| Eligibility |
Inclusion Criteria:
- Subjects who meet all of the following criteria are allowed to be enrolled into this
study:
- Volunteer to participate in clinical research;To fully understand and understand
this study and to sign the Informed Consent Form (ICF);Willing to follow and able
to complete all test procedures.
- The age of signing ICF is = 18 years old and = 75 years old.
- Subjects with advanced hepatocellular carcinoma (HCC) diagnosed by histopathology
or cytology, or clinically diagnosed as meeting the criteria for hepatocellular
carcinoma of the American association of liver diseases (AASLD).
- arm A?B Failure or intolerable toxicity after at least one standard first-line
systemic treatment for advanced hepatocellular carcinoma.Previous standard
first-line systemic therapy included sorafenib, renvastinib and oxaliplatin based
chemotherapy.
- arm D never used systemic treatment
- Barcelona Clinic Liver Cancer (BCLC) (appendix I) stage C;BCLC stage B patients
who are not suitable for locoregional therapy may also be enrolled.
- At least one measurable lesion assessed by IRRC according to RECIST v1.1
(appendix ii) has not been treated locally for this lesion (e.g., radiotherapy,
radiofrequency ablation, TACE, ultrasound focusing knife, etc.).
- The end of previous systematic treatment must be = 2 weeks after the first
medication in this study, and the treatment-related AE should be restored to the
level of ci -CTCAE = 1 (except hair loss).
- Child-pugh liver function rating within 7 days before the first administration of
the study drug (appendix iii) : grade A and good grade B (= 7 points).
- The ECOG physical performance score (appendix iv) for the 7 days prior to the
first administration of the study drug was 0 or 1.
- Expected survival = 12 weeks.
- Subjects of HBsAg (-) and HBcAb (-) were admitted into the group;If HBsAg (+) or
HBcAb (+), hbv-dna must be = 500 IU/mL to be included in the group, and those
with elevated hbv-dna must agree to receive nucleoside anti-hepatitis b virus
treatment.Subjects with negative HCV antibody (-) or hcv-rna were admitted.If
hcv-rna is positive, subjects must have ALT and AST = 3×ULN to be
enrolled.Subjects with co-infection of hepatitis b and c should be excluded.
- Major organs function normally and meet the following criteria (no blood
transfusion, albumin, recombinant human thrombogenin or colony stimulating factor
(CSF) treatment was received within 14 days prior to the first administration of
this study)
- Female subjects must meet:
Menopause (defined as having not had menstruation for at least 1 year and having no other
known cause other than menopause), or Surgical sterilization (removal of ovaries and/or
uterus), or have fertility, but must meet: serum pregnancy test must be negative within 7
days prior to first administration, and , agreed to the annual failure rate < 1% of
contraception or abstinence (avoid heterosexual intercourse) (from signed informed consent
to test drugs at the end of the time at least 120 days) after the treatment (annual failure
rate < 1% of contraceptive methods including bilateral tubal ligation, male sterilization
techniques, the correct use can inhibit ovulation hormonal contracepties, releasing hormone
of intrauterine contraceptive device and copper intrauterine contraceptive device), and do
not breastfeed.
• Male subjects must be satisfied: agree with abstinence (avoid heterosexual intercourse)
or contraceptive measures, the rules are as follows: spouse or partner has been pregnant
for childbearing age women, male subjects must be at the end of the experiment during drug
dosage and drug time at least 120 days after the treatment, keep abstinence or use condoms
for birth control in order to prevent drug exposure in the embryo.The duration of the
clinical study and the reliability of the subjects' preferences and daily lifestyle
measures of abstinence should be considered.Regular abstinence (e.g., calender days,
ovulation, basal body temperature, or post-ovulation methods) and ejaculation are not
acceptable methods of contraception.
Exclusion Criteria:
- Subjects who meet any of the following criteria are not allowed to be enrolled in this
study:
- Hepatobiliary duct cell carcinoma, mixed cell carcinoma, or fibroblastic layer
cell carcinoma are known.
- Other active malignancies within 5 years prior to the first administration of the
study drug.Curable localized tumors, such as basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, superficial bladder carcinoma, carcinoma in
situ of the prostate, cervical carcinoma in situ, and carcinoma in situ of the
breast, can be included in the group.
- People who are ready to undergo or have received organ or bone marrow
transplants.
- After appropriate intervention, uncontrollable pleural effusion, pericardial
effusion or ascites still need to be drained frequently (once a month or more
frequently).
- Symptomatic, untreated, or progressive central nervous system (CNS) or meningeal
metastasis.Asymptomatic subjects treated for CNS lesions can be enrolled if all
of the following criteria are met:
1. in addition to CNS, there must be lesions that can be measured according to
RECIST v1.1;
2. the patient had no history of intracranial or spinal bleeding;
3. metastatic lesions were limited to cerebellum or supratentorial areas (i.e.,
no mesencephalon, pons, medulla or spinal cord metastatic lesions);
4. there was no evidence of progress between the completion of CNS oriented
therapy and the start of research and treatment;
5. the patients did not receive stereotactic radiotherapy within 7 days before
the study treatment, did not receive whole-brain radiotherapy within 14 days
before the study treatment, and did not receive neurosurgical resection
within 28 days before the study treatment;
6. patients have no need for continuous use of glucocorticoids in the treatment
of CNS diseases.Stable doses of anticonvulsant therapy are permitted;
7. asymptomatic patients with newly detected CNS metastases during screening
are eligible to participate in the study after receiving radiotherapy or
surgical treatment, and there is no need to repeat screening of brain scan
results.
- Cerebrovascular accident, myocardial infarction, unstable angina pectoris and
poorly controlled arrhythmia occurred within half a year (including QTc interval
= 450 ms for men and = 470 ms for women) (QTc interval was calculated by
Fridericia formula).
- According to the New York heart association (NYHA) standard (appendix 5) levels ?
or ? cardiac insufficiency or heart colour to exceed examination: LVEF, left
ventricular ejection fraction < 50%.
- A history of hepatic encephalopathy.
- According to the images, portal vein invasion, inferior vena cava or cardiac
involvement of HCC main portal branch (Vp4) were present.Patients with cancer
thrombus in main portal vein but smooth blood flow in contralateral branch can be
enrolled.
- Involving major airways, vessels, or large mediastinal mass located centrally (<
30 mm from the crest).
- Human immunodeficiency virus (HIV) infection.
- Active tuberculosis.
- Patients with previous and current cases of interstitial pneumonia,
pneumoconiosis, radioactive pneumonia, drug-related pneumonia, and severe
impairment of lung function that may interfere with the detection and management
of suspected drug-related lung toxicity.
- Known activity or autoimmune disease or history.
- The study drug was treated with live attenuated vaccine within 28 days prior to
its first administration.
- Subjects requiring systemic treatment with corticosteroids (> 10 mg/ day or
equivalent dose of prednisone) or other immunosuppressants within 14 days prior
to or during the study.In the absence of active autoimmune disease, the
inhalation or topical use of steroids, or adrenal hormone replacement at doses
less than 10 mg/ day of prednisone efficacy, is permitted.
- Within 14 days prior to the first administration of the study drug, any active
infection requiring systematic anti-infective treatment occurs.
- Major surgery was performed within 28 days prior to the first administration of
the study drug. Major surgery in this study was defined as the minimum recovery
time of 3 weeks after surgery before the surgery treated in this study could be
performed.
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