Study of Pembrolizumab With or Without Defactinib Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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This study will test the effectiveness (anti-tumor activity), safety, and ability to increase the body's immune system to fight pancreatic cancer by combining standard chemotherapy before and after surgery, with study drug PD-1 antibody, pembrolizumab, with and without study drug, focal adhesion kinase inhibitor (FAK), defactinib, in people with high risk resectable (surgically removable) pancreatic cancer. The purpose of this study is to evaluate if reprograming the tumor microenvironment by targeting FAK following chemotherapy can potentiate anti-programmed death-1 (PD-1) antibody.

Official Title
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A Randomized Phase II Study of Pembrolizumab With or Without Defactinib, a Focal Adhesion Kinase Inhibitor Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma (PDAC)

Conditions
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Resectable Pancreatic Ductal Adenocarcinoma (PDAC), Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Defactinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Has pancreatic ductal adenocarcinoma Has resectable disease at the time of diagnosis Has not received any systemic therapy for pancreatic ductal adenocarcinoma Has stage ≤ IIb disease at time of diagnosis and enrollment Elevated tumor marker, CA (carbohydrate antigen) 19-9 >200 ECOG performance status 0 or 1 Patient must have adequate organ function defined by the study-specified laboratory tests. Must use acceptable form of birth control while on study. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Patients who have received any prior chemotherapy, radiotherapy or investigational agents for pancreatic cancer. Patients who have received prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Has received prior therapy with FAK inhibitor. Woman who are pregnant or breastfeeding. Have received a live vaccine or live-attenuated vaccine within 30 days prior to study drug. Is currently or has participated in another investigational study within 4 weeks prior to receiving study drug. History or current use of immunosuppressive medications within 7 days prior to study medications. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years or that is expected to require active treatment within two years. Has active autoimmune disease that has required systemic treatment in the past 2 years. Has a history of (non-infectious) pneumonitis/interstitial lung disease or current pneumonitis. Has an active infection requiring systemic therapy. Infection with HIV or hepatitis B or C. Patient with uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Known allergy or hypersensitivity to the study drugs. Received any growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration. Has history of any organ transplant, including corneal transplants.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Pembrolizumab and Defactinib<br> | Drug: Pembrolizumab<br>* Following standard of care neoadjuvant chemotherapy, subjects will receive two doses of pembrolizumab (200mg) IV 3 weeks apart prior to surgery. After surgery, subjects will receive adjuvant standard of care chemotherapy. Following adjuvant chemotherapy, subjects will receive 8 doses of pembrolizumab (200mg) IV 3 weeks apart.<br>* Other names: Keytruda;Drug: Defactinib<br>* Following 2 cycles of standard of care neoadjuvant chemotherapy, subjects will receive 400 mg defactinib twice a day up until 2 days preceding their surgery (approximately 6 weeks) during the immunotherapy cycles with pembrolizumab. After surgery, subjects will receive adjuvant standard of care chemotherapy. Following adjuvant chemotherapy, subjects will receive 400mg defactinib twice a day for 24 weeks.<br>|
| Experimental: Arm B - Pembrolizumab<br> | Drug: Pembrolizumab<br>* Following standard of care neoadjuvant chemotherapy, subjects will receive two doses of pembrolizumab (200mg) IV 3 weeks apart prior to surgery. After surgery, subjects will receive adjuvant standard of care chemotherapy. Following adjuvant chemotherapy, subjects will receive 8 doses of pembrolizumab (200mg) IV 3 weeks apart.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response (pCR) rate | Percent of subjects with a pathologic complete response (pCR) per the tumor regression grade scores established by the College of American Pathologist: Grade 0= complete response (no viable cancer cells), Grade 1= near complete response (single cells or rare small groups of cancer cells), Grade 2= partial response (residual tumor with evidence of regression), or Grade 3= no response (extensive residual tumor with no evidence of regression). | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Number of months until death | 4 years | 
| Disease free survival (DFS) | Number of months until disease recurrence | 4 years | 
| Number of participants experiencing study drug-related toxicities | Number of participants experiencing drug-related adverse events as defined by CTCAE v5.0 | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pembrolizumab, Defactinib, Immunotherapy, Anti-PD-1, Antibody, PD-L1, Pancreatic cancer, Neoadjuvant chemotherapy, Adjuvant chemotherapy, PDAC - Pancreatic Ductal Adenocarcinoma, FAK (focal adhesion kinase) inhibitor, Resectable Pancreatic Adenocarcinoma, High Risk Resectable Pancreatic Cancer, Tumor microenvironment, CA 19-9, Surgery, Pancreatectomy