IIT Study of M1-c6v1 Combined With SHR-1210 and Apatinib in Patients With HCC

Inclusion Criteria:

1. Aged 18-65 years old, both genders.
2. To be confirmed to meet the clinical diagnosis standard, histologically orcytologically confirmed with hepatocellular carcinoma
3. Life expectancy of at least 3 months.
4. Patients was not received any systemic therapies to HCC.
5. For patients with advanced hepatocellular carcinoma, liver function status Child-PughClass A or B (score<=7).
6. HCC staging is evaluated according to Diagnostic and therapeutic criteria for livercancer (2019 Edition, National health commission, P.R.A)

• a: with vascular invasion and no extrahepatic metastasis, no matter the tumorcondition; Child-Pugh A/B；PS 0~2.
• b: with extrahepatic metastasis, no matter the tumor condition and vascularinvasion; Child-Pugh A/B；PS 0~2, not eligible for surgical and/or locoregionaltherapies.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.
8. Patients must have at least 1 lesion that is measurable using RECIST v1.1 criteria (The long diameter of the lesion on spiral CT scan was more than or equal to 10 mm orthe short diameter of enlarged lymph node was more than or equal to 15 mm).
9. Patients must have adequate organ function (without blood transfusion, without growthfactor or blood components support within 14 days before enrollment)as determined by: ① Blood system: Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥1.5×109/L;Platelet count ≥ 75×109/L. ② Liver function: Serum total bilirubin (TBIL)≤2 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5×upperlimit of normal(ULN), Serum albumin ≥ 28 g/L; Alkaline phosphatase(ALP) ≤5×ULN; ③ Kidney function: Calculated creatinine clearance (CrCl) > 50 mL/min (Cockcroft-Gaultformula will be used to calculate CrCl); Creatinine (Cr) ≤ 1.5×ULN; Urine protein <2+or Baseline of urine protein ≥ 2+ and 24h urinary protein quantity ≤ 1g. ④ Coagulation function: International Normalized Ratio (INR) or Activated partialthromboplastin time (APTT) ≤ 1.5×ULN
10. Reproductive subjects (male and female) must agree to use effective birth controlmeasures with their partners for at least 180 days after the last medication.
11. Volunteer to participate in clinical research; fully understand and be able to signthe informed consent form (ICF); willing to follow and have the ability to completeall trial procedures.

Exclusion Criteria:

1. Patients must not have had prior treatment with SHR-1210 or any other PD-L1 or PD-1antagonists or any other oncolytic virus, and must not have had be enrolled in thephase III Study of Apatinib After Systemic Therapy in Patients With HepatocellularCarcinoma.
2. Patients with any active autoimmune disease or history of autoimmune disease,including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism,and hypothyroidism, except for subjects with vitiligo or resolved childhoodasthma/atopy. Asthma that requires intermittent use of bronchodilators or othermedical intervention should also be excluded.
3. Concurrent medical condition requiring the use of immunosuppressive medications, orimmunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10mg/day prednisone or equivalent are prohibited within 2 weeks before study drugadministration. Note: corticosteroids used for the purpose of IV contrast allergyprophylaxis are allowed.
4. Known history of hypersensitivity to any components of the SHR-1210 formulation, orM1-c6v1 (mannitol, human albumin, trehalose).
5. Active central nervous system (CNS) metastases with clinical symptoms (includingcerebral edema, steroid requirement, or progressive disease). Subjects with brain ormeningeal metastases that were previously treated must be clinically stable (magneticresonance imaging [MRI] at least 4 weeks apart do not show evidence of new orenlarging metastases) and have discontinued immunosuppressive doses of systemicsteroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks before study drugadministration.
6. Patients with other malignant tumor (except cured skin basal cell carcinoma andcervical carcinoma).
7. Clinically significant cardiovascular and cerebrovascular diseases, including but notlimited to severe acute myocardial infarction within 6 months before enrollment,unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class > 2), ventricular arrhythmia which needmedical intervention, left ventricular ejection fraction(LVEF) < 50%.
8. Hypertension and unable to be controlled within normal level following treatment ofanti-hypertension agents(within 3 months): systolic blood pressure > 140 mmHg,diastolic blood pressure > 90 mmHg.
9. Coagulation abnormalities (PT>16s、APTT>43s、TT>21s、Fbg<2g/L), with bleeding tendency orare receiving thrombolytic or anticoagulant therapy.
10. Prior systemic chemotherapy, radiotherapy, immunotherapy, hormone therapy, surgery ortarget therapy within 4 weeks (Or 5 half-life of the drug, calculate the longer )before the study drug administration, or any unresolved AEs > Common TerminologyCriteria for Adverse Events (CTCAE) Grade 1 (with the exception of any stable chronictoxicities not expected to resolve).
11. Patients with clinical symptoms of ascites or pleural effusion, need therapeuticpuncture and drainage.
12. Previous digestive tract bleeding history within 3 months or evident gastrointestinalbleeding tendency, such as: esophageal varices, local active ulcerative lesions,gastric ulcer and duodenal ulcer, the ulcerous colitis, gastrointestinal diseases suchas portal hypertension or resection of tumor with bleeding risk, etc.
13. Patients with or previous with serious hemorrhage (bleeding > 30 ml within 3 months),haemoptysis (> 5 ml within 4 weeks) of thromboembolic events within 12 months (including stroke events and/or transient ischemic attack).
14. Active infection or an unexplained fever > 38.5°C during screening visits or on thefirst scheduled day of dosing (at the discretion of the investigator, subjects withtumor fever may be enrolled).
15. Objective evidence of previous or current pulmonary fibrosis history, interstitialpneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, pulmonaryfunction damaged seriously etc.
16. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease, or active hepatitis (transaminase does not meet the inclusion, hepatitis B virus (HBV) DNA ≥10⁴ /ml orhepatitis C virus (HCV) RNA≥103 /ml or higher); Chronic hepatitis B virus carriers whoHBV DNA<2000 IU/ml(<104/ml), must receive anti-viral treatment throughout the study.
17. Participated in other clinical trials, or finish other clinical trials within 4 weeks.
18. Patients who may receive other anti-tumor systemic chemotherapy during the study.
19. Patients who has bone metastasis, have received Palliative radiotherapy (radiotherapyarea > 5% marrow area).
20. Patients who may receive vaccination during the study, or previous had vaccinationwithin 4 weeks.
21. Mental disorders history, or psychotropic drug abuse history.
22. Any other medical, psychiatric, or social condition deemed by the investigator to belikely to interfere with a subject's rights, safety, welfare, or ability to signinformed consent, cooperate, and participate in the study or would interfere with theinterpretation of the results.