A multi-institutional double-blind phase II study evaluating response and surrogate biomarkers to carboplatin and nab-paclitaxel (CP) with or without vorinostat as preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer (TBCRC008).

Abstract

TPS111 Background: Traditionally, systemic treatment recommendations for women with breast cancer have been based on clinicopathologic factors following definitive surgery. PST allows for improved surgical outcomes and assessment of response without compromising long- term outcomes. Chemotherapy is currently the most effective treatment for women with triple-negative (ER-, PR-, HER2-) or luminal type B breast cancers. Many women suffer recurrence and death despite optimal chemotherapy, emphasizing the need for new strategies. Epigenetic modifiers may sensitize tumors to chemotherapy and enhance outcomes. We hypothesized that preoperative CP combined with the histone deacetylase inhibitor vorinostat is a better option than CP alone in women with triple-negative or luminal type B breast cancer who are candidates for PST. Methods: This study includes both a run-in phase to investigate the safety of 12 weekly doses of C (AUC 2) and P (100 mg/m2) with vorinostat 400mg po daily (first 3 out of every 7 days) in women with unresected stage II-III HER2-negative breast cancer and a randomized phase II portion. Eligible women are stratified by hormone receptor status and randomly assigned in a 1:1 ratio to CP plus placebo or vorinostat. The primary endpoint is rate of pathologic complete response (pCR) with secondary endpoints including correlation of baseline and change in standardized uptake values on positron emission tomography with pCR and clinical CR, evaluation of safety and long-term outcomes. Exploratory endpoints include comparison of pCR and clinical CR in women with triple- negative/basal-like features versus those without and evaluation of baseline and change in candidate gene methylation, gene expression and histone acetylation in tumor tissue. A sample size of 31 patients per arm will enable detection of a 25% pCR rate from a null response rate of 10% using a Simon two-stage design with 80% power and a 10% type I error rate. To date, 6 women have completed the run-in phase without dose-limiting toxicities and one woman has completed the phase II portion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth AstraZeneca Abraxis BioScience, Merck, Novartis, Pfizer