| Eligibility |
Inclusion Criteria:
1)Voluntary admission and signature of written informed consent;
2)18~75 years of age (including 75 years), male and female;
3)Hepatocellular carcinoma underwent radical resection 4~8 weeks before enrolled.
4)Pathologically diagnosed as hepatocellular carcinoma with any of the following
conditions: a)Microvascular invasion (MVI); b)Satellite nodules were found in specimens;
c)Multiple tumor nodules(>3 nodules); d)Portal vein tumor thrombosis (PVTT): The tumor
thrombosis invades the left or right branches of portal vein, with or without hepatic vein
invasion;
5)=4 weeks after radical resection, the imaging examination confirmed no recurrence and
metastasis.
6)Liver function Child-Pugh grade A (5~6);
7)Physical condition was scored 0~1 according to the ECOG criteria.
8)Expected lifetime >3 months;
9)HBV DNA<10^4 copy/ ml (2000 IU/ ml); if HBV DNA =10^4 copy/ ml, antiviral therapy should
be given, until the HBV DNA drops below 10^4Copy/ml patient can be enrolled in the study.
And during the study, antiviral drugs should be continued, and liver function and hepatitis
B virus load should be monitored;
10)The results of the serum pregnancy test must be negative for women with fertility (i.e.
non-menopausal or surgical sterilization) within 7 days prior to the study of drug
administration;
11)The main organs function normally: Blood routine examination (no transfusion, no use of
G-CSF within 14 days before screening): a)Hemoglobin =90 g/L; b)Absolute neutrophil count
(ANC)=1.5×10^9/L; c)Platelet count =75×10^9/L; Blood biochemical examination (albumin not
used within 14 days before screening): d)Albumin =28 g/L; e)Total bilirubin =1.5× ULN;
f)Aspartate aminotransferase (AST), alanine aminotransferase (ALT )=3× ULN; g)Serum
creatinine =1.5×ULN; Coagulation function: h)The international standardized ratio (INR) or
prothrombin time (PT )=1.5×ULN;. i)Activated partial thromboplastin time (APTT )=1.5×ULN.
Exclusion Criteria:
1. Histopathological diagnosis of hepatocellular carcinoma - intrahepatic
cholangiocarcinoma (HCC-ICC) mixed type;
2. Positive resection margin or tumor rupture;
3. Operation of recurrent liver cancer;
4. Other malignancies within 5 years unless the patient has received a possible cure and
there is no evidence of the disease within 5 years, but this time requirement (i.e.
within 5 years) is not applicable to patients with skin basal cell carcinoma, skin
squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ or
other carcinoma in situ who have successfully undergone excision;
5. Previous or present congenital or acquired immunodeficiency disease;
6. Active or previously documented autoimmune or inflammatory diseases (including but not
limited to: autoimmune hepatitis, interstitial pneumonia, inflammatory bowel disease,
systemic lupus erythematosus, vasculitis, uveitis, pituitary inflammation,
hyperthyroidism or hypothyroidism, asthma requiring treatment with bronchiectasis,
etc.), asthma with vitiligo or which has been completely relieved in childhood without
inclusion of any intervention in adults;
7. History of severe mental illness;
8. Suffer from diseases (e.g. severe vomiting, chronic diarrhea, intestinal obstruction,
absorption disorders, etc.) that affect the absorption, distribution, metabolism or
clearance of the study drug;
Past or combined medication/treatment:
9. Had major surgery (defined by the investigators) within 4 weeks before admission, or
expected to require major surgery during study therapy;
10. Previous transplantation of allogeneic stem cells or parenchymal organs;
11. Preoperative treatment with sorafenib, valvatinib, regofenib or immunomodulator such
as anti PD-1? PD-L1? anti CTLA-4;
12. Patients who have received other systemic anti-tumor treatments before surgery,
including traditional Chinese medicine with anti-tumor indications, have had less than
2 weeks or 5 half-time (whichever is longer) between the completion of the treatment
and the use of the drugs before the study, or who have not recovered to =CTCAE 1 level
of adverse events caused by preoperative treatment;
13. Other adjuvant therapy (except antiviral therapy) was performed after operation.
14. Systemic immunosuppressive drugs have been used within 2 weeks before admission or are
expected to be required during the study period, except in the following cases:
a)Intra-nasal, inhalation, topical or topical (e.g. intra-articular) corticosteroids;
b)Prednisone = 10 mg/day or other equivalent systemic corticosteroid; c)Prophylactic
use of corticosteroids for hypersensitivity;
15. Take drugs that may prolong QTc and/or induce advanced torsional ventricular
tachycardia (Tdp) or affect drug metabolism;
16. Patients with known or suspected history of allergies to Donafenib or similar drugs,
hypersensitivity to chimeric or humanized antibodies or fusion proteins, or to
excipients used to study drugs;
17. The presence of uncontrollable hepatic encephalopathy, hepatorenal syndrome, ascites,
pleural effusion or pericardial effusion;
18. Active bleeding or abnormal coagulation function, bleeding tendency or undergoing
thrombolytic, anticoagulant or antiplatelet therapy;
19. There was a history of gastrointestinal bleeding or a definite tendency of
gastrointestinal bleeding in the past 4 weeks (e.g. local active ulcer lesions, stool
occult blood= ++ , e.g. continuous stool occult blood +, gastroscopy should be
performed), or other conditions (e.g. severe gastric fundus/esophageal varices) that
the researchers determined might cause gastrointestinal bleeding;
20. Gastrointestinal perforation, abdominal fistula or abdominal abscess occurred within 6
months.
21. Thrombosis or thromboembolic events, such as stroke and/or transient ischemic attack,
deep vein thrombosis, pulmonary embolism, etc., occurred within 6 months.
22. With significant clinical significance, including but not limited to previous 6 months
of acute myocardial infarction, severe/unstable angina, or coronary artery bypass
grafting, congestive heart failure (New York Heart Association NYHA Grade > Grade 2),
Poor control or arrhythmia requiring pacemaker therapy, Uncontrolled hypertension
(systolic blood pressure =140 mmHg and/or diastolic blood pressure =90 mmHg);
23. Active infections, including: a)HIV (HIV 1/2 antibody) positive; b)Active hepatitis B
(HBsAg positive and abnormal liver function); c)Active hepatitis C (HCV antibody
positive or HCV RNA=10^3 copy/ ml and abnormal liver function); d)Active tuberculosis;
e)Other uncontrolled active infections (CTCAE V5.0> level 2);
24. Other significant clinical and laboratory abnormalities, the researchers believe
affect safety evaluation, such as: uncontrolled diabetes, chronic kidney disease,
peripheral neuropathy (CTCAE V5.0) of grade II or above, thyroid dysfunction, etc.
25. Has not recovered from surgery, such as the presence of unhealed incisions or severe
postoperative complications;
26. Received any live attenuated vaccine within 4 weeks of admission or during the study
period;
27. Pregnant or lactating women, as well as women or men with fertility who are unwilling
or unable to take effective contraception;
28. A history of alcohol, psychotropic or other substance abuse within 6 months;
29. Enrolled in other clinical trials within 4 weeks before admission.
30. Failure to follow the study protocol for treatment or scheduled follow-up;
31. Any other factors evaluated by investigators that patients cannot be enrolled.
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