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

Drug: mFOLFOXIRI plus Bevacizumab Bevacizumab (5 mg/kg on day 1) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1). A local MDT will assess the efficiency every 4 cycles of the treatment. The maximum period of conversion therapy is 12 cycles.

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

Drug: mFOLFOX6 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). A local MDT will assess the efficiency every 4 cycles of the treatment. The maximum period of conversion therapy is 12 cycles.

oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1

mFOLFOXIRI regimen

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

mFOLFOX regimen

Jianmin Xu, MD, Ph.D.

Wentao Tang, MD, Ph.D.

Jianmin Xu, M.D. Ph.D

Wentao Tang, M.D. Ph.D

Kefeng Ding, M.D. Ph.D

Shan Zeng, M.D. Ph.D

Zhenning Wang, M.D. Ph.D

Tao Zhang, M.D. Ph.D

Lechi Ye, M.D. Ph.D

Chunkang Yang, M.D. Ph.D

Guiying Wang, M.D. Ph.D

Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined.

In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be tested for RAS and BRAF tumor mutation status. Patients with RAS mutant and BRAF wild type will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab and modified FOLFOX6 (mFOLFOX6) 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), numbers of liver metastases (\<5 or ≥5) and primary tumor resected or unresected.

Patients with RAS mutated primary tumors will be randomized between mFOLFOXIRI plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 165 mg/m\^2 i.v. in 60 minutes, followed by oxaliplatin 85 mg/m\^2 i.v. 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 mFOLFOX6 plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m\^2 i.v. together with leucovorin 400 mg/m\^2 i.v. in 120 minutes, followed by bolus 5FU 400 mg/m\^2, all on day 1, 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. These patients will continue with bevacizumab plus fluoropyrimidine until progression or unacceptable toxicity.

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, in these patients mFOLFOXIRI should not be continued after surgery and replaced by mFOLFOX6. Bevacizumab will continued after surgery for both groups.

mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS Mutant Unresectable Colorectal Liver-limited Metastases

mFOLFOXIRI Plus Bevacizumab Versus mFOLFOX6 Plus Bevacizumab for the First Line Treatment of RAS Mutant Unresectable Colorectal Liver-limited Metastases

R0 resection rate upon conversion treatment with chemotherapy plus bevacizumab

from the first day of assigned treatment to death or last known to be alive

from the first day of assigned treatment to progression or death whichever comes first

Patients will be evaluated for Adverse Events at the start of each treatment cycle according to CTCAE version 5.0

Patients will be evaluated for surgical morbidity during 1 month. Postoperative morbidity will be scored according 'Clavien-Dindo Grade'.

The maximum tumor shrinkage rates by Response Evaluation Criteria in Solid Tumors (RECIST) throughout the treatments

The rates of tumor shrinkage by RECIST at 8 weeks

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS Mutant Unresectable Colorectal Liver-limited Metastases	NCT04781270	Colorectal Carc... Liver Metastase...	mFOLFOXIRI regi... mFOLFOX regimen Bevacizumab	18 Years - 75 Years	Fudan University
mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS Mutant Unresectable Colorectal Liver-limited Metastases	NCT04781270	Colorectal Carc... Liver Metastase...	mFOLFOXIRI regi... mFOLFOX regimen Bevacizumab	18 Years - 75 Years	Fudan University

Spots Global Cancer Trial Database for mfolfoxiri regimen