Background: Standard treatment for patients (pts) with LARC consists of chemoradiation followed by surgery. To achieve higher response rates and reduce risk of recurrence, further optimization is needed. Veliparib (ABT-888), a potent orally bioavailable PARP1/2 inhibitor, has been shown to enhance antitumor activity of chemotherapy and radiotherapy (RT) in preclinical models. Herein, we present the final results from a phase Ib dose-escalation study (NCT01589419) of veliparib plus capecitabine (C) and RT (C/RT) in pts with LARC. Methods: Stage II/III rectal cancer pts ( ≥ 18 years) received C (p.o. 825 mg/m² BID) and RT (1.8 Gy QD) for approx. 5.5 weeks (5 days/week). Veliparib (p.o. 20–400 mg BID) was administered from day 2 until 2 days after RT (7 days/week). Pts underwent surgery 5–10 weeks after RT. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib plus C/RT, using an exposure-adjusted continual reassessment method. Safety, pharmacokinetics (PK), and antitumor activity were also assessed. Results: As of 23 Nov 2014, 32 pts (81% male, median age 57 years) received study treatment (veliparib < 400 mg, n = 16; 400 mg, n = 16). Most common adverse events possibly or probably related to treatment were fatigue (41%), nausea (41%), diarrhea (25%), and vomiting (22%); grade 3/4 events were diarrhea (n = 2), anemia, lymphopenia, and pulmonary embolism (n = 1 each). Dose-limiting toxicities (grade 2) occurred in 2 pts: radiation skin injury, and nausea and vomiting, at 70 and 400 mg veliparib, respectively. The MTD was not reached. The RP2D for veliparib was 400 mg BID. Veliparib (20–70 mg BID) PK was dose proportional, with no clear impact on the PK of C. Postsurgery tumor downstaging was observed in 72% of 32 evaluable pts; 28% achieved a pathologic complete response. Sphincter-sparing surgery was performed in 70% of 30 evaluable pts. Conclusions: Veliparib plus C/RT had an acceptable safety profile in LARC pts and the RP2D is 400 mg BID. Veliparib showed a dose-proportional PK profile and no effect on the PK of C. The combination treatment showed promising preliminary antitumor activity. Clinical trial information: NCT01589419