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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma Stage IIIa

Intervention / Treatment
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* Drug: Lenvatinib
* Drug: mFOLFOX regimen
* Drug: ROX regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary participation and informed consent, aged 18-75; Patients with HCC confirmed by histopathology or meeting the clinical diagnostic criteria in the 2019 edition of the diagnostic and therapeutic criteria for primary liver cancer; BCLC stage C patients with vascular invasion and without extrahepatic metastasis; Child Pugh liver function classification: A or B grade; ECOG physical strength score was 0-2 points; No previous systemic or local treatment, and the expected survival time is more than 3 months; According to recist1.1, the patient must have at least one measurable target lesion that has passed CT or MRI examination, and the tumor imaging evaluation was conducted within 2 weeks before receiving the study drug; Full organ and bone marrow function: WBC ≥ 3.0 × 109/L； NE≥1.5 × 109/L； PLT≥75 × 109/L； Liver and kidney function ALT and AST ≤ 5uln; TBIL≤2ULN； Albumin ≥ 28g / L; Cr≤1.5 ULN； International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) exceeding the normal control range ≤ 4 seconds; Exclusion Criteria: Hepatocholangiocarcinoma, mixed cell carcinoma and fibrolamellar cell carcinoma are known; Uncontrollable ascites, hepatic encephalopathy or esophageal variceal bleeding; Patients with hypertension who can not be reduced to normal range after antihypertensive drug treatment (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg); Patients with myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmia, myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmia (QTc interval ≥ 450 ms) (QTc interval was calculated by fridericia formula); Patients with history of gastrointestinal bleeding or definite tendency of gastrointestinal bleeding in the past 3 months, such as esophageal varices with bleeding risk, local active ulcer lesions, fecal occult blood ≥ +, can not be included in the group; Pregnant or lactating women, patients with fertility are unwilling or unable to take effective contraceptive measures; patients with a history of HIV infection; The researcher judges other situations that may affect the clinical research and the judgment of research results;

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
Interventional Model Description: Prospective, multi-center, randomized controlled study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenvatinib，Then HAIC of mFOLFOX regimen<br>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. | Drug: Lenvatinib<br>* 8mg lenvatinib (weight<60kg) or 12mg lenvatinib (weight>60kg) QD<br>* Other names: LENVIMA;Drug: mFOLFOX regimen<br>* 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.<br>* Other names: Oxaliplatin+Leucovorin+Fluorouracil;|
| Experimental: Lenvatinib，Then HAIC of ROX regimen<br>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. | Drug: Lenvatinib<br>* 8mg lenvatinib (weight<60kg) or 12mg lenvatinib (weight>60kg) QD<br>* Other names: LENVIMA;Drug: ROX regimen<br>* 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.<br>* Other names: Raltitrexed+Oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate and Disease Control Rate of the HCC Participants | ORR and DCR are validated indicators of the short-term clinical effects of hepatocellular carcinoma | from admission to discharge, up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival and Progression-free Survival of the HCC Participants | OS and PFS are validated indicators of the long-term clinical effects of hepatocellular carcinoma | six months and twelve months | 
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 | Treatment-Related Adverse Events are important indicators of the safety for tumor treatment | from admission to discharge, up to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, Lenvatinib, HAIC