Lenvatinib or Regorafenib for Advanced Hepatocellular Carcinoma After Immunotherapy (REVIVE)

NCT07495579 | Not Yet Recruiting Phase 2

• 2 other identifiers: KCSG HB25-15HB25-15
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if lenvatinib or regorafenib can help treat people with advanced liver cancer (hepatocellular carcinoma, HCC) that cannot be removed with surgery after first treatment with immunotherapy-based drug combinations. It will also look at the safety of these treatments. The main questions this study aims to answer are:

• How long lenvatinib can delay cancer growth in people with good liver function (Child-Pugh)A after dual immunotherapy
• How long people with reduced liver function (Child-Pugh B7-B8) live after treatment with lenvatinib or regorafenib after first-line immunotherapy-based combination treatment
• What side effects people experience during treatment
• How many people have their tumors shrink or disappear The study has two parts: In REVIVE-1, participants with Child-Pugh A liver function will receive lenvatinib. In REVIVE-2, participants with Child-Pugh B7 to B8 liver function will receive either lenvatinib or regorafenib. Participants will:
• take lenvatinib or regorafenib by mouth
• visit the clinic regularly for physical exams, blood and urine tests, and safety checks
• have computed tomography (CT) scans every 8 weeks to check their cancer
• be followed during and after treatment to assess outcomes and side effects

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

Hepatocellular Carcinoma; Lenvatinib; Regorafenib; Second-line Therapy; Dual Immune Checkpoint Inhibitor; Child-Pugh B

Outcome Measures

Primary Outcomes (2)

• Progression-Free Survival (PFS) in REVIVE-1

  Progression-free survival is defined as the time from first dose of study treatment to disease progression according to RECIST v1.1 or death from any cause, whichever occurs first, in the REVIVE-1 cohort.

  Up to 24 months

• Overall Survival (OS) in REVIVE-2

  Overall survival is defined as the time from first dose of study treatment to death from any cause in the REVIVE-2 cohort.

  Up to 30 months

Secondary Outcomes (5)

• Overall Survival (OS) in REVIVE-1

  Up to 24 months

• Progression-Free Survival (PFS) in REVIVE-2

  Up to 30 months

• Objective Response Rate (ORR)

  Up to 24 months

• Incidence of Treatment-Emergent Adverse Events

  Up to 30 months

• Time to Liver Function Deterioration in REVIVE-2

  Up to 30 months

Study Arms (3)

REVIVE-1: Lenvatinib

EXPERIMENTAL

Participants with Child-Pugh A liver function whose disease has progressed after dual immune checkpoint inhibitor therapy will receive lenvatinib administered orally once daily at a dose based on body weight (12 mg for ≥60 kg or 8 mg for \<60 kg) until disease progression or unacceptable toxicity.

Drug: Lenvatinib

REVIVE-2: Lenvatinib

EXPERIMENTAL

Participants with Child-Pugh B7-B8 liver function whose disease has progressed after first-line immunotherapy-based combination therapy will receive lenvatinib administered orally once daily at a starting dose of 4 mg or 8 mg based on body weight, with step-up to 8 mg or 12 mg after 2 weeks if tolerated, and with subsequent dose modifications permitted according to protocol, until disease progression or unacceptable toxicity.

Drug: Lenvatinib

REVIVE-2: Regorafenib

EXPERIMENTAL

Participants with Child-Pugh B7-B8 liver function whose disease has progressed after first-line immunotherapy-based combination therapy will receive regorafenib administered orally at a starting dose of 80 mg once daily for 3 weeks followed by 1 week off in each 4-week cycle, with step-up to 120 mg after 2 weeks if tolerated, and with subsequent dose modifications permitted according to protocol, until disease progression or unacceptable toxicity.

Drug: regorafenib

Interventions

Lenvatinib DRUG

Lenvatinib is an oral multikinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), platelet-derived growth factor receptor alpha (PDGFR-α), RET, and KIT. In this study, lenvatinib is administered orally as second-line treatment according to protocol-defined dosing based on liver function and body weight.

REVIVE-1: Lenvatinib; REVIVE-2: Lenvatinib

regorafenib DRUG

Regorafenib is an oral multikinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases including VEGFR, FGFR, PDGFR, KIT, RET, and RAF kinases. In this study, regorafenib is administered orally as second-line treatment according to protocol-defined dosing.

REVIVE-2: Regorafenib

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 19 years or older
• Diagnosis of hepatocellular carcinoma according to the American Association for the Study of Liver Diseases (AASLD) guidelines
• Unresectable or metastatic hepatocellular carcinoma not amenable to curative treatments such as surgical resection, liver transplantation, or local ablation
• Prior first-line systemic treatment with an immune checkpoint inhibitor-based combination regimen, defined as dual immune checkpoint inhibitor therapy (e.g., nivolumab plus ipilimumab or durvalumab plus tremelimumab) for the REVIVE-1 cohort, and immune checkpoint inhibitor-based combination therapy (e.g., atezolizumab plus bevacizumab, durvalumab plus tremelimumab, nivolumab plus ipilimumab, camrelizumab plus rivoceranib, or similar regimens) for the REVIVE-2 cohort; prior participation in clinical trials using these regimens is allowed
• Radiologic disease progression after at least 2 cycles of first-line treatment
• At least one measurable lesion according to RECIST v1.1
• Recovery from toxicities related to prior therapy to grade 1 or lower, except for clinically stable or non-clinically significant toxicities
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 12 weeks
• Absolute neutrophil count ≥ 1.0 × 10⁹/L
• Platelet count ≥ 75 × 10⁹/L for REVIVE-1 or ≥ 50 × 10⁹/L for REVIVE-2
• Hemoglobin ≥ 9 g/dL
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 40 mL/min
• Proteinuria \<3 g in 24-hour urine collection or urine protein-to-creatinine ratio \<3 mg/mg
• Child-Pugh A (score 5-6) for REVIVE-1 cohort or Child-Pugh B (score 7-8) for REVIVE-2 cohort

You may not qualify if:

• Known fibrolamellar hepatocellular carcinoma or mixed hepatocellular-cholangiocarcinoma
• Prior treatment with lenvatinib or regorafenib
• Receipt of two or more prior systemic treatment regimens for advanced hepatocellular carcinoma
• Known brain metastases or epidural disease unless adequately treated and clinically stable for at least 3 months
• Congestive heart failure greater than New York Heart Association class II
• Unstable angina, myocardial infarction, or stroke within 6 months
• Clinically significant cardiac arrhythmia requiring treatment
• Uncontrolled hypertension despite optimal medical therapy (systolic blood pressure \>150 mmHg or diastolic blood pressure \>90 mmHg)
• Active bleeding disorders or high risk of severe bleeding
• Tumor invasion of major blood vessels with high risk of bleeding
• Gastrointestinal conditions with high risk of perforation or fistula, including active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis, or recent gastrointestinal perforation
• Major surgery within 2 months before enrollment or incomplete recovery from surgery
• Moderate to severe ascites
• Known hypersensitivity to study drugs or their components
• Pregnancy or breastfeeding

Sponsors & Collaborators

• Asan Medical Center: lead
• Korean Cancer Study Group: collaborator
• Boryung Pharmaceutical Co., Ltd: collaborator

Study Sites (1)

Asan Medical Center

Seoul, 05505, South Korea

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

lenvatinib; regorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Changhoon Yoo

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Changhoon Yoo

CONTACT

82-2-3010-1727; cyoo.amc@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: This study includes two cohorts. REVIVE-1 is a single-arm phase 2 cohort evaluating lenvatinib in participants with Child-Pugh A liver function after progression on dual immune checkpoint inhibitor therapy. REVIVE-2 is a randomized, non-comparative phase 2 cohort evaluating lenvatinib or regorafenib in participants with Child-Pugh B7-8 liver function after progression on immunotherapy-based combination therapy.

Study Record Dates

• First Submitted: March 22, 2026
• First Posted: March 27, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)