Abstract OT1-05-01: A pilot study of the combination of entinostat with capecitabine in metastatic and high risk breast cancer after neoadjuvant therapy
Authors: Millard TA , Wages NA , Petroni GR , Brenin CM , Dillon PM 
Published: May 2019

Abstract
Background:
HDAC inhibitors (HDACi) upregulate thymidine phosphorylase resulting in enhanced conversion of capecitabine to active 5-fluorouracil and in synergistic anti-proliferative effects. HDACi's down regulate thymidine synthase and may prevent resistance to fluoropyrimidines. Entinostat is a well-tolerated class I HDACi in phase III trials for metastatic breast cancer.
Specific Aims:
The primary objective is to determine the maximum tolerated dose combination (MTDC) of entinostat and capecitabine in participants with metastatic breast cancer. It is hypothesized that entinostat and capecitabine is a synergistic, safe, and tolerable combination.
An expansion phase will assess the safety of the MTDC from Part A in participants with high risk breast cancer after neoadjuvant therapy. The expansion phase will generate a preliminary estimate of disease-free survival. Exploratory objectives include estimates of the association of volume of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) with the presence of residual disease and if it decreases following treatment with the combination of entinostat and capecitabine.
Trial Design:
The dose escalation phase (Part A) will accrue participants with metastatic breast cancer using an adaptive design to determine the MTDC. The starting doses will be entinostat 3mg po weekly and capecitabine 800mg/m2 po bid, 14 days on and 7 days off with 21 day cycles. Patients will be monitored for toxicity and adverse events. The MTDC is defined as the dose combination with DLT rate closest to the target DLT rate of 25%.
The expansion phase (Part B) will accrue breast cancer participants with residual invasive disease after neoadjuvant therapy starting at the MTDC estimated in Part A. The adaptive modeling design will be used in Part B to establish the MTDC in this patient population. Participants will be treated with the MTDC for a total of 8 cycles.
Blood samples will be obtained from all enrolled patients in the expansion phase prior to the start of adjuvant treatment with entinostat and capecitabine so that ctDNA and CTCs can be measured as correlative studies. Measurements will be repeated at the end of the eighth cycle.
Eligibility Criteria:
Part A: Dose Escalation Phase: Stage IV breast cancer patients; Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 year and older
Part B: Expansion Phase: Stage I-III high risk breast cancer patients; Completed at least four cycles of neoadjuvant taxane or anthracycline based chemotherapy; Residual invasive disease (ypT1a or greater) or known positive lymph nodes (ypN0(itc) or greater); Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 years and older
Statistical Methods:
The trial is designed to determine the MTDC, defined by acceptable toxicity of the combination, for two study populations. A Bayesian adaptive design is being used to guide accrual decisions based on the occurrence of DLTs, and the minimum follow-up period for determination of escalation is 3 weeks.
Accrual:
Maximum target accrual is 55 participants. Accrual is estimated at 1-2 participants per month.
Contact Info:
Trish Millard, MD
tas9g@virginia.edu
Citation Format: Millard TA, Wages NA, Petroni GR, Brenin CM, Dillon PM. A pilot study of the combination of entinostat with capecitabine in metastatic and high risk breast cancer after neoadjuvant therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-05-01.