| Eligibility |
Inclusion Criteria:
1. Subjects who voluntarily sign the informed consent form (ICF);
2. Male or female subjects who are aged 18-75 years old;
3. Subjects with histologic, cytologic or clinical confirmed diagnosis of advanced HCC
(Phase I could include intrahepatic cholangiocarcinoma or mixed
hepatocellular-cholangiocarcinoma), and are not suitable for surgery or loco-regional
therapy or have progressed following surgery and/or loco-regional therapy;
4. Subject who has at least one measurable lesion according to RECIST v1.1 criteria.
5. Phase I study: subjects who have previously received at least one line of systemic
therapy, including immune checkpoint inhibitors, molecular targeted drugs or
systematic chemotherapy, alone or in combination, and failed (progression confirmed by
imaging) or were intolerant at the discretion of investigator; PhaseII:Advanced HCC
cohort with subjects who have previously received immune checkpoint inhibitor
treatment: subjects who have failed (progression confirmed by imaging) prior one line
immune checkpoint inhibitor treatment, including anti-PD-1 antibody/anti-PD-L1
antibody and / or anti-CTLA-4 antibody, and/or molecular targeted therapy or
systematic chemotherapy (monotherapy or in combination); Phase II: Advanced HCC cohort
with subjects who have not previously received immune checkpoint inhibitor treatment:
subjects who have failed (progression confirmed by imaging) or were intolerant to (at
the discretion of investigator) previous molecular targeted therapy or systematic
chemotherapy, without receiving immune checkpoint inhibitor treatment (including
anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, and bispecific
antibodies including the above targets).
6. Previous anti-tumor therapy must be completed no less than 2 weeks prior to the study
treatment and all adverse events related to previous treatment must have recovered to
CTCAE Grade =1; if subjects who have received prior immune checkpoint inhibitors have
immune-related endocrinopathy, it should be controlled with hormone replacement
therapy.
7. Phase I: Child-Pugh Class A; Phase II: Child-Pugh Class A or B with a score of = 7;
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
9. Subjects with life expectancy =12 weeks;
10. Subjects with chronic HBV infection must have HBV-DNA <500 IU/ml, and have received at
least 14 days of anti-HBV treatment (e.g. entecavir, tenofovir) prior to the
initiation of study treatment and are willing to receive antiviral treatment
throughout the study; Subjects with RNA-positive HCV must have received standard
antiviral treatment and the elevation of their liver enzymes must not exceed the level
of CTCAE Grade 1;
11. Adequate vital organ function as shown below:
(1) Blood system function (subjects must have not received blood transfusion or stimulating
growth factors within 14 days prior to screening test): neutrophil count =1.5×109/L,
platelet count = 75×109/L, hemoglobin = 90 g/L; (2) Liver and kidney function (no albumin
transfusion within 14 days prior to screening test): serum total bilirubin = 2.5×ULN, serum
albumin = 29 g/L, ALT and AST = 5×ULN; serum creatinine <1.5×ULN or eGFR (Cockcroft-Gault
formula) = 60 ml/min; (3) Coagulation function: international normalized ratio (INR)=2.3 or
prothrombin time (PT) of = 6 seconds above control; (4) Left ventricular ejection fraction
(LVEF) =50% by two-dimensional echocardiography.
12. Female subjects (except for females who have underwent surgical sterilization and those
have been menopausal for more than one year) who are of childbearing potential are required
to adopt a medically proven method for contraception (e.g. intrauterine contraception
device, contraceptive pill or condom) throughout the study and up to 120 days after the
last dose of investigational products; females who are of childbearing age and who do not
underwent surgical sterilization must have negative serum or urine HCG tests within 7 days
prior to enrollment; female subjects must not be breastfeeding; male subjects whose
partners are of childbearing potential should use effective contraceptive methods
throughout the study and up to 120 days after the last dose of investigational product.
13. Subjects who are willing to provide oncological tissues (if applicable) for biomarker
test.
Exclusion Criteria:
1. Subjects who have known fibrolamellar carcinoma of liver for phase I and subjects who
have fibrolamellar carcinoma, mixed HCC- cholangiocarcinoma or cholangiocarcinoma for
phase II;
2. Subjects with brain metastasis or leptomeningeal metastasis confirmed by brain MRI
during screening period;
3. Subjects with a diagnosis of other malignant tumors within 5 years prior to first
administration, except for skin basal cell carcinoma, skin squamous cell carcinoma
and/or in situ cancer following radical resection;
4. Subjects who had liver or other sites loco-regional treatment (including transcatheter
arterial chemoembolization (TACE), transcatheter arterial embolization (TAE), hepatic
artery infusion (HAI), local radiotherapy, radioembolization, radiofrequency ablation,
cryoablation or percutaneous ethanol injection) , or who had major surgery of liver or
other sites within 4 weeks prior to first administration, or had minor surgical
procedures (e.g. simple excision, tooth extraction) within one week prior to first
administration, or had received palliative radiotherapy for bone metastasis within 2
weeks and radiotherapy-related toxicity = CTCAE Grade 2.
5. Subjects who have moderate or severe ascites (detected by B-ultrasound or CT), or
require therapeutic abdominal paracentesis or drainage;
6. Subjects with a history of hepatic encephalopathy;
7. Subjects with a history of unhealed wounds or ulcers or bone fractures within 3 months
prior to study enrollment;
8. Subjects who plan to have or had allogenic organ or bone marrow transplantation;
9. Subjects who are at increased risk of bleeding or have history of thrombosis:
(1) Clinically significant bleeding within 3 months prior to screening or clear bleeding
tendency; (2) Gastrointestinal hemorrhage within 6 months prior to screening or clear
tendency of gastrointestinal hemorrhage; (3) Arterial/venous thromboembolic events within 6
months prior to screening, such as cerebrovascular accident (including transient ischemic
attack), pulmonary embolism, etc.; (4) Require anticoagulation therapy with an agent such
as warfarin or heparin; (5) Require chronic anti-platelet therapy (such as aspirin=100
mg/day, clopidogrel, etc.); 10. Subjects who have clinically significant cardiovascular
diseases:
1. NYHA (New York Heart Association)stage 3 and 4 congestive heart failure;
2. Unstable angina pectoris or newly diagnosed angina pectoris or myocardial infarction
within 12 months prior to screening;
3. Arrhythmias requiring medications other than ß-blockers;
4. Valvular heart disease of = CTCAE grade 2;
5. Hypertension inadequately controlled by drugs (systolic pressure >150 mmHg or
diastolic pressure >90 mmHg); 11. Subjects who have history of symptomatic pulmonary
fibrosis, or have interstitial pneumonitis, pneumoconiosis, radiation pneumonitis,
drug-related pneumonitis, severe impairment of pulmonary function, or other suspicious
pulmonary diseases that may interfere with drug-related pulmonary toxicity detection
and treatment; 12. Subjects who have suffered active bacterial or fungal infections
requiring systemic treatment within 7 days prior to screening; or active tuberculosis;
13. Subjects with active co-infection of Hepatitis B and C, confirmed by positive HBV
surface antigen or HBV DNA and HCV RNA 14. Subjects who have any active, known or
suspected autoimmune disease; 15. Subjects with a condition requiring systematic
treatment with corticosteroids (>10 mg/day prednisone or equivalent) or other
immunosuppressive drugs within 14 days before administration of the investigational
drug. In the absence of active autoimmune diseases, inhalation or topical use of
steroids (>10 mg/day prednisone or equivalent) is allowed; 16. Other laboratory
abnormalities:
(1) Hyponatremia, hypokalemia or hypophosphatemia that have occurred before the first
administration, and failed to restore to normal level after electrolyte supplementation
therapy; (2) Confirmed diagnosis of thyroid dysfunction, which cannot be maintained within
normal range following thyroid hormone replacement therapy; (3) Positive Human
immunodeficiency virus (HIV) test; 17. QTc interval >480 ms on two consecutive ECGs; 18.
Female subjects during pregnancy or lactation; female subjects of childbearing potential or
male subjects who are not willing to use contraception or contraceptive measures during the
study; 19. Subjects who have previously received two lines and above tumor immune
checkpiont inhibitor treatment, mainly including anti-PD-1, anti-PD-L1 and anti-CTLA-4
antibodies, etc, or bispecific antibodies including the above targets, or received
anti-LAG-3 antibody; whether subjects who have previously received other tumor
immunotherapy can be enrolled should be determined by the sponsor; 20. Known or suspected
history of severe allergy to investigational drugs; 21. Subjects who have received live
attenuated vaccines or any investigational drugs that have not been marketed in China
within 4 weeks prior to first administration; 22. If subjects who have previously used
immune checkpoint inhibitors (such as anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies) have
the following drug-related adverse events, they will be not suitable for inclusion
regardless of recovered or not:
1. = Grade 3 eye-related adverse events
2. Grade 4 abnormal liver function
3. = Grade 3 neurotoxicity
4. = Grade 3 colitis
5. = Grade 3 renal toxicity
6. = Grade 3 pneumonitis 23. Subjects who are not suitable for inclusion as judged by the
investigators.
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