None listed
Conditions
Interventions
Drug : - experimental arm: Fostrox30mg, QD, PO(5 days on, 16 days off) + Lenvatinib12mg(=60kg) or 8mg(400 ng/mL
Fostrox (30 mg) will be administered orally once daily (QD) from Days 1 to Day 5 in eac
Sponsors
Bundang CHA General Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
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 (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, have no evidence of recurrent bleeding for at least 6 months, show no high-risk features on a recent endoscopic examination, and are currently assessed by the investigator 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 stud
Exclusion criteria
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 with received first-line systemic therapy for locally advanced unresectable or metastatic HCC other than an IO combination 3) Patients with 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objective response rate (ORR) as determined by an independent review facility (IRF) according to RECIST v1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| ORR: The proportion of complete response (CR) or partial response (PR) assessed by the investigator according to RECIST v1.;ORR: The proportion of complete response (CR) or partial response (PR) assessed by the investigator according to mRECIST;DOR: The time from the first occurrence of CR or PR to disease progression or death, as assessed by the investigator according to RECIST v1.1;DOR: The time from the first occurrence of CR or PR to disease progression or death, as assessed by the investigator according to mRECIST;DCR: The proportion of CR, PR, or stable disease (SD), as assessed by the investigator according to RECIST v1.1;DCR: The proportion of CR, PR, or stable disease (SD), as assessed by the investigator according to mRECIST; PFS: PFS as assessed by the investigator according to RECIST v1.1;PFS: PFS as assessed by the investigator according to mRECIST;TTP: TTP as assessed by the investigator according to RECIST v1.1;TTP: TTP as assessed by the investigator according to or mRECIST;DOR, PFS and TTP as assessed by IRF according to RECIST v1.1;OS: The time to death from any causes;Safety and tolerability assessement: Incidence and severity of adverse events (AEs) as assessed according to NCI CTCAE v5.0 | — |
Countries
Korea, Republic of
Contacts
Public ContactMi Ri Jeong
Bundang CHA General Hospital
Outcome results
None listed