Combination Therapy of HAIC, Sintilimab and Bevacizumab for Advanced Hepatocellular Carcinoma

Inclusion Criteria:

1. Written informed consent should be signed before implementing any trial-relatedprocedures 2. ECOG PS scores 0-1 3. Histologically/cytologically confirmed HCC or cirrhosismeeting the clinical diagnostic criteria of HCC by American Association for the Study ofLiver Diseases (AASLD) 4. Barcelona Clinic Liver Cancer (BCLC) stage C 5. Newly diagnosedHHC patients without any previous treatment for the tumor 6. Child Pugh score of ≤ 7. 7.Estimated survival > 12 weeks 8. At least one measurable lesion according to RECIST V1.1 9.Sufficient organ and bone marrow functions, with the laboratory test values within 7 daysbefore the enrollment meeting the following requirements (no blood components, cell growthfactors, albumin, and other drugs via intravenous or subcutaneous administrations areallowed for correction treatment within the first 14 days after the laboratory test resultsare obtained). The specific information is as follows:
2. Routine blood test: absolute neutrophil count (ANC) ≥ 1.5 × 109/L; platelet count (PLT) ≥ 75 × 109/L; hemoglobin (HGB) ≥ 9.0 g/dL.
3. Hepatic function: total bilirubin (TBIL) ≤ 3 × upper limit of normal (ULN), alanineaminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN; serum albumin ≥ 28 g/L; alkaline phosphatase (ALP) ≤ 5 × ULN.
4. Renal function: serum creatinine (Cr) ≤ 1.5 × ULN or clearance of creatinine (CCr) ≥ 50 mL/min (Cockcroft Gault formula); urinalysis results showing urine protein < 2+;patients whose baseline urinalysis results show urine protein ≥ 2+ should undergo 24 hurine collection and the 24 h urine protein quantitation test result should be lowerthan 1 g.
5. Blood coagulation function: international normalized ratio (INR) and activated partialthromboplastin time (APTT) ≤ 1.5 × ULN.
6. Female patients of childbearing age or male patients with female sexual partners ofchildbearing age should take effective contraceptive measures throughout the treatment and 6 months after the last dose.

Exclusion Criteria:

1. Histologically/cytologically confirmed fibrolamellar hepatocellular carcinoma,sarcomatoid hepatocellular carcinoma, and cholangiocarcinoma.
2. History of hepatic encephalopathy or liver transplantation.
3. Symptomatic pleural effusion, ascites, and pericardial effusion that require drainage.
4. Acute or chronic active hepatitis B or C infection; hepatitis B virus (HBV) DNA > 2000IU/mL or 104 copies/mL; hepatitis C virus (HCV) RNA > 103 copies/mL; hepatitis Bsurface antigen (HbsAg) and anti HCV antibody positive concurrently.
5. Presence of metastasis to the central nervous system.
6. Presence of bleeding events from esophageal or gastric varices caused by portalhypertension within the past 6 months. Presence of known severe (G3) varicose veins inendoscopy within 3 months before the first dose. Evidence of portal hypertension (including the finding of splenomegaly in imaging studies) with a high risk ofbleeding assessed by the investigator.
7. Presence of any life-threatening bleeding events within the past 3 months, includingthe need for transfusion, surgery or local treatment, and continuous medicationtherapy.
8. Any arterial/venous thromboembolic events within 6 months, including myocardialinfarction, unstable angina, cerebrovascular accident or transient cerebral ischemicattack, pulmonary embolism, deep vein thrombosis, or any other history of seriousthromboembolism. Presence of implantable venous port or catheter derived thrombosis,or superficial venous thrombosis, barring stable thrombosis following the conventionalanticoagulation treatment. Prophylactic use of low dose low molecular weight heparin (e.g., enoxaparin 40 mg/day) is permitted.
9. Involvement of both the main portal vein and the left and right branches by portalvein tumor thrombus, or of both the main trunk and the superior mesenteric veinconcurrently. Presence of tumor thrombus of inferior vena cava.
10. A 10-day consecutive dosing of aspirin (> 325 mg/day) or other drugs, e.g.,dipyridamole and clopidogrel, known to inhibit the platelet function within 2 weeksbefore the first dose.
11. Uncontrolled hypertension (systolic greater than 140 mmHg or diastolic greater than 90mmHg) after the optimal medical treatment, history of hypertensive crisis orhypertensive encephalopathy.
12. Toxicity (excluding alopecia, events not clinically significant, and asymptomaticlaboratory abnormalities) caused by previous therapy that has not yet resolved tograde 0 or 1 (National Cancer Institute Common Terminology Criteria for Adverse EventsV5.0 (NCI CTCAE V5.0)) before the first dose of study drugs.
13. Symptomatic congestive cardiac failure (NYHA Class II IV). Symptomatic or poorlycontrolled arrhythmia. History of congenital long QT syndrome or corrected QTc > 500ms (calculated using Fridericia formula) during screening.
14. Serious hemorrhagic tendency or coagulopathy, or currently receiving thrombolytictherapy.
15. History of gastrointestinal perforation and/or fistula, history of bowel obstruction (including incomplete bowel obstruction requiring parenteral nutrition), extensivebowel resection (partial colectomy or extensive small bowel resection accompanied withchronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea within thepast 6 months.
16. Receipt of immunosuppressants within 4 weeks before the first dose, excluding localglucocorticoids administered by nasal, inhaled, or other topical routes, or systemicglucocorticoids of physiological doses (no more than 10 mg/day of prednisone orequivalents), while the temporary use of glucocorticoids for preventing allergies ortreating dyspneic symptoms of such diseases as asthma and chronic obstructivepulmonary disease is permitted.
17. Receipt of a live attenuated vaccine within 4 weeks before the first dose or plannedto receive a live attenuated vaccine during the study.
18. Receipt of major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeksbefore the first dose or having unhealed wounds, ulcers, or fractures. Receipt oftissue biopsy or other minor surgeries within 7 days before the first dose, barringvenipuncture and catheterization for intravenous infusion.
19. Receipt of local treatment for liver cancer within 4 weeks before the first dose.
20. Receipt of systemic treatment with traditional Chinese medicines with cancerindications or immunomodulators (including thymosin, interferon, and interleukin,barring local use for controlling pleural fluid or ascites) within 2 weeks before thefirst dose.
21. Uncontrolled/uncorrectable metabolic disorders, other non malignant organ diseases,systemic diseases, or cancer related secondary diseases with the potential to cause arelatively high medical risk and/or survival evaluation uncertainties unsuitable forsubject enrollment as judged by the investigator; other circumstances unsuitable forsubject enrollment as judged by the investigator.
22. Other malignancies diagnosed within 5 years before the first dose, excluding radicallytreated basal cell carcinoma of skin, squamous cell carcinoma of skin, and/orradically resected carcinoma in situ. If other malignancies were diagnosed over 5years pre dose, the liver lesions should still be subjected to pathological orcytological diagnosis even if they meet the clinical diagnostic criteria for HCC byAASLD; individuals with confirmed HCC can be enrolled.