Precision Promise Platform Trial for Metastatic Pancreatic Cancer

∙ A participant will be eligible to participate in Precision Promise if all the below inclusion criteria are met:

• Age ≥ 18 years

• Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC) and eligible for treatment in the first line or second line settings.

• Acceptable histologies include adenosquamous carcinoma, mucinous adenocarcinoma, hepatoid carcinoma, medullary carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like-cells, and adenocarcinoma. Pancreatic neuroendocrine tumors (PNET) are excluded.

• Radiographically measurable disease by computed tomography (CT) scan or magnetic resonance imaging (MRI) as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Imaging results must be obtained within the 28-day window, prior to randomization.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Adequate organ function (lab results must be obtained within the 28-day window prior to randomization)

‣ Absolute neutrophil count ≥ 1500/mm3

⁃ Hemoglobin ≥ the lower limit of normal (LLN) or 9g/dL

⁃ Platelets ≥ 100,000/mm3

⁃ Serum creatinine ≤ 1.0 x upper limit normal (ULN), or calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault)

⁃ Albumin ≥ 3.0 g/dL

⁃ Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x ULN (up to ≤ 5 x ULN in presence of liver metastasis).

⁃ Total bilirubin ≤ 1.5 x ULN

⁃ INR ≤ 1.5 x ULN (up to ≤ 2 x ULN for participants on anticoagulation therapy).

• Participants must be willing to provide protocol-mandated tissue and blood samples for diagnostic and research purposes as a condition of enrollment into the trial.

• Able to swallow pills, capsules or tablets.

• Able to adhere to study visit schedule and other protocol requirements.

• Participants of childbearing potential \[defined as a person assigned as female at birth who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)\] must:

‣ Have a negative serum or urine pregnancy test (β-human chorionic gonadotropin \[β-hCG\]) as verified by the study doctor within 14 days prior to randomization.

⁃ Commit to complete abstinence from sexual contact with persons assigned as male at birth or agree to use medical doctor-approved contraception without interruption while participating in the study, during dose interruptions and for at least 6 months following last dose of study treatment.

• Participants assigned as males at birth must practice complete abstinence or agree to use a condom (even if he has undergone a successful vasectomy) during sexual contact with persons of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following last dose of study treatment.

• known HIV-infected participants on effective anti-retroviral therapy are eligible if the most recent viral load test performed within six months of screening (based on medical chart review) is negative. If this is not the case, an HIV viral load test should be performed at screening and be negative (i.e., undetectable).

• Known HBV-infected participants are eligible if the most recent viral load test performed within six months of screening (based on medical chart review) is negative. If this is not the case, an HBV viral load test should be performed at screening and be negative (i.e., undetectable).

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with known HCV infection who are currently on treatment are eligible if the most recent viral load test performed within six months of screening (based on medical chart review) is negative. If this is not the case, an HCV viral load test should be performed at screening and be negative (i.e., undetectable).

• Participants with a history of brain metastases are eligible provided they show evidence of stable lesions (and no new lesions) with no evidence of tumor progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. In addition, any neurological symptoms that developed either as a result of the brain metastases or their treatment, must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed \> 7 days prior to the first dose of trial therapy.

• No known leptomeningeal disease.

• Participants with a prior or concurrent malignancy whose natural history does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible. Participants receiving any active therapy for a concurrent secondary malignancy are excluded.

• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using New York Heart Association Functional Classification. To be eligible for this trial, participants should be Class 2 or better. Class 2 is defined as slight limitation of physical activity, in which ordinary physical activity leads to fatigue, palpitation, or dyspnea; the person is comfortable at rest.

• Understands the nature of the study and has agreed to participate by voluntarily signing the IRB approved informed consent.