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

Phase 3

Completed

• Conditions: Pancreatic Cancer; Carcinoma
• Interventions: Drug: Gemcitabine; Drug: Folinic Acid; Drug: 5-Fluoro-uracil; Drug: Oxaliplatin; Drug: Irinotecan; Drug: L-folinic

• Registration Number: NCT02539537
• Lead Sponsor: UNICANCER

Brief Summary

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

Detailed Description

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

Study Timeline

• Study First Submitted: 2015-08-03
• Study First Submitted QC: 2015-08-31
• Study First Posted: 2015-09-03
• Study Start: 2015-10-23
• Primary Completion: 2022-02
• Study Completion: 2023-09-25
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-08
• Last Update Posted: 2024-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 171

Inclusion Criteria

1. Histologically or cytologically confirmed adenocarcinoma of the pancreas

2. Proven unresectability after multidisciplinary discussion involving radiologist and a surgeon

3. 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)

4. Measurable tumor lesions with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan according RECIST 1.1

5. WHO Performance status (PS) 0-1

6. Age ≥18 years

7. 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

8. Adequate vital functions

9. 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.

10. Patient information and signed informed consent form

11. Public or private health insurance coverage

12. Uracilemia < 16 ng/ml

Exclusion Criteria

1. 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
2. Patient with metastasis or with history of metastasis
3. 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)
4. Major comorbidity, active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes that may preclude the delivery of the treatment
5. Pre-existing neuropathy (Grade ≥ 2), Gilbert's disease or genotype UGT1A1 * 28 / * 28
6. Pregnant woman
7. Fructose intolerance
8. Patients currently treated by warfarin
9. Persons deprived of liberty or under guardianship
10. Psychological condition, family-, sociological- or geographical situation potentially hampering compliance with the study protocol and the follow-up schedule

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: Folfirinox	5-Fluoro-uracil	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).
Arm B: Folfirinox	L-folinic	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).
Arm A: Gemcitabine	Gemcitabine	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).
Arm B: Folfirinox	Folinic Acid	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).
Arm B: Folfirinox	Oxaliplatin	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).
Arm B: Folfirinox	Irinotecan	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).

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Until death, assessed up 128 weeks after randomization	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.
Percentage of secondarily curative-intent surgery	Until surgery, if applicable, up until 128 weeks after randomization	Percentage of patients who will undergo an exeresis of their pancreatic tumor, with R0 resection confirmed by anatomopathic pathology.
Objective tumour response, disease control and their duration	Until disease progression or date of death, assessed up until 128 weeks after randomization	Objective tumour response, disease control and their duration (RECIST version 1.1),
Time to treatment failure	From randomisation to the end of treatment	Time to treatment failure
Quality of life questionnaire - Core 30 (QLQ-C30)	assessed up until 128 weeks after randomization	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.
Adverse events (NCI-CTCAE version 4.0); observance of chemotherapy	During treatment phase, 24 weeks	Observance of chemotherapy
Composite index for treatment early severe toxicity	First four chemotherapy cycles, 16 weeks	Biliary tract infection Grade 3-4 + any grade 5 toxicities + chemotherapy interruption for toxicity during the first four cycles.
Progression-free survival: pattern of failure	Until Disease Progression, assessed uo until 128 weeks after randomization	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.

Trial Locations

Locations (45)

Hôpital Trousseau; 🇫🇷 Chambray-les-tours, France

Hôpital Avicenne; 🇫🇷 Bobigny, France

CHU Amiens - Hôpital Nord; 🇫🇷 Amiens, France

CHU d'Angers; 🇫🇷 Angers, France

CHU Côte de Nacre; 🇫🇷 Caen, France

CHD Vendée; 🇫🇷 La Roche Sur Yon, France

Centre hospitalier Henri Duffaut; 🇫🇷 Avignon, France

Polyclinique Bordeaux Nord; 🇫🇷 Bordeaux, France

Centre Hospitalier Intercommunal Aix-Pertuis; 🇫🇷 Aix-en-Provence, France

Groupe hospitalier Pitié Salpétrière; 🇫🇷 Paris, France

CHU Rouen; 🇫🇷 Rouen, France

Hôpital Privé des Côtes d'Armor; 🇫🇷 Saint Brieuc, France

Clinique mutualiste de l'Estuaire; 🇫🇷 Saint-Nazaire, France

Hôpital Saint Antoine; 🇫🇷 Paris, France

CHR d'Orléans La Source; 🇫🇷 Orléans, France

Centre hospitalier d'Auxerre; 🇫🇷 Auxerre, France

Institut Bergonié; 🇫🇷 Bordeaux, France

Centre François Baclesse; 🇫🇷 Caen, France

CH Boulogne sur Mer; 🇫🇷 Boulogne sur Mer, France

CH de Dijon; 🇫🇷 Dijon, France

Centre Hospitalier de Laon; 🇫🇷 Laon, France

Hôpital Edouard Herriot - Lyon; 🇫🇷 Lyon, France

Centre Oscar Lambret; 🇫🇷 Lille, France

CHU de Limoges; 🇫🇷 Limoges, France

Centre Regional René Gauducheau; 🇫🇷 Saint Herblain, France

Hôptal Européen; 🇫🇷 Marseille, France

Hôpital De La Timone; 🇫🇷 Marseille, France

Centre Hospitalier de Saint Malo; 🇫🇷 Saint Malo, France

CHU Hotel Dieu; 🇫🇷 Nantes, France

Centre Hospitalier de Meaux; 🇫🇷 Meaux, France

Institut de cancérologie Lucien Neuwirth; 🇫🇷 Saint Priest En Jarez, France

CHI Elbeuf; 🇫🇷 Saint-Aubin-lès-Elbeuf, France

Centre Hospitalier de Soissons; 🇫🇷 Soissons, France

Centre Hospitalier de Rangueil; 🇫🇷 Toulouse, France

CH Annecy Genevois; 🇫🇷 Pringy, France

Centre Paul Strass; 🇫🇷 Strasbourg, France

Hôpital Saint Joseph Saint Luc; 🇫🇷 Lyon, France

Polyclinique de l'Ormeau-GROP; 🇫🇷 Tarbes, France

Hôpitaux civils de Colmar; 🇫🇷 Colmar, France

Groupe Hospitalier du Havre Jacques Monod; 🇫🇷 Montivilliers, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Groupe hospitalier Paris Saint Joseph; 🇫🇷 Paris, France

CHU - Robert Debre; 🇫🇷 Reims, France

Hôpital privé Saint Claude; 🇫🇷 Saint-quentin, France

Gustave Roussy; 🇫🇷 Villejuif, France