AGEN1423 and Botensilimab w/ or w/o Chemo in PDAC

Inclusion Criteria:

* 18 year and older
* Ability to understand and willingness to sign a written informed consent prior to entering the study.
* Histologically or cytologically confirmed (either previously or newly biopsied) metastatic or locally advanced unresectable pancreatic adenocarcinoma, including intraductal papillary mucinous neoplasm.
* Have measurable disease (≥ 1 measurable lesion) based on RECIST v1.1 as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Previous treatment lines

  * Cohort 1: Have documented objective radiographic progression on or after stopping treatment with first-line or further therapy, i.e. chemotherapy and or radiotherapy. If subjects received prior neoadjuvant or adjuvant chemotherapy and progressed within 3 months of the last dose, then this should be considered as a prior line of systemic therapy.
  * Cohort 2: Have documented objective radiographic progression on or after stopping treatment with first-line, fluorouracil-based chemotherapy.
* For Cohort 1, willing to submit an evaluable fresh tumor tissue sample, unless tumor is considered inaccessible, or biopsy is otherwise considered not in the subject's best interest.
* Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia and peripheral neuropathy). If the subject received major surgery or radiation therapy of \> 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
* ECOG status ≤1
* Life expectancy of at least 3 months
* Participants must have adequate organ and marrow function as defined below. All laboratory assessments should be performed within 10 days of treatment initiation

  * Hematological:

    * Hemoglobin ≥ 9g/dL (without transfusion within 7 days of assessment)
    * Leukocytes ≥3,000/µL
    * Absolute neutrophil count ≥1,500/µL
    * Absolute lymphocyte count ≥700/µL
    * Platelets ≥100,000/µL
  * Hepatic Function

    * Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN)
    * AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
  * Renal Function

    ---Creatinine Clearance \> 50 mL/min as calculated per Cockcroft-Gault formula
  * Nutritional

    ---Serum Albumin ≥ 3 g/dL
  * Coagulation

    * INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
    * aPTT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Subjects must use effective contraception:

  * Female subjects must be of non-childbearing potential or, if of childbearing potential, must agree to use a highly effective method of birth control (Appendix B), during the study and for 6 months following the last dose of study medication and must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons):

    ---≥45 years of age and has not had menses for over 2 years

    ---Amenorrhoeic for \> 2 years without a hysterectomy and oophorectomy
  * Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation at least 6 weeks prior to Screening. Information must be captured appropriately within the medical records.
  * Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

* Has a pancreatic tumor other than adenocarcinoma, including: adenosquamous, acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell carcinoma, Vater and periampullary duodenal or common bile duct malignancies.
* Subjects with a bowel obstruction.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
* Has an active infection requiring systemic therapy or has an uncontrolled infection.
* Has an underlying medical condition that would preclude study participation.
* Has a disease that is suitable for therapy administered with curative intent.
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AE due to agents administered more than 4 weeks earlier.
* Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at Baseline) from AE due to a previously administered agent (Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study. If subject underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy)
* An active autoimmune disease that has required systemic treatment in the 2 years preceding the study (i.e., with the use of disease-modifying agents, corticosteroids or immuno-suppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* Has a history of interstitial lung disease.
* O2 saturation \< 92% (on room air).
* Has unstable angina, new onset angina within the last 3 months, myocardial infarction within the last 6 months, and current congestive heart failure New York Heart Association Class III or higher. For Cohort 2: has ventricular arrhythmias, hypertensive urgency, or severe arterial thromboembolic events less than 6 months prior to study initiation.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 120 days after the last dose of trial treatment. Women with a positive pregnancy test within 72 hours from Baseline.
* Has a positive Human immunodeficiency virus (HIV) positive test. Participants with HIV positive test on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Has known history of Chronic Hepatitis B or C. For participants with evidence of chronic hepatitis B virus (HBV) infection, if the HBV viral load is undetectable while on suppressive therapy the subject can participate on the study. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or computerized tomography (CT) scan, for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
* Has received a live vaccine within 30 days of the planned start of study therapy. Seasonal flu vaccines or COVID-19 vaccines that do not contain live virus are permitted.
* Drainage of ascitic or pleural fluid 2 or more times in the 4 weeks prior to the first dose of study drug or permanent drain in place (eg, PleurX®) for ascites or pleural effusion symptom management.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition of AGEN1423 or Botensilimab.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.