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Clinical Trial NCT07493668 (FLEX-HCC) for Hepatocellular Carcinoma (HCC) is not yet recruiting. See the Trial Radar Card View and AI discovery tools for all the details. Or ask anything here. | ||
CHA UniversityFostrox Plus Lenvatinib vs Lenvatinib in Advanced Hepatocellular Carcinoma After First-line Immunotherapy (FLEX-HCC) Phase 2 80 Immunotherapy Biomarker-Driven Randomized Open-Label
Approximately 80 patients will be en...
Show MoreA Phase 2, Multicenter, Randomized, Open-label Study Comparing Fostrox + Lenvatinib vs. Lenvatinib in Patients With Locally Advanced or Unresectable Advanced Hepatocellular Carcinoma (HCC) Who Have Received First-line Combination Immunotherapy
- 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.
- Chon HJ, Heo J, Reig Monzon ME, et al. 176P - Liver pharmacodynamics in an ope...
- FLEX-HCC
- 2026-02-022
| Participant Group/Arm | Intervention/Treatment |
|---|---|
ExperimentalFostrox + Lenvatinib 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). | Fostrox 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 wate...Show More Lenvatinib 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. |
Active ComparatorLenvatinib Lenvatinib: Oral daily, continuous; 12 mg QD (≥60 kg) or 8 mg QD (\<60 kg) | Lenvatinib 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. |
| Outcome Measure | Measure Description | Time Frame |
|---|---|---|
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 |
| Outcome Measure | Measure Description | Time Frame |
|---|---|---|
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. | 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 | 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). | 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 | 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. | 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 | 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. | 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 | DCR is defined as the proportion of participants with a best overall response of CR, PR, or stable disease (SD), as assessed by the 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 |
Disease Control Rate (DCR) by Investigator According to mRECIST | DCR is defined as the proportion of participants with a best overall response of CR, PR, or SD, as assessed by the 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 |
Progression-Free Survival (PFS) by Investigator According to RECIST v1.1 | PFS is defined as the time from randomization to the first documented disease progression or death from any cause, as assessed by the investigator according to RECIST v1.1. | From randomization until first documented disease progression or death from any cause, up to approximately 36 months |
Progression-Free Survival (PFS) by Investigator According to mRECIST | PFS is defined as the time from randomization to the first documented disease progression or death from any cause, as assessed by the investigator according to mRECIST. | From randomization until first documented disease progression or death from any cause, up to approximately 36 months |
Time to Progression (TTP) by Investigator According to RECIST v1.1 | TTP is defined as the time from randomization to the first documented disease progression, as assessed by the investigator according to RECIST v1.1. Death without prior documented progression will not be counted as a progression event. | From randomization until first documented disease progression, up to approximately 36 months |
Time to Progression (TTP) by Investigator According to mRECIST | TTP is defined as the time from randomization to the first documented disease progression, as assessed by the investigator according to mRECIST. Death without prior documented progression will not be counted as a progression event. | From randomization until first documented disease progression, up to approximately 36 months |
Duration of Response (DOR) by Independent Review Facility (IRF) 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 an Independent Review Facility (IRF) according to RECIST v1.1, among participants who achieve CR or PR. | From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months |
Progression-Free Survival (PFS) by Independent Review Facility (IRF) According to RECIST v1.1 | PFS is defined as the time from randomization to the first documented disease progression or death from any cause, as assessed by an Independent Review Facility (IRF) according to RECIST v1.1. | From randomization until first documented disease progression or death from any cause, up to approximately 36 months |
Time to Progression (TTP) by Independent Review Facility (IRF) According to RECIST v1.1 | TTP is defined as the time from randomization to the first documented disease progression, as assessed by an Independent Review Facility (IRF) according to RECIST v1.1. Death without prior documented progression will not be counted as a progression event. | From randomization until first documented disease progression, up to approximately 36 months |
Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | From randomization until death from any cause, up to approximately 36 months |
Incidence and Severity of Adverse Events | Safety and tolerability will be assessed by evaluating the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs), graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. | From signing of informed consent until 28 days after the last dose of study drug, or until resolution/stabilization as clinically indicated, up to approximately 36 months |
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
- Serum total bilirubin ≤3.0 x ULN
- International normalized ratio (INR) ≤1.5 or prothrombin time ≤1.5 x ULN
- Activated partial thromboplastin time (aPTT) ≤1.5 x ULN
Child Pugh A within 7 days prior to randomization
Negative HIV test at screening
Documented hepatitis virus status for HBV and HCV confirmed at screening
- For patients with active HBV: HBV DNA <500 IU/mL during screening; initiation of antiviral therapy at least 14 days prior to randomization; willingness to continue antiviral therapy during the study
- For patients with active or past HCV infection: confirmed negative viral load using HCV PCR
- For patients with concurrent HBV and HCV infection: not eligible
Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤1 before participation, except alopecia
Patients with a prior history of gastric or esophageal variceal bleeding may be eligible if they have received appropriate treatment with no evidence of recurrent bleeding for at least 6 months, have no high-risk features on a recent endoscopy, and are currently assessed to be at low risk of bleeding.
Female subjects
- Eligible if postmenopausal
- Female patient who is a woman of childbearing potential (WOCBP) (post menarchal) who agrees to use a highly efficient method of contraception (a method with less than 1% failure rate \[e.g. sterilization, hormone implants, hormone injections, intrauterine devices, vasectomized partner, or combined birth control pills\]) from screening until at least 6 months after the last dose of study drug
- WOCBP must have a negative urine pregnancy test at screening and negative urine pregnancy test within 72 hours before the first dose of study drug.
- If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female patients must agree not to breast feed after the time of consent and for at least 6 months after the administration of the last dose of study drug.
Male subjects
- Male patient who has had a successful vasectomy (confirmed azoospermia)
- Male patient agrees to use effective contraception, including condom use, from screening until at least 3 months after the last dose of study drug (no sperm donation is allowed during the study period and for at least 3 months after study drug discontinuation)
- Male patient with a female partner who is a WOCBP and is using a highly efficient method of contraception as described above
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)
Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study
Patients with active malignancy within the past 36 months prior to randomization (except for completed resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in-situ, intramucosal carcinoma, superficial bladder cancer, or other cancers with no recurrence for ≥3 years)
Patients with gastric or esophageal varices that require interventional treatment within 28 days prior to randomization. Prophylaxis with pharmacologic therapy (e.g. nonselective beta-blocker) is permitted.
Patients with bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring (e.g. warfarin etc.). Treatment with low molecular weight heparin and factor X inhibitors which do not require INR monitoring is permitted.
Systolic blood pressure (BP) >160 mmHg or diastolic BP >100 mmHg despite optimal antihypertensive therapy, or uncontrolled without changes in antihypertensive agents within 1 week prior to screening
Clinical ascites regardless of the severity (mild, moderate, or severe). Radiological ascites managed with diuretics and a low-sodium diet are accepted if the Child-Pugh score is A.
History of encephalopathy within the 6 months prior to randomization or current hepatic encephalopathy
Receiving drugs that are extensively metabolized by CYP3A4 that have a narrow therapeutic index must be discontinued 5 half-lives before the first dose of study drug (fostrox). Information on CYP3A4 was referenced from the following websites:
- CredibleMeds (https://crediblemeds.org)
- DrugBank (https://go.drugbank.com/categories/DBCAT002646)
Receiving drugs that are strong inhibitors of P-glycoprotein (P-gP) and/or breast cancer resistance protein (BCRP)
Proteinuria as defined by urine protein ≥1 g/24 hours at screening. Patients having >2+ proteinuria on urine dipstick testing will undergo a 24 hour urine collection or urine protein-to-creatinine ratio (UPCR) test for quantitative assessment of proteinuria.
Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
Receiving anticancer therapy for HCC within 4 weeks prior to the first dose of study drug (fostrox)
Receiving any other investigational agent within 4 weeks prior to screening
Enrolled in another clinical study with an investigational drug
Are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study drug
Any other condition that precludes adequate understanding, cooperation, and compliance with study procedures or any condition that could pose a risk to the patient's safety, as per the investigator's judgment
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