A clinical study to compare Toripalimab (JS001) combined with Lenvatinib versus placebo combined with Lenvatinib as the 1st-line therapy for advanced hepatocellular carcinoma (HCC)

Prior treatment

• Other obvious hemorrhagic tendency or evidence on important coagulation disorder: ⚫ Clinically significant hemoptysis or tumor hemorrhage for any reason within two weeks prior to randomization; ⚫ Thrombosis or embolic event within 6 months prior to randomization; ⚫ Use of anticoagulation therapy for therapeutic purpose within two weeks prior to randomization (except low molecular weight heparin); ⚫ Requiring antiplatelet therapy.
• Medium to large surgical treatment within 4 weeks prior to randomization, not including diagnostic biopsy.
• Vaccination of live vaccine within 30 days prior to randomization.
• Presence of immunodeficiency or receiving long-term systemic steroid therapy within 7 days prior to randomization (daily dose >10 mg Prednisone or other equivalent glucocorticoid), or other immunosuppressive therapy.
• Active tuberculosis or received antituberculosis therapy within 1 year prior to randomization.
• Previously receiving allogeneic stem cell or solid organ transplantation.
• Hepatic surgery and/or local therapy or treatment with investigational product for HCC within 4 weeks prior to randomization; palliative radiation therapy for bone metastatic lesion within 2 weeks prior to randomization; use of Chinese medicine preparations with anti-liver cancer effect within two weeks prior to randomization. Toxicity induced by previous therapy (except alopecia) not recovered to ≤ grade 1 (NCI-CTCAE v5.0).
• Prior use of other anti-PD-1 antibody or other immunotherapy targeting PD1/PD-L1.
• History of gastrointestinal hemorrhage within 6 months prior to randomization or clear tendency of gastrointestinal hemorrhage (including severe esophageal-gastric varices with hemorrhagic risk, locally active peptic ulcer, persistent fecal occult blood (+)).

Other illness

• Serious, uncured wound, active ulcer or untreated bone fracture.
• Active autoimmune diseases requiring systemic treatment (i.e., immunomodulatory drug, corticosteroid or immunosuppressant) in the past two years; however, replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency) will not be considered as systemic therapy and is allowed to be used.
• History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy.
• Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.
• Malignant tumor except HCC within 5 years: however, localized tumor cured in the study is excluded, including cervical carcinoma in situ, skin basal cell carcinoma and carcinoma in situ of prostate.
• Known history of human immunodeficiency virus (HIV) infection.
• Inability to swallow tablets, malabsorption syndrome or any other condition that affects gastrointestinal absorption.
• Known history of serious allergy to any monoclonal antibody, antiangiogenesis drug.
• Having ≥ grade 3 (NCI-CTCAE v5.0) gastrointestinal or non-gastrointestinal fistula at present.
• Cancer thrombus invasion in the main trunk of portal vein (Vp4) (more than 1/2 of the lumen), inferior vena cava cancer thrombus or cardiac involvement in accordance with CT/MRI.

Lab values

• Serious cardiovascular and cerebrovascular diseases: ⚫ New York Heart Association (NYHA) class II or above congestive heart failure, unstable angina pectoris, myocardial infarction, cerebrovascular accident or poorly controlled arrhythmia within 12 months prior to randomization. ⚫ Left ventricular ejection fraction (LVEF) <50% in color Doppler echocardiography. ⚫ Corrected QT interval (QTc) >480 ms (calculated using Fridericia method, in case of abnormal QTc, it can be detected for consecutive three times at an interval of 2 minutes and the average will be taken). ⚫ Hypertension that can not be controlled by drug (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100mmHg) (based on the mean value obtained from ≥2 measurements). ⚫ Previous occurrence of hypertensive crisis or hypertensive encephalopathy.

Other

• Known cholangiocellular carcinoma (ICC) or mixed hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma and hepatic fibrolamellar carcinoma.
• Know central nervous system metastasis; cranial and/or spinal MRI is needed for exclusion if central nervous system metastasis is suspected.
• Other participants who are unsuitable for inclusion as judged by the investigator.
• Uncontrolled pericardial effusion, uncontrolled pleural effusion or clinically obvious moderate or severe peritoneal effusion at screening, defined as reaching the following criteria: having clinical symptoms and pleural and peritoneal effusion detected in physical examination at screening; or puncture for drainage required for pleural and peritoneal effusion and/or intracavitary administration during screening.

• Age of 18-75 full years (inclusive), male or female.
• In case of HBsAg (+) and/or HBcAb (+), HBV DNA is required to be < 1000 IU/mL (if the lowest detectable value at the local center is higher than 1000IU/mL, enrollment can be determined based on the specific condition after discussed with sponsor), and it is required to continue original anti-HBV therapy in the full course, or start to use Entecavir or tenofovir in the full course after screening during the study.
• Female patients of childbearing potential must receive serum pregnancy test within 7 days before randomization, have negative result, and are willing to use reliable and effective contraceptive methods during the trial and within 5 months after last administration. Male patients whose partners are women of childbearing potential must agree to use reliable and effective contraceptive methods during the trial and within 5 months after last administration.
• Being voluntary to participate in the study, sufficiently informed consent and sign the written informed consent form, with good compliance.
• Histopathologically or cytologically confirmed HCC or participants with liver cirrhosis meet the clinical diagnostic criteria for HCC of the American Association for the Study of Liver Diseases (AASLD).
• Stage B (intermediate stage) or C (advanced stage) HCC determined in accordance with Barcelona Clinic Liver Cancer staging system (BCLC stage), be unsuitable for surgery and/or local therapy, or have progression of disease after surgery and/or local therapy.
• No previous use of any systemic therapy for HCC (mainly including systemic chemotherapy, antiangiogenic drugs or other molecular targeted therapy, immunotherapy containing CTLA-4, PD-1/PD-L1 monoclonal antibody).
• Having ≥ 1 measurable lesion in accordance with RECIST v1.1. Requirement: the selected target lesion has not been treated locally before, or is located in the area of previous local therapy and subsequently determined as PD through radiological examination and in accordance with RECIST v1.1.
• Child-Pugh class A or ≤7 class B, with no history of hepatic encephalopathy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0-1.
• Expected survival ≥12 weeks.
• Main organ function meets the following requirements: no blood transfusion within 14 days prior to screening, no use of hematopoietic stimulating factor (including G-CSF, GM-CSF, EPO and TPO etc.) or human albumin preparation. ⚫ Absolute neutrophil count ≥1.5×10 9 /L; ⚫ Platelet count ≥ 75×10 9 /L; ⚫ Haemoglobin ≥ 90 g/L; ⚫ Serum albumin ≥ 29 g/L; ⚫ Serum total bilirubin ≤2 × upper limit of normal (ULN); ⚫ Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 5×ULN; ⚫ Serum creatinine (Cr) ≤1.5×ULN or Cr clearance ≥50 mL/min (calculated by Cockcroft-Gault formula) ⚫ International normalized ratio (INR) ≤2 and prothrombin time (PT) ≤6 seconds exceeding ULN; ⚫ Urine protein < 2+ (If urine protein ≥2+, 24h urine protein quantification should be performed, the patients with 24h urine protein quantification <1.0g can be enrolled).