Preoperative Folfirinox for Resectable Pancreatic Adenocarcinoma - A Phase II Study

Study Overview
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Brief Summary
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This phase II trial studies how well combination chemotherapy works in treating patients with pancreatic cancer before undergoing surgery. Drugs used in chemotherapy, such as irinotecan hydrochloride, oxaliplatin, leucovorin calcium, and fluorouracil (FOLFIRINOX), 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 more than one drug (combination chemotherapy) before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine feasibility of preoperative FOLFIRINOX for resectable pancreatic adenocarcinoma. SECONDARY OBJECTIVES: I. To determine safety and toxicity of preoperative FOLFIRINOX. II. To determine response rate. III. To determine proportion achieving major pathologic response - per College of American Pathologists (CAP) criteria. IV. To determine proportion achieving R0 resection. V. To determine perioperative (30-day) mortality. VI. To determine the role of cancer antigen (CA)19.9 as potential prognostic and/or predictive biomarker. VII. To determine progression-free survival. VIII. To determine overall survival. OUTLINE: Patients receive FOLFIRINOX regimen comprising irinotecan hydrochloride intravenously (IV) over 90 minutes, oxaliplatin IV over 120 minutes, leucovorin calcium IV over 120 minutes, and fluorouracil IV over 1-2 minutes and then continuously over 46 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
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Preoperative Folfirinox for Resectable Pancreatic Adenocarcinoma - A Phase II Study

Conditions
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Pancreatic Adenocarcinoma, Poorly Differentiated Malignant Neoplasm, Resectable Pancreatic Cancer, Stage IA Pancreatic Cancer, Stage IB Pancreatic Cancer, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer, Stage III Pancreatic Cancer, Undifferentiated Pancreatic Carcinoma

Intervention / Treatment
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* Drug: Irinotecan Hydrochloride
* Drug: Oxaliplatin
* Drug: Leucovorin Calcium
* Drug: Fluorouracil
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed carcinoma of the pancreas; most cases will be adenocarcinoma; cases with undifferentiated or poorly differentiated carcinoma will also be eligible There should be no evidence of metastatic disease on imaging of the chest, abdomen, and pelvis; this imaging should be either a contrast-enhanced computed tomography (CT) scan, or a contrast-enhanced magnetic resonance imaging (MRI) scan; positron emission tomography (PET) scans alone will not be adequate alternatives; there should be no evidence of occult metastatic disease in the abdomen, confirmed by laparoscopic examination The primary tumor must be resectable, defined as no involvement (abutment or encasement) of the major arteries (celiac, common hepatic, superior mesenteric) and interface between tumor and vessel (portal, superior mesenteric veins) wall to be less than 180 degrees of the circumference of the vessel wall; this should be confirmed by imaging of the abdomen, either by a contrast-enhanced computed tomography (CT) scan, or a contrast-enhanced magnetic resonance imaging (MRI) scan; PET scans will not be adequate alternatives; for each patient, the resectability must be reviewed by one of the study surgeons Patient must not have received any cancer-directed therapy (e.g., surgery, chemotherapy, radiation therapy, biologic therapy) for the index diagnosis Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Hemoglobin >= 10.0 g/dl Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Total bilirubin =< 1.5 X institutional upper limit of normal Serum creatinine within normal institutional limits, or creatinine clearance (calculated by Cockcroft-Gault) >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Women of child-bearing potential and men must agree to use adequate contraception (double-barrier method of birth control or abstinence) for the duration of study participation and for 6 months after completing chemotherapy; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately Subjects must have the ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or breastfeeding women Pre-existing peripheral neuropathy (grade I or higher)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 (FOLFIRINOX)<br>Patients receive FOLFIRINOX regimen comprising irinotecan hydrochloride IV over 90 minutes, oxaliplatin IV over 120 minutes, leucovorin calcium IV over 120 minutes, and fluorouracil IV over 1-2 minutes and then continuously over 46 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Irinotecan Hydrochloride<br>* Given IV<br>Drug: Oxaliplatin<br>* Given IV<br>Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: CF;Drug: Fluorouracil<br>* Given IV<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Undergoing Surgical Resection After Receiving at Least 4 of the 6 Courses of Preoperative Chemotherapy | Proportion will be estimated using a binomial test. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Time from enrollment to the earlier of death or disease progression. Will be estimated with Kaplan Meier curves. | Up to 2 years | 
| Overall Survival | Time from enrollment to death from any cause. Will be estimated with Kaplan Meier curves. | Up to 2 years | 
| Incidence of Toxicities Greater Than Grade 2, Using the Common Terminology Criteria for Adverse Events Version 4.0 | Toxicity evaluation will be enumeration of all major toxicities, with proportions calculated for each. | Up to 30 days after end of treatment or to the day prior to surgery | 
| Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 | Will be calculated as a binary outcome. Exact 95% confidence intervals will be calculated for binary outcomes. | Up to 2 years | 
| Number of Participants Achieving Major Pathologic Response | Will be calculated as a binary outcome. Exact 95% confidence intervals will be calculated for binary outcomes. | Up to 2 years | 
| Number of Participants Achieving R0 Resection | Will be calculated as a binary outcome. Exact 95% confidence intervals will be calculated for binary outcomes. | Up to 2 years | 
| Number of Participants Experiencing Perioperative (30-day) Mortality | Will be calculated as a binary outcome. Exact 95% confidence intervals will be calculated for binary outcomes. | Up to 30 days |