Background: This phase I/II study evaluates safety and efficacy of veliparib, a PARP inhibitor, with induction carbo-tax in patients (pts) with locoregionally advanced HNSCC. Since PARP is involved in DNA repair, inhibition of PARP may augment damaging effects of chemotherapy on tumor DNA. We report on the completed phase I portion of the trial. Methods: Eligible pts had newly diagnosed stage IVa-b non-oropharyngeal cancer (OPC) or stage IVa-b, human papillomavirus-negative OPC. The primary endpoint is the maximum tolerated dose (MTD) or recommended phase II dose using a 3+3 pt cohort design. Pts received induction carboplatin (AUC 6 day 1), paclitaxel (100 mg/m² day 1, 8, 15), and veliparib (days 1-7) every 21 days for 2 cycles. Veliparib doses were 200, 250, 300 and 350 mg BID. Standard chemoradiotherapy followed induction. Results: 20 pts enrolled. Two withdrew prior to treatment, leaving 18 pts for analysis. Median age was 62.5 years: 50% were female. Primary sites (# pts) included hypopharynx (5), larynx (5), oral cavity (4), oropharynx (3) and nasal cavity (1). The most common grade (gr) 3+ adverse events (AEs) were decreased neutrophil count (33%), decreased platelet count (33%) and anemia (11%). Gr 3+ hematologic AEs were more common at higher veliparib doses. Three pts had gr 4 AEs, all hematologic (1 pt: neutropenia, 1 pt: thrombocytopenia (dose-limiting), 1 pt: both). The recommended phase II dose and MTD for veliparib in combination with carbo-tax is 350 mg. Of 13 pts currently evaluated for response, 9 (69%) had partial or complete response. At an early median follow-up of 16.7 months (mo) across dose levels for all pts, the 12-mo overall survival was 76% (95% CI: 55-100%), and 12-mo progression-free survival was 75% (95% CI: 54-100%). Medians have not been reached. Data for 350 mg is not fully mature. Conclusions: Addition of veliparib 350 mg BID on days 1-7 to carbo-tax was well tolerated in pts with advanced HNSCC. This dose is higher than previously tested in other trials. Hematologic toxicities were the most common AEs. Support: U10CA180821, U10CA180882; Clinical trial information: NCT01711541