Abstract OT2-01-12: ENCORE 602: A randomized, placebo-controlled, double-blind, multicenter phase 2 study (with a phase 1b lead-in) of atezolizumab with or without entinostat in patients with advanced triple negative breast cancer (aTNBC)
Authors: Forero A , Stroyakovskiy D , Cha E , Cruickshank S , Hasapidis J , Meyers ML , Slamon DJ 
Published: March 2017

Background: Atezolizumab, a humanized anti-PDL1 antibody, has shown encouraging single agent activity in triple negative breast cancer. Entinostat is an oral, class I selective histone deacetylase (HDAC) inhibitor. In animal models, entinostat has been shown to selectively reduce immunosuppressive myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), enhancing response to immune checkpoint blockade. It is hypothesized that entinostat in combination with atezolizumab will show improved efficacy compared to atezolizumab alone.

Trial Design: ENCORE 602 is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in patients with aTNBC. The study has 2 phases: an open-label Dose Determination Phase (Phase 1b) followed by Phase 2. The objective of the Dose Determination Phase is to establish the recommended Phase 2 dose (RP2D) of weekly entinostat when given in combination with atezolizumab 1200 mg every 3 weeks. Phase 2 will evaluate the efficacy and safety of entinostat at the RP2D with atezolizumab in patients with aTNBC in a randomized (1:1), double-blind, placebo-controlled setting. The randomization will be stratified by geographic location (US vs ex-US).

Key Eligibility Criteria: Eligible patients will have 1) histologically- or cytologically-confirmed triple negative breast carcinoma that is either metastatic (stage IV of the TNM classification) or locally recurrent and not amenable to local curative treatment, 2) measurable disease based on imaging studies within 28 days before the first dose of study drug, and 3) received 1-2 prior lines of systemic therapy for locally recurrent and/or metastatic disease. Previous treatment with a PD-1/PD-L1-blocking antibody or a HDAC inhibitor is not permitted.

Specific Aims: In Phase 2, the primary endpoint is progression free survival (PFS), as assessed by the investigators using RECIST 1.1. Secondary endpoints include PFS by immune response RECIST (irRECIST), overall response rate, clinical benefit rate, overall survival, safety, and duration and time to response for those patients achieving a complete or partial response. Exploratory endpoints include PK, protein lysine acetylation, and immune correlates.

Statistical Methods: The primary analysis of PFS will be performed using a stratified log-rank test. Estimation of the hazard ratio for treatment effect will be determined using a stratified Cox proportional hazards model. 60 PFS events are estimated to provide 80% power to detect the targeted improvement in PFS with one-sided significance level of 0.1. An independent data safety monitoring board will meet at regular intervals to oversee trial conduct and patient safety.

Accrual: Up to 88 evaluable patients are anticipated if the study completes all phases of evaluation (6-18 patients in Phase 1b, 70 patients in Phase 2). The study was activated in May 2016 (NCT02708680).

Citation Format: Forero A, Stroyakovskiy D, Cha E, Cruickshank S, Hasapidis J, Meyers ML, Slamon DJ. ENCORE 602: A randomized, placebo-controlled, double-blind, multicenter phase 2 study (with a phase 1b lead-in) of atezolizumab with or without entinostat in patients with advanced triple negative breast cancer (aTNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-12.