Adjuvant FOLFIRI Based-chemotherapy After Resection of CLM Responding to Preoperative FOLFIRI

NCT ID: NCT06501482

Last Updated: 2024-07-15

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 254 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-30
• Study Completion Date: 2030-09-30

Brief Summary

Eligible patients are patients with contraindication to preoperative oxaliplatin based-chemotherapy who underwent resection of no more than 10 colorectal liver metastases after preoperative FOLFIRI based chemotherapy with or without targeted agents. These patients must have objective response to treatment (radiologic or pathologic response). The standard care for these patients is no postoperative treatment although benefit of reintroduction of FOLFIRI chemotherapy in good responders could be expected.

This study is a National, multicenter, open-label randomized, 2-arm, phase III superiority trial comparing postoperative reintroduction of FOLFIRI based-chemotherapy (experimental arm) vs no treatment (control arm) in patients undergoing resection of colorectal liver metastases after good response to FOLFIRI-based chemotherapy with or without targeted agent.

The primary endpoint of the study is 3-year disease free survival. Based on published data, 3-year DFS in control group (absence of postoperative treatment is 25%. Expected 3-year DFS in the experimental group is 40%. The study will randomize 254 patients (127 in the chemotherapy group and 127 in the no treatment group) in 30 french academic centers.

Detailed Description

This study is a National, multicenter, open-label randomized, 2-arm, phase III superiority trial comparing postoperative reintroduction of FOLFIRI based-chemotherapy (experimental arm) vs no treatment (control arm) in patients undergoing resection of colorectal liver metastases after good response to FOLFIRI-based chemotherapy with or without targeted agent.

Inclusion criteria are:

• Histologically proven resected metachronous CLM with curative intent that could not be treated with perioperative oxaliplatin-based chemotherapy for oncologic or tolerability reasons. For this study, metachronous CLM is defined as liver recurrence occurring more than 12 months after treatment of the primary colorectal cancer.
• No more than 10 treated CLM at surgery
• At least 2 cycles and no more than 8 cycles of preoperative FOLFIRI based chemotherapy ± targeted therapy.
• Preoperative FOLFIRI based chemotherapy ± targeted therapy administered no more than 12 weeks before surgery
• R0/R1resection ± radiofrequency ablation with curative intent of all liver deposits with no macroscopic residual liver disease
• Objective response to preoperative therapy defined as complete or partial radiological response and/or major or complete pathologic response
• No extrahepatic or residual liver disease on baseline work-up including thoraco-abdominal CT scan within 6 weeks after surgery. 1 non-specific lung nodule of less than 10 mm in maximum diameter is not considered as extra-hepatic metastases
• Primary tumor (or liver metastasis) of CRC must be characterized for RAS and BRAF status
• No contraindication to FOLFIRI based chemotherapy
• Patients must be 18 years old or older
• A WHO performance status of 0 or 1
• Participants must be affiliated to a social security scheme The primary objective is demonstrate an improvement of disease-free survival rate at 3 years.

In the experimental arm, patients will be treated with irinotecan 180 mg/m2 + leucovorin 400 mg/m2 at day 1 then 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 h biweekly. For a total of 12 cycles of perioperative chemotherapy including the preoperative chemotherapy.

In the control arm, patients do not receive any adjuvant treatment. This is an intention-to-treat trial. Based on published data, 3-year DFS in the control arm is 25%. Expected 3-year DFS in the experimental group is 40%. The sample size in each group is 127, with a total number of 185 events required, an exponential maximum likelihood test of equality of survival curves with a 0,050 two-sided significance level will have 80% power to detect the difference between groups (constant hazard-ratio of 0,662); assuming a 36 month length of accrual period, a 72 maximum length of follow up and 5% annual attrition (following exponential model) over study period (following exponential model) over study period.

Conditions

Colorectal Cancer; Colorectal Liver Metastases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Postoperative FOLFIRI group

Irinotecan 180 mg/m2 + leucovorin 400 mg/m2 at day 1 then 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 h biweekly. For a total of 12 cycles of perioperative chemotherapy including the preoperative chemotherapy

Group Type: EXPERIMENTAL

Postoperative reintroduction of FOLFIRI based chemotherapy

Intervention Type: DRUG

Postoperative reintroduction of FOLFIRI: irinotecan 180 mg/m2 + leucovorin 400 mg/m2 at day 1 then 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 h biweekly. For a total of 12 cycles of perioperative chemotherapy including the preoperative chemotherapy

No treatment group (control group)

No treatment

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Postoperative reintroduction of FOLFIRI based chemotherapy

Postoperative reintroduction of FOLFIRI: irinotecan 180 mg/m2 + leucovorin 400 mg/m2 at day 1 then 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 h biweekly. For a total of 12 cycles of perioperative chemotherapy including the preoperative chemotherapy

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histologically proven resected metachronous CLM with curative intent that could not be treated with perioperative oxaliplatin-based chemotherapy for oncologic or tolerability reasons. For this study, metachronous CLM is defined as liver recurrence occurring more than 12 months after treatment of the primary colorectal cancer.
• No more than 10 treated CLM at surgery
• At least 2 cycles and no more than 8 cycles of preoperative FOLFIRI based chemotherapy ± targeted therapy.
• Preoperative FOLFIRI based chemotherapy ± targeted therapy administered no more than 12 weeks before surgery
• R0/R1resection ± radiofrequency ablation with curative intent of all liver deposits with no macroscopic residual liver disease
• Objective response to preoperative therapy defined as complete or partial radiological response and/or major or complete pathologic response
• No extrahepatic or residual liver disease on baseline work-up including thoraco-abdominal CT scan within 6 weeks after surgery. 1 non-specific lung nodule of less than 10 mm in maximum diameter is not considered as extra-hepatic metastases
• Primary tumor (or liver metastasis) of CRC must be characterized for RAS and BRAF status
• No contraindication to FOLFIRI based chemotherapy
• Patients must be 18 years old or older
• A WHO performance status of 0 or 1
• Participants must be affiliated to a social security scheme

Exclusion Criteria

• Palliative/R2 resection of CLM
• 10 lesions or more treated at the time of surgery
• Patients undergoing only radiofrequency ablation of all liver deposit (this situation precludes the assessment of pathologic response to preoperative chemotherapy)
• Extra-hepatic or residual metastasis of CRC
• Absence of objective response to therapy (radiological or pathological response )
• Inflammatory bowel disease
• Known UGT1A1*28 allele homozygosity
• complete absence of dihydropyrimidine dehydrogenase (DPD) activity (blood uracil level ≥ 150 ng/ml
• Contraindications to investigational medicinal products (irinotecan, 5-FU, folinic acid) and to auxiliary medicinal products (ondansetron, methylprednisolone)
• Persistent toxicity ≥ grade 1 related to preoperative FOLFIRI based chemotherapy
• Known pregnancy (pregnancy test for women of childbearing) or breastfeeding women

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric VICAUT, MHD, PHD

Role: STUDY_CHAIR

APHP

Eric VICAUT, MHD, PHD

Role: PRINCIPAL_INVESTIGATOR

APHP

Locations

Hôpital Kremlin Bicêtre

Paris, Île-de-France Region, France

Countries

France

Central Contacts

Stéphane BENOIST, MHD, PHD

Role: CONTACT

Stephane.benoist@aphp.fr

33 1 45 21 34 72

Antoine BROUQUET, MHD, PHD

Role: CONTACT

Anoine.brouquet@aphp.fr

+33 1 45 21 34 70

Facility Contacts

stéphane BENOIST, MHD, PHD

Role: primary

Stephane.benoist@aphp.fr

+33 1 45 21 34 72

Antoine BROUQUET

Role: backup

Anoine.brouquet@aphp.fr

+33 1 45 21 34 70

Other Identifiers

2023-504831-42-00

Identifier Type: CTIS

Identifier Source: secondary_id

220917

Identifier Type: -

Identifier Source: org_study_id