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

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.

Hepatocellular carcinoma (HCC) is the predominant histologic subtype of primary liver cancer and remains associated with poor clinical outcomes, particularly in patients with locally advanced or unresectable disease. In recent years, first-line treatment for advanced HCC has shifted from tyrosine kinase inhibitors (TKIs) to immune checkpoint inhibitor-based combination regimens. Although these regimens have improved outcomes for some patients, a substantial proportion of patients experience disease progression and require second-line treatment. In this setting, there are limited prospective data to guide treatment selection, and additional therapeutic options are needed. Fostrox is an orally administered, liver-directed prodrug of troxacitabine monophosphate designed to enhance delivery of active metabolite to the liver while limiting systemic exposure. Following intracellular activation, fostrox generates metabolites that are retained within cells, including the active metabolite troxacitabine triphosphate, which is incorporated into DNA during replication and leads to DNA chain termination, DNA damage responses, and cytotoxicity. This liver-directed mechanism is intended to maximize exposure in hepatic tissue and reduce off-target toxicity. Lenvatinib is a multikinase inhibitor with antiangiogenic and antitumor activity and is widely used in the management of advanced HCC. Based on their distinct and potentially complementary mechanisms of action, the combination of fostrox and lenvatinib may provide additional clinical benefit in patients whose disease has progressed after first-line combination immunotherapy. This study is a multicenter, randomized, open-label Phase 2 trial evaluating fostrox plus lenvatinib versus lenvatinib alone in patients with locally advanced or unresectable advanced HCC previously treated with first-line combination immunotherapy. The study is designed as a proof-of-concept trial to assess the relative clinical benefit and safety profile of the combination regimen and to inform future development decisions. Approximately 80 patients will be randomized in a 1:1 ratio to receive either 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 together with continuous daily lenvatinib administered according to the approved weight-based dosing regimen. Patients assigned to the control arm will receive lenvatinib alone. Randomization will be stratified according to prior treatment category, presence or absence of extrahepatic spread and/or macrovascular invasion, and alpha-fetoprotein level greater than 400 ng/mL. The study population includes adult patients with radiologically, histologically, or cytologically confirmed 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. Patients must have measurable disease, adequate hematologic and hepatic function, and Child-Pugh class A liver function. Key exclusion criteria include prior exposure to TKI-containing immunotherapy combinations, central nervous system metastasis, major uncontrolled cardiovascular disease, clinically significant uncontrolled hypertension, clinically significant ascites, active hepatic encephalopathy, certain bleeding or thrombotic conditions, and other medical conditions that could interfere with study participation or interpretation of results. The primary endpoint is objective response rate as assessed by an Independent Review Facility according to RECIST version 1.1. Secondary efficacy endpoints include investigator-assessed objective response rate according to RECIST v1.1 and mRECIST, duration of response, disease control rate, progression-free survival, time to progression, and overall survival. Safety and tolerability will be assessed throughout the study by monitoring adverse events, serious adverse events, laboratory abnormalities, and clinical findings. Exploratory evaluations will include peripheral blood-based biomarker analyses, metabolic assessments, collection and storage of DNA and RNA for exploratory research, and pharmacokinetic assessment of fostrox and its metabolite troxacitabine in patients receiving the combination regimen. Tumor imaging will be performed at protocol-defined intervals, and response assessments will be conducted using standardized radiologic criteria. Independent radiologic review will be incorporated to support objectivity in efficacy evaluation. This study is intended to further characterize the antitumor activity and safety of fostrox in combination with lenvatinib in a second-line advanced HCC population following prior combination immunotherapy.