Lenvatinib Plus Nivolumab Versus Lenvatinib for Advanced Hepatocellular Carcinoma With Hepatitis B Virus Infection

A Randomized, Phase IIb Study of Lenvatinib Plus Nivolumab Versus Lenvatinib for Advanced Hepatocellular Carcinoma (HCC) With Hepatitis B Virus (HBV) Infection

The purpose of this study is to investigate the efficacy and safety of lenvatinib plus nivolumab compared with lenvatinib monotherapy for patients with advanced hepatitis B virus infection-related hepatocellular carcinoma.

Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma, and nivolumab was effective and tolerable in patients with advanced hepatocellular carcinoma. No study has evaluated the efficacy and safety of lenvatinib plus nivolumab compared with lenvatinib monotherapy. Thus, the investigators carried out this prospective, randomized, phase IIb study to find out it.

Inclusion Criteria:

Patients who meet all of the following criteria in screening tests and observations within 14 days before enrollment will be included in the study.

1. Signed Informed Consent Form

2. Males and Females, 18 years or older at time of signing Informed Consent Form

3. Ability to comply with the study protocol, in the investigator's judgment

4. HCC with diagnosis confirmed by histology/cytology by AASLD criteria

5. Barcelona clinic liver cancer (BCLC) C stage.

6. No prior systemic therapy for HCC

7. Patients must not be appropriate for surgery or loco-regional therapy. Patients can receive no previous anti-cancer therapy or have progressed or have intolerable adverse events after surgery or loco-regional therapy. Surgery or locoregional therapy include hepatic resection, ablation, transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), radiotherapy, and must have been completed at least 4 weeks (washout period) prior to the baseline scan. In addition, all acute toxic effects of the locoregional procedure must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade<=1.

8. At least one tumor lesion that can be accurately measured according to the RECIST 1.1

9. ECOG Performance Status of 0 or 1

10. No cirrhosis or cirrhotic status of Child-Pugh class A only. Documented virology status of HBV, as confirmed by screening HBV serology test, as evidenced by detectable HBV surface antigen. (there is no lower and upper limit of HBV DNA, but patients must be on effective antiviral therapy if HBV DNA is positive [greater than zero]).

11. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior torandomization, unless otherwise specified:

    1. white blood cell count ≥ 3.0×10⁹ per L
    2. absolute neutrophil count ≥ 1.5×10⁹ per L
    3. platelet count ≥ 75×10⁹ per L
    4. Hemoglobin ≥ 8.5 g/dL
    5. Prothrombin time (PT)-international normalized ratio (INR) ≤ 2.3 or Prothrombin time (PT) ≤ 6 seconds above control
    6. total bilirubin ≤ 30mmol/L
    7. serum albumin ≥ 30 g/L
    8. aspartate transaminase and alanine transaminase ≤ 5×upper limit of the normal
    9. creatinine clearance of ≤1.5×upper limit of the normal or a creatinine clearance > 50 mL/min (Cockcroft-Gault formula)
    10. left ventricular ejection fraction (LEVF) ≥45% as measured by echocardiography

12. Reproductive status: Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within one day prior to the start of study drug. Women must not be breastfeeding.

Exclusion Criteria:

Patients who meet one of the following criteria in screening tests and observations before enrollment will be excluded from the study:

1. Fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC was excluded.
2. Any history of hepatic encephalopathy
3. Any prior (within 30 days) or current clinically significant gastrointestinal bleeding or clinically significant ascites as measured by physical examination and that requires active paracentesis for control
4. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
5. Known history of hepatitis C virus (HCV) or hepatitis D virus (HDV) infection
6. Active bacterial or fungal infections requiring systemic treatment within 7 days prior to study drug dosing
7. Prior organ allograft such as liver transplant, etc. or allogeneic bone marrow transplantation
8. Known or suspected allergy to the investigational agents or any agent given in association with this trial
9. Subjects with any active autoimmune disease or history of known or suspected autoimmune disease except for subjects with vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement. psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
10. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 30 days of study administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease
11. Treatment with anti-platelet therapy (aspirin at dose>=300 mg/day, clopidogrel at dose>=75 mg/day) or current anticoagulation therapy
12. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
13. All toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4.03) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae are permitted to enroll. Neuropathy must have resolved to Grade 2 (NCI CTCAE version 4.03).
14. Known central nervous system tumors including metastatic brain disease
15. Patients who are pregnant or breastfeeding. Women with a positive pregnancy test at enrollment or prior to administration of study medication
16. Other invasive malignant diseases
17. Prisoners, or subjects who are compulsory detained
18. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness