Study of CRS-207, Pembrolizumab, Ipilimumab, and Tadalafil in Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Study of the Safety, Efficacy, and Immune Response of CRS-207, Pembrolizumab, Ipilimumab, and Tadalafil in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Pembrolizumab
* Drug: Ipilimumab
* Drug: CRS-207


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Tadalafil, Pembrolizumab, Ipilimumab, CRS-207<br> | Drug: Tadalafil<br>* Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Tadalafil (20 mg) will be administered orally every day on days 3-21 for cycles 1-6.<br>Drug: Pembrolizumab<br>* Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on Day 1 of cycles 1-6.<br>* Other names: KEYTRUDA®;Drug: Ipilimumab<br>* Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Ipilimumab (50mg) will be administered IV on Day 1 of Cycles 1, 3, and 5.<br>* Other names: YERVOY®;Drug: CRS-207<br>* Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 [1 × 109 colony forming units (CFU) in 100ml NS] will be administered IV on Day 2 of Cycles 1-6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (irORR) using immune Response Evaluation Criteria for Solid Tumors (iRECIST) | irORR is defined as the number of patients achieving a complete response (irCR) or partial response (irPR) based on the immune Response Evaluation Criteria in Solid Tumors (iRECIST) at any time during the study. irCR = disappearance of all target lesions, irPR is =>30percent decrease in sum of diameters of target lesions, progressive disease (irPD) is >20percent increase in sum of diameters of target lesions, stable disease (irSD) is <30percent decrease or <20percent increase in sum of diameters of target lesions. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing grade 3 or above drug-related toxicities | When calculating the incidence of adverse event (AE)s, each AE (as defined by NCI CTCAE v5.0) will be counted only once for a given subject. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic cancer, Pembrolizumab, Ipilimumab, CRS-207, Tadalafil, Immunotherapy, Anti-PD-1, Anti-CTLA-4, Adenocarcinoma, Carcinoma