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Background: The majority of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemo-radiation (CRT) is used in this setting in attempt to control regional disease, and possibly downstage to resectable disease. We report a phase I/II trial of a novel combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with regionally advanced disease. Methods: Patients with biopsy-proven borderline resectable or locally advanced unresectable pancreatic adenocarcinoma were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) and oxaliplatin weekly for 5 weeks. Oxaliplatin was escalated from 30mg/m2 in 10mg intervals up to 60mg/m2. Concurrent radiation therapy consisted of 4500 cGy in 25 fractions (180 cGy/fx/d) followed by a conedown to the tumor and margin for an additional 540cGy x3 (total dose 5040 cGy in 28 fractions). Following completion of CRT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (PD) received mFOLFOX6 x6 cycles. Survival was calculated using Kaplan-Meier analysis. End points of the phase II portion were resectability and survival.Results: Fifteen patients were initially enrolled in the Phase I component of the study and all completed neoadjuvant therapy. The highest dose (60mg/m2) of oxaliplatin was well tolerated and this was carried forward in the phase II portion of the study. Grade 4 toxicities were observed during Phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leucopenia and thrombocytopenia). Additional 9 patients were treated in the phase II portion. Overall, 24 subjects (14 men and 10 women, mean age 65 years) were enrolled and received CRT; 12 of the 24 did not complete the treatment. Reasons for not completing treatment included progression (7), withdrawal of consent (2), grade 4 toxicity (3). Following CRT, 8 (33%) patients were deemed possibly resectable and were explored. Two additional patients were found to have PD (carcinomatosis). Four had stable disease (SD) but remained unresectable and 2 (8% of all study subjects) were resected for cure with negative margins. Follow up was available for 23 patients. Median overall survival was 14 months (9 and 15 months respectively for PD and SD). Of the 2 resected patients, one died of disease at 21 months and one is alive without disease at 11 months from trial entry. Conclusions: Combined modality treatment for regionally advanced pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen are comparable to others for locally advanced pancreas cancer.