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cetuximab 500mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 165 mg/m2 + folinic acid 400 mg/m2 + 5-fluorouracil 2400 mg/m2 46h infusion starting on day 1, every 2 weeks

mFOLFOXIRI plus Cetuximab

bevacizumab 5mg/kg + oxaliplatin 85 mg/m2 + irinotecan 165 mg/m2 + folinic acid 400 mg/m2 + 5-fluorouracil 2400 mg/m2 46h infusion starting on day 1, every 2 weeks

mFOLFOXIRI Plus Bevacizumab

Jianmin Xu, MD, Ph.D.

Wentao Tang, MD, Ph.D.

Jianmin Xu, MD,Ph.D

Zhen Lou, M.D. Ph.D

Zhigang Wang, M.D. Ph.D

Tao Zhang, M.D. Ph.D

Sheng Wang, M.D. Ph.D

Kejing Huang, M.D. Ph.D

Minhao Yu, M.D. Ph.D

Zihua Chen, M.D. Ph.D

Yong Chen, M.D.

Rui Zhang, M.D.

Yifei Pan, M.D.

Chunkang Yang, M.D.

Yijiu Shi, M.D.

Guiying Wang, M.D.

Zhenning Wang, M.D.

Lingjun Zhu, M.D.

Evidence suggests that the addition of cetuximab or bevacizumab to doublet regimens could improve response rate and resectability rate of liver metastases and survival in colorectal liver metastases (CRLM). Moreover, it is observed that FOLFOXIRI yields higher response and resection rates compared with doublet regimens. However, which is better in conversion therapy of RAS/BRAF wild-type initially unresectable CRLM, FOLFOXIRI plus cetuximab or bevacizumab, remains unknown.

In this study, RAS/BRAF wild-type colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and mFOLFOXIRI plus bevacizumab. Patient imaging will be reviewed for resectability by MDT, consisting of at least one radiologist and three liver surgeons every assessment. MDT review will be performed prior to randomization as well as during treatment, as described in the protocol.

Patients will be stratified for primary tumor location (right-sided or left sided) and numbers of liver metastases (\<5 or ≥5).

Patients with RAS mutated primary tumors will be randomized between mFOLFOXIRI plus cetuximab (cetuximab 500 mg/m\^2 in 60 minutes i.v., followed by oxaliplatin 85 mg/m\^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m\^2 i.v. in 60 minutes, together with leucovorin 400 mg/m\^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m\^2 in 46 hours, every 2 weeks) or mFOLFOXIRI plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m\^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m\^2 i.v. in 60 minutes, together with leucovorin 400 mg/m\^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m\^2 in 46 hours, every 2 weeks).

Patients will be evaluated every 8 weeks by MRI or CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months MDT concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment.

In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months. However, the postoperative chemotherapy regimen was determined by the investigator.

Conversion Therapy of RAS/BRAF Wild-Type Colorectal Cancer Patients With Initially Unresectable Liver Metastases

Conversion Therapy of RAS/BRAF Wild-Type Colorectal Cancer Patients With Initially Unresectable Liver Metastases: mFOLFOXIRI Plus Cetuximab Versus mFOLFOXIRI Plus Bevacizumab

Rate of conversion from initially unresectable liver metastases to resectable ones

The rates of tumor shrinkage by RECIST at 8 weeks

the maximum tumor shrinkage rates by RECIST during the treatment of the study

Time interval from the beginning of treatment to hepatectomy

Fudan University

Deputy director of the department of general surgery

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Protective Agents

Vitamin B Complex

Trace Elements

Patients will receive mFOLFOXIRI plus bevacizumab once every two weeks for 8 cycles as the first-line treatment.

Patients will receive mFOLFOX6 plus bevacizumab once every two weeks for 8 cycles as the first-line treatment.

Bevacizumab (5 mg/kg on day 1) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 8 cycles and followed by bevacizumab and fluoropyrimidine based maintence treatment

mFOLFOXIRI plus Bevacizumab

mFOLFOX6 (oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 8 cycles and followed by bevacizumab and fluoropyrimidine based maintence treatment

mFOLFOX6 Plus Bevacizumab

Yanhong Deng, M.D.

Yanghong Deng, PhD

Yanhong Deng, PhD

The current clinical trials and data on the triplet regimen combined with bevacizumab for first-line treatment of metastatic colorectal cancer were from European and American populations. The triplet regimens recommended by the NCCN and ESMO guidelines using irinotecan and 5-FU at a higher dose intensity cause a high incidence of adverse events in Asian population, and there was no high-quality data on efficacy in Chinese population, both of which have limited the clinical applications of the regimens in China. This study intends to conduct an improved triplet regimen (mFOLFOXIRI) combined with bevacizumab versus mFOLFOX6 combined with bevacizumab as a first-line multicenter, randomized, controlled phase III clinical trial in patients with advanced colorectal cancer. Progression-free survival (PFS), observable response rate (ORR), overall survival (OS), disease control rate (DCR), surgical resection rate, and safety and health-related quality of life (HRQoL) were assessed in the two groups of subjects.

Bevacizumab Plus mFOLFOXIRI as First-line Treatment for Patients With Unresectable Metastatic Colorectal Cancer

Bevacizumab Plus mFOLFOXIRI or mFOLFOX-6 as First-line Treatment for Patients With Unresectable Metastatic Colorectal Cancer: a Randomised, Open-label, Phase 3 Trial

The PFS is defined as the time from the start of treatment to the date of first documented PD or death as a result of any cause, whichever occurred first.

The percentage of subjects with total number of Complete Response (CR) + total number of Partial Response (PR).

OS is defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.

The grade of toxicity will be assessed using the NCI common toxicity criteria, version 5.0.

Yanhong Deng

Professor

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Conversion Therapy of RAS/BRAF Wild-Type Colorectal Cancer Patients With Initially Unresectable Liver Metastases	NCT04687631	Colorectal Canc... Liver Metastase...	mFOLFOXIRI plus... mFOLFOXIRI Plus...	18 Years - 75 Years	Fudan University
Bevacizumab Plus mFOLFOXIRI as First-line Treatment for Patients With Unresectable Metastatic Colorectal Cancer	NCT04230187	Colorectal Canc...	mFOLFOXIRI plus... mFOLFOX6 Plus B...	18 Years - 70 Years	Sun Yat-sen University

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