Abstract OT3-02-09: Phase II pre-surgical window trial of telapristone acetate (TPA) in early breast cancer and DCIS patients: Distribution of TPA in plasma, normal breast tissue and tumors

Abstract

Abstract Background:In vitro and preclinical data support the notion that anti-progesterone therapy will have activity against both estrogen and progesterone receptors (ER/PR) positive and negative breast cancer, but biomarkers of efficacy may differ in different types of breast cancer. We have conducted a pre-surgical window trial of oral telapristone acetate (TPA, CDB-4124) treatment in early breast cancer patients. This first ever trial of oral TPA for breast cancer and DCIS patients will provide us pilot biologic data that will help select the right population and the right biomarkers for future trials. Here we report distribution of TPA in plasma and breast normal tissue and tumors collected at surgery. Methods:our trial was a 1:1 randomized, double-blind, and placebo-controlled pre-surgical window trial of oral TPA 12mg (Proellex, CDB-4124, Repros Therapeutics Inc.) treatment for 2-10 weeks. 70 pre and postmenopausal women undergoing surgery for Stage 0-II breast cancer were recruited to the study. The surgical samples of 61 patients were used to determine the concentrations of TPA and its mono-demethylated metabolite (dTPA, CDB-4453) in plasma and matched normal tissue and tumor by Liquid chromatography–tandem mass spectrometry at the Illinois Institute of Technology, while maintaining the blind for the primary endpoint of cell proliferation. Statistical significance and analysis were calculated by Wilcoxon matched-pairs signed rank test and non-parametric Spearman correlation. Results: We found that 32/61 women displayed detectable plasma concentrations of TPA and dTPA (median with IQR) 109ng/mL (71.3, 216) and 46.5 ng/mL (34.2, 73.7), respectively. TPA concentration was 2.3 times higher than dTPA in plasma (p<0.0001). The normal and tumor tissue samples of these 32 women were further analyzed. In normal tissue samples, the concentrations of TPA and dTPA were 283 ng/g (70.7, 326) and 51.0 ng/g (24.4, 122), respectively. TPA concentration was 5.5 fold higher than dTPA in normal tissue (p<0.0001). In tumors, the TPA and dTPA concentrations were 137 ng/g (31.1, 278) and 36.4 ng/g (17.3, 68.7), respectively. TPA concentration was 3.8 fold higher than dTPA in tumors (p<0.0001).Interestingly, TPA and dTPA were more abundant in normal tissue than in tumors (p=0.0005 for TPA, and p=0.0013 for dTPA). We found that TPA and dTPA was highly correlated in plasma (r=0.492, p=0.0042). Plasma TPA concentration was highly correlated with normal tissue concentration (r=0.61, p=0.0003) but non-significantly correlated with tumor concentration (r=0.32, p=0.147). However, the normal and tumor tissue concentrations of TPA and dTPA were highly correlated (r=0.71, p=0.0002 for TPA and r=0.556, p=0.0072 for dTPA). Conclusions: Plasma TPA concentrations reflect concentration in normal breast tissue better than in tumors. However, within the breast, TPA concentration in normal and tumor tissue is correlated. Our trial is to be unblended shortly, and we plan to relate these results to the proliferative rates in tumor and normal tissue. The variability observed in plasma and tissue concentrations also suggests that pharmacogenomics studies may be appropriate in the future. Citation Format: Lee O, Muzzio M, Ivancic D, Rogers C, Allu S, Khan SA. Phase II pre-surgical window trial of telapristone acetate (TPA) in early breast cancer and DCIS patients: Distribution of TPA in plasma, normal breast tissue and tumors [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 OT3-02-09.