Adjuvant Everolimus in High-Risk Hepatocellular Carcinoma After Curative Resection (SEVERANCE Trial)

Inclusion criteria

• Alkaline phosphatase level > 2.5 times the ULN
• Proteinuria defined as a urine protein-to-creatinine ratio > 1.0 g/gCr or ≥ 2+ on urine dipstick
• Patients who received systemic therapy prior to hepatic resection
• Prior treatment with anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapies
• Renal impairment with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m² (based on MDRD formula)
• Total cholesterol > 350 mg/dL or triglycerides > 500 mg/dL
• History of severe acute (within the past 4 weeks) or chronic hypersensitivity reactions requiring treatment to everolimus or drugs with a similar chemical structure
• Pregnant or breastfeeding women, women who are possibly pregnant, or women of childbearing potential who are unable to use highly effective contraception† during the study period and for 8 weeks after the last dose
• Any condition deemed by the investigator to render the patient unsuitable for participation in the clinical trial

• Highly effective contraception is defined as methods with a failure rate of less than 1% per year, including bilateral tubal occlusion, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs. Methods such as calendar-based methods, ovulation prediction, symptothermal methods, and post-ovulation methods are not considered adequate contraception.

Exclusion criteria

• Patients diagnosed with combined hepatocellular-cholangiocarcinoma (HCC-CCC)
• Presence of clinically significant ascites
• History of hepatic encephalopathy
• History of variceal bleeding within 6 months prior to hepatic resection
• Autoimmune diseases or immunodeficiency disorders
• Serious cardiovascular diseases, including acute myocardial infarction, acute coronary syndrome, stroke, or heart failure of New York Heart Association (NYHA) Class II or higher
• History of malignancies other than HCC within the past 5 years
• Patients with hereditary metabolic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• Patients currently taking medication for psychiatric disorders
• Absolute neutrophil count (ANC) < 1500/μL or platelet count < 75,000/μL
• AST, ALT, or total bilirubin levels > 3 times the upper limit of normal (ULN)
• Alkaline phosphatase level > 2.5 times the ULN
• Proteinuria defined as a urine protein-to-creatinine ratio > 1.0 g/gCr or ≥ 2+ on urine dipstick
• Patients who received systemic therapy prior to hepatic resection
• Prior treatment with anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapies
• Renal impairment with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m² (based on MDRD formula)
• Total cholesterol > 350 mg/dL or triglycerides > 500 mg/dL
• History of severe acute (within the past 4 weeks) or chronic hypersensitivity reactions requiring treatment to everolimus or drugs with a similar chemical structure
• Pregnant or breastfeeding women, women who are possibly pregnant, or women of childbearing potential who are unable to use highly effective contraception† during the study period and for 8 weeks after the last dose
• Any condition deemed by the investigator to render the patient unsuitable for participation in the clinical trial

• Highly effective contraception is defined as methods with a failure rate of less than 1% per year, including bilateral tubal occlusion, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs. Methods such as calendar-based methods, ovulation prediction, symptothermal methods, and post-ovulation methods are not considered adequate contraception.