Phase I study of ABT-888 in combination with carboplatin and gemcitabine in subjects with advanced solid tumors.

Abstract

2584^ Background: Veliparib (V) is an oral inhibitor of poly(ADP-ribose) polymerases (PARP)-1 and -2, which are essential for base excision repair of ssDNA breaks. BRCA deficient tumors are more sensitive to PARP inhibitors when used as monotherapy or in combination with DNA-damaging agents. The objectives of this study were to determine the maximum tolerated dose (MTD), pharmacokinetic interactions, and safety/tolerability profile of V in combination with carboplatin (C) and gemcitabine (G). Methods: Eligibility criteria included patients (pts) with metastatic or unresectable solid tumors for which C/G was a treatment option. During the study, eligibility was amended to limit prior chemotherapy regimens to ≤ 2. C AUC 4 /G 800 mg/m2was given intravenously on Day 1 and G given on Day 8 of 21 day cycles. To assess tolerability of C/G prior to V, V was started in Cycle 2. When C/G was stopped, pts could stay on monotherapy V until progression. Dose-escalation used a Bayesian continual reassessment method. Results: 59 pts (51 female, median age 52) were enrolled. The most common tumor types were ovarian (n=39) and breast (n=10). Germline BRCA mutations were known in 24 ovarian pts. 58 pts had prior chemotherapy (1-6 regimens, median 2), and 51 had prior platinum. Grade 3/4 AEs in >10% of pts were neutropenia, thrombocytopenia, anemia, and leukopenia. Dose limiting toxicities were thrombocytopenia (n=3) and neutropenia at V 310 mg twice daily (BID) and thrombocytopenia at 250 mg BID. Other frequent AEs were nausea, constipation, and fatigue. Preliminary results showed co-administration of V did not affect C or G pharmacokinetics. Treatment cycles (range, median) were 1-28, 5 for V; 2-10, 5 for C; and 2-10, 4 for G. Day 8 G was stopped in some pts to improve tolerability. 28 pts stayed on monotherapy V (1-23 cycles). Partial and complete responses were seen in 11 and 2 pts. Response rates were 47% (8/17) in known BCRA deficient ovarian, 25% (3/12) in other ovarian, and 13% (2/15) in other evaluable pts. Conclusions: V combined with C and G was tolerated with a safety profile similar to C and G alone. The MTD was V 250 mg BID, C AUC 4.0, G 800 mg/m2. Promising anti-tumor activity was observed in BRCA deficient ovarian pts. Clinical trial information: NCT01063816.