Donafenib Combine With Sintilimab and HAIC (Hepatic Artery Infusion Chemotherapy，HAIC）in the First-line Treatment of Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

1. Voluntarily join the study and sign the informed consent;
2. Age 18 \~ 80 years old (including 80 years old), male and female;
3. Patients with hepatohcellular carcinoma diagnosed clinically or confirmed by histology / cytology according to the code for diagnosis and treatment of primary liver cancer (2019 Edition);
4. Patients with unresectable or metastatic hepatocellular carcinoma;
5. No systematic treatment. If receiving adjuvant chemotherapy after local treatment more than 12 months, and patients with disease progression or metastasis can also be included in the group;
6. The end time of the last intervention, radiotherapy and ablation should be \> 4 weeks;
7. Patients who underwent hepatectomy in the past should be R0 resection, and the tumor recurrence should be more than 24 months after operation;
8. At least one assessable lesion (RECIST 1.1 criteria);
9. Expected survival time ≥ 3 months;
10. ECOG 0 \~ 1;
11. Child Pugh ≤ 7;
12. Be able to cooperate to observe adverse events;
13. Major organs are functioning normally.

    1. Hemoglobin ≥ 90 g / L;
    2. ANC ≥ 1.5 × 109/L；
    3. Platelet count ≥ 75 × 109/L；
    4. Albumin ≥ 28 g / L;
    5. Total bilirubin ≤ 2 × ULN;
    6. AST, ALT ≤ 5 × ULN；
    7. ALP ≤ 5 × ULN；
    8. Creatinine ≤ 1.5 × ULN；
    9. INR or PT ≤ 1.5 × ULN； J) APTT ≤ 1.5 × ULN。

Exclusion Criteria:

1. Fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma and other components confirmed by histology / cytology in the past;
2. Have a history of malignancy other than hepatocellular carcinoma unless the following criteria are met:

   A) The patient has received possible curative treatment and there is no evidence of the disease within 5 years; B) Successful resection of basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder carcinoma, carcinoma in situ of cervix and other cancers in situ
3. Diffuse tumor lesions;
4. Tumor vascular invasion occurs in one or more of the following situations:

   1. Involving superior mesenteric vein;
   2. Involving inferior vena cava;
5. History of hepatic encephalopathy, hepatorenal syndrome, or history of liver transplantation;
6. Pleural effusion, ascites and pericardial effusion with clinical symptoms requiring drainage;
7. Central system metastasis;
8. Previous history of severe mental illness;
9. Have a disease that affects absorption, distribution, metabolism, or clearance of the drug under study (such as severe vomiting, chronic diarrhea, intestinal obstruction, absorption disorder, etc.);
10. Previous allogeneic stem cell or parenchymal organ transplantation;
11. Previously received targeted therapy of anti VEGF and / or signal pathways such as VEGFR, RAF and MEK, such as sorafenib, renvatinib and regofinib, or immunomodulator therapy such as anti-PD-1, anti-PD-L1 and anti-CTLA-4;
12. Patients who have received other anti-tumor systemic treatment in the past, including traditional Chinese medicine with anti-tumor indications less than 2 weeks before the administration of this study, or the adverse events caused by previous treatment have not recovered to ≤ CTCAE level 1; The toxicity of previous anti-tumor treatment did not include grade 1 / 2 neurotoxicity and hair loss caused by oxaliplatin;
13. Taking drugs that may prolong QTc and / or induce tip twist transition ventricular tachycardia (TDP) or drugs that affect metabolism at the same time;
14. Previous or current congenital or acquired immunodeficiency disease;
15. Active or previously documented autoimmune disease or inflammatory disease.
16. Previous allogeneic stem cell or parenchymal organ transplantation;
17. Systemic immunosuppressive drugs were used within 2 weeks before enrollment, or systemic immunosuppressive drugs expect to be needed during the study, except for the following:

    d) Intranasal, inhalation, topical or local injection (such as intra-articular injection) of corticosteroids; e) Systemic corticosteroids with dose not exceeding 10 mg / day, prednisone or other effects; f) Prophylactic use of corticosteroids for hypersensitivity;
18. Allergy to Donafenib or similar drugs, or history of hypersensitivity to chimeric or humanized antibodies or fusion proteins, or allergy to the excipients of the study drugs;
19. Have active bleeding or abnormal coagulation function, have bleeding tendency or are receiving thrombolytic, anticoagulant or antiplatelet therapy;
20. Thrombosis or thromboembolism events occurred in the past 6 months, such as stroke and / or transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc;
21. Bleeding events of esophageal or gastric varices caused by portal hypertension in the past 6 months, or any life-threatening bleeding events in 3 months;
22. Cardiovascular diseases with significant clinical significance, including but not limited to acute myocardial infarction, severe / unstable angina or coronary artery bypass grafting in the past 6 months, congestive heart failure (NYHA grade \> 2), arrhythmias poorly controlled or requiring pacemaker treatment, and hypertension not controlled by drugs (systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg);
23. Other significant clinical and laboratory abnormalities considered by the investigator to affect safety;
24. Severe infections in the active stage or under clinical control; Active infections include:

    1. HIV1/2 is positive.
    2. HBsAg positive or HBV DNA \> 2000iu/ml and abnormal liver function;
    3. HCV antibody positive or HCV RNA ≥ 103 copies/ml and abnormal liver function;
    4. Active tuberculosis;
    5. Other uncontrollable active infections (CTCAE V5.0 \> grade 2);
25. Not recovered from the operation, such as unhealed incision or serious postoperative complications;
26. Pregnant or lactating women, and women or men with fertility are unwilling or unable to take effective contraceptive measures.