Background: Patients (pts) with LARC treated with neoadjuvant RT/C and then surgery have significant relapse rates with low rates of complete response. V is a potent, orally bioavailable PARP inhibitor that has been shown to enhance the efficacy of chemotherapy and RT in preclinical models. This study sought to establish the recommended phase 2 dose (RPTD) as well as to assess safety, pharmacokinetics (PK), and preliminary activity of V + RT/C in pts with LARC. Methods: Pts with stage II-III rectal cancer received RT (50.4Gy/1.8Gy/fraction) with C (825 mg/m²BID) five days per week (W) for 5.5W. Dosing of V (BID, 20mg-400mg) continued from W1D2 to 2 days past RT. Pts underwent surgery 5-10W following RT. Assessments include identification of RPTD with the Exposure Adjusted Continual Reassessment Method, adverse events (AEs), PK, and pathological response: no disease present on pathologic review (ypCR), microscopic disease only (yCR), and tumor downstaging. Results: As of Dec 8, 2013, 18 pts have been enrolled, 12/6 male/female, median age 55 yrs; 1 pt discontinued due to an AE. The most common treatment-emergent AEs (>20% pts, n ≥ 4) were diarrhea (39%), nausea (39%), fatigue (33%), radiation skin injury (33%), dysuria (22%), and constipation (22%). One Grade 3/4 event of diarrhea and one post-operative event of anastomosis dehiscence were deemed at least possibly related to V. One dose limiting toxicity (DLT) occurred at 70mg BID V (radiation skin injury requiring dose interruption); 1 pt at 400 mg BID described ongoing intolerable nausea not meeting the criteria of a DLT. The RPTD is 400 mg V in combination with RT/C. PK results from 16 pts suggest that V PK was approximately dose proportional when administered with RT/C and that V had no effect on the PK of C. To date, 11/15 (73%) pts have been downstaged post-surgery; with 4/16 (25%) ypCR and 4/16 (25%) yCR. Conclusions: V at 400 mg in combination with RT/C has an acceptable safety profile, and the combination will move forward in an expanded cohort to better define toxicity and efficacy. Escalations of V resulted in approximately dose proportional increases in the V PK with no clear effect on C PK. Clinical trial information: NCT01589419.