Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 weeks followed by weekly evaluation for an additional 3 weeks. G (1000 mg/m2) is administered on days 1, 8, 15. RT (36 Gy) is given in 15 fractions (2.4 Gy/day). V is administered BID in 20 mg increments beginning at a dose of 20 mg. Inclusion criteria: histolopathological diagnosis of borderline resectable or LAPC, age > 18 years, KPS > 70%, life expectancy > 6 months, normal organ and marrow function, and negative pregnancy test. Dose escalation follows a Bayesian escalation without control (EWOC) design, where time to DLT is modeled using a proportional hazards model with constant baseline hazard rate. Secondary objectives: 1) measure clinical activity using RECIST 1.1 for PFS, OS; 2) evaluate pre-treatment tumor biopsy specimen and longitudinal blood samples for baseline levels of DNA repair proteins (ERCC1, XRCC1, PAR, etc.) as potential prognostic, predictive and correlative biomarkers; and 3) assess BRCA1/2, PALB2, PTEN germline and somatic mutations using validated gene sequencing, immunohistochemical and quantitative PCR methods. Since December 2013, 26 patients have consented with 22 enrolled. Clinical trial information: NCT01908478