Carcinoma, Hepatocellular, Lenvatinib, Treatment Failure
Conditions
Brief summary
The purpose of this clinical trial is to evaluate the efficacy and safety of regorafenib as a subsequent therapy for patients with hepatocellular carcinoma (HCC) who have failed prior lenvatinib treatment. This investigational study aims to assess the therapeutic benefits and safety profile of regorafenib in patients whose disease has progressed following the use of lenvatinib, a targeted therapy for hepatocellular carcinoma
Detailed description
Lenvatinib is currently recognized as a standard first-line treatment for advanced hepatocellular carcinoma (HCC), having demonstrated non-inferiority to sorafenib in a phase 3 randomized clinical trial. It is also utilized as a second-line option following the failure of immunotherapy-based regimens. However, unlike sorafenib, there is a lack of prospective data regarding subsequent therapies following lenvatinib failure, which poses significant challenges in clinical decision-making. Regorafenib has demonstrated clinical efficacy and significant survival benefits compared to placebo in the RESORCE trial as a second-line treatment after sorafenib for Child-Pugh class A patients. Nevertheless, evidence supporting its use specifically in patients who have failed lenvatinib remains insufficient. This multicenter, single-arm, phase 2 study is designed to evaluate the efficacy and safety of regorafenib as a subsequent therapy for patients with unresectable HCC who have experienced disease progression or unacceptable toxicity during prior treatment with lenvatinib. Enrolled participants will receive regorafenib orally. The starting dose for Cycle 1 will be determined by the baseline Child-Pugh classification (160 mg once daily for Child-Pugh A; 120 mg once daily for Child-Pugh B). From Cycle 2 onwards, patients will maintain a standard regimen of 3 weeks on and 1 week off at the maximum tolerated dose. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The study will assess key efficacy endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR), alongside comprehensive safety evaluations.
Interventions
"Participants with unresectable hepatocellular carcinoma who have failed prior lenvatinib treatment will receive oral regorafenib. The starting dose for Cycle 1 is 160 mg once daily for patients with Child-Pugh class A, and 120 mg once daily for patients with Child-Pugh class B. From Cycle 2 onwards, regorafenib will be administered at the maximum tolerated dose on a schedule of 3 weeks on and 1 week off (28-day cycle). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.
Sponsors
Ju Hyun Shim
Boryung Pharmaceutical Co., Ltd
Samsung Medical Center
Seoul National University Hospital
Seoul National University Bundang Hospital
National Cancer Center, Korea
Hanyang University Guri Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm study. All enrolled participants will be assigned to a single group and receive the investigational treatment, regorafenib, according to their baseline Child-Pugh classification. There is no control group or randomization in this study
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form. 2. Age ≥ 19 years at the time of signing the informed consent form. 3. Diagnosis of hepatocellular carcinoma (HCC) confirmed histologically or clinically according to the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines. 4. Patients with unresectable HCC who have experienced disease progression or treatment discontinuation due to toxicity during prior treatment with lenvatinib. 5. Presence of at least one measurable target lesion according to RECIST v1.1. 6. Child-Pugh classification A or B7 (score 7). 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 8. Adequate hematologic and end-organ function defined by the following laboratory test results obtained within 14 days prior to testing (or enrollment): * Hemoglobin ≥ 8.5 g/dL * Absolute neutrophil count (ANC) ≥ 1,200/mm³ * Platelet count ≥ 60,000/μL * Total bilirubin \< 3.5 mg/dL * Serum albumin ≥ 2.5 g/dL * AST and ALT ≤ 7 × upper limit of normal (ULN) * Prothrombin time (INR ≤ 1.8 × ULN) * Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault equation) 9. Virological status of hepatitis confirmed and recorded through HBV and HCV screening. * Participants with HBV or HCV infection must be receiving antiviral therapy according to institutional guidelines. 10. Women of childbearing potential must agree to maintain abstinence or use effective contraception (with an annual failure rate of \< 1%) from the time of signing the informed consent until at least 6 months after the last dose of the study drug. Male participants must agree to maintain abstinence or use effective contraception (with an annual failure rate of \< 1%) and refrain from sperm donation from the time of signing the informed consent until at least 6 months after the last dose of the study drug.
Exclusion criteria
1. Albumin-bilirubin (ALBI) grade 3. 2. Fibrolamellar carcinoma or sarcomatoid carcinoma. 3. Prior treatment with regorafenib. 4. History of allogeneic stem cell transplantation or solid organ transplantation. 5. Active brain metastases or leptomeningeal metastases. 6. History of malignancy other than hepatocellular carcinoma (HCC) within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year survival rate \> 90%). 7. Severe cardiovascular disease within 3 months prior to the start of study therapy (e.g., New York Heart Association \[NYHA\] Class II or higher heart disease, myocardial infarction, or cerebrovascular accident); uncontrolled serious medical comorbidities, including unstable arrhythmia or unstable angina; or other significant medical conditions or abnormal findings that, in the opinion of the investigator, may increase the risk associated with study participation. 8. Female participants who are pregnant or breastfeeding, or male or female participants of reproductive potential who are unwilling to use effective contraception from screening until 6 months after the last dose of the study drug. 9. Participants deemed by the investigator to be unlikely to comply with study procedures, restrictions, and requirements. 10. Patients who have received locoregional therapy (e.g., radiofrequency ablation \[RFA\], microwave ablation \[MWA\], transarterial chemoembolization \[TACE\], transarterial radioembolization \[TARE\], transarterial embolization \[TAE\], radiation therapy, etc.) after discontinuation of lenvatinib treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| progression free survival | From date of first dose until the date of first documented disease progression or death from any cause, whichever occurs first, assessed up to 36 months. | Tumor assessments every 12 weeks (±7 days) after treatment discontinuation without documented progression until progression, death, or end of follow-up, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | From date of first dose until the date of first documented disease progression or death from any cause, whichever occurs first, assessed up to 36 months. | Survival follow-up assessments are conducted every 12 weeks (±7 days) after treatment discontinuation due to disease progression or withdrawal until death or end of follow-up. |
| time to progression | From treatment initiation until first documented progression or start of subsequent systemic anticancer therapy, assessed up to 36 months. | Baseline and scheduled tumor imaging assessments every 12 weeks (±7 days) thereafter (date of documented PD per RECIST v1.1). |
| objective response rate | From treatment initiation until first documented progression or start of subsequent systemic anticancer therapy, assessed up to 36 months. | Assessment of Best Overall Response (CR/PR) at scheduled tumor imaging time points (every 12 weeks ±7 days) from treatment initiation until first PD or start of subsequent systemic anticancer therapy. |
| disease control rate | From treatment initiation until first documented progression or start of subsequent systemic anticancer therapy, assessed up to 36 months. | Assessment of Best Overall Response (CR/PR/SD) at scheduled tumor imaging time points (every 12 weeks ±7 days) from treatment initiation until first PD or start of subsequent systemic anticancer therapy. |
| Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose of study drug until 30 days after last dose, assessed up to 24 months. | Adverse events will be graded according to the NCI CTCAE version 5.0. |
Countries
South Korea
Contacts
CONTACTJu Hyun Shim, MD PhD
PRINCIPAL_INVESTIGATORJu Hyun Shim, MD PhD
Asan Medical Center
Outcome results
None listed