Phase III Study of Toripalimab（JS001） Combined With Lenvatinib for Advanced HCC

A Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter Phase III Study to Compare Toripalimab Combined With Lenvatinib Versus Placebo Combined With Lenvatinib as the 1st-line Therapy for Advanced HCC

This is a prospective, randomized, placebo-controlled, double-blind, multicenter phase III registration clinical study to observe, compare and evaluate the efficacy and safety of Toripalimab combined with Lenvatinib versus placebo combined with Lenvatinib as the 1st-line therapy for advanced HCC.

Eligible subjects will be randomized at a ratio of 2:1 to receive Toripalimab combined with Lenvatinib (experimental group) or Placebo combined with Lenvatinib (control group).

Inclusion criteria:

1. Age of 18-75 full years (inclusive), male or female.
2. 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).
3. 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.
4. 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).
5. 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.
6. Child-Pugh class A or ≤7 class B, with no history of hepatic encephalopathy.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0-1.
8. Expected survival ≥12 weeks.
9. 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.
10. 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.
11. Female patients at childbearing age 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.
12. Being voluntary to participate in the study, sufficiently informed consent and sign the written informed consent form, with good compliance.

Exclusion criteria:

1. Known cholangiocellular carcinoma (ICC) or mixed hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma and hepatic fibrolamellar carcinoma.
2. 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.
3. 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).
4. Prior use of other anti-PD-1 antibody or other immunotherapy targeting PD-1/PD-L1.
5. 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.
6. 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 (+)).
7. Having ≥ grade 3 (NCI-CTCAE v5.0) gastrointestinal or non-gastrointestinal fistula at present.
8. 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.
9. Serious cardiovascular and cerebrovascular diseases:
10. Other obvious hemorrhagic tendency or evidence on important coagulation disorder:
11. Medium to large surgical treatment within 4 weeks prior to randomization, not including diagnostic biopsy.
12. Know central nervous system metastasis; cranial and/or spinal MRI is needed for exclusion if central nervous system metastasis is suspected.
13. Serious, uncured wound, active ulcer or untreated bone fracture.
14. Vaccination of live vaccine within 30 days prior to randomization.
15. Presence of immunodeficiency or receiving long-term systemic steroid therapy within 7 days prior to randomization (daily dose >10mg Prednisone or other equivalent glucocorticoid), or other immunosuppressive therapy.
16. 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.
17. History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy.
18. Active tuberculosis or received antituberculosis therapy within 1 year prior to randomization.
19. Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.
20. Known history of human immunodeficiency virus (HIV) infection.
21. Previously receiving allogeneic stem cell or solid organ transplantation.
22. Inability to swallow tablets, malabsorption syndrome or any other condition that affects gastrointestinal absorption.
23. Known history of serious allergy to any monoclonal antibody, anti-angiogenesis drug.
24. Other participants who are unsuitable for inclusion as judged by the investigator."