The purpose of this study is to evaluate the safety and clinical activity of tadalafil, pembrolizumab, ipilimumab, and CRS-207 in subjects with metastatic pancreatic adenocarcinoma who have progressed after at least 1 prior chemotherapy regimen.

Inclusion Criteria:

• Age ≥18 years.
• Have histologically or cytologically proven adenocarcinoma of the pancreas.
• Have previously treated metastatic disease.
• Have radiographic disease progression.
• Patients with the presence of at least one measurable tumor lesion.
• Patient's acceptance to have a tumor biopsy at baseline and on
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Patients must have adequate organ and marrow function defined by study-specified laboratory tests.
• For both Women and Men, must use acceptable form of birth control while on study.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Known history or evidence of brain metastases.
• Had chemotherapy, radiation, or biological cancer therapy within the last 14 days.
• Have received an investigational agent or device within the last 28 days.
• Had surgery within the last 28 days.
• Expected to require any other form of systemic or localized cancer therapy while on study.
• Have received a vaccine within the last 14 days (7 days for the COVID vaccine) or received a live vaccine within the last 30 days.
• Have received steroids within the last 14 days.
• Use more than 4 g/day of acetaminophen.
• Use of organic nitrates.
• Use of guanylate cyclase (GC) stimulators such as riociguat.
• Consumption of substantial amounts of alcohol (≥5 units/day)
• Use of strong or moderate cytochrome P450 3A4 (CYP3A4) inhibitor or inducer.
• Patients on immunosuppressive agents within the last 7 days
• Known allergy to both penicillin and sulfa.
• Severe hypersensitivity reaction to any monoclonal antibody.
• History of severe hypersensitivity to tadalafil.
• Have implant(s) or device(s) that has not and cannot be easily removed.
• Have artificial joints or implanted medical devices that cannot be easily removed.
• Have any evidence of clinical or radiographic ascites.
• Have significant and/or malignant pleural effusion
• Uncontrolled intercurrent illness.
• Subjects with active, known or suspected autoimmune disease.
• Have a tissue or organ allograft, including corneal allograft.
• Have been diagnosed HIV, Hepatitis B or C positive.
• Is on supplemental home oxygen.
• Has an unhealed surgical wound or ulcer, or a bone fracture considered non-healing.
• Has clinically significant heart disease
• Prior history of non-arterial ischemic optic retinopathy.
• History of significant hypotensive episode requiring hospitalization within 6 months.
• Has insufficient peripheral vein access.
• Is unwilling or unable to follow the study schedule for any reason.
• Is pregnant or breastfeeding.

Serious and Other (Not Including Serious) Adverse Events were evaluated for up to 12 months. All-cause mortality was evaluated for up to 16 months.