SBRT Plus Lenvatinib and TACE for Advanced Primary HCC: A Phase 3 Trial (SEARCH)

Study Overview
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Brief Summary
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This is a phase 3, multicentri, randomised, open label study. The purpose is to investigate the safety and efficacy of stereotactic body radiation therapy (SBRT) combined with transarterial chemoembolization (TACE) and lenvatinib (LEN) in the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombus.

Official Title
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Stereotactic Body Radiation Therapy Plus Lenvatinib and Transarterial Chemoembolization for Advanced Primary Hepatocellular Carcinoma: A Phase 3, Multicentric, Randomized Controlled Trial

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Lenvatinib
* Procedure: TACE
* Radiation: SBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years old; Patients with primary advanced HCC (in accordance with AASLD2018 guidelines for the diagnosis of HCC), without any previous treatment; There is at least one measurable lesion in the liver according to mRECIST criteria, single tumor ≤ 10.0 cm or multiple tumors and tumor burden ≤50% , with portal vein tumor embolus; ECOG score 0-1; Child-Pugh class A; Expected survival time ≥ 3 months; Blood, liver and kidney function meet the following conditions: Neutrophil count ≥ 1.5 × 10 9 /L; Platelet count ≥ 60 × 10 9 /L; Hemoglobin ≥ 90 g/L; Serum albumin ≥ 30 g/L; Bilirubin ≤ 50 umol/L; AST, ALT ≤ 5 times the upper limit of normal, ALP ≤ 4 times the upper limit of normal; Prolongation of prothrombin time not to exceed the upper limit of normal by 6 seconds; Creatinine ≤ 1.5 times the upper limit of normal. Exclusion Criteria: Extrahepatic metastases; Previous history of liver or adjacent tissue radiation; Previous history of hepatic encephalopathy, refractory ascites or gastric esophageal varices; There are contraindications to TACE treatment, such as portosystemic shunt, liver flow ablation, significant atherosclerosis; Hypersensitivity to intravenous contrast agents; Pregnant or lactating women or subjects with family planning within two years; With HIV, syphilis infection; Accompanied by other malignant tumors or suffering from other malignancies within 5 years before enrollment; Allogeneic organ transplant recipients; Severe dysfunction of heart and kidney or other organs; Active severe infection > grade 2 (NCI-CTC version 5); Suffering from mental and psychological diseases may affect informed consent; Unable to take oral medication; Participated in other drug clinical trials within 12 months before enrollment; Active gastric or duodenal ulcers within 3 months before enrollment.

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT+TACE+Lenvatinib<br>Patients in SBRT+TACE+Lenvatinib group will take oral lenvatinib within 3 days of randomization and receive TACE 1 day after oral administration of lenvatinib. SBRT will begin within 3 weeks after the first TACE. | Drug: Lenvatinib<br>* Lenvatinib will be taken within 3 days of randomization (dose: 8 mg qd for patients <60kg, and 12 mg qd for patients ≥ 60kg)<br>Procedure: TACE<br>* TACE will be performed one day after oral administration of lenvatinib. Either cTACE or DEB-TACE can be used, depending on the condition of each center.<br>Radiation: SBRT<br>* SBRT will be given within 3 weeks after the first TACE with linear accelerator-based photon beams. Gross tumor volume is defined as intrahepatic tumor and vascular invasion including a 1-cm margin into the contiguous HCC. Prescription dose will be 4500-5000 cGy in 5-8 fractions.<br>|
| Active Comparator: Lenvatinib<br>Patients in Lenvatinib group will take oral lenvatinib alone. | Drug: Lenvatinib<br>* Lenvatinib will be taken within 3 days of randomization (dose: 8 mg qd for patients <60kg, and 12 mg qd for patients ≥ 60kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from first treatment to death, regardless of disease recurrence. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the first treatment to progression or death. | Up to 2 years | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients who have achieved complete response (CR) or partial response (PR), as measured by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. | Up to 2 years | 
| Disease Control Rate (DCR) | DCR is defined as the percentage of patients who have achieved CR, PR or stable disease(SD), as measured by mRECIST criteria. | Up to 2 years | 
| Incidence of Adverse Events (AE) | Incidence of AE is defined as the percentage of patients who suffer adverse events from the first treatment to last follow-up, assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. | Up to 2 years | 
| Time to Progression （TTP） | TTP is defined as the time from the first treatment to progression. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SBRT, TACE, Lenvatinib