TACE Combined with Sintilimab Plus Bevacizumab Biosimilar in Patients with Advanced Hepatocellular Carcinoma (TASK-02)

Inclusion Criteria:

• Written informed consent obtained.

• Age ≥ 18 years at time of study entry.

• Barcelona Clinic Liver Cancer stage C.

• Histologically confirmed diagnosis of HCC.

• At least one measurable site of disease as defined by RECIST1.1criteria with spiralCT scan or MRI，apart from one liver lesion to serve for TACE.

• Child-Pugh scores 5-7, performance status (PS) ≤ 2 (ECOG scale).

• Subjects with chronic HBV infection must have HBV DNA viral load < 100 IU/mL atscreening. In addition, they must be on antiviral therapy per regional standard ofcare guidelines prior to initiation of study therapy.

• Life expectancy of at least 12 weeks.

• Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥60 x103/L; Total bilirubin ≤ 3x upper normal limit; AspartateAminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; SerumCreatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (ifusing the Cockcroft-Gault formula)

• Female patients with reproductive potential must have a negative urine or serumpregnancy test within 7 days prior to start of trial.

• Subject is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment, adherence to contraceptive measures, scheduledvisits and examinations including follow up.

Exclusion Criteria:

• Patients on a liver transplantation list or with advanced liver disease.

• Total thrombosis or total invasion of the main branch of the portal vein.

• History of cardiac disease, including clinically significant gastrointestinalbleeding within 4 weeks prior to start of study treatment

• Thrombotic or embolic events such as cerebrovascular accident (including transientischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 monthsPrior to the first dose of study drug with the exception of thrombosis of asegmental portal vein.

• Prior systemic anti-cancer therapy OR endocrine- OR immunotherapy

• Prior treatment with TACE

• RFA and resection administered less then 4 weeks prior to study treatment start.

• Radiotherapy administered less then 4 weeks prior to study treatment start.

• Major surgery within 4 weeks of starting the study treatment OR subjects who havenot recovered from effects of major surgery.

• Patients with second primary cancer, except adequately treated basal skin cancer orcarcinoma in-situ of the cervix.

• Immunocompromised patients, e.g. patients who are known to be serologically positivefor human immunodeficiency virus (HIV).

• Participation in another clinical study with an investigational product during thelast 30 days before inclusion or 7 half-lifes of previously used trial medication,whichever is longer.

• Previous treatment in the present study (does not include screening failure).

• Any condition or comorbidity that, in the opinion of the investigator, wouldinterfere with evaluation of study Treatment or interpretation of patient safety orstudy results, including but not limited to:

1. history of interstitial lung disease

2. Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e doubleinfection)

3. known acute or chronic pancreatitis

4. active tuberculosis

5. any other active infection (viral, fungal or bacterial) requiring systemictherapy

6. history of allogeneic tissue/solid organ transplant

7. diagnosis of immunodeficiency or patient is receiving chronic systemic steroidtherapy or any other form of immunosuppressive therapy within 7 days prior tothe first dose of nivolumab-monotherapy treatment.

8. Has an active autoimmune disease requiring systemic treatment within the past 3months or a documented history of clinically severe autoimmune disease, or asyndrome that requires systemic steroids or immunosuppressive agents.Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I orresolved childhood asthma/atopy are an exception to this rule. Subjects thatrequire intermittent use of bronchodilators or local steroid injections wouldnot be excluded from the study. Subjects with Hashimoto thyroiditis,hypothyroidism stable on hormone replacement or psoriasis not requiringtreatment are not excluded from the study.

9. Live vaccine within 30 days prior to the first dose of nivolumab-monotherapytreatment or during study treatment.

10. History or clinical evidence of Central Nervous System (CNS) metastasesExceptions are: Subjects who have completed local therapy and who meet both ofthe following criteria: I. are asymptomatic and II. have no requirement forsteroids 6 weeks prior to start of nivolumab-monotherapy treatment. Screeningwith CNS imaging (CT or MRI) is required only if clinically indicated or if thesubject has a history of CNS.

• Medication that is known to interfere with any of the agents applied in the trial.

• Any other efficacious cancer treatment except protocol specified treatment at studystart.

• Patient has received any other investigational product within 28 days of studyentry.

• Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1,anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a memberof the Tumor Necrosis Factor Receptor (TNFR) family), or anti-CytotoxicT-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab orany other antibody or drug specifically targeting T-cell co-stimulation orcheckpoint pathways).

• Female subjects who are pregnant, breast-feeding or male/female patients ofreproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are:implants, injectable contraceptives, combined oral contraceptives, intrauterinepessars (only hormonal devices), sexual abstinence or vasectomy of the partner].Women of childbearing potential must have a negative pregnancy test (serum β-HCG) atscreening.

• Patient with any significant history of non-compliance to medical regimens or withinability to grant reliable informed consent.