P1-17-04: Phase I Study of PARP Inhibitor ABT-888 (Veliparib) in Combination with Cisplatin and Vinorelbine for Patients with Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer.

Abstract

Abstract Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown preclinical and clinical activity in targeting tumors with pre-existing DNA repair defects, in particular BRCA1 and BRCA2 deficient tumors. Cisplatin (CP) has demonstrated synergy with ABT-888 (veliparib) in breast cancer xenograft models and has anti-tumor activity in triple negative (TN) and BRCA-1 deficient breast cancer. Vinorelbine (V) combined with CP has shown safety and efficacy in patients with pretreated metastatic breast cancer. Methods: We are conducting a phase I study to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic profiles (PD), and preliminary anti-tumor activity of veliparib in combination with CP and V in patients (pts) with metastatic breast cancer who are either TN or who have BRCA1 or BRCA2 mutation associated breast cancer. Cohorts receive escalating doses of ABT-888 orally BID days 1–14, CP 75 mg/m2 intravenously (IV) day 1 and V 25 mg/m2 IV days 1,8 every 21 days, in a 3+3 design. Results: As of 6/14/11, 18 eligible female pts have been enrolled. The median age at registration was 50 years (range 34–78 years). Sixteen pts received at least one prior metastatic regimen (range 0–8). Three pts had previously treated brain metastases. BRCA mutation status was as follows: BRCA1+ (3 pts); BRCA2+ (2 pts); confirmed mutation negative (8 pts); unknown (5 pts). Four pts received the 20 mg BID veliparib dose (one patient in the cohort died of progressive disease early in cycle 1 and was replaced), 3 received 30 mg BID, 6 received 40 mg BID, and 5 have been enrolled at dose level 4 (60 mg BID). Dose limiting toxicities occurred in one patient at the 40 mg BID dose (grade 4 thrombocytopenia), and one patient at the 60 mg BID dose (grade 3 neutropenic fever). Adverse events are typical for a platinum-based chemotherapy regimen and include nausea, fatigue, thrombocytopenia, and neutropenia. MTD has not been reached. Of 11 pts evaluable for radiographic response to date, 6 (55%) had a PR (3 of whom have a BRCA mutation) and 5 (45%) had stable disease. Correlative studies will use immunohistochemistry and gene expression array to evaluate the profile of TN breast cancer and predictors of response to treatment. Conclusion: Veliparib in combination with CP and V has been generally well tolerated to date. Objective anti-tumor activity was seen in BRCA mutation carriers and in pts with sporadic TN breast cancer. PK, PD, and biomarker analysis is underway. Enrollment continues in the dose escalation cohorts. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-04.