A phase I study of veliparib (ABT-888) in combination with weekly carboplatin and paclitaxel in advanced solid malignancies and enriched for triple-negative breast cancer (TNBC).

Abstract

1015 Background: Veliparib (ABT-888) is an oral, potent small molecule inhibitor of poly-ADP-ribose polymerase (PARP). The combination of veliparib (V) with carboplatin (C) and paclitaxel (P) dosed every 3 weeks has been shown to be safe with early signs of efficacy in a phase I study conducted by our group. In breast cancer patients (pts), weekly P improves disease-free and overall survival vs. every three week P with comparable safety (ECOG 1199), thus supporting the exploration of weekly C and P in combination with V. This study is designed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), adverse events (AEs), anti-tumor activity, and pharmacokinetic (PK) parameters of this combination. Methods: A standard 3+3 design was used with 4 escalating V dose levels ranging from 50-200 mg bid. C (AUC 2) and P (80 mg/m2) were administered on a weekly basis over a 21-day cycle on all dose levels. Dose escalation was followed by dose expansion in pts with TNBC with mandatory tumor biopsies. Results: A total of 30 pts were enrolled (median age 52 yr [range 33-83]; 27 female; median prior treatments 3 [range 0-8]; 24 breast [22 TNBC], 2 lung, 1 cervix, 1 ovarian, 1 prostate, 1 gastric). DLTs occurred at the following dose levels: prolonged gr 2 thrombocytopenia at 150 mg bid, and gr 4 neutropenia at 200 mg bid. The RP2D of veliparib was established to be 150 mg bid. The most common all-grade and grade 3/4 AEs included: neutropenia (gr 3/4 in 18 pts [60%]), anemia (gr 3/4 in 5 pts [17%]), and thrombocytopenia (gr 3/4 in 3 pts [10%]). PK parameters of V in this trial were comparable to historical single-agent V. Of the 27 evaluable pts, 13 (48%) responded (1 CR, 12 PR), 10 (37%) had SD, and 4 (15%) had PD. Objective response rate in TNBC was 52%. Among 21 evaluable TNBC pts, response was 60% in BRCA1/2+ pts (3/5 PR), 67% in non-BRCA1/2 pts (1/9 CR; 5/9 PR) and 29% in unknown status pts (2/7 PR). The only ovarian cancer pt was BRCA2+ and had PR. Conclusions: V in combination with weekly C and P was well tolerated with acceptable safety profile. Promising anti-tumor activity was observed, particularly in TNBC. Clinical trial information: NCT01281150.