The purpose of this study is to combine standard radiation therapy with drugs that encourages the body's immune system against cancer cells and simultaneously adding drugs which also target the pathway that the tumor uses to evade the immune system (CD73 and A2a/b). The study hopes that these drugs will work in concert with radiation therapy to kill cancer cells.

The specific goal of this study is to ensure that treatment with zimberelimab and stereotactic body radiation therapy (SBRT) alone or in combination with quemliclustat (a drug which blocks CD73), with or without etrumadenant (a drug which blocks the A2a/b) given before surgery is safe and if it can further increase the immune response against the tumor.

The overall objective of this study is to combine standard radiation therapy with drugs that stimulate the body's immune system against cancer cells (by targeting the protein programmed cell death (PD-1), while adding drugs which also target the pathway that the tumor uses to evade the immune system (the CD73 and A2a/b pathways).The main goal of this study is to find out if study treatment with zimberelimab (an antibody which binds the protein PD-1) and stereotactic body radiation therapy (SBRT) alone or in combination with quemliclustat (a drug which blocks CD73), with or without etrumadenant (a drug which blocks the A2a/b) given before surgery is safe and if it can further increase the immune response against the tumor.

The study is divided into two parts (Stage 1 and Stage 2). In Stage 1 participants will undergo 5 days of SBRT and receive zimberelimab, quemliclustat and etrumadenant (Arm A) for 7 weeks before surgery. If this combination is considered safe, the study will proceed to Stage 2. In Stage 2, participants will be randomized into one of three different treatment arms (B - D). All participants will undergo SBRT and will receive either Zimberelimab alone (Arm B), a combination of zimberelimab with quemliclustat (Arm C), or will receive combination of zimberelimab, quemliclustat and etrumadenant (Arm D) for 7 weeks prior to surgery.

Inclusion Criteria:

• Histological or pathological confirmation of pancreatic adenocarcinoma Cytologic or histologic proof of pancreatic ductal adenocarcinoma (PDAC) needs to be verified by the treating institution pathologist. A pathological report from non-treating institutions is sufficient to consent and to initiate investigational therapy if tissue sample is unavailable for evaluation at time of consent or enrollment. However, in such a case, PDAC diagnosis should be confirmed by the treating institution pathologist at a later time.
• Completed 8 cycles of neoadjuvant modified FOLFIRINOX. Omission of oxaliplatin due to adverse events may be allowed in cycles 5-8 with consultation with the principal investigator.
• Patients with surgically resectable PDAC who are considered appropriate to undergo the applicable operation.
• Eligible to undergo SBRT.
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• No prior surgical, systemic, or radiotherapy for PDAC except for mFOLFIRINOX.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Age ≥ 18 years.
• Adequate hematological and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of investigational treatment:

Exclusion Criteria:

• Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.

• Patients who are receiving any other investigational agents concurrently.

• Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).

• Uncontrolled pleural effusion, pericardial effusion, or ascites.

• Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy.

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (some exceptions permissible as outlined per protocol).

• History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

  • History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• Positive HIV test at screening or at any time prior to screening.

• Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening.

  --Note: Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study.

• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.

• Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease.

• Known active tuberculosis.

• Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.

• Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents and breastfeeding should be discontinued.

• History of allergy or hypersensitivity to oxaliplatin, irinotecan, leucovorin, fluorouracil, pegfilgrastim, or any excipients.

• History of Gilbert's disease or known genotype UGT1A1 *28/*28.

• Inflammatory disease of the colon or rectum, or severe uncontrolled diarrhea.

• Active or history of celiac disease.

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.