HAIC Combined With Sintilimab and Bevacizumab Biosimilar for Unresectable HCC

Inclusion Criteria:

• Written informed consent should be signed before implementing any trial-relatedprocedures;
• Age ranges from 18 to 75 years old.
• CNLC-IIb to IIIb HCC based on the Criteria for diagnosis and treatment ofhepatocellular carcinoma (2019 edition)
• At least ≥ 1 measurable lesions per mRECIST;
• Child-Pugh grade A or B;
• ECOG PS scores 0-1;
• No prior therapy for HCC.
• Expected survival time > 6 months;
• Sufficient organ functions, the subjects need to meet the following laboratoryindicators:
• No blood transfusion, no use of hematopoietic stimulators (including g-csf,gm-csf, EPO and TPO) and infusion of human albumin preparations within 14 daysprior to screening:Neutrophil absolute count ≥1.5×10^9/L;Platelet count ≥ 100×10^9/L;Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN); or total bilirubin > ULN butdirect bilirubin ≤ ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN;
• Serum creatinine ≤ 1.5 × ULN and creatinine clearance rate (calculated byCockcroft-Gault formula) ≥ 60 ml/min;
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN
• Normal thyroid function, defined as thyroid stimulating hormone (TSH) within thenormal range. If the baseline TSH exceeds the normal range, the subjects can alsobe included in the group in case total T3 (or FT3) and FT4 are within the normalrange;
• Myocardial enzyme spectrum should be within the normal range (if the investigatorcomprehensively judges that the simple laboratory abnormality is not clinicallysignificant, the subject is also included);
• Female subjects of childbearing age should receive a urine or serum pregnancy test andthe result is negative, 3 days prior to accept the first study drug administration (day 1 of cycle 1). In case the urine pregnancy test result cannot be confirmed asnegative, a blood pregnancy test is required. Meanwhile, voluntary use of appropriatecontraceptive methods shall be taken during the observation period and within 8 weeksof the last administration of the study drug; Women of non-bearing age are defined asat least 1 year after menopause, or those who have undergone surgical sterilization orhysterectomy; For males, appropriate contraceptive methods should be taken during theobservation period and within 8 weeks after the last dose of the study drug.
• If there is a risk of pregnancy, all subjects (regardless of male and female) need toadopt contraceptives with an annual failure rate of less than 1% during the entiretreatment period until 120 days after the last administration of the study drug (or 180 days after the last chemotherapeutic drug administration).

Exclusion Criteria:

• known as Inhibition of fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinomaand HCC；Previous HCC recurrence；Hepatic encephalopathy has been clinically diagnosedin the past 6 months .
• Autoimmune hepatitis (requiring liver puncture).
• History of organ transplantation or hepatic encephalopathy.
• Diffuse hepatoma.
• Clinical symptoms requiring drainage including pleural effusion, ascites, andpericardial effusion.
• History of nephropathy or nephrotic syndrome.
• Bleeding from a varicose vein in the esophagus or gastric fundus caused by portalhypertension in the past 6 months; Presence of severe (G3) varicose veins identifiedby endoscopy 3 months prior to initial administration; Evidence of portal hypertension (including imaging findings that the length of the spleen exceeds 10 cm and theplatelets lower than 100), with a high risk of hemorrhage assessed by theinvestigator.
• Arteriovenous thromboembolic events in the past 6 months, including history ofmyocardial infarction, unstable angina, cerebrovascular accident or transient ischemicattack, pulmonary artery embolism, deep vein thrombosis or any other seriousthromboembolism. Implantable venous infusion port or catheter-derived thrombosis, orsuperficial venous thrombosis, except for those with stable thrombosis afterconventional anticoagulation therapy.
• Severe bleeding tendency or coagulation dysfunction, or under thrombolytic therapy.
• Acceptance of preventive use of low-dose low-molecular-weight heparin (such asEnoxaparin 40 mg/day), except for vitamin K antagonists (such as warfarin).
• Requiring long-term medication for the inhibition of platelet function, such asaspirin, dipyridamole or clopidogrel.
• Uncontrollable hypertension, systolic blood pressure > 140 mmHg or diastolic bloodpressure > 90 mmHg after optimized medical treatment, history of critical hypertensionor hypertensive encephalopathy.
• Symptomatic congestive heart failure (New York Heart Association class II-IV),symptomatic or poorly controlled arrhythmia, congenital long QT syndrome history orQTc > 500 ms corrected at screening (calculated using the Fridericia method).
• History of gastrointestinal perforation and or fistula, intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition),extensive bowel resection (partial colectomy or extensive small bowel resection,complicated by chronic diarrhea), Crohns disease, ulcerative colitis, or long-termchronic diarrhea in the past 6 months.
• Received major surgery (craniotomy, thoracotomy or laparotomy) or unhealed wounds,ulcers or fractures within 4 weeks prior to the first administration, except forreceived tissue biopsy or other minor surgery within 7 days prior to the firstadministration, venipuncture catheterization for intravenous infusion.
• Past and present history of lung diseases including pulmonary fibrosis, interstitialpneumonia, pneumoconiosis, drug-related pneumonia, and severely impaired lungfunctions.
• Acute or chronic active hepatitis B or C infection.
• Active tuberculosis (TB), under anti-tuberculosis treatment or anti-tuberculosistreatment within 1 year prior to the first administration.
• Infected by human immunodeficiency virus (HIV) and known syphilis infection.
• Severe infections in active phase or poorly controlled clinically. Severe infectionwithin 4 weeks prior to the first administration.
• Have used immunosuppressive drugs within 4 weeks before the first dose
• Received live attenuated vaccines within 4 weeks before the first dose or plan toreceive live attenuated vaccines during the study period
• Received Chinese medicine with anti-tumor indications, or received drugs withimmunomodulatory effect within 2 weeks before the first administration
• Received any anti-PD-1 antibody, anti-PD-L1/L2 antibody, anti-CTLA4 antibody, or otherimmunotherapy
• Allergic to Sintilizumab, Bevacizumab preparations and excipients, or had severeallergic reactions to other monoclonal antibodies in the past
• Received treatment from other clinical trials within 4 weeks before the first dose
• Female subjects who are pregnant or breastfeeding
• Other conditions that the subjects are not suitable to participate in this studyaccording to the judgment of the investigator.