Phase I study of veliparib in combination with gemcitabine.

BACKGROUND: Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine.

METHODS: Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated.

RESULTS: Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥ 3 adverse events were myelosuppression-related. The MTD was determined to be 750-mg/m2 gemcitabine IV on days 1 and 8- and 20-mg PO veliparib BID days 1-14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy.

CONCLUSIONS: Gemcitabine at 750-mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20-mg PO BID days 1-14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting.