Fostrox Plus Lenvatinib vs Lenvatinib in Advanced Hepatocellular Carcinoma After First-line Immunotherapy

NCT07493668 | Recruiting Phase 2

• 1 other identifier: 2026-02-022
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 2, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of fostrox in combination with lenvatinib compared with lenvatinib alone in patients with locally advanced or unresectable advanced hepatocellular carcinoma (HCC) who have experienced radiologically confirmed disease progression following first-line combination immunotherapy. Approximately 80 patients will be enrolled at 9 study sites and randomized in a 1:1 ratio to 1 of 2 treatment arms: fostrox plus lenvatinib or lenvatinib alone. Patients assigned to the investigational arm will receive fostrox orally once daily on Days 1 through 5 of each 21-day cycle in combination with continuous daily lenvatinib. Patients assigned to the control arm will receive lenvatinib alone according to the approved weight-based dosing regimen. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria are met. The study population includes adult patients with locally advanced or unresectable metastatic HCC who have received at least 2 cycles of first-line systemic therapy with an immunotherapy combination and have radiologically confirmed disease progression. Eligible patients must have measurable disease according to RECIST version 1.1 and mRECIST, adequate organ function, and Child-Pugh class A liver function. The primary objective is to assess objective response rate (ORR) as determined by an Independent Review Facility (IRF) according to RECIST v1.1. Secondary objectives include evaluation of ORR by investigator assessment according to RECIST v1.1 and mRECIST, duration of response, disease control rate, progression-free survival, time to progression, overall survival, and safety and tolerability. Safety evaluations will include assessment of adverse events, serious adverse events, laboratory parameters, vital signs, and other clinical assessments. Exploratory objectives include evaluation of peripheral blood-based biomarkers, metabolic changes associated with study treatment, collection and storage of DNA and RNA for exploratory analyses, and pharmacokinetic assessment of fostrox and its metabolite troxacitabine in patients receiving fostrox in combination with lenvatinib. Tumor assessments will be performed at protocol-defined intervals using radiologic imaging. The primary efficacy analysis will be based on IRF assessment according to RECIST v1.1. This study is intended to characterize the clinical activity and safety profile of fostrox plus lenvatinib compared with lenvatinib alone in this patient population and to generate data to inform future clinical development.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

HCC

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) by Independent Review Facility (IRF) According to RECIST v1.1

  Objective response rate (ORR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR), as determined by an Independent Review Facility (IRF) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary efficacy analysis population is the Full Analysis Set (FAS), defined as all randomized participants who receive at least 1 dose of study treatment and undergo at least 1 post-baseline efficacy assessment.

  From randomization until disease progression, withdrawal of consent, or end of study, whichever occurs first; assessed every 6 weeks from Cycle 1 Day 1 through Week 54 and every 9 weeks thereafter, up to approximately 36 months

Secondary Outcomes (15)

• Objective Response Rate (ORR) by Investigator According to RECIST v1.1

  From randomization until disease progression, withdrawal of consent, or end of study, whichever occurs first; assessed every 6 weeks from Cycle 1 Day 1 through Week 54 and every 9 weeks thereafter, up to approximately 36 months

• Objective Response Rate (ORR) by Investigator According to mRECIST

  From randomization until disease progression, withdrawal of consent, or end of study, whichever occurs first; assessed every 6 weeks from Cycle 1 Day 1 through Week 54 and every 9 weeks thereafter, up to approximately 36 months

• Duration of Response (DOR) by Investigator According to RECIST v1.1

  From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months

• Duration of Response (DOR) by Investigator According to mRECIST

  From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months

• Disease Control Rate (DCR) by Investigator According to RECIST v1.1

  From randomization until disease progression, withdrawal of consent, or end of study, whichever occurs first; assessed every 6 weeks from Cycle 1 Day 1 through Week 54 and every 9 weeks thereafter, up to approximately 36 months

Other Outcomes (4)

• Percentage or Count of Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMCs)

  Baseline (Cycle 1 Day 1), every 2 cycles up to Week 54, every 3 cycles thereafter, and at the End of Treatment visit.

• Percentage Change from Baseline in the Concentration of Targeted Blood Metabolites

  Baseline (Cycle 1 Day 1), every 2 cycles up to Week 54, every 3 cycles thereafter, and at the End of Treatment visit (estimated up to 36 months).

• Number of Participants with Specific Genetic Alterations Identified via ctDNA and RNA Sequencing

  Baseline, every 2 cycles up to Week 54, every 3 cycles thereafter, and at the End of Treatment visit.

Study Arms (2)

Fostrox + Lenvatinib

EXPERIMENTAL

Fostrox: Oral, once daily for 5 days (Day 1-5) followed by 16-day rest in a 21-day cycle. Lenvatinib: Oral daily, continuous; 12 mg QD (≥60 kg) or 8 mg QD (\<60 kg).

Drug: Fostrox; Drug: Lenvatinib

Lenvatinib

ACTIVE COMPARATOR

Lenvatinib: Oral daily, continuous; 12 mg QD (≥60 kg) or 8 mg QD (\<60 kg)

Drug: Lenvatinib

Interventions

Fostrox DRUG

Fostrox is an orally administered troxacitabine monophosphate prodrug designed to achieve selective activation within hepatocytes. In this study, Fostrox is given once daily on Days 1-5 of each 21-day treatment cycle, followed by a 16-day rest period. On Cycle 1 Day 1, dosing occurs on-site; subsequent doses (Days 2-5) may be administered at home. Fostrox is taken on an empty stomach with approximately 200 mL of water, and food intake is allowed at least 1 hour after dosing.

Fostrox + Lenvatinib

Lenvatinib DRUG

Lenvatinib will be administered orally once daily on a continuous basis according to the approved weight-based dosing regimen. Patients weighing ≥60 kg will receive 12 mg once daily, and patients weighing \<60 kg will receive 8 mg once daily.

Fostrox + Lenvatinib; Lenvatinib

Eligibility Criteria

• Age: 19 Years+
• Gender Eligibility Details: Participants of any gender identity may be eligible to participate, provided they meet the protocol-defined sex-specific eligibility criteria, including reproductive and contraception requirements.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a diagnosis of locally advanced or unresectable metastatic HCC confirmed by radiology, histology, or cytology
• Received at least 2 cycles of first-line systemic therapy with immunotherapy (IO) combination (atezolizumab + bevacizumab, ipilimumab + nivolumab, or durvalumab + tremelimumab), with radiologically confirmed disease progression
• Patients with measurable lesion in the liver (at least one target lesion) according to RECIST v1.1 and mRECIST
• \- Patients who received prior local therapy (e.g., radiofrequency ablation, cryoablation, percutaneous ethanol or acetic acid injection, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1
• Patients who are not amenable for curative surgery or locoregional therapy
• ECOG performance status of 0 or 1 within 7 days prior to randomization
• Life expectancy of at least 3 months
• Subjects age ≥19 years at the time of signing the informed consent form (ICF)
• Subjects who are capable of providing signed informed consent to comply with requirements and limitations described in the ICF and this protocol and express obvious and voluntary agreement prior to the start of the study
• Subjects with adequate hematological function and hepatic function without using blood transfusion or growth factors within 7 days prior to randomization
• Hemoglobin (Hb) ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥1,500/μl
• Platelet count ≥75,000/μl
• Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) estimated by Cockcroft-Gault equation ≥60 mL/min
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5.0 x ULN

You may not qualify if:

• Patients who have received more than 1 prior systemic therapy (i.e., fostrox + lenvatinib or lenvatinib must be administered as second-line treatment)
• Patients who have received first-line systemic therapy for locally advanced unresectable or metastatic HCC other than an IO combination
• Patients who have received a prior TKI (e.g. lenvatinib, regorafenib, cabozantinib etc.) in the IO combination
• Patients with a history of hypersensitivity to lenvatinib or any of its components (active ingredient or excipients)
• Patients with fibrolamellar HCC, sarcomoid HCC, or a mix of HCC and intrahepatic cholangiocarcinoma (iCCA)
• Patients with central nervous system metastasis
• Patients with VP4 portal vein tumor thrombosis (PVTT)
• Patients with significant cardiovascular disease within 3 months prior to randomization
• New York Heart Association (NYHA) Class III or IV congestive heart failure
• Unstable angina
• Myocardial infarction
• Cardiac arrhythmia associated with hemodynamic instability
• Subjects with Corrected QT interval (QTcF) \>470 msec at Screening (corrected by Fridericia Formula)
• Patients with prior allogeneic stem cell or solid organ transplantation
• Patients with systemic infection requiring treatment including active tuberculosis within 14 days prior to the first dose of study drug (prophylactic oral antibiotics are permitted)

Sponsors & Collaborators

• CHA University: lead

Study Sites (1)

CHA Bundang Medical Center

Seongnam-si, Gyeonggi-do, 13496, South Korea

RECRUITING

Related Publications (28)

• Evans TRJ, Chon HJ, Kim DY, et al. (Poster) Final safety and efficacy results from the phase 1b/2a study of fostrox plus lenvatinib in second/third line patients with advanced hepatocellular carcinoma who progressed on immunotherapy. EASL Liver Cancer Summit. 2025.

  BACKGROUND

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MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

lenvatinib

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

Central Study Contacts

Hong Jae Chon, MD, PhD

CONTACT

82-31-780-3928; hongjaechon@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: Principal Investigator

Model Details: Participants will be randomized in a 1:1 ratio to 2 parallel treatment arms to receive either fostrox plus lenvatinib or lenvatinib alone.

Study Record Dates

• First Submitted: March 17, 2026
• First Posted: March 25, 2026
• Study Start: May 14, 2026
• Primary Completion (Estimated): April 27, 2028
• Study Completion (Estimated): April 27, 2029
• Last Updated: May 22, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)