Background: Veliparib is a potent, oral PARP inhibitor that inhibits DNA repair, primarily through single strand break repair. BRCA1/2 mutated tumors are defective in homologous recombination, leading to more error prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Veliparib and TMZ recently demonstrated promising activity in BRCA1/2 mutation carriers, and veliparib and C/P is being evaluated in a CTEP Phase 1 study. This Phase 2 multinational study will evaluate veliparib in combination with TMZ and in combination with C/P compared to an active, placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer.

Methods: Approximately 240 subjects will be randomized in a 1:1:1 ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150–200 mg/m2 QD D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 + C (AUC 6, D3) and P (175 mg/m2, D3) of every 21 day cycle or 3) placebo BID D1-7 + C/P. Key eligibility includes known deleterious BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and no prior platinum agent. Randomization will be stratified by hormone receptor positive versus negative, prior vs. no prior cytotoxic therapy, and ECOG 0–1 vs 2.

The primary objective is progression-free survival (PFS) using RECIST 1.1. Secondary objectives include overall survival, objective response rate, duration of response and safety/tolerability. Optional paired tissue biopsies will be obtained at baseline and at progression to evaluate markers of response and resistance. Additional correlatives for response include assessment of peripheral blood, CTCs, and archived tissue for markers of disease status, gene methylation and mutational status, and tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. Using the log-rank test for PFS, with 150 PFS events the study will have ≥ 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect assuming a true hazard ratio of 0.58 favoring the 2 treatment groups containing veliparib. As of June 11, 2012, 5 subjects have been enrolled.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-07.