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

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

Study Overview

• Status: Enrolling by invitation
• Conditions: Hepatocellular Carcinoma Stage IIIa
• Intervention / Treatment: Drug: Lenvatinib; Drug: mFOLFOX regimen; Drug: ROX regimen

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • The Cancer Hospital of the University of Chinese Academy of Sciences（Zhejiang Cancer Hospital）

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Voluntary participation and informed consent, aged 18-75;
2. 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;
3. BCLC stage C patients with vascular invasion and without extrahepatic metastasis;
4. Child Pugh liver function classification: A or B grade;
5. ECOG physical strength score was 0-2 points;
6. No previous systemic or local treatment, and the expected survival time is more than 3 months;
7. 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;
8. 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:

1. Hepatocholangiocarcinoma, mixed cell carcinoma and fibrolamellar cell carcinoma are known;
2. Uncontrollable ascites, hepatic encephalopathy or esophageal variceal bleeding;
3. 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);
4. 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);
5. 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;
6. Pregnant or lactating women, patients with fertility are unwilling or unable to take effective contraceptive measures;
7. patients with a history of HIV infection;
8. The researcher judges other situations that may affect the clinical research and the judgment of research results;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight and Height	Weight and Height will be combined to report BMI in kg/m^2	from admission to discharge, up to 1 week
Age	Age is divided into >50 and ≤50	from admission to discharge, up to 1 week
Sex	Sex is divided into Male and Female	from admission to discharge, up to 1 week
ECOG score	ECOG score is divided into 0,1,2	from admission to discharge, up to 1 week
Tumor size	Tumor size is divided into >10cm and ≤10cm	from admission to discharge, up to 1 week
Tumor number	Tumor number is divided into single and multiple	from admission to discharge, up to 1 week
AFP	AFP is divided into >1000ug/L and ≤1000ug/L	from admission to discharge, up to 1 week
Portal vein invasion	Portal vein invasion is divided into Vp1-2, Vp3, Vp4	from admission to discharge, up to 1 week
Extrahepatic spread	Extrahepatic spread is divided into Yes and No	from admission to discharge, up to 1 week
Hepatitis B infection	Hepatitis B infection is divided into Yes and No	from admission to discharge, up to 1 week

Collaborators and Investigators

• Sponsor: Zhejiang Cancer Hospital
• Collaborators: First Affiliated Hospital of Zhejiang University; Second Affiliated Hospital of Wenzhou Medical University; First Affiliated Hospital of Wenzhou Medical University; Shaoxing People's Hospital; Jinhua Central Hospital; The Third Affiliated Hospital of Wenzhou Medical University
• Investigators: Study Chair: Jiaping Zheng, Doctor, Zhejiang Cancer Hospital

Publications and helpful links

General Publications

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• Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.
• Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, Xie Q, Guo R, Shi M, Xu L, Cai X, Wu P, Zhao M. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):60-69. doi: 10.1016/j.jhep.2018.02.008. Epub 2018 Feb 20.
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• Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, Anders R, Are C, Brown D, Chang DT, Cloyd J, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Hammond LJ, Darlow SD. Guidelines Insights: Hepatobiliary Cancers, Version 2.2019. J Natl Compr Canc Netw. 2019 Apr 1;17(4):302-310. doi: 10.6004/jnccn.2019.0019.
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Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Anticipated): June 30, 2022
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: August 12, 2021
• First Posted (Actual): August 16, 2021

Study Record Updates

• Last Update Posted (Actual): August 16, 2021
• Last Update Submitted That Met QC Criteria: August 12, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: HCC; Lenvatinib; HAIC
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Protein Kinase Inhibitors; Vitamins; Antidotes; Vitamin B Complex; Folic Acid Antagonists; Fluorouracil; Oxaliplatin; Leucovorin; Lenvatinib; Raltitrexed
• Other Study ID Numbers: ZJPIRB-2021-211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No