Abstract
147 Background: The PARP inhibitor, ABT-888 is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. The sensitizing effects of ABT-888 are magnified when cancer cells harbor underlying defects in DNA repair mechanisms, such as BRCA2 mutations. Methods: We have initiated a Phase I/II trial, and we present here the data from the Phase I portion. Patients (pts) with MPC who had any number of prior therapies were eligible. A standard 3+3 dose escalation of ABT-888 was employed, in cohorts of 40, 60, 80, 100, 150, 200, 250, and 300mg orally twice a day, days 1-7 of a 14 day cycle. Pts also received 85mg/m2 of Ox, 400mg/m2 of 5-FU, and 400mg/m2 of leucovorin on Day 1, and 2400mg/m2 of 5-FU continuous infusion Days 1-3. Restaging studies were performed every 4 cycles. The primary objective was to determine the Recommended Phase II Dose (RP2D) of ABT-888 combined with 5-FU and Ox. Secondary clinical objectives included an assessment of the pharmacokinetics (PKs) of ABT-888 metabolism, as well as response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Between 01-2011 and 09-2012, 22 pts received treatment. 55% were male; median age = 64, most with an ECOG PS of 1. 55% were previously untreated. The first 6 pts experienced persistent ≤Grade 2 myelosuppression, primarily thrombocytopenia, prompting an amendment to drop the 5-FU bolus. In the latter 16 pts, the combination of ABT-888 plus 5-FU and Ox was well tolerated, with no DLTs. The RP2D is expected to be 300mg BID of ABT-888, with the final analysis including ABT-888 PKs to be presented. For the 22 pts, the RR was 14%, and the PFS and OS were 2.9 and 5.4 months, respectively. Of the 11 previously untreated pts, the RR was 18%, and the PFS and OS were 4.3 and 7.7 months, respectively. 2 pts with deleterious mutations in BRCA2 were included: Pt 6 had a PR and remains on study after 17 months; Pt 14 had a CR and a normalization of CA 19-9, and is still on treatment after 10 months. Conclusions: The combination of ABT-888, 5-FU, and Ox is safe and well tolerated. The combination has demonstrated promising efficacy in MPC, particularly in pts with BRCA2 gene mutations. Clinical trial information: NCT01489865.
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