PROJECT SUMMARY/ABSTRACT – RP1 Surgery is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC) but is available to only <20% of patients. For the 20%-30% of patients with borderline resectable or locally advanced (BR/LA; involving major abdominal vasculature) PDAC, neoadjuvant therapy with induction chemotherapy, with or without radiotherapy, is the emerging standard. This sequence with chemotherapy up-front provides the opportunity to downstage tumors to allow curative resection. Importantly, early treatment of micrometastatic disease helps select patients who are likely to benefit from surgery and spares unnecessary surgery in those who would not benefit. Evidence to date supports neoadjuvant therapy, but a more-structured, comprehensive approach is needed, which requires rigorous prospective evaluation. Moreover, there are currently no biomarkers that reliably predict treatment response or resistance. This knowledge is essential to appropriately select patients who will benefit from specific treatment regimens and to modulate treatment for individual patients. We will evaluate the efficacy of total neoadjuvant therapy (TNT) combining novel triplet chemotherapy with ablative-dose radiotherapy (AD-XRT), given before surgery, in a phase II trial (Aim 1). This trial will assess the promising 5-fluorouracil/leucovorin + liposomal-irinotecan + oxaliplatin (NALIRIFOX) regimen, administered entirely up-front for 4 months, followed by AD-XRT (biological equivalent dose of 100 Gy, delivered in 15-25 fractions, with capecitabine as radiosensitizer). The primary endpoint is event-free survival, with events defined as progression, recurrence after surgery, or death. Toward the development of biomarkers of treatment response after TNT, we will assess the potential of (Aim 2A) radiomics analysis of CT images and (Aim 2B) functional FDG-PET and novel immunoPET using 89Zr- HuMab-5B1 that recognizes cancer antigen 19-9 (CA19-9) to monitor treatment response, assess surgical resectability, and predict survival. Using blood samples collected on the trial, we will also evaluate circulating tumor DNA (measured by MSK-ACCESS targeted sequencing) and serum CA19-9 for the same purpose (Aim 3). This clinical trial aims to define TNT as a new treatment standard for BR/LA PDAC. The planned correlative studies promise to identify noninvasive biomarkers of response after TNT that may be rapidly translated to the clinic to allow adaptive disease management. As patients with BR/LA PDAC stand to benefit greatly from improvements in treatment and monitoring, because of the opportunity to enable curative resection, this project will likely have a major impact on outcomes in PDAC overall.