A Phase 1 Dose-Escalation Study of Veliparib with Bimonthly Folfiri in Patients with Advanced Solid Tumors.

2574 Background: Veliparib (V; ABT-888), a potent, competitive poly (ADP-ribose) polymerase (PARP)-1 and -2 inhibitor enhances the activity of irrinotecan (IRI). This study seeks to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of V in combination with bimonthly FOLFIRI. Methods: Solid tumorpatients (pts; ≤3 prior DNA-damaging regimens) were administered V BID (days 1-5; 15–19) and FOLFIRI in three parts (P) : (P1) IRI 150 mg/m2; (P2) IRI 180 mg/m2 with 5-FU 400 mg/m2 bolus; or (P3) IRI 180mg/m2. All regimens included folinic acid 400 mg/m2, immediately followed by 5-FU 46-hour continuous infusion. Dose escalation began with V 10 mg BID in P1 and 100 mg BID in P2 and P3. Two expansion cohorts were evaluated in gastric or colorectal cancer pts with no prior PARP inhibitor therapy. Results: 96 pts (median age 54.5 years; range, 24–77) were enrolled in cohorts from 10–300 mg BID V. Tumor types were: other (n=30); gastric (n=20); pancreatic (n=14); ovarian, breast, and colorectal (each, n=9). 88 pts discontinued: 83 due to progressive disease; 2 withdrew consent; and 3 other. Most common AEs (>40% pts) were diarrhea (61%), nausea (60%), neutropenia (59%), vomiting (48%), fatigue (47%), anemia and alopecia (each, 41%). Grade 3/4 AEs (>30 pts) were neutropenia (47%), nausea (38%), and diarrhea (34%). Four DLTs occurred: neutropenia (n=3; P1, 160 mg and 270 mg BID V; P2, 100 mg BID V); and gastritis and vomiting (P1, 270 mg BID V). 12 pts (gastric, n=3; ovarian, breast, pancreatic, and other, each n=2; colorectal, n=1) achieved a partial response and 1 (ovarian) a complete response. V exposure was approximately dose-proportional in combination with FOLFIRI. FOLFIRI PKs were comparable with or without V administration, indicating the lack of drug-drug interaction. Conclusions: V in combination with chemotherapy was generally well-tolerated without drug-drug interactions. Ovarian and breast cancer pts experienced the greatest anti-tumor activity with an objective response rate of 33% and 22%, respectively. The RPTD was 200 mg BID V with bimonthly FOLFIRI (IRI 150 or 180 mg/m2 without 5-FU bolus). This study supports further evaluation of V in combination with FOLFIRI in specific tumor types. Clinical trial information: NCT01123876.