Abstract OT2-1-03: A pilot and phase II study of entinostat and anastrozole/tamoxifen in women with triple negative breast cancer (TNBC) to evaluate biomarkers and surrogates for response
Authors: Chumsri Saranya , Sabnis Gauri , Tait Nancy , Lewis Jane , Bellavance Emily , Kesmodel Susan , Feigenberg Steven , Tkaczuk Katherine RH , Ordentlich Peter , Edelman Martin J , Brodie Angela H 
Published: May 2015

Abstract
Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lack ER, PR, and HER2. TNBC is inherently resistant to endocrine therapy (ET) such as aromatase inhibitor (AI) and tamoxifen. Previous studies suggested that the loss of ER/PR expression in TNBC is due to epigenetic silencing. We have demonstrated histone deacetylase inhibitor (HDACi), entinostat, can induce expression of functional ER and render TNBC sensitive to ET both in vitro and in vivo (Sabnis et al. Cancer Research 2011). Furthermore, the combination of entinostat and AI can induce prolonged tumor regression and significantly reduce lung metastasis in vivo.
Trial Design: This is a single arm phase I/II study of entinostat in combination with ET. There are 2 cohorts in this study: cohort 1 – operable stage I-II TNBC, cohort 2 – metastatic and unresectable locally advanced TNBC. For ET, anastrozole will be used in postmenopausal women and tamoxifen in premenopausal women. The treatment regimen is: entinostat started on day 1 followed by ET on day 4. In cohort 1, paraffin embedded tissue from core needle biopsy and surgical specimens will be collected. In cohort 2, biopsies before and after 15-29 days of treatment are required.
Eligibility Criteria: Female age ≥ 18 with ECOG PS ≤ 2 and TNBC defined as ER and PR &lt; 1% with no HER2 overexpression. Cohort 1 includes pts with operable stage I-II and cohort 2 includes pts with metastatic and unresectable locally advanced with ≤ 2 prior lines of chemotherapy who have accessible tumors for biopsies, excluding bone only metastasis.
Specific Aims: To determine ER expression as well as the percentage change in proliferation index (Ki67) after treatment. Moreover, safety and tolerability of the combination given either in neoadjuvant or metastatic setting will be evaluated. Response is defined as ≥ 50% reduction in Ki67 AND ≥ 1% ER-positivity OR pathologic complete response in the post-treatment surgical specimens.
Statistical Methods: For the pilot phase, a 3+3 cohort design is employed. The Simon’s two-stage design is used in the phase II. The total sample size for the phase II is 32 with 12 and 20 pts in the first and second stage respectively. The study will be terminated if there is no response among the first 12 pts. If ≥ 1 response in these 12 pts is observed, then 20 more pts will be accrued. The combination will be considered promising, if ≥ 4 out of 32 pts have a response. This design yields 87% power. The probability of early stopping and declaring that this combination has no sufficient activity is 0.54, if the true success rate is 5% and 0.07 if the true response rate is 20%. If the true proportion of pts with Ki67 reduction combined with ER up-regulation is 0.20, the probability of concluding that the drug has sufficient activity is 0.87 and 0.07 if the true proportion is 0.05. To allow about 10% inevaluability, the phase II trial will accrue 35 eligible pts. Therefore, the total target accrual is 41 pts.
To date, there are a total of 7 pts enrolled. Accrual is currently ongoing. Please contact ntait@umm.edu for further information.
Citation Format: Saranya Chumsri, Gauri Sabnis, Nancy Tait, Jane Lewis, Emily Bellavance, Susan Kesmodel, Steven Feigenberg, Katherine RH Tkaczuk, Peter Ordentlich, Martin J Edelman, Angela H Brodie. A pilot and phase II study of entinostat and anastrozole/tamoxifen in women with triple negative breast cancer (TNBC) to evaluate biomarkers and surrogates for response [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 OT2-1-03.