A Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine With Concurrent IMRT in Patients

Study Overview
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Brief Summary
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The investigators hypothesize that the combination of the FOLFIRINOX regimen (a combination of 5-fluorouracil, irinotecan and oxaliplatin chemotherapy) to provide maximal systemic disease control and FDR-gemcitabine chemotherapy with concurrent IMRT (Radiation therapy) to address local disease, will achieve a significant improvement R0 resection (Radiation oncology repeat surgeries) rate in borderline resectable (surgical) pancreatic cancer and enhance disease free and overall survival in this patient population.

Detailed Description
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Gemcitabine has been the cornerstone of systemic therapy for pancreas cancer over this past decade. Recently, a combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was reported to have significant efficacy in advanced pancreatic cancer. Preclinical data suggests synergy between irinotecan and 5FU as well as between oxaliplatin and 5FU. Results of a phase II trial in advanced disease were reported in 2005 demonstrating a 26% confirmed response rate and median overall survival of 10.2 months. A follow-up phase III trial comparing FOLFIRINOX with gemcitabine for patients <75 years of age with advanced pancreatic cancer was presented at ASCO 2010 revealing improvement in PFS (6.4 vs 3.3 months, p=<.0001) and improved disease control rate (CR+PR+SD) (70.2% vs 50.9%, p=.0003). The most notable result was an impressive improvement in median overall survival with FOLFIRINOX compared to gemcitabine (11.1vs 6.8 months, p-value = <.0001, HR=.57). The main toxicity was grade 3/4 neutropenia (45.7% vs 18.7%, p=.0001) and increased risk of febrile neutropenia (5.4% vs 0.6%, p=.009)31.

Official Title
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A Phase II Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine With Concurrent IMRT in Patients With Borderline Resectable Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: FOLFIRINOX
* Radiation: Intensity-modulated radiotherapy (IMRT)
* Procedure: Surgical Exploration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have cytologic or histologic confirmation of carcinoma arising in the pancreas. Patients must be deemed to have borderline resectable disease with no radiologic evidence of distant metastatic disease prior to registration. Specifically, patients must have at least one designation of borderline resectable and no designation of unresectable disease. Patients must have a life expectancy of at least 12 weeks, a Zubrod performance status of < 1 and be willing and medically able to undergo surgical resection. Patients must have adequate organ function defined as follows: absolute neutrophil count of > 1500/mm3, platelets > 100,000/mm3, serum Cr < 1.5 mg/dl, total bilirubin < 2.0 mg/dl with relief of biliary obstruction if present (PTC tube or endobiliary stent). Patients must be free of other active systemic malignancy, ongoing infection, or any other serious uncontrolled, concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy. Patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial due to the unacceptable teratogenic toxicity of abdominal radiation and cytotoxic chemotherapy. Patients must be aware of the investigational nature of the therapy and provide written informed consent. Exclusion Criteria: Patients with neuroendocrine tumors are excluded. Active systemic malignancy, ongoing infection, or any other serious uncontrolled, concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy. Patients with preexisting peripheral neuropathy > grade 2 are ineligible Pregnant or nursing women are ineligible. Patients must have no history of previous chemotherapy for pancreatic cancer or any abdominal radiation therapy. Patients may not have used any investigational agent within 4 weeks prior to enrollment into the study.

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: Study Treatment<br>Patients will receive FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease will be offered surgical exploration. | Drug: FOLFIRINOX<br>* Starting dose levels as following: Oxaliplatin 85mg/m2 intravenously over 120 minutes on day 1. Irinotecan 180mg/m2 intravenously over 90 minutes on day 1. NOTE: patients homozygous for the UGT1A1 (TA)7 promoter allele will be treated at an initial lower dose 140mg/m2 (please see Section 6.3.a) Leucovorin 400mg/m2 intravenously over 90 minutes on day 1. 5FU 400mg/m2 as bolus intravenous injection following leucovorin on day 1. 5FU 2,400mg/m2 infused intravenously as a continuous infusion over 46 hours following the bolus 5FU, beginning on day 1.<br>Radiation: Intensity-modulated radiotherapy (IMRT)<br>* 50.0Gy in 2.0Gy per fraction<br>Procedure: Surgical Exploration<br>* Patients without metastatic disease will be offered surgical exploration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Patients That Underwent an R0 Resection | To determine the frequency of achieving an R0 resection using a neoadjuvant regimen of FOLFIRINOX followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine in patients with borderline resectable pancreatic cancer. R0 resection indicates a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the primary tumor bed. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival Time | To estimate progression-free survival as a function of time from study enrollment. Progression is defined as at least a 20% increase in the LD (longest diameter) of the primary lesion or the appearance of one or more new lesions | up to 2 years | 
| Median Overall Survival Time | To estimate overall survival as a function of time from study enrollment. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant FOLFIRINOX, FDR-Gemcitabine, Concurrent, IMRT, Borderline Resectable Pancreatic Cancer