Efficacy of Neoadjuvant Folfirinox Regimen in Patients With Resectable Locally Advanced Rectal Cancer (Néofirinox)

Randomized Phase III Study Comparing Preoperative Chemoradiotherapy Alone Versus Neoadjuvant Chemotherapy With Folfirinox Regimen Followed by Preoperative Chemoradiotherapy for Patients With Resectable Locally Advanced Rectal Cancer

National, multi-center, open-label,randomized, 2-arm phase III superiority trial, comparing neoadjuvant chemotherapy (CT) with mFolfirinox followed by preoperative chemoradiotherapy (CRT), versus preoperative CRT in patients with locally advanced rectal cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Cancer of the Rectum
• Intervention / Treatment: Radiation: Radiotherapy 50 Gy; Drug: Capecitabine; Procedure: TME surgery; Drug: mFolfox6 or capecitabine; Drug: mFolfirinox

Detailed Description

Methodology This is a biomedical research, national, multicenter, open-label randomized, 2-arm phase III superiority trial, comparing neoadjuvant CT with mFolfirinox then preoperative CRT, versus immediate preoperative CRT, in patients with locally advanced rectal cancer Randomized Phase III study with stopping rules Stratification : center, gender, tumor location in the rectum (<6 cm from anal verge versus ≥6 cm), initial stage (cT3 vs cT4, and cN0 vs cN+)

• Study Type: Interventional
• Enrollment (Actual): 461
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Centre Hospitalier Universitaire d'Amiens
  • Angers, France
    • ICO - Site Paul Papin
  • Auxerre, France
    • Centre Hospitalier d'Auxerre
  • Beauvais, France
    • Centre Hospitalier De Beauvais
  • Besancon, France
    • Institut de Cancérologie de Franche Comté
  • Blois, France
    • Centre Hospitalier de Blois
  • Bobigny, France
    • Hôpital Avicenne
  • Bordeaux, France
    • Institut Bergonie
  • Bordeaux, France
    • Hopital Saint André
  • Bordeaux, France
    • Clinique Tivoli
  • Caen, France
    • Centre Francois Baclesse
  • La Roche-sur-yon, France
    • Chd de La Roche Sur Yon - Les Oudairies
  • Lille, France
    • Centre OSCAR LAMBRET
  • Lille, France
    • Centre Bourgogne
  • Lyon, France
    • Centre LEON BERARD
  • Lyon, France
    • Hopital Prive Jean Mermoz
  • Marseille, France
    • Ap Hm - Hopital de La Timone - Adultes
  • Montbeliard, France
    • Institut de Cancérologie de Franche Comté
  • Mougins, France
    • Centre Azuréen de Cancérologie
  • Mulhouse, France
    • Hôpital Emile Muller
  • Nancy, France
    • Centre Alexis Vautrin
  • Nancy, France
    • Polyclinique de Gentilly
  • Nice, France
    • Centre Antoine Lacassagne
  • Paris, France
    • Institut Mutualiste Montsouris
  • Paris, France
    • Groupe Hospitalier La Pitie-Salpetriere
  • Pessac, France
    • Hôpital Haut Lévêque
  • Pringy, France
    • Centre Hospitalier Regional D'Annecy
  • Reims, France
    • Institut Jean Godinot
  • Reims, France
    • Hôpital Robert Debré
  • Saint-brieuc, France
    • Clinique Armoricaine de Radiologie
  • Saint-gregoire, France
    • Hopital Saint Gregoire
  • Saint-nazaire, France
    • Clinique Mutualiste de l'Estuaire
  • Saint-pierre, France
    • Centre Hospitalier de la Réunion - Site du GHSR
  • St Herblain, France
    • ICO - Site René Gauducheau
  • Strasbourg, France
    • Centre Paul Strauss
  • Villejuif, France
    • Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically proven rectal adenocarcinoma
• Stages cT3 with risk of local recurrence or cT4, M0 and for which a multidisciplinary meeting recommend preoperative CRT
• Resectable tumor, or considered as potentially resectable after CRT
• No distant metastases
• Patient eligible for surgery
• Patient aged from 18 to 75 years
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status 0/2.
• No heart failure or coronary heart disease symptoms (even controlled).
• No peripheral neuropathy > grade 1
• No prior radiotherapy of the pelvis for any reason and no previous CT
• No major comorbidity that may preclude the delivery of treatment and no active infection (HIV or chronic hepatitis B or C).
• Adequate contraception in fertile patients.
• Adequate hematologic function
• Adequate hepatic function
• Signed written informed consent

Exclusion Criteria:

• Metastatic disease
• Unresectable rectal cancer, including prostatic involvement or extension to pelvic floor muscles
• Contraindication to 5-FU, or to oxaliplatin or to irinotecan, including Gilbert disease or genotype UGT1A1
• Medical history of chronic diarrhea or inflammatory disease of the colon or rectum
• Medical history of angina pectoris or myocardial infarction
• Progressive active infection or any other severe medical condition that could jeopardize treatment administration
• Other concomitant cancer, or medical history of cancer other than treated in situ cervical carcinoma or basocellular carcinoma or spinocellular carcinoma
• Patient included in another clinical trial testing an investigational agent.
• Pregnant or breast-feeding woman.
• Persons deprived of liberty or under guardianship or incapable of giving consent
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A : Radiotherapy + capecitabine; Chemoradiotherapy 5 weeks (50 Grays (Gy), 2 Gy/session ; 25 fractions) + capecitabine 800 mg/m² twice daily 5 days/7, excluding weekends), then 6-8 weeks after chemoradiation, surgery with total mesorectal excision (TME), followed by adjuvant chemotherapy for 6 months, either mFolfox6 or capecitabine, depending on the center's choice.	Radiation: Radiotherapy 50 Gy; 5 radiations per week of 2 Gy for 5 weeks; Drug: Capecitabine; 1600 mg/m² (800 mg/m² twice daily) for 5 weeks; Procedure: TME surgery; Drug: mFolfox6 or capecitabine; oxaliplatine 85 mg/m² (day 1 of cycle; perfusion in 2h), folinic acid 400 mg/m² (day 1 of cycle perfusion in 2h), 5-FU (bolus 400 mg/m² in 10 min and 2400 mg/m² perfusion continuous 46h). Arm A - 12 cycles ; Arm B - 6 cycles OR Capecitabine 2500 mg/m²/day (Each cycle consists of 1250 mg/m² twice daily for D1-14 then pause therapeutic from D15-21). Arm A - 8 cycles; Arm B 4 cycles.
Experimental: Arm B : Chemotherapy then radiochemotherapy; Drug: Chemotherapy mFolfirinox Investigational arm: Neoadjuvant CT mFolfirinox, 6 cycles (ca. 3 months; each cycle = 2 weeks): oxaliplatin: 85 mg/m² in 2 hours at D1 irinotecan: 180 mg/m² in 90 min at D1 folinic acid: 400 mg/m² simultaneously in 2 hours at D1 during the irinotecan infusion 5-fluorouracil (5-FU): 2400 mg/m² continuous infusion during 48 hours (1200 mg/m² at D1 and D2), every 14 days during 2 months (4 cycles). Then followed by 5 weeks of chemoradiotherapy 50 Gy (2 Gy/session, 5 sessions per week) + capecitabine 800 mg/m² twice daily 5 days/7), then surgery with TME 6-8 weeks after chemoradiation, followed by 3 months of adjuvant chemotherapy, either mFolfox6 or capecitabine depending on the center's choice.	Radiation: Radiotherapy 50 Gy; 5 radiations per week of 2 Gy for 5 weeks; Drug: Capecitabine; 1600 mg/m² (800 mg/m² twice daily) for 5 weeks; Procedure: TME surgery; Drug: mFolfox6 or capecitabine; oxaliplatine 85 mg/m² (day 1 of cycle; perfusion in 2h), folinic acid 400 mg/m² (day 1 of cycle perfusion in 2h), 5-FU (bolus 400 mg/m² in 10 min and 2400 mg/m² perfusion continuous 46h). Arm A - 12 cycles ; Arm B - 6 cycles OR Capecitabine 2500 mg/m²/day (Each cycle consists of 1250 mg/m² twice daily for D1-14 then pause therapeutic from D15-21). Arm A - 8 cycles; Arm B 4 cycles.; Drug: mFolfirinox; Investigational arm: Neoadjuvant chemotherapy mFolfirinox, 4 cycles: oxaliplatin: 85 mg/m² in 2 hours at D1 irinotecan: 180 mg/m² in 90 min at D1 folinic acid: 400 mg/m² simultaneously in 2 hours at D1 during the irinotecan infusion 5-FU: 2400 mg/m² continuous infusion during 48 hours (1200 mg/m² at D1 and D2), every 14 days during 2 months (4 cycles), then CRT (50 Gy (2 Gy/session, 25 fractions) + capecitabine 800 mg/m² twice a day 5 days/7), then surgery with TME 6-8 weeks after chemoradiation, and 4 months of adjuvant CT depending on the center's choice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease-free survival	To compare the 3-year disease-free survival between the investigational arm and the control arm.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival will be defined as the time from randomisation to the time of occurrence of the first death regardless to its cause. Patients alive at the time of analysis will be censored at the date of the last follow up.	7 years

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Thierry CONROY, PROF, centre Alexis Vautrin les Nancy

Publications and helpful links

General Publications

• Conroy T, Bosset JF, Etienne PL, Rio E, Francois E, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouche O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardiere C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. doi: 10.1016/S1470-2045(21)00079-6. Epub 2021 Apr 13.

Helpful Links

• Lancet Oncology 2021 Apr 13: publication of results

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2012
• Primary Completion (Actual): September 1, 2019
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: March 4, 2013
• First Posted (Estimated): March 5, 2013

Study Record Updates

• Last Update Posted (Actual): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: cancer; rectum; locally advanced
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: PRODIGE 23 - UCGI 23; 2011-004406-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.
• IPD Sharing Time Frame: The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.
• IPD Sharing Access Criteria: Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No