Background: Only 15% of patients with pancreatic ductal adenocarcinoma (PDAC) are eligible for resection. Patients with locally advanced PDAC may become candidates for surgery following donwstaging with neoadjuvant therapy. PDAC often exhibits a high degree of desmoplasia, characterized by extensive connective tissue stroma. FG-3019 is a recombinant human monoclonal antibody that binds to connective tissue growth factor and significantly reduces tumor growth, neovascularization, and metastases in mouse models of PDAC. Therefore, FG-3019 may change the fibrotic character of PDAC to one more amenable to resection. In a phase I trial of stage III/IV patients, FG-3019 did not add toxicity when combined with gemcitabine and erlotinib. Methods: Phase 1/2, randomized, open-label trial to evaluate safety and tolerability of gemcitabine plus Nab-paclitaxel with FG-3019 or gemcitabine plus Nab-paclitaxel in subjects with locally advanced, unresectable PDAC (clinicaltrials.gov #NCT02210559). Primary endpoint is treatment-related adverse events. Secondary endpoints include R0 resection rate, surgical complications, tumor response, and survival. Patients with biopsy-proven PDAC are included following radiographic and laparoscopic confirmation of irresectability and no metastases. Sample size of 40 is based on clinical judgment for initial exploration of safety, tolerability, and treatment effect. Each cycle is 28 days and subjects receive up to six cycles of treatment. Those who complete treatment undergo resection based on the following criteria: reduction in CA 19-9 level by more than 50%, FDG-PET SUV_max decrease by >30%, or radiological tumor response per RECIST to meet the definition of resectable or borderline resectable. Safety will be assessed through adverse event monitoring, clinical laboratory testing, ECG, ECOG performance status, vital signs, and physical exam until 28 days after the last FG-3019 infusion. All resected subjects will be followed for 30 days after discharge and undergo safety assessment per standard of care. Since the trial opened in 8/2014, we have enrolled 1/40 patients. Clinical trial information: NCT02210559