| Eligibility |
Inclusion Criteria:
- 1. Age =18 years old and =75 years old, regardless of gender;
- 2. Hepatocellular carcinoma confirmed by histology or cytology;
- 3. Have not received any previous systematic therapy for HCC;
- 4. Barcelona (BCLC) has stage B-C and is not suitable for surgical local treatment, or
progresses after surgery and/or local treatment;
- 5. Child-Pugh liver function grade A and good grade B (=7 points)
- 6. ECOG score 0-1;
- 7. Have at least one measurable lesion (according to RECIST v1.1 assessment criteria);
- 8. Expected survival time =3 months;
- 9. The functional level of vital organs must meet the requirements before the first
use of the experimental drug; (1) Blood system function (no blood transfusion and no
cell growth factor correction within 14 days before screening) : neutrophil count =
1.5×109/L, platelet count = 100×109/L, hemoglobin = 90 g/L; (2) Liver and kidney
function (no albumin infusion within 14 days before screening) : serum total bilirubin
= 1.5 times the upper limit of normal (ULN), serum albumin = 29 g/L, ALT and AST =
2.5×ULN; Serum creatinine =1.5×ULN or endogenous creatinine clearance (Cockcroft-Gault
formula) =60ml/min; (3) Coagulation function: International standardized ratio (INR)
=1.5 or prothrombin time (PT) exceeding the normal control range =6 seconds; (4) Left
ventricular ejection fraction (LVEF) = 50% by two-dimensional echocardiography;
- 10. Subjects (both female and male) agree to use effective contraceptive methods for
contraception from the date of signing the informed consent to 180 days after the last
use of the experimental drug. A woman of childbearing age cannot be pregnant or
lactating;
- 11. Patients with active hepatitis B infection who had HBV DNA<2000 IU/ml during the
28 days prior to study entry and who were receiving treatment and taking stable doses
of antiviral drugs for at least 7 days upon study entry;
- 12. Any acute, clinically significant treaty-related toxicity must be restored to =
grade 1 (according to CTCAE v5.0) prior to initial use of the investigational drug,
except for hair loss;
- 13. Voluntarily participate in this clinical trial and sign a written informed
consent.
Exclusion Criteria:
- 1. Imaging examination showed that large intrahepatic hemangioma thrombus was
complicated (including synchronous thrombus of main portal vein and left and right
branches, synchronous thrombus of main portal vein and superior mesenteric vein, and
inferior vena cava thrombus);
- 2. Subjects with symptomatic central nervous system (CNS) metastases are not admitted.
Subjects with a history of treated CNS metastases (surgical treatment or radiotherapy)
were not eligible for inclusion unless they were stable for =4 weeks after treatment
and had stopped systemic sex hormone therapy (at any dose) for > 2 weeks;
- 3. Patients who had clinically uncontrollable pleural effusion, peritoneal effusion,
pericardial effusion, etc. before receiving the study for the first time and could not
be enrolled by the researchers. ;
- 4. Patients with a history of other malignancies within 5 years prior to signing
informed consent (except cured basal cell skin cancer, skin squamous cell carcinoma,
and/or carcinoma in situ after radical resection)
- 5. Active autoimmune disease that may worsen in the course of receiving
investigational drug therapy
- 6. In the judgment of the investigator, there are conconitant diseases that seriously
threaten the safety of the subjects or affect the completion of the study, such as
hypertension (systolic blood pressure =160mmHg and/or diastolic blood pressure
=100mmHg) that cannot be controlled by two or more antihypertensive drugs, and
diabetes that is not well controlled;
- 7. History of hypertensive crisis or hypertensive encephalopathy
- 8. The presence of disease requiring systemic treatment with corticosteroids (>10 mg
daily or equivalent of prednisone) or other immunosuppressive agents within 2 weeks
prior to initial study treatment
- 9. History of allogeneic hematopoietic stem cell transplantation or organ
transplantation (except corneal transplantation)
- 10. Systemic infections or other serious infections requiring intravenous antibiotic
treatment >7 days within 2 weeks prior to first use of the experimental drug
- 11. HIV positive; HCV antibody positive and HCV RNA positive [Note: if the HCV RNA
test result is negative, it can be considered not infected with HCV]; Patients with
co-infection of HBV and HCV
- 12. People who are known to have received anti-tuberculosis therapy within one year
prior to first receiving study therapy
- 13. Subjects with any of the following cardiovascular diseases were excluded: a) acute
myocardial infarction occurred within 6 months prior to first administration of the
investigational drug. b) Past and/or current New York Heart Association Class III or
IV heart failure. c) Currently has poorly controlled cardiovascular disease, including
angina, pulmonary hypertension, or severe heart rhythm or conduction abnormalities. d)
Prior to first administration of the trial drug, the 12-lead ECG showed an average QT
interval (QTcF) of >450 ms (male) or >470 ms (female).
- 14. The patient is known to have a history of psychotropic substance abuse, alcohol
abuse or drug use; A clear history of neurological or psychiatric disorders, including
epilepsy or dementia or hepatic encephalopathy.
- 15. People who have participated in other clinical studies and used other clinical
trial drugs within 4 weeks before using the experimental drug.
- 16. Previously received immunotherapy, including immune checkpoint inhibitory
antibodies (such as anti-PD-1, PD-L1, CTLA-4 antibodies, etc.), immune checkpoint
activating antibodies (such as: Anti-icos, CD40, CD137, GITR, OX40 antibody, etc.),
and immune cell therapy, or have previously received anti-VEGF, VEGFR targeted therapy
or HDACi therapy.
- 17. Chinese patent medicine treatment: Subjects who had received Chinese patent
medicine for primary liver cancer before enrollment could be enrolled only after 4
weeks of elution, and the use was prohibited during the trial.
- 18. The patient is known to have a prior allergy to macromolecular protein
preparations, or to any investigational drug component.
- 19. Live vaccine was administered within 4 weeks prior to the first administration of
the experimental drug.
- 20. Underwent major surgery within 4 weeks prior to the first use of the
investigational drug or anticipated major surgery during the study period.
- 21. Persons with past or current interstitial lung disease, coniosis, radiation
pneumonia, severe impairment of lung function, etc. that may interfere with the
detection and management of suspected drug-related pulmonary toxicity.
- 22. Patients with a history of hemoptysis (i.e., coughing up at least 1/2 TSP (2.5ml)
of bright red blood) or a history of gastrointestinal bleeding within 2 months prior
to the first use of the trial drug who were judged by the investigator to be
ineligible for admission.
- 23. Presence of intestinal obstruction and/or previous clinical signs or symptoms of
gastrointestinal obstruction prior to initial use of the investigational drug.
Subjects with symptoms and signs of incomplete obstruction/obstruction at initial
diagnosis who are treated and whose symptoms have resolved may be enrolled upon
investigator assessment.
- 24. Major vascular disease (e.g., aortic aneurysms requiring surgical repair or recent
peripheral arterial thrombosis) occurred 6 months before the first use of the
investigational drug.
- 25. Evidence of bleeding tendency and major clotting disorder.
- 26. Previous history of intracranial or spinal bleeding; Patients with a history of
gastrointestinal bleeding or a clear tendency to gastrointestinal bleeding or portal
hypertension within 6 months prior to the first use of the investigatory drug, and
patients considered to be at high risk of bleeding (including moderate to severe
esophageal and gastric varices at risk of bleeding, locally active gastrointestinal
ulcers, and persistent positive fecal occulting blood), should undergo gastroscopy.
Patients with "red sign" were excluded.
- 27. Severe open wounds or active peptic ulcers or untreated fractures prior to first
use of the experimental drug.
- 28. Current or recent (within 10 days prior to first administration) treatment with
aspirin (> 325 mg/ day), clopidogrel (> 75mg/ day) or current or recent treatment with
dipyridamole, ticlopidine, and ciliostazole; Therapeutic anticoagulant therapy (except
low molecular weight heparin) was used within 2 weeks prior to enrollment.
- 29. Patients who, in the judgment of the investigator, may increase risks associated
with the study, may interfere with the interpretation of the study results, or who are
deemed unsuitable for enrollment by the investigator and/or sponsor.
- 30. Abdominal or bronchoesophageal fistula, gastrointestinal perforation, or internal
abdominal abscess developed within 6 months prior to first administration of the
experimental drug.
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