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

Study Overview
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Brief Summary
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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.

Detailed Description
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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+)

Official Title
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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

Conditions
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Cancer of the Rectum

Intervention / Treatment
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* Drug: mFolfirinox
* Radiation: Radiotherapy 50 Gy
* Drug: Capecitabine
* Procedure: TME surgery
* Drug: mFolfox6 or capecitabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 : Radiotherapy + capecitabine<br>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<br>* 5 radiations per week of 2 Gy for 5 weeks<br>Drug: Capecitabine<br>* 1600 mg/m² (800 mg/m² twice daily) for 5 weeks<br>Procedure: TME surgery<br> <br> Drug: mFolfox6 or capecitabine<br>* 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.<br>|
| Experimental: Arm B : Chemotherapy then radiochemotherapy<br>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<br>* 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.<br>Radiation: Radiotherapy 50 Gy<br>* 5 radiations per week of 2 Gy for 5 weeks<br>Drug: Capecitabine<br>* 1600 mg/m² (800 mg/m² twice daily) for 5 weeks<br>Procedure: TME surgery<br> <br> Drug: mFolfox6 or capecitabine<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectum, cancer, locally advanced