Abstract OT2-1-06: E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer
Authors: Connolly Roisin M , Zhao Fengmin , Miller Kathy D , Tevaarwerk Amye J , Wagner Lynne I , Lee Min-Jung , Murray Judy , Gray Robert , Piekarz Richard L , Zujewski Jo Anne A , Sparano Joseph A 
Published: May 2015

Abstract
Background:
Epigenetic alterations in the genome, including abnormal DNA methylation and histone hypoacetylation, initiate and promote cancerous changes. A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. Results from ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression on a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), the primary endpoint, and overall survival (OS), an exploratory endpoint. Based on the OS results, entinostat has been designated a Breakthrough Therapy by the FDA when used in combination with exemestane in HR-positive advanced breast cancer.
Trial design:
E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer who have experienced disease progression on a NSAI (n=600). Patients will receive exemestane 25mg po daily and entinostat/placebo 5mg po every week (28 day cycle). Staging every 12 weeks.
Eligibility Criteria:
Postmenopausal women and men (≥ 18 years), ECOG performance status 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy. Prior CDK inhibitor or everolimus permitted, but not exemestane or fulvestrant. One prior chemo permitted in metastatic setting.
Specific Aims:
Both PFS (defined by central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence.
Statistical Methods:
One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months)
Present and Targeted Accrual: This study was activated in March 2014 and accrual is anticipated to complete in 40 months.
Contact Person: Dr. Roisin Connolly, Email: rconnol2@jhmi.edu
Funding: ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute, and Syndax Pharmaceuticals.
Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Amye J Tevaarwerk, Lynne I Wagner, Min-Jung Lee, Judy Murray, Robert Gray, Richard L Piekarz, Jo Anne A Zujewski, Joseph A Sparano. E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-06.