A Study of Nofazinlimab (CS1003) in Subjects With Advanced Hepatocellular Carcinoma

This is a multi-center, double-blind, randomized, phase III study to investigate the efficacy and safety of Nofazinlimab (CS1003) in combination with lenvatinib and placebo in combination with lenvatinib in the treatment of subjects with no prior systemic treatment and with unresectable advanced hepatocellular carcinoma (HCC). Subjects cannot be eligible for locoregional therapy. In this study, Nofazinlimab (CS1003) (or placebo) and lenvatinib are both considered as the study treatment while Nofazinlimab (CS1003) (or placebo) is the investigational product of and lenvatinib is selected as the basic treatment for HCC.


Eligibility Criteria:
Inclusion criteria

1. Age ≥18 years on the day of signing informed consent-(For Taiwan, the lower limit of age is 20 years).
2. Subjects with unresectable advanced HCC, that is not eligible for surgery and/or locoregional therapy (Stage B or C based on Barcelona Clinic Liver Cancer \[BCLC\] staging system, and meets either one of the following criteria: 1) histologically or cytologically confirmed diagnosis of HCC, 2) clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases (AASLD) criteria. Patients without cirrhosis require histological confirmation of diagnosis.
3. With at least one measurable lesion can be assessed
4. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
5. Life expectancy ≥ 3 months.
6. Child-Pugh A
7. No prior systemic treatment for advanced HCC
8. Subjects with hepatitis B virus (HBV) infection, are willing to continue receiving antiviral treatment while on study.
9. Subjects have adequate organ and marrow function. Female subjects with childbearing potential must have negative serum pregnancy test result at screening. Female subjects with childbearing potential, and male subjects and their female partners with childbearing potential must agree to use an contraceptive method(s) from the day of signing informed consent form (ICF), during the study and till at least 6 months after the last dose of study treatment.

   Exclusion criteria
10. Fibrolamellar-HCC, sarcomatoid, cholangiocellular carcinoma or mixed cholangiocarcinoma and HCC.
11. A prior bleeding event due to esophageal within 6 months or other gastrointestinal bleeding events within 28 days prior to screening.
12. Malabsorption syndrome or inability to take oral medication due to other causes.
13. HBV and HCV co-infection.
14. Investigator evaluates to increase the drug related risk caused by enrolling subjects in trial and taking study drug, or any serious or uncontrolled systematic disease that confound the drug absorption or the study outcome, e,g diabetes mellitus, hypertension, rheumatoid arthritis, major cardiovascular disease and so on.
15. Surgery or locoregional therapy for palliative purpose within 4 weeks prior to study treatment.
16. History of other malignancy(ies) in the past 5 years, except for malignant disease treated with curative intent and without active disease.
17. Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
18. Current or prior use of systemic corticosteroid (\> 10 mg/day prednisone or equivalent) or other immunosuppressive medication within 14 days prior to the first dose of study treatment.
19. History of bone marrow transplantation or organ transplantation.
20. History of anaphylaxis or hypersensitivity to any ingredient of the investigational product.
21. Any contraindication of lenvatinib.
22. Known history of drugs abuse that would interfere with cooperation with the requirements of the trial.
23. Pregnant or lactating female subjects.
24. History of psychiatric disease that would interfere with cooperation with the requirements of the trial; lack of or with restricted physical capability.
25. QTc interval \> 470 msec (as calculated with Fridericia's formula) at screening electrocardiogram (ECG);
26. Any condition that would in the investigator's judgment, prevent the subject from participating in this study.