The goal of this clinical trial is to test if the addition of botensilimab to standard chemotherapy improves the efficacy compared to just chemotherapy alone in participants with metastatic pancreatic cancer. One group of participants will only receive chemotherapy while a second group of participants will receive botensilimab and chemotherapy.

This will be a prospective, multicenter, clinical trial of botensilimab in combination with nab-paclitaxel + gemcitabine or nab-paclitaxel + gemcitabine alone. The trial will be conducted in 2 parts. Part 1 will be a safety lead-in to establish the safety and dose of botensilimab for Part 2. Part 2 will be a randomized, open-label assessment of botensilimab (at the dose level determined in Part 1).

Inclusion Criteria:

• Histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. Note: fine needle aspirate/cytology of tumor in the presence of a pancreatic mass that confirms ductal adenocarcinoma is acceptable.
• Must have had disease progression on any version of FOLFIRINOX for metastatic disease (including onivyde + oxaliplatin + 5-fluorouracil [5-FU] + leucovorin [NALIRIFOX]). Clarification: Participant with initial diagnosis of locally advanced disease may be eligible if upon retrospective review of initial scans, previously unappreciated metastases are able to be identified; Investigator must provide documentation that participant had metastatic disease at the time the participant received FOLFIRINOX. Notes: Progression on a reduced or maintenance fluoropyrimidine based regimen in the metastatic setting is allowed (for example, leucovorin + 5-FU + oxaliplatin [FOLFOX], leucovorin + 5-FU + irinotecan [FOLFIRI], 5-FU, or capecitabine), provided the participant received at least 1 dose of all of the drugs in a FOLFIRINOX regimen.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Life expectancy of at least 3 months.
• Measurable disease on baseline imaging per RECIST 1.1 criteria.
• A < Grade 2 pre-existing peripheral neuropathy per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Because NCI CTCAE v5.0 grading for peripheral neuropathy does not include guidance for "mild" neuropathy, these cases can be graded per the NCI CTCAE v5.0 grading for general adverse events which includes "mild" under Grade 1.
• Acceptable coagulation status as indicated by an international normalized ratio ≤ 1.5 x institutional ULN, except participants on anticoagulation who can be included at the discretion of the investigator.
• Adequate organ function.
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study drugs).
• Male participants with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study.

Exclusion Criteria:

• Received more than one prior regimen (that is, FOLFIRINOX) for their metastatic disease. (Progression on a reduced or maintenance fluoropyrimidine-based regimen in the metastatic setting is allowed. [for example, FOLFOX, FOLFIRI, 5-FU, or capecitabine], provided the participant received at least 1 dose of all of the drugs in a FOLFIRINOX regimen.)

• History of central nervous system (CNS) metastasis or active CNS metastasis.

• Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study drugs (that is, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years prior to first dose of study drugs and the participant has no evidence of disease). Participants with history of prior early-stage basal/squamous cell skin cancer or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.

• Uncontrolled intercurrent illness, including but not limited to clinically significant (that is, active) cardiovascular disease.

• Active, uncontrolled infections, requiring systemic intravenous anti-infective treatment within 2 weeks prior to first dose of study drugs.

• Major surgery within 4 weeks prior to signing of informed consent form (ICF).

• Prior treatment with an immune checkpoint inhibitor.

• Refractory ascites.

• Partial or complete bowel obstruction within the last 3 months prior to signing of ICF, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction.

• Clinically significant gastrointestinal disorders.

• Treatment with one of the following classes of drugs within the delineated time window prior to first dose of study drugs:

  • Cytotoxic agent within 3 weeks or 5 half-lives (whichever is greater).
  • Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or investigational drug, within 4 weeks, or 5 half-lives, whichever is shorter.
  • Small molecule targeted therapies/tyrosine kinase inhibitors within 14 days or 5 half-lives (whichever is greater).
  • Radiotherapy within 7 days.

• Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to first dose of study drugs.

• Received a vaccine, including SARS-CoV-2 vaccine, < 7 days prior to first dose of study drugs.

• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

• Symptomatic interstitial lung disease (ILD), history of ILD, or any lung disease which may interfere with detection and management of new immune-mediated pulmonary toxicity.

• History of allogeneic organ transplant.

• Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 milligrams [mg] daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days prior to the first dose of study drugs. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent), are permitted in the absence of active autoimmune disease.

• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years prior to first dose of study drugs (that is, with use of disease-modifying agents or immunosuppressive drugs).

• Pregnant or breastfeeding participants.

• Uncontrolled infection with human immunodeficiency virus.

• Known to be positive for hepatitis B (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection.

• Known active hepatitis C as determined by positive serology and confirmed by polymerase chain reaction.

• Dependence on total parenteral nutrition.

• Participants with concurrent diarrhea > grade 1 at time of randomization despite optimal treatment with standard of care pancreatic enzymes.

• Known active or latent tuberculosis.

• Any condition in the opinion of the principal investigator that might interfere with the participant's participation in the study or in the evaluation of the study results.

• Unwillingness or inability to comply with procedures required in this protocol.