A Randomized Phase III Trial Comparing Folfirinox to Gemcitabine in Locally Advanced Pancreatic Carcinoma

Study Overview
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Brief Summary
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French national multicentric phase III trial evaluating chemotherapy with Folfirinox or gemcitabine in locally advanced pancreatic carcinoma.

Detailed Description
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Comparative interventional prospective phase 3, randomized, open-label, multicentric trial comparing chemotherapy with Folfirinox to Gemcitabine in locally advanced pancreatic carcinoma.

Official Title
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A Randomized Phase III Trial Comparing Chemotherapy With Folfirinox to Gemcitabine in Locally Advanced Pancreatic Carcinoma

Conditions
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Pancreatic Cancer, Carcinoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Folinic Acid
* Drug: 5-Fluoro-uracil
* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: L-folinic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the pancreas Proven unresectability after multidisciplinary discussion involving radiologist and a surgeon Locally advanced (i.e.: no metastasis or suspicion of metastasis) and unresectable tumors: for example mesenteric or portal vein involvement, or > 180° encasement of the superior mesenteric artery, or celiac abutment (NCCN 2012 criteria) Measurable tumor lesions with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan according RECIST 1.1 WHO Performance status (PS) 0-1 Age ≥18 years Patient with organ function as follows: Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L Hemoglobin ≥ 10 g/dL Platelets (PTL) ≥ 75 x 10⁹/L Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) Bilirubin ≤ 1.5 x ULN Creatinine ≤ 2 x ULN Albumin > 0.75 x lower limit of normal (LLN) Urea ≤ 2 x ULN Adequate vital functions Patient of child-bearing potential (for female patient: study entry after a menstrual period and a negative pregnancy test) must agree to use medically acceptable methods of contraception during the study and for 4 months after the last intake of study treatment for women and for 6 months after for men. Patient information and signed informed consent form Public or private health insurance coverage Uracilemia < 16 ng/ml Exclusion Criteria: Patient treated for a cancer other than pancreatic cancer within 5 years before enrolment, with the exception of basal cell carcinoma or in situ cervical cancer Patient with metastasis or with history of metastasis Patient with grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e. congestive heart failure, myocardial infarction within 6 months before baseline) Major comorbidity, active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes that may preclude the delivery of the treatment Pre-existing neuropathy (Grade ≥ 2), Gilbert's disease or genotype UGT1A1 * 28 / * 28 Pregnant woman Fructose intolerance Patients currently treated by warfarin Persons deprived of liberty or under guardianship Psychological condition, family-, sociological- or geographical situation potentially hampering compliance with the study protocol and the follow-up schedule

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Gemcitabine<br>Gemcitabine 1000 mg/m² IV infusion over 30 minutes on D1 of each week for the 4 weeks of the first cycle (1 cycle = 4 weeks). For the following five cycles, gemcitabine infusion on D1, D8, and D15 of each cycle, followed by 1 week without injection (i.e. in total 4 cycles over 24 weeks; with 19 administrations of Gemcitabine). | Drug: Gemcitabine<br> <br> |
| Experimental: Arm B: Folfirinox<br>Administered once every 14 days for 24 weeks (12 cycles). A cycle equals 14 days with injection on D1 of each cycle. Treatment starts with oxaliplatin (85 mg/m²) administration; IV infusion over 2 hours, followed by the simultaneous administration (using a Y-tubing) of folinic acid 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) IV infusion over 2 hours and irinotecan 180 mg/m² IV infusion over 90 minutes. The irinotecan will begin 30 minutes after the start of the folinic acid infusion. 5-Fluoro-uracil (5-FU) IV 2,400 mg/m²/h will be administered over 46 hours after the end of the folinic acid infusion, i.e. 1200 mg/m²/day for the duration of 2 days. Treatment will be continued for 24 weeks (12 cycles). | Drug: Folinic Acid<br> <br> Drug: 5-Fluoro-uracil<br> <br> Drug: Oxaliplatin<br> <br> Drug: Irinotecan<br> <br> Drug: L-folinic<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free-Survival (PFS) | To compare Progression-Free-Survival (PFS) between the two treatment arms | From randomization until disease progression or date of death, assessed up until to 128 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite index for treatment early severe toxicity | Biliary tract infection Grade 3-4 + any grade 5 toxicities + chemotherapy interruption for toxicity during the first four cycles. | First four chemotherapy cycles, 16 weeks | 
| Adverse events (NCI-CTCAE version 4.0); observance of chemotherapy | Observance of chemotherapy | During treatment phase, 24 weeks | 
| Overall Survival | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. The outcome is to evaluate whether SRBT improves overall survival compared to standard of care. | Until death, assessed up 128 weeks after randomization | 
| Progression-free survival: pattern of failure | The progression-free survival is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. | Until Disease Progression, assessed uo until 128 weeks after randomization | 
| Percentage of secondarily curative-intent surgery | Percentage of patients who will undergo an exeresis of their pancreatic tumor, with R0 resection confirmed by anatomopathic pathology. | Until surgery, if applicable, up until 128 weeks after randomization | 
| Objective tumour response, disease control and their duration | Objective tumour response, disease control and their duration (RECIST version 1.1), | Until disease progression or date of death, assessed up until 128 weeks after randomization | 
| Time to treatment failure | Time to treatment failure | From randomisation to the end of treatment | 
| Quality of life questionnaire - Core 30 (QLQ-C30) | Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | assessed up until 128 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FOLFIRINOX, locally advanced pancreatic carcinoma