Overview

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.

Eligibility

Inclusion Criteria:

1. Patients with a diagnosis of locally advanced or unresectable metastatic HCC confirmed by radiology, histology, or cytology
2. 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
3. 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

4. Patients who are not amenable for curative surgery or locoregional therapy
5. ECOG performance status of 0 or 1 within 7 days prior to randomization
6. Life expectancy of at least 3 months
7. Subjects age ≥19 years at the time of signing the informed consent form (ICF)
8. 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
9. 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
10. Child Pugh A within 7 days prior to randomization
11. Negative HIV test at screening
12. 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
13. Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤1 before participation, except alopecia
14. 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.
15. 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.
16. 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

Exclusion Criteria:

1. Patients who have received more than 1 prior systemic therapy (i.e., fostrox + lenvatinib or lenvatinib must be administered as second-line treatment)
2. Patients who have received first-line systemic therapy for locally advanced unresectable or metastatic HCC other than an IO combination
3. Patients who have received a prior TKI (e.g. lenvatinib, regorafenib, cabozantinib etc.) in the IO combination
4. Patients with a history of hypersensitivity to lenvatinib or any of its components (active ingredient or excipients)
5. Patients with fibrolamellar HCC, sarcomoid HCC, or a mix of HCC and intrahepatic cholangiocarcinoma (iCCA)
6. Patients with central nervous system metastasis
7. Patients with VP4 portal vein tumor thrombosis (PVTT)
8. 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
9. Subjects with Corrected QT interval (QTcF) \>470 msec at Screening (corrected by Fridericia Formula)
10. Patients with prior allogeneic stem cell or solid organ transplantation
11. 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)
12. Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study
13. 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)
14. 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.
15. 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.
16. 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
17. 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.
18. History of encephalopathy within the 6 months prior to randomization or current hepatic encephalopathy
19. 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)
20. Receiving drugs that are strong inhibitors of P-glycoprotein (P-gP) and/or breast cancer resistance protein (BCRP)
21. 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.
22. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
23. Receiving anticancer therapy for HCC within 4 weeks prior to the first dose of study drug (fostrox)
24. Receiving any other investigational agent within 4 weeks prior to screening
25. Enrolled in another clinical study with an investigational drug
26. Are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study drug
27. 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