Comparing Neoadjuvant/Adjuvant GVAX vs a mKRASvax Given With Anti-PD-1 and Anti-CD137 for Surgically Resectable Pancreatic Cancer

The purpose of this study is to determine the optimal dose of AGEN2373 that is safe when given in combination with balstilimab and Pancreatic GVAX Whole Cell Vaccine and evaluate the safety and clinical activity of balstilimab and AGEN2373 in combination with GVAX (Arm 1) or mKRASvax (Arm 2) in surgically resectable pancreatic adenocarcinoma.

Drug: AGEN2373. 1. Up to 3 doses (1 mg/kg, 3 mg/kg, and 10 mg/kg) will be tested in Phase I to determine the dose to be used in Phase II. AGEN2373 will be administered as a 60 minute IV infusion (-5/+15 min) on Day 1 of each cycle for a total of 6 cycles of treatment. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: 1 mg/kg, 3 mg/kg, and 10 mg/kg IV

Drug: Balstilimab. 1. 450 mg will be administered as a 30 minute IV Infusion (-5/+15 min) on day 1 of each cycle for a total of 6 cycles of treatment. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: 450 mg IV

Drug: Cyclophosphamide. 1. 200 mg/m2 will be administered as a 30 minute IV infusion (-5/+15 min) on day 1 of each cycle for a total of 6 cycles of treatment. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: 200 mg/m2 IV

Drug: GVAX. 1. Vaccine (5 × 108 cells) will be administered on Day 2 of each cycle for a total of 6 cycles of treatment. Six intradermal injections will be given in the upper thighs and non-dominant arms. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: GVAX

Drug: AGEN2373 (RP2D). 1. Drug: Up to 3 doses (1 mg/kg, 3 mg/kg, and 10 mg/kg) will be administered as a 60 minute IV. Infusion (-5/+15 min) on Day 1 of each cycle for a total of 6 cycles of treatment. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: 1 mg/kg, 3 mg/kg, and 10 mg/kg IV

Drug: Balstilimab. 1. 450 mg will be administered as a 30 minute IV. Infusion (-5/+15 min) on day 1 of each cycle for a total of 6 cycles of treatment. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. Drug: 450 mg IV

Drug: mKRASvax. 1. mKRASvax will be administered on Day 1 of each cycle and on Day 8 of Cycle 1 only. mKRASvax is given as 5 subcutaneous injections administered in the upper thighs and arms. Cycle 1 (14 days) is prior to surgical resection, Cycle 2 (14 days) is after surgery and prior to standard of care chemotherapy, and Cycles 3-6 (21 days) are given after completion of chemotherapy. 2. 0.3 mg per peptide vaccine + 0.5mg Poly-ICLC

Arm 1 - AGEN2373/Balstilimab/Cyclophosphamide/GVAX (experimental):

Arm 2 - AGEN2373/Balstilimab/mKRASvax (1.8mg total peptides +0.5mg each poly-ICLC) (experimental):

Dose Limiting Toxicities in Phase I participants. Phase I participants will be evaluated for dose limiting toxicities (DLTs) during the first 14 day cycle and 14 days post-operatively for the purpose of determining the recommended phase II dose of AGEN2373 when given concurrently with balstilimab and cancer vaccination. Time frame: 1 month.

Number of participants experiencing Grade 3 or Higher study drug-related toxicities. Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0 Time frame: 2 years.

Number of participants who form Intratumoral tertiary lymphoid structures (TLS). Number of participants who form at least one tertiary lymphoid structure (TLS) following one cycle of study drugs. The presence of at least 50 CD20+ B cells and 50 CD3+ T cells in a ≥50 µM area of surgical tissue is considered "positive" for TLS. Time frame: 2 weeks.

Pathologic overall response rate (pORR). Time frame: evaluated at time of surgery, approximately 2 weeks from first dose of study drug.

CD3+CD8+CD137+ T cell density in Tumor Tissue. Time frame: evaluated at time of surgery, approximately 2 weeks from first dose of study drug.

Change in peripheral interferon-gamma (IFNγ) producing mutant KRAS-specific T cells. Time frame: 13 weeks.

Inclusion Criteria: * Have a newly diagnosed, biopsy-proven adenocarcinoma of the pancreas. * Tumor must be deemed resectable by the study team * Patient's acceptance to have a tumor biopsy. * Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1. * Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures. * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test. * For both Women and Men, must use acceptable form of birth control while on study. Exclusion Criteria: * Received any anti-pancreatic cancer therapy (symptomatic therapies are allowed), or any prior anti-cancer immunotherapy. * Diagnosed with another cancer whose natural history or treatment could interfere with safety or efficacy assessments on this study. * Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements. * Active autoimmune disease. * Systemic steroid therapy (\> 10mg daily prednisone equivalent) or immunosuppressive therapy within 14 days of first dose of study drug administration. * Active infection requiring systemic therapy. * Known history of human immunodeficiency virus (HIV). * Active or chronic hepatitis B or hepatitis C. * Known active tuberculosis. * History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, chronic obstructive pulmonary disease (COPD), asthma requiring medication, etc. * Prior allogeneic stem cell transplantation or organ transplantation. * Any major surgical procedure requiring general anesthesia ≤ 28 days before first dose of study drug. * Received a live vaccine ≤ 28 days before first dose of study drug. * History of severe hypersensitivity reaction to any monoclonal antibody * Concurrent participation in another therapeutic clinical study * Pregnant or breastfeeding

Enrollment: 38 participants (estimated).