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

Sponsor

UNICANCER (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01804790

Collaborator

(none)

461

Enrollment

Locations

Arms

136

Anticipated Duration (Months)

12.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cancer of the Rectum	Drug: mFolfirinox Radiation: Radiotherapy 50 Gy Drug: Capecitabine Procedure: TME surgery Drug: mFolfox6 or capecitabine	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

461 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Sep 1, 2019

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

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.	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. 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.

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.

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.

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

Outcome Measures

Primary Outcome Measures

disease-free survival [3 years]
To compare the 3-year disease-free survival between the investigational arm and the control arm.

Secondary Outcome Measures

Overall survival [7 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	Centre hospitalier Universitaire d'Amiens	Amiens	France
2	ICO - Site Paul Papin	Angers	France
3	Centre hospitalier d'Auxerre	Auxerre	France
4	Centre Hospitalier de Beauvais	Beauvais	France
5	Institut de Cancérologie de Franche Comté	Besancon	France
6	Centre Hospitalier de Blois	Blois	France
7	Hopital Avicenne	Bobigny	France
8	Clinique Tivoli	Bordeaux	France
9	Hopital Saint Andre	Bordeaux	France
10	Institut Bergonie	Bordeaux	France
11	Centre Francois Baclesse	Caen	France
12	Chd de La Roche Sur Yon - Les Oudairies	La Roche-sur-yon	France
13	Centre Bourgogne	Lille	France
14	Centre Oscar Lambret	Lille	France
15	Centre Léon Bérard	Lyon	France
16	Hopital Prive Jean Mermoz	Lyon	France
17	Ap Hm - Hopital de La Timone - Adultes	Marseille	France
18	Institut de Cancérologie de Franche Comté	Montbeliard	France
19	Centre Azuréen de cancérologie	Mougins	France
20	Hopital Emile Muller	Mulhouse	France
21	centre Alexis Vautrin	Nancy	France
22	Polyclinique de Gentilly	Nancy	France
23	Centre Antoine Lacassagne	Nice	France
24	Groupe Hospitalier La Pitie-Salpetriere	Paris	France
25	Institut Mutualiste Montsouris	Paris	France
26	Hopital Haut Leveque	Pessac	France
27	Centre Hospitalier Regional D'Annecy	Pringy	France
28	Hopital Robert Debre	Reims	France
29	Institut Jean Godinot	Reims	France
30	Clinique Armoricaine de Radiologie	Saint-brieuc	France
31	Hopital Saint Gregoire	Saint-gregoire	France
32	Clinique Mutualiste de L'Estuaire	Saint-nazaire	France
33	Centre Hospitalier de la Réunion - Site du GHSR	Saint-pierre	France
34	ICO - Site René Gauducheau	St Herblain	France
35	Centre Paul Strauss	Strasbourg	France
36	Gustave Roussy	Villejuif	France