Nivolumab in Combination With Chemotherapy Pre-Surgery in Treating Patients With Borderline Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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This pilot and feasibility study studies how well nivolumab and combination chemotherapy work before surgery in treating patients with pancreatic cancer that could possibly be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab in combination with chemotherapy before surgery may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate development of clinically relevant pancreatic fistula in the post-operative period after neoadjuvant treatment with nivolumab and fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (FOLFIRINOX) (FFX). II. To evaluate pathologic complete response after neoadjuvant nivolumab and FOLFIRINOX (FFX). SECONDARY OBJECTIVES: I. To evaluate early efficacy measured by percent change of CA 19-9 response rate, R0 resection rate, overall response rate (ORR) and disease free survival (DFS). EXPLORATORY OBJECTIVES, OTHER ASSESSMENTS: I. To determine degree of changes in the tumor microenvironment (TME) of nivolumab and modified (m) FFX on cell proliferation and apoptosis. OUTLINE: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Patients also receive fluorouracil IV over 10 minutes and over 46 hours, irinotecan hydrochloride IV over 90-120 minutes, leucovorin calcium IV over 120 minutes, and oxaliplatin IV over 120 minutes on days 1 and 15. Treatments repeat every 28 days for 3-6 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients with resectable disease undergo surgery. Within 8-12 weeks after surgery, patients with successful resection may receive 6 additional cycles of fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2-3 months.

Official Title
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A Pilot and Feasibility Study of PD-1 Blockade With Nivolumab in Combination With Chemotherapy in Patients With Borderline Resectable Pancreatic Adenocarcinoma

Conditions
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Borderline Resectable Pancreatic Adenocarcinoma, Resectable Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Fluorouracil
* Drug: Irinotecan
* Drug: Irinotecan Hydrochloride
* Drug: Leucovorin
* Drug: Leucovorin Calcium
* Biological: Nivolumab
* Drug: Oxaliplatin
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed pancreatic adenocarcinoma One of the following: Borderline resectable disease. There are multiple definitions of borderline resectable pancreatic ductal adenocarcinoma (PDAC) including the MD Anderson definition and the criteria developed during the Consensus Conference sponsored by the American Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, and Society for Surgery of the Alimentary Tract. Borderline resectable PDAC cases will be identified per the definition developed in the currently running inter-group pilot trial for borderline resectable pancreatic cancer (NCT01821612). Per this trial, borderline resectable PDAC is defined as the presence of any one or more of the following on computed tomography (CT): An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring >= 180 degrees of the circumference of the vessel wall Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction Short segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction An interface between the tumor and superior mesenteric artery (SMA) measuring < 180 degrees of the circumference of the vessel wall Performance status of Eastern Cooperative Oncology Group (ECOG) of 0-1 Therapy naive Absolute neutrophil count (ANC) >= 1500/mm^3 Platelets >= 100,000/mm^3 Hemoglobin >= 9 g/dl Serum total bilirubin =< 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN Alkaline phosphatase =< 2.5 x ULN Serum creatinine (sCr) =< 1.5 x ULN or creatinine clearance (Ccr) >= 40 mL/min as calculated by the modified Cockcroft-Gault formula Peripheral neuropathy < grade 2 Exclusion Criteria: Locally advanced (clearly unresectable) or metastatic disease Known status of human immunodeficiency virus (HIV) which is not well-controlled at the time of study eligibility Untreated hepatitis B infection Active infection or antibiotics within 48 hours prior to study Currently active second primary malignancy or history of malignancy less than 5 years prior to the time of study eligibility (patients with history of skin cancers excluding melanoma will be eligible for participation) Serious medical comorbidities such as New York Heart Association class III/IV cardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 months Known, existing uncontrolled coagulopathy. Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a grade 2 or greater bleeding episode in the 3 weeks before day 1 Prior history of cerebrovascular accident or transient ischemic attack, or pre-existing carotid artery disease Known pregnancy, nursing women or positive pregnancy test. Requirement for women of childbearing potential (WOCBP) must have a pregnancy test every 4 weeks and WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab Any prisoners, or subjects who are compulsory detained are excluded Any condition that would preclude informed consent, consistent follow-up and compliance for the study participation

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: Treatment (nivolumab, mFOLFIRINOX)<br>Patients receive nivolumab IV over 60 minutes on day 1. Patients also receive fluorouracil IV over 10 minutes and over 46 hours, irinotecan hydrochloride IV over 90-120 minutes, leucovorin calcium IV over 120 minutes, and oxaliplatin IV over 120 minutes on days 1 and 15. Treatments repeat every 28 days for 3-6 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients with resectable disease undergo surgery. Within 8-12 weeks after surgery, patients with successful resection may receive 6 additional cycles of fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin in the absence of disease progression or unacceptable toxicity. | Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Irinotecan<br>* Given IV<br>Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically relevant pancreatic fistula in the post-operative period after neoadjuvant treatment with nivolumab and fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (FOLFIRINOX) (mFFX) chemotherapy | Descriptive statistics with frequency and proportion will be used. | Up to 3 years | 
| Pathologic complete response after nivolumab and mFFX treatment | Descriptive statistics with frequency and proportion will be used. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change of CA 19-9 response rate | Descriptive statistics with frequency and proportion will be used to analyze the CA19-9 response rate. | Baseline up to 3 years | 
| R0 resection rate |  | Up to 3 years | 
| Overall response rate (ORR) | Descriptive statistics with frequency and proportion will be used to analyze ORR. | Up to 3 years | 
| Disease free survival (DFS) | Kaplan-Meier methods will be used to analyze DFS with median and 95% confidence interval (CI). | Up to 3 years | 
| Incidence of adverse events | Will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.3. | Up to 28 days after last dose of study drug | 
| Delayed wound healing |  | Up to 3 years | 
| Wound dehiscence |  | Up to 3 years | 
| Wound infection |  | Up to 3 years |