancer Invest) and inhibit the growth factor signaling pathways that drive breast cancer growth (Huang et al 2009 Canc Res). Entinostat is an oral class 1 HDAC selective inhibitor that has been well tolerated to date and may be combined with aromatase inhibitors. The purpose of this ongoing clinical trial is to assess whether the addition of entinostat to the steroidal aromatase inhibitor exemestane can overcome and/or delay the acquired resistance to aromatase inhibitors in MBC. Methods: Post-menopausal females with ER+ MBC progressing on a non-steroidal aromatase inhibitor are eligible for this study. Target patient population consists of 80% of patients having measurable disease with 20% of patients having nonmeasurable disease only. 114 patients (pts) are planned to be randomized in a double-blind, placebo-controlled manner to either exemestane (25 mg QD) + entinostat (5 mg once weekly) or to exemestane (25 mg QD) + placebo. The study is designed to evaluate the hypothesis that the addition of entinostat to exemestane will increase the PFS by 2.3 months. (i.e. 3.7 months with exemestane versus 6 months with combination; 1-sided=10%, power= 80%). Correlative studies include analysis of changes in acetylation and gene expression in peripheral blood monocytes, and levels of circulating endothelial cells before and after initiation of treatment. The study is open in the United States, Hungary, Czech Republic, and Russia and current enrollment is 70% complete. No significant financial relationships to disclose.