Background: F-NOX is utilized in LAPC due to improved response over gemcitabine, with theoretical potential for curative resection. However the response rate remains well below 50%. Preclinical data suggest that inhibition of the renin-angiotensin system with losartan reduces the activity of TGF-B1, enhancing intratumoral penetration of chemotherapy by remodeling desmoplastic stroma and improving vascular perfusion. In this study, we evaluate the feasibility of adding losartan to F-NOX in LAPC. Methods: Pts ECOG PS 0-1 with LAPC (NCCN criteria) were enrolled in a single institution, NCI-sponsored phase II study (NCT01821729). Pts received F-NOX/losartan for 8 cycles. If the tumor was radiographically resectable after chemotherapy, pts received short-course chemoradiation (CRT) in 5 fractions (protons 25 GyE, capecitabine 825 mg/m2 bid). If it was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint was proportion of pts remaining progression-free after 8 cycles of F-NOX/losartan. Results: 32 pts were enrolled from 8/2013 to 6/2016. One pt withdrew prior to treatment, 6 pts are still receiving F-NOX/losartan or CRT. 25 were included in this analysis. Median age was 62y (46-75). Median tumor size was 42mm (22-68). Tumor was in the head of the pancreas in 16 (64%) pts. Of evaluable pts, 18 (72%) completed F-NOX/losartan followed by CRT. Reasons for discontinuation included losartan intolerance (3), failure to thrive (2), investigator discretion (1), and progression (1). Grade 3 or greater toxicity occurred in 11 (40%) pts, including diarrhea (4, 16%), thrombocytopenia (3, 12%), nausea (3, 12%), neutropenia (2, 8%), and febrile neutropenia (1, 4%). Two pts (8%) had short course CRT, 16 (64%) had long course CRT. In evaluable pts, 4 remained unresectable while one pt had R1 resection. R0 resection was achieved in 13 (52%). Conclusions: Based on the low discontinuation rate of the F-NOX/losartan combination, it met criteria for feasibility. The high R0 resection rate in the feasibility cohort has prompted expansion as a phase II study with an R0 resection endpoint. Clinical trial information: NCT01821729