A Randomized, Open-label Trial Comparing Immune Checkpoint Therapy vs Target Therapy in Reducing Serum HBsAg Levels in Patients With HBeAg-positive Advanced Stage Hepatocellular Carcinoma (VICI-5)
It is estimated that over 50% of HCC cases worldwide are related to chronic HBV. There are approximately 350-400 million people across the world infected with HBV, the majority reside in or originate from Asia. Each year HBV accounts for 749,000 new cases of HCC and 692,000 HCC-related deaths. The annual incidence of HCC is estimated to be \<1% for non-cirrhotic HBV infected patients and 2-3% for those with cirrhosis. While the most approved nucleos(t)ide analogues (NA) suppress HBV replication through inhibition of HBV-DNA polymerase and are reported to reduce the risk of HCC incidence, however, such risk is not completely eliminated under NA treatment. The recent availability of commercial quantitative assays of serum hepatitis B surface antigen (HBsAg) has enabled quantitative HBsAg to be used as a biomarker for prognosis and treatment response in CHB. It has been suggested that HBsAg decline during lamivudine or entecavir therapy is slower and less pronounced compared to interferon treatment, despite a higher effect on HBV DNA suppression. Based on HBsAg kinetics, it has been estimated that the predicted median time to HBsAg loss in patients treated with lamivudine or entecavir is more than 30 years. Thus, treatment that can induce rapid decline of HBsAg would have clear advantage in reducing the treatment duration required to achieve HBsAg-loss. Interestingly, in a recent preliminary study, 12-weeks of treatment with nivolumab has showed the modest effect on HBsAg decline in HBeAg negative CHB patients. Thus, in this clinical trial, the investigator will investigate whether immune checkpoint therapy is more effective in inducing HBsAg decline compared with target therapy in HBsAg-positive patients with advanced stage HCC.
• HBsAg positive with serum HBsAg levels ≥ 2 log IU/ml
• Age ≥ 18 years old on the day of consent
• Capable of understanding and complying with the protocol requirements and signed informed consent
• Documented histological or cytological diagnosis of HCC within 1 year
• Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C
• Child-Pugh Score class A or B
• ECOG performance status of 0 or 1 at enrollment.
• Treated with either entecavir or tenofovir or TAF before initiation of anti-PDL1 or TKI
• At least 1 measurable lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion which progressed after previous ablation or TACE could be measurable if it meets these criteria
⁃ Adequate organ and marrow function, as defined below. Criteria a, b, c, and f cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose.
∙ Hemoglobin ≥9 g/dL
‣ Absolute neutrophil count ≥1000/μL
‣ Platelet count ≥75000/μL
‣ Total bilirubin (TBL) ≤2.0× upper limit of normal (ULN)
‣ AST and ALT ≤5×ULN
‣ Albumin ≥2.8 g/dL
‣ International normalized ratio (INR) ≤1.6
‣ Calculated creatinine clearance ≥50 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance