TPS630 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE is an open-label, non-randomized, phase II trial to assess the efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase < 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase > 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI of 0.41 - 076. To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. We are collecting tumors to correlate deep multi-omic analytics with clinical data. The study is open with 6 patients enrolled at time of submission. Clinical trial information: NCT04539808.