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.
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 are not amenable for curative surgery or locoregional therapy
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)
Parallel
Fostrox
DrugFostrox 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.
Lenvatinib
DrugLenvatinib 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.
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.
Objective Response Rate (ORR) by Investigator According to RECIST v1.1
ORR is defined as the proportion of participants with a best overall response of CR or PR, as assessed by the investigator according to RECIST v1.1.
Objective Response Rate (ORR) by Investigator According to mRECIST
ORR is defined as the proportion of participants with a best overall response of CR or PR, as assessed by the investigator according to modified RECIST (mRECIST).
Duration of Response (DOR) by Investigator According to RECIST v1.1
DOR is defined as the time from the first documented occurrence of CR or PR to the first documented disease progression or death from any cause, as assessed by the investigator according to RECIST v1.1, among participants who achieve CR or PR.
Duration of Response (DOR) by Investigator According to mRECIST
DOR is defined as the time from the first documented occurrence of CR or PR to the first documented disease progression or death from any cause, as assessed by the investigator according to mRECIST, among participants who achieve CR or PR.
Percentage or Count of Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMCs)
Evaluation of the baseline percentage or absolute count of specific immune cell subsets within PBMCs and subsequent changes following study drug administration to identify potential response factors.
Percentage Change from Baseline in the Concentration of Targeted Blood Metabolites
Evaluation of metabolic changes mediated by the study drug by measuring the percentage change from baseline in the concentration of targeted endogenous blood metabolites.
Number of Participants with Specific Genetic Alterations Identified via ctDNA and RNA Sequencing
Investigation of genetic alterations that may affect responses (i.e., distribution, safety, tolerability, and efficacy) to study treatment and/or susceptibility to diseases.
Plasma Concentration of Fostrox and Troxacitabine
Evaluation of the pharmacokinetics of troxacitabine (the metabolite of fostrox) by measuring whole blood plasma concentrations in participants receiving fostrox in combination with lenvatinib.
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