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