NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer

PRIMARY OBJECTIVE: I. To determine the rate of margin-negative (R0) resection in participants with resectable or borderline resectable pancreatic cancer (BRPC) following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA). SECONDARY OBJECTIVES: I. To determine the progression-free survival (PFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA). II. To determine the PFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy, plus preoperative radiation therapy (RT). III. To determine the disease-free survival (DFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA). IV. To determine the DFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT. V. To determine the overall survival (OS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy. VI. To determine the OS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT. VII. To assess the surgical complications of resectable or BRPC participants that undergo surgical resection. VIII. To assess 30-day post-operative mortality of participants with resectable or BRPC that undergo surgical resection. IX. To assess safety of NeoOPTIMIZE adaptive therapy (all participants). EXPLORATORY OBJECTIVES: I. To monitor changes in CA19-9 levels (all participants). II. To determine the rate of margin-negative (R0) resection in patients with locally advanced pancreatic cancer (LAPC), following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA). III. To determine the PFS of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA). IV. To determine the PFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative radiation therapy (RT). V. To determine the disease-free survival (DFS) of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA). VI. To determine the DFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT. VII. To determine the OS of LAPC participants that received NeoOPTIMIZE adaptive therapy. VIII. To determine the OS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT. IX. To assess the surgical complications of LAPC participants that undergo surgical resection. X. To assess 30-day post-operative mortality of LAPC participants who undergo surgical resection. OUTLINE: mFOLFIRINOX REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1. Patients also receive fluorouracil IV over 46 hours starting on day 1. Treatment with mFOLFIRINOX repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo disease restaging (re-stage I). Patients with radiographic response and no disease progression receive mFOLFIRINOX for an additional 2 months (approximately 4 cycles). Patients then undergo second re-staging (re-stage II). GA REGIMEN: After re-stage I, patients with disease progression or toxicity to mFOLFIRINOX (per assessment of the treating physician) switch to receive the GA regimen comprising gemcitabine hydrochloride IV over 30-60 minutes and nab-paclitaxel IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo second re-staging (re-stage II). Patients may be switched to GA regimen from FOLFIRINOX regimen prior to re-stage I (per assessment of the treating physician). LOSARTAN: Starting cycle 1 day 1, patients also receive losartan potassium orally (PO) once daily (QD) until completion of RT in the absence of disease progression or unacceptable toxicity. RT/SURGERY: Patients with no vascular tumor involvement at re-stage II, undergo surgery 1-4 after completion of chemotherapy. Patients with resolution of tumor contact with pancreatic vasculature at re-stage II, undergo short-course RT to receive a total of 10 fractions over 5 days weekly (Monday-Friday). Patients with tumor vessel involvement that is persistent at re-stage II, undergo long-course RT to receive a total of 15-25 fractions over 5 days weekly (Monday-Friday), and receive capecitabine PO twice daily (BID) on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks after completion RT. Patients undergo diagnostic imaging as clinically indicated throughout the trial. Patients also undergo blood sample collection throughout the trial. After completion of study treatment, patients are followed up as clinically indicated and following institutional standards, and then every 3 months for 6 months, and then every 6 months for up to 2 years.