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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

Fudan University

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Liver Diseases

Lenvatinib

Raltitrexed

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Vitamin B Complex

Trace Elements

Protein Kinase Inhibitors

Enzyme Inhibitors

Folic Acid Antagonists

Cohort1：Participants were treated with 8mg lenvatinib (weight\<60kg) or 12mg lenvatinib (weight\>60kg) orally once daily on days 1 through 21, and HAIC regimen was performed every 3 weeks. The mFOLFOX regimen was administered via hepatic artery: oxaliplatin , 85mg/m2 , from hour 0 to 2 on day1 ; leucovorin , 400mg/m2 , from hour 2 to 3 on day 1 ; fluorouracil , 400mg/m2 , bolus at hour 3 ; and 2400mg/m2 over 46 hours on days 1 and 2.

Cohort2：Participants were treated with 8mg lenvatinib (weight\<60kg) or 12mg lenvatinib (weight\>60kg) orally once daily on days 1 through 21, and HAIC regimen was performed every 3 weeks. The ROX regimen was administered via hepatic artery: oxaliplatin , 100mg/m2 , from hour 0 to 4 on day1 ;raltitrexed , 3mg/m2 , from hour 4 to 5 on day 1.

8mg lenvatinib (weight\<60kg) or 12mg lenvatinib (weight\>60kg) QD

HAIC was performed every 3 weeks. The mFOLFOX regimen was administered via hepatic artery: oxaliplatin , 85mg/m2 , from hour 0 to 2 on day1 ; leucovorin , 400mg/m2 , from hour 2 to 3 on day 1 ; fluorouracil , 400mg/m2 , bolus at hour 3 ; and 2400mg/m2 over 46 hours on days 1 and 2.3mg/m2 , from hour 4 to 5 on day 1.

HAIC was performed every 3 weeks. The ROX regimen was administered via hepatic artery: oxaliplatin , 100mg/m2 , from hour 0 to 4 on day1 ;raltitrexed , 3mg/m2 , from hour 4 to 5 on day 1.

ROX regimen

Jiaping Zheng, Doctor

Lenvatinib Plus Hepatic Arterial Infusion of Modified FOLFOX Regime vs Lenvatinib Plus Hepatic Arterial Infusion of Oxaliplatin Plus Raltitrexed in Patients with Advanced Hepatocellular Carcinoma

Hepatic arterial infusion chemotherapy is one of the important means for the treatment of advanced liver cancer. A multicenter randomized controlled study has confirmed that modified FOLFOX hepatic arterial infusion chemotherapy can significantly improve the prognosis of patients with advanced liver cancer and prolong the survival period of patients. The 2020 edition of CSCO guidelines for the diagnosis and treatment of liver cancer has recommended oxaliplatin based FOLFOX arterial infusion regimen as the first-line treatment of advanced liver cancer. FOLFOX regimen is safe and effective, but fluorouracil needs more than 46 hours of long-term infusion, patients have difficulty in moving during catheterization, and increase the risk of thrombosis, so it is urgent to find a short-term infusion of fluorouracil. As a new antimetabolic drug, raltitrexed can be used for short-term infusion, and its plasma concentration half-life is longer than that of fluorouracil. Previous studies have shown that compared with FOLFOX arterial infusion regimen, oxaliplatin combined with raltitrexed regimen has longer overall survival (OS) and progression free survival (PFS) in the treatment of advanced liver cancer. In addition, as an advanced liver cancer, lenvastinib has been recommended as a targeted drug for the first-line treatment of advanced HCC. This study intends to explore the efficacy and safety of modified FOLFOX regimen compared with oxaliplatin combined with raltitrexed (Rox regimen) in the treatment of lenvastinib combined with HAIC, so as to provide more clinical schemes for further improving the survival rate of patients with advanced liver cancer.

Prospective, multi-center, randomized controlled study

60 HCC participants were divided into test group and control group by random drawing

Lenvatinib Plus HAIC of Modified FOLFOX Regime vs Lenvatinib Plus HAIC of ROX Regime in Patients With Advanced HCC

Lenvatinib Combined With Hepatic Arterial Infusion of Modified FOLFOX Regimen Versus Lenvatinib Combined With Hepatic Arterial Infusion of ROX Regimen in the Treatment of Advanced Hepatocellular Carcinoma

Weight and Height will be combined to report BMI in kg/m\^2

Tumor size is divided into \>10cm and ≤10cm

Tumor number is divided into single and multiple

AFP is divided into \>1000ug/L and ≤1000ug/L

Portal vein invasion is divided into Vp1-2, Vp3, Vp4

Extrahepatic spread is divided into Yes and No

Hepatitis B infection is divided into Yes and No

ORR and DCR are validated indicators of the short-term clinical effects of hepatocellular carcinoma

OS and PFS are validated indicators of the long-term clinical effects of hepatocellular carcinoma

Treatment-Related Adverse Events are important indicators of the safety for tumor treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
Lenvatinib Plus HAIC of Modified FOLFOX Regime vs Lenvatinib Plus HAIC of ROX Regime in Patients With Advanced HCC	NCT05007587	Hepatocellular ...	Lenvatinib mFOLFOX regimen ROX regimen	18 Years - 75 Years	Zhejiang Cancer Hospital

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