A Study of Administering FOLFIRINOX Before Surgery For Potentially Curable Pancreatic Cancer

Study Overview
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Brief Summary
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Pancreatic cancer is a serious condition and is one of the leading cause of cancer related health problem. It is estimated that in 2016, 5,200 Canadians will be diagnosed with pancreatic cancer, and approximately 20% (1 in 5) of patients will have localized cancer (cancer that is limited to pancreas and there is no evidence of cancer in other parts of the body). Localized cancer is earlier stage of disease and surgery to remove the cancer is standard of care in this condition. However, recent scientific and clinical studies show that using the chemotherapy medication before surgery can improve the overall survival in patents with localized pancreatic cancer. One of these chemotherapy regimen is combination of fluorouracil, oxaliplatin, irinotecan, leucovorin (FOLFIRINOX) that we are going to evaluate its effect in this study. Because of promising result of this combination in more advanced stage of pancreatic cancer, this study is going to examine its efficiency in earlier stage of pancreatic cancer (localized form). Total number of participant in this study will be 20 patients with localized form of pancreatic cancer without any evidence of cancer in other parts of the body. Laboratory tests show that it works by slowing down the growth of cancer or may cause cancer cells to die. It is hoped that by shrinking the tumor size, the surgeon will be able to remove the cancer and improve the overall survival. Procedures start with 2 weeks of comprehensive evaluation. Approximately 20 eligible subjects, based on this study criteria, will receive 6 treatment of this regimen every 2 weeks. Once 6 treatments have been completed, comprehensive re-evaluation procedures will be repeated, and subjects without disease progression or unacceptable toxicity will continue on their treatment based on treating team decision (surgical intervention, radiation therapy or continue FOLFIRINOX or different regimen). Patients then will follow with CT scan, blood test and physical examination every 3 months.

Detailed Description
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Approximately 20% of patients present with potentially curable pancreatic cancers-resectable or borderline resectable tumors- for which surgical resection is an appropriate consideration. However, even after multimodality therapy that includes surgical resection, 5-year OS rates only reach 25% to 30% at best. Surgical resection represents the standard of care for patients with early-stage pancreatic cancer. However, while surgical morbidity and mortality have improved over the past few decades, overall survival for pancreatic cancer has remained low. Given the increasing survival rates associated with modern chemotherapy regimens, the risks of surgery, the likelihood of R0 resection, the likelihood of subclinical metastatic disease, and the likelihood of receiving postoperative therapy (50% of patients receive post-operative chemotherapy) are our logic to evaluate preoperative chemotherapy as an alternative treatment strategy for these patients. The main advantage of neoadjuvant chemotherapy in treating pancreatic cancer is that it significantly increases the likelihood of receiving both surgery and chemotherapy. (Winner et al., Seminars in Oncology, 2015). It is well accepted that the best results are achieved when both modalities are used. Recently, the use of FOLFIRINOX has emerged as an alternative in pancreatic cancer. A randomized trial of FOLFIRINOX versus gemcitabine in metastatic pancreatic cancer showed improved median survival from 6.8 to 11.1 months. According to ACCORD-11 trial,FOLFIRINOX in advanced metastatic disease have demonstrated improved response rates compared with gemcitabine and other historical treatments while maintaining or improving quality of life with the median overall survival was 11.1 months FOLFIRINOX group as compared with 6.8 months in the gemcitabine group. Median progression-free survival was 6.4 months in the study regimen group and 3.3 months in the gemcitabine group, and at 6 months, 31% of the patients FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group. The role of preoperative therapy for patients with potentially curable pancreatic cancer is still unclear. The ongoing study (adjuvant gemcitabine versus neoadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer) is a prospective randomized clinical trial that is anticipated to clarify the role of preoperative chemotherapy. However, this ongoing clinical trial does not use contemporary chemotherapy regimens with proven efficacy in higher stage settings such as FOLFIRINOX. There are only few studies evaluate this regimen in this setting.The encouraging results reported from ACCORD-11 and consequent clinical investigations prompted our group to evaluate our experience with FOLFIRINOX regimen in a selected population composed of patients with potentially curable pancreatic cancer (resectable and borderline resectable). In this clinical trial, our primary objective is to evaluate and estimate Time to Progression (TTP). However, our secondary objectives are to determine Overall Response Rate (ORR), R0 and R1 Resection Rate, assessment of safety and toxicity associated with study regimen, and finally, to investigate Overall survival (OS). Pre-treatment procedures start with 2 weeks of comprehensive staging evaluation. Approximately 20 eligible subjects, based on inclusion/exclusion criteria will receive study regimen for 6 treatment every 2 weeks. Once 6 treatments have been completed, comprehensive re-staging procedures will be repeated, and subjects without disease progression or unacceptable toxicity will continue on their treatment contingent upon treating team decision (surgical intervention, radiation therapy or continue chemotherapy with FOLFIRINOX or different regimen). Patients then follow with CT scan, cancer antigen 19-9 and physical examination every 3 months. Subjects will be considered active study participants from enrollment up to survival follow-up period until documented disease progression, withdrawal of consent, lost to follow-up, or death (by any cause), whichever is earliest.

Official Title
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A Study of Preoperative FOLFIRINOX For Potentially Curable Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: ≥ 18 years of age at the time of signing the informed consent form. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures conducted. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Performance status or Comorbidity condition not currently appropriate (but potentially reversible) for a major abdominal operation. Acceptable hematology parameters: Absolute neutrophil count (ANC) ≥ 1500 cell/mm3 Platelet count ≥ 100,000/mm3 without transfusion support. Hemoglobin (Hgb) ≥ 9 g/dL Acceptable blood chemistry levels: Hepatic transaminases (ALT and AST) less than 2.5× the upper limits of normal (ULN) Total bilirubin level less than 1.5 × the upper limits of normal (ULN) or in patient with Biliary stenting less than 2 mg/dL Serum creatinine level less than 1.5 × the upper limits of normal (ULN) or creatinine clearance (Ccr) ≥ 40 mL/min. Alkaline phosphatase ≤ 2.5 x ULN Serum albumin > 3 g/dL Absence of poorly controlled comorbid conditions: Congestive heart failure (CHF) Chronic obstructive pulmonary disease (COPD) Uncontrolled diabetes mellitus (DM) Neurologic disorders (not acutely related to pancreatic cancer) or limit function Radio-graphically suspicious but not diagnostic for extra-pancreatic disease, Superior mesenteric vein and portal vein confluence that can be reconstructed even if short segment venous occlusion is present (i.e. a suitable portal vein above, and a suitable Superior mesenteric vein below the area of occlusion); Tumor abutment of the Superior mesenteric artery of ≤180⁰, Short segment encasement of the hepatic artery amenable to resection and reconstruction (this is usually at the origin of the gastroduodenal artery and reconstruction may or may not require interposition grafting with a short segment of reversed saphenous vein). Cancer antigen 19-9 level (in absence of jaundice) ≥ 100u/ml suggestive of disseminated disease. Preoperative treatment is recommended as an alternative for patients with potentially curable pancreatic cancer who meet all of the following criteria: no clinical evidence for metastatic disease, a performance status and comorbidity condition appropriate for a major abdominal operation, no radiographic interface between primary tumor and mesenteric vasculature on imaging, an acceptable Cancer antigen 19-9 level. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Pancreatic tumors of endocrine or mixed origin. Prior anticancer therapy for pancreatic carcinoma. Presence of or history of metastatic pancreatic adenocarcinoma. Any other malignancy within 5 years prior to enrollment, with the exception of adequately treated in-situ carcinoma of the prostate (Gleason score ≤ 7), cervix, uteri, or non-melanomatous skin cancer (all treatment of which should have been completed 6 months prior to enrollment). Active bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subject receiving immunosuppressive or myelo-suppressive medications that would, in the opinion of the Investigator, increase the risk of serious neutropenic complications. History of allergy or hypersensitivity to study regimen or any of their excipients. Peripheral sensory neuropathy Grade > 1. Clinically significant ascites. Plastic biliary stent. (Metal biliary stent is allowed.) Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the subject's safety or the integrity of the study data. These include, but are not limited to: History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa) History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or multiple allergies History of the following within 6 months prior to treatment 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder Enrollment in any other clinical protocol or investigational study with an interventional agent or assessments that may interfere with study procedures. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Any condition that confounds the ability to interpret data from the study. Unwillingness or inability to comply with study procedures. Pregnant or breast feeding.

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: FOLFIRINOX<br>Oxaliplatin, Irinotecan, Leucovorin, Fluorouracil | Drug: Oxaliplatin<br>* Patients receive Oxaliplatin 85 mg/m2 over 2 hours.<br>* Other names: Study regimen;Drug: Irinotecan<br>* Oxaliplatin is followed by Irinotecan (CPT-11) 180 mg/m2 over 90 min.<br>* Other names: Study regimen;Drug: Leucovorin<br>* Oxaliplatin and Irinotecan is followed by Leucovorin (LV) 400 mg/m2 over 2 hours day1<br>* Other names: Study regimen;Drug: Fluorouracil<br>* Oxaliplatin and Irinotecan and Leucovorin is followed by Fluorouracil (5-FU) 400 mg/m2 bolus day1 and 2,400 mg/m2 46h continuous infusion.<br>* Other names: Study regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP). | Time to Progression (TTP) is defined as the time from the first cycle of chemotherapy until objective tumor progression. | Through study completion, an average of 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate will be summarized based on RECIST V1.1 | Through study completion, an average of 1 year | 
| Residual (R) tumor status | The R classification is based on International Union Against Cancer (UICC). | Through study completion, an average of 1 year. | 
| Incidence of Treatment related Adverse Events [Safety and Tolerability] | Safety and toxicity variable is the incidence of treatment related adverse effect, serious adverse effect, laboratory abnormalities and other safety parameters. | Through study completion, an average of 1 year. | 
| Overall survival (OS) | Overall survival indicates the interval between the first cycle of chemotherapy and the occurrence of death from any cause. | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Potentially Curable, Preoperative, FOLFIRINOX