Background: Curative treatment for potentially resectable (resectable or borderline resectable) pancreatic adenocarcinoma, despite recent advances, leads to only suboptimal outcomes. Recent US national cooperative group trials have demonstrated the safety and feasibility of neoadjuvant chemotherapy (PMID 33475684, PMID 35834226), and also show that the two frontline regimens, FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP), are comparable in this setting. Finally, ability to undergo resection remains the key driver of cure. Therefore, an approach that selects chemotherapy based on early response assessment, to maximize the probability of resection, is likely to improve curative outcomes. Methods: This is a phase II study intended to maximize the probability of surgical resection for pancreatic cancer. Key eligibility requirements include adult patients with a confirmed histopathologic diagnosis of pancreatic carcinoma or adenocarcinoma, an ECOG PS ≤ 1, resectable or borderline resectable disease by central radiology review, no prior therapy for index pancreatic cancer, and adequate bone marrow, liver and kidney function. Treatment includes 4 doses (~ 2 months total treatment time) of FOLFIRINOX (“Chemo1”). After a re-evaluation, using radiologic response, CA19.9 response, and chemotherapy toxicity, patients will either continue with “Chemo1” for another 4 cycles (8 doses) or switch to GnP (“Chemo2”) which will be administered for 4 cycles (12 doses, for ~4 month total treatment time), followed by surgical resection. Primary outcome will measure the proportion of patients undergoing surgical resection using historical dated compared to 32 patients in a current study with a time frame of 16 months. Using historical data, the expected proportion of patients undergoing resection is ~60%. The goal of this study is to increase this to 80% or higher. With a one-sided of 0.05 and power of 80%, 32 patients will be needed to demonstrate this difference. Key translational correlatives will include serial circulating tumor DNA assessment and extensive tumor molecular profiling. Clinical trial information: NCT04594772.