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Inclusion criteria
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(1) 18 years old ≤ age ≤80 years old, gender is not limited;
(2) Patients with advanced hepatocellular carcinoma (HCC) who meet the clinical diagnostic criteria of the Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2022 edition) and/or have been confirmed by pathologic/cytological examination;
(3) Have at least one measurable lesion (≥10mm spiral CT scan diameter or ≥15mm enlarged lymph node short diameter as required by RECIST version 1.1), or a measurable lesion with clear progression after local treatment (based on RECIST V1.1 criteria);
(4) TCM syndrome differentiation is syndrome of stasis and poison accumulation;
(5) Patients who have not received any systemic therapy for primary hepatocellular carcinoma (including systemic chemotherapy, targeted therapy, immunotherapy, biotherapy, combined therapy, etc.), and patients who receive adjuvant therapy after radical hepatocellular carcinoma surgery must have recurred at least 6 months from the end of treatment to the screening period and have not received systemic therapy;
(6) Primary hepatocellular carcinoma is unresectable and not suitable for local treatment, with Barcelona clinical liver cancer stage (BCLC stage) stage B and C and China Clinical liver Cancer stage (CNLC stage) stage Ⅱb, Ⅲa and Ⅲb;
(7) Child-Pugh liver function rating: Grade A or good grade B (≤7 points);
(8) The expected survival time at enrollment was greater than 3 months;
(9) ECOG PS score within 1 week before enrollment: 0-1;
(10) Female patients of childbearing age or male patients whose sexual partner is a female of childbearing age should take effective contraceptive measures during the entire treatment period and 90 days after the last medication;
(11) The function of the major organs is normal (no blood component, cell growth factor, infusion of albumin preparation correction therapy has been given within 14 days before obtaining laboratory tests), that is, the following criteria are met:
① Blood routine: a) Hemoglobin ≥90g/L; b) Neutrophils ≥1.5×109/L; c) Platelet count ≥75×109/L;
② Liver function: ALT and AST≤5.0× upper limit of normal range (ULN), serum albumin ≥28g/L; Total bilirubin (TBIL) ≤2×ULN; Alkaline phosphatase (ALP) ≤5×ULN
(3) Renal function: serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (Ccr) ≥50mL/min;
④ Urine protein <2 (+) was detected by routine urine test; If urinary protein ≥2 (+) at baseline, the 24-hour urinary protein dose must be ≤1.0g;
⑤ Coagulation function: activated partial thromboplastin time (APTT), International standardized ratio (INR), prothrombin time (PT) ≤1.5×ULN;
Cardiac echocardiography: left ventricular ejection fraction (LVEF) ≥50%;
(12) Sign a written informed consent and be able to comply with the visit and related procedures required by the program.
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Exclusion criteria：
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(1) fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, hepatocellular carcinoma of hepatobiliary duct, mixed hepatocellular carcinoma, etc. previously confirmed by histology or cytology;
(2) Have a history of hepatic encephalopathy, or a history of liver transplantation;
(3) Portal vein cancer thrombus involved the main trunk and left and right branches, or involved the main trunk and superior mesenteric vein at the same time, or had inferior vena cava cancer thrombus or heart involvement;
(4) those diagnosed with other malignancies within 5 years prior to initial administration, excluding radical basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radical resection of carcinoma in situ;
(5) Moderate or severe ascites or clinical symptoms requiring drainage of pleural fluid, ascites, pericardial effusion within 4 weeks before the first administration;
(6) Toxicity from prior treatment that did not return to NCI CTCAE 5.0 level 0 or 1 before the first dose of investigational therapy (excluding hair loss, non-clinically significant, and asymptomatic laboratory abnormalities);
(7) Received local treatment for liver cancer within 4 weeks prior to initial administration; Or received Chinese medicines with anti-tumor indications or immunomodulatory effects (including thymosin, interferon, interleukin, except for local use to control pleural fluid or ascites) within 2 weeks before the first administration;
(8) Patients with acute or chronic active hepatitis B or hepatitis C, hepatitis B virus (HBV) DNA>2000IU/ml or 104 copies /ml; Hepatitis C virus (HCV) RNA>103 copies /ml; Hepatitis B surface antigen (HbsAg) and anti-HCV antibody were positive simultaneously. Those who had received antiviral therapy below the above criteria and were willing to continue receiving antiviral therapy during the study period could be enrolled;
(9) With known active central nervous system metastases (CNS) and/or cancerous meningitis: Subjects with previously treated BMS may participate in the study provided that they are clinically stable for at least 2 weeks, there is no evidence of new or expanded BMS, and steroids are discontinued 14 days prior to study drug administration. Stable brain metastases in this definition should be determined before the first administration of the investigational drug. Subjects with asymptomatic BMS (i.e. no neurological symptoms, no need for corticosteroids, and no lesions > 1.5cm) may participate, but require regular brain imaging as a disease site;
(10) Esophageal or fundus variceal bleeding events caused by portal hypertension occurred within 6 months before screening. The presence of severe varicose veins on endoscopy is known within 3 months prior to initial administration. Evidence of portal hypertension with a high risk of bleeding as assessed by the investigator;
(11) Any life-threatening bleeding event in the 3 months prior to screening, including the need for transfusion therapy, surgery or local therapy, and ongoing medication; Have severe bleeding tendency or coagulation dysfunction, or are receiving thrombolytic therapy;
(12) History of arterial and venous thromboembolism events in the 6 months prior to screening, including myocardial infarction, unstable angina pectoris, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other severe thromboembolism. Implantable intravenous infusion port or catheter-derived thrombosis, or superficial venous thrombosis, except in cases where the thrombus has stabilized after conventional anticoagulant therapy. Allow the prophylactic use of low-dose, low-molecular heparin (e.g., enoxaparin 40 mg/ day);
(13) Use aspirin (> 325mg/ day) or other drugs known to inhibit platelet function, such as dipyridamole or clopidogrel, for 10 consecutive days within 2 weeks of initial administration;
(14) Uncontrolled hypertension, systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg after standard treatment, hypertensive crisis or hypertensive encephalopathy history;
(15) Symptomatic congestive heart failure (New York Heart Association Grade II-IV), symptomatic or poorly controlled arrhythmias. A QTc>500 ms corrected for congenital long QT syndrome history or screening (calculated using the Fridericia method);
(16) A history of gastrointestinal perforation and/or fistula, abdominal abscess, intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive enterectomy (partial colectomy or extensive enterectomy with chronic diarrhea), Crohn's disease, ulcerative colitis, or long-term chronic diarrhea within the 6 months prior to screening;
(17) Previous or current history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia, severe impairment of lung function and other lung diseases;
(18) Severe infections that are active or poorly controlled clinically. People with active tuberculosis (TB) who are receiving anti-TB therapy or who have received anti-TB therapy within 1 year prior to first dosing; People infected with human immunodeficiency virus (HIV 1/2 antibody positive), known syphilis infection requiring treatment; And severe infection in the 4 weeks prior to initial dosing, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia;
(19) An active autoimmune disease requiring systemic treatment, such as disease-modifying drugs, corticosteroids, or immunosuppressants, has occurred within 2 years prior to initial administration. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are permitted. Known history of primary immunodeficiency. Only patients with positive autoimmune antibodies should be confirmed whether there is an autoimmune disease according to the judgment of the investigator.
(20) Immunosuppressive drugs are required within 4 weeks of initial dosing or during the study period, excluding the following:
① Local glucocorticoids by nasal spray, inhalation or other means;
Physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/ day of prednisone or equivalent doses of other glucocorticoids);
(3) Temporary (≤7 days) use of glucocorticoids to prevent allergic reactions or treat dyspnea symptoms of asthma, chronic obstructive pulmonary disease and other diseases;
(21) Major surgical procedures (craniotomy, thoracotomy, or laparotomy) or unhealed wounds, ulcers, or fractures within 4 weeks prior to initial dosing. Have undergone tissue biopsy or other minor surgical procedures within 7 days prior to initial administration, except for venipuncture for intravenous infusion;
(22) Have previously received any anti-PD-1 antibody, anti-PD-L1 /L2 antibody, anti-CTLA4 antibody, or other immunotherapy. People who have previously received targeted therapy against VEGF and/or VEGFR, RAF, MEK, PDGFR, FGFR and other signaling pathways;
(23) people who are known to be allergic to any of the ingredients of Dabersyl ® and Dabertong ®; Or have had severe allergic reaction to other monoclonal antibodies in the past, or have been allergic to the known ingredients of Pien Tze Huang in the past;
(24) received treatment in other clinical trials within 4 weeks prior to initial dosing;
(25) Receive live attenuated vaccine within 4 weeks prior to initial administration or during the study period;
(26) Pregnant or nursing female patients;
(27) Any other disease, metabolic disorder, or laboratory test abnormality that the investigator deems the patient ineligible for study drug treatment, or that will affect the interpretation of study results, or place the patient at high risk, or affect the collection of data and samples.
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