Background: FFX is under study in LAPC for its potential for curative resection, but the downstaging rate remains low. Preclinical data suggest that inhibition of the renin-angiotensin system with losartan reduces TGF-b1 activity, enhancing intratumoral penetration of chemotherapy by remodeling desmoplasia and improving perfusion. This study investigated the R0 resection rate of FFX/losartan in LAPC. Methods: LAPC pts (per NCCN criteria), ECOG PS 0-1 were enrolled in a single institution NCI-sponsored phase II study (NCT01821729). Pts received 8 cycles FFX/losartan. 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 the tumor still abutted vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. Primary endpoint was R0 resection rate. Secondary endpoints were mPFS, mOS and circulating biomarkers of losartan activity. Results: 50 pts enrolled from 8/2013 to 7/2017. One pt withdrew consent, and 49 pts were evaluable for this analysis. Median age was 63y (42-78), tumor size was 41mm (18-68). Tumor was in the pancreatic head in 31 (63%) of pts. 39 pts received 8 cycles of FFX/losartan, while 10 had fewer than 8 cycles due to progression (4), losartan intolerance (3), and toxicity (3). Grade 3 or greater toxicity occurred in 25 (51%) pts, including diarrhea , thrombocytopenia, nausea, and neutropenia/febrile neutropenia. No single grade 3+ toxicity occurred in more than 14% of pts. 46 pts recieved CRT: 7 pts (14%) had short-course, while 39 pts (80%) had long-course CRT. 39 pts underwent attempted surgery, with 34 pts resected. R0 resection was achieved in 30 pts (61% of evaluable pts, 88% of resected pts), with R1 resection in 4 pts. Overall mPFS was 17.5 months and mOS 31.4 months. Among resected pts, mPFS was 21.3 months and mOS was 33.0 months. Biomarker analysis showed superior OS in pts with lower plasma levels of HGF at baseline. Conclusions: FFX/losartan achieved a remarkably high (61%) R0 resection rate in LAPC pts. A multi-center randomized Phase II trial is planned. Clinical trial information: NCT01821729