A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. Patients and Methods: We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1-7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations. Results: The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and theORRoverall was 26%. There was greater activity in platinum-naive patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naive patients was 57%. Conclusions: The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naive disease that harbors a pathogenic HR-DDR mutation.