Ignite Creation Date:
2026-03-26 @ 3:16 PM
Ignite Modification Date:
2026-03-30 @ 2:03 AM
Study NCT ID:
NCT07493668
Status:
NOT_YET_RECRUITING
Last Update Posted:
2026-03-25
First Post:
2026-03-17
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Fostrox Plus Lenvatinib vs Lenvatinib in Advanced Hepatocellular Carcinoma After First-line Immunotherapy
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2026-03-25'}, 'conditionBrowseModule': {'meshes': [{'id': 'D006528', 'term': 'Carcinoma, Hepatocellular'}], 'ancestors': [{'id': 'D000230', 'term': 'Adenocarcinoma'}, {'id': 'D002277', 'term': 'Carcinoma'}, {'id': 'D009375', 'term': 'Neoplasms, Glandular and Epithelial'}, {'id': 'D009370', 'term': 'Neoplasms by Histologic Type'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D008113', 'term': 'Liver Neoplasms'}, {'id': 'D004067', 'term': 'Digestive System Neoplasms'}, {'id': 'D009371', 'term': 'Neoplasms by Site'}, {'id': 'D004066', 'term': 'Digestive System Diseases'}, {'id': 'D008107', 'term': 'Liver Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'C531958', 'term': 'lenvatinib'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Participants will be randomized in a 1:1 ratio to 2 parallel treatment arms to receive either fostrox plus lenvatinib or lenvatinib alone.'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 80}}, 'statusModule': {'overallStatus': 'NOT_YET_RECRUITING', 'startDateStruct': {'date': '2026-04-27', 'type': 'ESTIMATED'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2026-03', 'completionDateStruct': {'date': '2029-04-27', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2026-03-20', 'studyFirstSubmitDate': '2026-03-17', 'studyFirstSubmitQcDate': '2026-03-20', 'lastUpdatePostDateStruct': {'date': '2026-03-25', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2026-03-25', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2028-04-27', 'type': 'ESTIMATED'}}, 'outcomesModule': {'otherOutcomes': [{'measure': 'Percentage or Count of Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMCs)', 'timeFrame': 'Baseline (Cycle 1 Day 1), every 2 cycles up to Week 54, every 3 cycles thereafter, and at the End of Treatment visit.', 'description': '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.'}, {'measure': 'Percentage Change from Baseline in the Concentration of Targeted Blood Metabolites', 'timeFrame': '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).', 'description': 'Evaluation of metabolic changes mediated by the study drug by measuring the percentage change from baseline in the concentration of targeted endogenous blood metabolites.'}, {'measure': 'Number of Participants with Specific Genetic Alterations Identified via ctDNA and RNA Sequencing', 'timeFrame': 'Baseline, every 2 cycles up to Week 54, every 3 cycles thereafter, and at the End of Treatment visit.', 'description': 'Investigation of genetic alterations that may affect responses (i.e., distribution, safety, tolerability, and efficacy) to study treatment and/or susceptibility to diseases.'}, {'measure': 'Plasma Concentration of Fostrox and Troxacitabine', 'timeFrame': 'Cycle 1 Day 1 at 30 minutes, 1 hour, 2 hours, and 4 hours after fostrox administration', 'description': 'Evaluation of the pharmacokinetics of troxacitabine (the metabolite of fostrox) by measuring whole blood plasma concentrations in participants receiving fostrox in combination with lenvatinib.'}], 'primaryOutcomes': [{'measure': 'Objective Response Rate (ORR) by Independent Review Facility (IRF) According to RECIST v1.1', 'timeFrame': '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', 'description': '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.'}], 'secondaryOutcomes': [{'measure': 'Objective Response Rate (ORR) by Investigator According to RECIST v1.1', 'timeFrame': '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', 'description': '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.'}, {'measure': 'Objective Response Rate (ORR) by Investigator According to mRECIST', 'timeFrame': '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', 'description': '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).'}, {'measure': 'Duration of Response (DOR) by Investigator According to RECIST v1.1', 'timeFrame': 'From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Duration of Response (DOR) by Investigator According to mRECIST', 'timeFrame': 'From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Disease Control Rate (DCR) by Investigator According to RECIST v1.1', 'timeFrame': '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', 'description': '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.'}, {'measure': 'Disease Control Rate (DCR) by Investigator According to mRECIST', 'timeFrame': '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', 'description': '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.'}, {'measure': 'Progression-Free Survival (PFS) by Investigator According to RECIST v1.1', 'timeFrame': 'From randomization until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Progression-Free Survival (PFS) by Investigator According to mRECIST', 'timeFrame': 'From randomization until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Time to Progression (TTP) by Investigator According to RECIST v1.1', 'timeFrame': 'From randomization until first documented disease progression, up to approximately 36 months', 'description': '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.'}, {'measure': 'Time to Progression (TTP) by Investigator According to mRECIST', 'timeFrame': 'From randomization until first documented disease progression, up to approximately 36 months', 'description': '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.'}, {'measure': 'Duration of Response (DOR) by Independent Review Facility (IRF) According to RECIST v1.1', 'timeFrame': 'From first documented CR or PR until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Progression-Free Survival (PFS) by Independent Review Facility (IRF) According to RECIST v1.1', 'timeFrame': 'From randomization until first documented disease progression or death from any cause, up to approximately 36 months', 'description': '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.'}, {'measure': 'Time to Progression (TTP) by Independent Review Facility (IRF) According to RECIST v1.1', 'timeFrame': 'From randomization until first documented disease progression, up to approximately 36 months', 'description': '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.'}, {'measure': 'Overall Survival (OS)', 'timeFrame': 'From randomization until death from any cause, up to approximately 36 months', 'description': 'OS is defined as the time from randomization to death from any cause.'}, {'measure': 'Incidence and Severity of Adverse Events', 'timeFrame': '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', 'description': '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.'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['HCC'], 'conditions': ['Hepatocellular Carcinoma (HCC)']}, 'referencesModule': {'references': [{'type': 'BACKGROUND', 'citation': '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.'}, {'type': 'BACKGROUND', 'citation': 'Chon HJ, Heo J, Reig Monzon ME, et al. 176P - Liver pharmacodynamics in an open-label phase Ib/IIa study of fostroxacitabine bralpamide (fostrox, MIV-818) in combination with lenvatinib in 2L/3L hepatocellular carcinoma. Ann Oncol. 2024;35(S1):S80.'}, {'type': 'BACKGROUND', 'citation': 'Oberg F, Bhoi S, Wallberg H, et al. PO-221 - Liver biopsy biomarkers in a phase 1 study of the prodrug MIV-818 demonstrates proof-of-concept for cancer in the liver. EASL. 2022.'}, {'type': 'BACKGROUND', 'citation': 'Sarker D, Evans J, Van Cutsem, et al. 527P - Phase I study of the novel prodrug MIV-818 in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM). Ann Oncol. 2021;32(S5):S594.'}, {'type': 'BACKGROUND', 'citation': 'Bethell R, Tunblad K, Rizoska B, et al. SAT-123 - Liver-targeting with the novel nucleotide prodrug MIV-818 designed for the treatment of liver cancers. EASL The International Liver Congress. 2017.'}, {'type': 'BACKGROUND', 'citation': 'NCCN Guidelines 2023. NCCN Guidelines for Patients with Hepatocellular Carcinoma.'}, {'pmid': '36435652', 'type': 'BACKGROUND', 'citation': 'Choi SH, Kang I, Lee SH, Kang B, Cheon J, Kim DJ, Kim G, Kwon CI, Ko KH, Chon HJ. Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma. Surgery. 2023 Feb;173(2):280-288. doi: 10.1016/j.surg.2022.09.028. Epub 2022 Nov 23.'}, {'pmid': '17565005', 'type': 'BACKGROUND', 'citation': 'Lam W, Leung CH, Bussom S, Cheng YC. The impact of hypoxic treatment on the expression of phosphoglycerate kinase and the cytotoxicity of troxacitabine and gemcitabine. Mol Pharmacol. 2007 Sep;72(3):536-44. doi: 10.1124/mol.106.033472. Epub 2007 Jun 12.'}, {'pmid': '37671815', 'type': 'BACKGROUND', 'citation': 'Buttell A, Qiu W. The action and resistance mechanisms of Lenvatinib in liver cancer. Mol Carcinog. 2023 Dec;62(12):1918-1934. doi: 10.1002/mc.23625. Epub 2023 Sep 6.'}, {'pmid': '41602061', 'type': 'BACKGROUND', 'citation': 'Wu Q, Qin Y, Li Q. Nivolumab plus ipilimumab versus lenvatinib or sorafenib for US and Chinese patients with unresectable hepatocellular carcinoma: a cost-effectiveness analysis. Front Public Health. 2026 Jan 12;13:1726477. doi: 10.3389/fpubh.2025.1726477. eCollection 2025.'}, {'pmid': '8797590', 'type': 'BACKGROUND', 'citation': 'Grove KL, Cheng YC. Uptake and metabolism of the new anticancer compound beta-L-(-)-dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res. 1996 Sep 15;56(18):4187-91.'}, {'pmid': '18829552', 'type': 'BACKGROUND', 'citation': 'Ewald B, Sampath D, Plunkett W. ATM and the Mre11-Rad50-Nbs1 complex respond to nucleoside analogue-induced stalled replication forks and contribute to drug resistance. Cancer Res. 2008 Oct 1;68(19):7947-55. doi: 10.1158/0008-5472.CAN-08-0971.'}, {'pmid': '7559445', 'type': 'BACKGROUND', 'citation': "Kukhanova M, Liu SH, Mozzherin D, Lin TS, Chu CK, Cheng YC. L- and D-enantiomers of 2',3'-dideoxycytidine 5'-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity. J Biol Chem. 1995 Sep 29;270(39):23055-9. doi: 10.1074/jbc.270.39.23055."}, {'pmid': '15570003', 'type': 'BACKGROUND', 'citation': 'Gourdeau H, Leblond L, Hamelin B, Dong K, Ouellet F, Boudreau C, Custeau D, Richard A, Gilbert MJ, Jolivet J. Species differences in troxacitabine pharmacokinetics and pharmacodynamics: implications for clinical development. Clin Cancer Res. 2004 Nov 15;10(22):7692-702. doi: 10.1158/1078-0432.CCR-04-0657.'}, {'pmid': '7606719', 'type': 'BACKGROUND', 'citation': 'Grove KL, Guo X, Liu SH, Gao Z, Chu CK, Cheng YC. Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res. 1995 Jul 15;55(14):3008-11.'}, {'pmid': '33197225', 'type': 'BACKGROUND', 'citation': 'Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, Goff L, Gupta S, Guy J, Harris WP, Iyer R, Jaiyesimi I, Jhawer M, Karippot A, Kaseb AO, Kelley RK, Knox JJ, Kortmansky J, Leaf A, Remak WM, Shroff RT, Sohal DPS, Taddei TH, Venepalli NK, Wilson A, Zhu AX, Rose MG. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020 Dec 20;38(36):4317-4345. doi: 10.1200/JCO.20.02672. Epub 2020 Nov 16.'}, {'pmid': '29433850', 'type': 'BACKGROUND', 'citation': 'Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.'}, {'pmid': '33090186', 'type': 'BACKGROUND', 'citation': 'Sonbol MB, Riaz IB, Naqvi SAA, Almquist DR, Mina S, Almasri J, Shah S, Almader-Douglas D, Uson Junior PLS, Mahipal A, Ma WW, Jin Z, Mody K, Starr J, Borad MJ, Ahn DH, Murad MH, Bekaii-Saab T. Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis. JAMA Oncol. 2020 Dec 1;6(12):e204930. doi: 10.1001/jamaoncol.2020.4930. Epub 2020 Dec 10.'}, {'pmid': '32402160', 'type': 'BACKGROUND', 'citation': 'Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.'}, {'pmid': '34902530', 'type': 'BACKGROUND', 'citation': 'Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. doi: 10.1016/j.jhep.2021.11.030. Epub 2021 Dec 11.'}, {'pmid': '38319892', 'type': 'BACKGROUND', 'citation': 'Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgue A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. doi: 10.1056/EVIDoa2100070. Epub 2022 Jun 6.'}, {'pmid': '35107390', 'type': 'BACKGROUND', 'citation': 'Hou JP, Shi YB, Fu YF, Li H. I-125 seeds insertion with TACE for advanced HCC: a meta-analysis of randomized controlled trials. Minim Invasive Ther Allied Technol. 2022 Aug;31(6):848-855. doi: 10.1080/13645706.2022.2033786. Epub 2022 Feb 2.'}, {'pmid': '22109811', 'type': 'BACKGROUND', 'citation': 'Senthilnathan S, Memon K, Lewandowski RJ, Kulik L, Mulcahy MF, Riaz A, Miller FH, Yaghmai V, Nikolaidis P, Wang E, Baker T, Abecassis M, Benson AB 3rd, Omary RA, Salem R. Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: analyzing patterns of progression in 285 patients. Hepatology. 2012 May;55(5):1432-42. doi: 10.1002/hep.24812. Epub 2012 Apr 4.'}, {'pmid': '37173972', 'type': 'BACKGROUND', 'citation': 'Lazzaro A, Hartshorn KL. A Comprehensive Narrative Review on the History, Current Landscape, and Future Directions of Hepatocellular Carcinoma (HCC) Systemic Therapy. Cancers (Basel). 2023 Apr 27;15(9):2506. doi: 10.3390/cancers15092506.'}, {'pmid': '33479224', 'type': 'BACKGROUND', 'citation': 'Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021 Jan 21;7(1):6. doi: 10.1038/s41572-020-00240-3.'}, {'pmid': '34801630', 'type': 'BACKGROUND', 'citation': 'Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Fuster J, Ayuso C, Bruix J. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681-693. doi: 10.1016/j.jhep.2021.11.018. Epub 2021 Nov 19.'}, {'pmid': '33716105', 'type': 'BACKGROUND', 'citation': 'Vogel A, Martinelli E; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org; ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021 Jun;32(6):801-805. doi: 10.1016/j.annonc.2021.02.014. Epub 2021 Mar 5. No abstract available.'}, {'pmid': '37199193', 'type': 'BACKGROUND', 'citation': 'Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023 Dec 1;78(6):1922-1965. doi: 10.1097/HEP.0000000000000466. Epub 2023 May 22. No abstract available.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nApproximately 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.\n\nThe 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.\n\nThe 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.\n\nTumor 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.', 'detailedDescription': '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.\n\nFostrox 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.\n\nThis 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.\n\nPatients 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.\n\nThe 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.\n\nThe 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.\n\nTumor 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '19 Years', 'genderBased': True, 'genderDescription': '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.', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n1. Patients with a diagnosis of locally advanced or unresectable metastatic HCC confirmed by radiology, histology, or cytology\n2. 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\n3. Patients with measurable lesion in the liver (at least one target lesion) according to RECIST v1.1 and mRECIST\n\n \\- 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\n4. Patients who are not amenable for curative surgery or locoregional therapy\n5. ECOG performance status of 0 or 1 within 7 days prior to randomization\n6. Life expectancy of at least 3 months\n7. Subjects age ≥19 years at the time of signing the informed consent form (ICF)\n8. 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\n9. Subjects with adequate hematological function and hepatic function without using blood transfusion or growth factors within 7 days prior to randomization\n\n * Hemoglobin (Hb) ≥9.0 g/dL\n * Absolute neutrophil count (ANC) ≥1,500/μl\n * Platelet count ≥75,000/μl\n * Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) estimated by Cockcroft-Gault equation ≥60 mL/min\n * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5.0 x ULN\n * Serum total bilirubin ≤3.0 x ULN\n * International normalized ratio (INR) ≤1.5 or prothrombin time ≤1.5 x ULN\n * Activated partial thromboplastin time (aPTT) ≤1.5 x ULN\n10. Child Pugh A within 7 days prior to randomization\n11. Negative HIV test at screening\n12. Documented hepatitis virus status for HBV and HCV confirmed at screening\n\n * 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\n * For patients with active or past HCV infection: confirmed negative viral load using HCV PCR\n * For patients with concurrent HBV and HCV infection: not eligible\n13. Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤1 before participation, except alopecia\n14. 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.\n15. Female subjects\n\n * Eligible if postmenopausal\n * 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\n * 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.\n * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.\n * 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.\n16. Male subjects\n\n * Male patient who has had a successful vasectomy (confirmed azoospermia)\n * 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)\n * Male patient with a female partner who is a WOCBP and is using a highly efficient method of contraception as described above\n\nExclusion Criteria:\n\n1. Patients who have received more than 1 prior systemic therapy (i.e., fostrox + lenvatinib or lenvatinib must be administered as second-line treatment)\n2. Patients who have received first-line systemic therapy for locally advanced unresectable or metastatic HCC other than an IO combination\n3. Patients who have received a prior TKI (e.g. lenvatinib, regorafenib, cabozantinib etc.) in the IO combination\n4. Patients with a history of hypersensitivity to lenvatinib or any of its components (active ingredient or excipients)\n5. Patients with fibrolamellar HCC, sarcomoid HCC, or a mix of HCC and intrahepatic cholangiocarcinoma (iCCA)\n6. Patients with central nervous system metastasis\n7. Patients with VP4 portal vein tumor thrombosis (PVTT)\n8. Patients with significant cardiovascular disease within 3 months prior to randomization\n\n * New York Heart Association (NYHA) Class III or IV congestive heart failure\n * Unstable angina\n * Myocardial infarction\n * Cardiac arrhythmia associated with hemodynamic instability\n9. Subjects with Corrected QT interval (QTcF) \\>470 msec at Screening (corrected by Fridericia Formula)\n10. Patients with prior allogeneic stem cell or solid organ transplantation\n11. 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)\n12. Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study\n13. 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)\n14. 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.\n15. 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.\n16. 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\n17. 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.\n18. History of encephalopathy within the 6 months prior to randomization or current hepatic encephalopathy\n19. 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:\n\n * CredibleMeds (https://crediblemeds.org)\n * DrugBank (https://go.drugbank.com/categories/DBCAT002646)\n20. Receiving drugs that are strong inhibitors of P-glycoprotein (P-gP) and/or breast cancer resistance protein (BCRP)\n21. 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.\n22. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment\n23. Receiving anticancer therapy for HCC within 4 weeks prior to the first dose of study drug (fostrox)\n24. Receiving any other investigational agent within 4 weeks prior to screening\n25. Enrolled in another clinical study with an investigational drug\n26. Are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study drug\n27. 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"}, 'identificationModule': {'nctId': 'NCT07493668', 'acronym': 'FLEX-HCC', 'briefTitle': 'Fostrox Plus Lenvatinib vs Lenvatinib in Advanced Hepatocellular Carcinoma After First-line Immunotherapy', 'organization': {'class': 'OTHER', 'fullName': 'CHA University'}, 'officialTitle': 'A 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', 'orgStudyIdInfo': {'id': '2026-02-022'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Fostrox + Lenvatinib', 'description': 'Fostrox: Oral, once daily for 5 days (Day 1-5) followed by 16-day rest in a 21-day cycle.\n\nLenvatinib: Oral daily, continuous; 12 mg QD (≥60 kg) or 8 mg QD (\\<60 kg).', 'interventionNames': ['Drug: Fostrox', 'Drug: Lenvatinib']}, {'type': 'ACTIVE_COMPARATOR', 'label': 'Lenvatinib', 'description': 'Lenvatinib: Oral daily, continuous; 12 mg QD (≥60 kg) or 8 mg QD (\\<60 kg)', 'interventionNames': ['Drug: Lenvatinib']}], 'interventions': [{'name': 'Fostrox', 'type': 'DRUG', 'description': '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.', 'armGroupLabels': ['Fostrox + Lenvatinib']}, {'name': 'Lenvatinib', 'type': 'DRUG', 'description': '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.', 'armGroupLabels': ['Fostrox + Lenvatinib', 'Lenvatinib']}]}, 'contactsLocationsModule': {'locations': [{'zip': '13496', 'city': 'Seongnam-si', 'state': 'Gyeonggi-do', 'country': 'South Korea', 'contacts': [{'name': 'Hong Jae Chon, MD. PhD', 'role': 'CONTACT', 'email': 'minidoctor@cha.ac.kr', 'phone': '82-31-780-3928'}, {'name': 'Hong Jae Chon, MD. PhD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'CHA Bundang Medical Center', 'geoPoint': {'lat': 37.43861, 'lon': 127.13778}}], 'centralContacts': [{'name': 'Hong Jae Chon, MD, PhD', 'role': 'CONTACT', 'email': 'hongjaechon@gmail.com', 'phone': '82-31-780-3928'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'CHA University', 'class': 'OTHER'}, 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Principal Investigator', 'investigatorFullName': 'Hong Jae Chon', 'investigatorAffiliation': 'CHA University'}}}}