A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer.

Abstract

1019 Background: Veliparib (ABT-888) is a novel oral inhibitor of Poly (ADP-Ribose) Polymerase (PARP) 1 and 2. Veliparib and temozolomide (TMZ) are synergistic in breast cancer xenograft models. TMZ has minimal activity in breast cancer likely due to robust repair methylated DNA adducts by the base excision repair (BER) pathway and MGMT. We hypothesized that combining veliparib with TMZ would be active in metastatic breast cancer (MBC). Methods: We conducted a single arm phase II trial of veliparib and TMZ in 41 MBC patients (pts). Eligibility included measurable MBC, >1 prior MBC therapy, and PS ≤ 2; previously treated stable brain metastases were allowed. Available archived tumor samples were collected. The initial Simon 2 stage design was modified to a single stage (n=41) due to rapid accrual. Patients received veliparib (40 mg PO BID days 1-7) and TMZ (150mg/m2 PO QD days 1-5) on a 28 day cycle. After higher than expected grade 4 thrombocytopenia was observed, the dose of veliparib was reduced to 30 mg BID. RECIST response was evaluated every 2 cycles. The primary endpoint was overall response rate. Secondary endpoints included PFS, OS, safety, and toxicity. Results: Between November 4, 2009 and December 28, 2009, 41 eligible pts (median age 51; range 32-67) were enrolled. At abstract submission, baseline characteristics for 35 evaluable pts include: median PS=0 (range 0-2); triple-negative (n=15), HER2+(n=5), and ER+/HER2- (n=15) subtypes; prior CNS disease (n=4). Toxicities: the most common grade 3/4 toxicities included thrombocytopenia (3 grade 3, 4 grade 4), and neutropenia (2 grade 3, 2 grade 4). Best response for 24 patients evaluable at the time of abstract submission includes 1 CR, 2 PR, 7 SD (all unconfirmed), and 14 PD; 17 pts are not yet evaluable for response. Conclusions: Combined veliparib and TMZ is active in MBC. Exploratory correlative studies including BRCA mutation analysis are underway to determine predictors of response. The dose and schedule of veliparib suggest the clinical activity seen is not likely due to veliparib alone but rather to the combination. Veliparib and TMZ may be a promising new strategy in MBC. The trial is fully accrued and final efficacy results will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Abbott Laboratories