Camrelizumab in Combination With Apatinib Plus NK Cell for Advanced HCC

Inclusion Criteria:

1. Age 18 ≤ 70, male or female;
2. Clinical or pathologically confirmed BCLC B (tumor numbers ≥ 4) or C stagehepatocellular carcinoma (except intracranial metastasis);
3. At least one intrahepatic evaluable tumor existed, intrahepatic tumor is the primarytumor burden (according to RECIST v1.1, the long diameter of spiral CT scan of themeasurable lesion is ≥ 10 mm or the short diameter of enlarged lymph nodes is ≥ 15mm);
4. No previous systematic (including systematic study drugs) HCC treatment;
5. No contraindications of carrizumab, apatinib and NK cell therapy;
6. Patients who have previously received local treatment (such as microwave ablation,radiofrequency ablation, absolute ethanol or acetic acid injection, cryoablation, highintensity focused ultrasound, transcatheter arterial chemoembolization or perfusionchemotherapy, etc.), A. if the focus has not received local treatment before, it canbe used as the target focus; b. If the focus has received local treatment before, itcan be used as the target focus after the progress is evaluated according to RECISTv1.1 standard;
7. Child-Pugh score small or equal to 7 points (Child-Pugh A-B);
8. Life expectancy of at least 12 weeks;
9. ECOG score: 0 to 1 (according to the ECOG score classification);
10. The subjects voluntarily joined the study, signed the informed consent form, had goodcompliance and cooperated with the follow-up;
11. For female that non-surgical sterilization or in childbearing age need to use amedically approved contraceptive (such as an intrauterine device, contraceptive orcondom) during the study period and within 3 months after the end of the studytreatment period; For female that non-surgical sterilization or in childbearing agemust have a negative serum or urine HCG test within 72 hours prior to studyenrollment; and must be nonlactating; for male patients whose partner in achildbearing age, effective methods of contraception should be given during the trialand at the end of Camrelizumab injection.
12. The laboratory parameters meets the following requirements (no blood components andcell growth factors are allowed within 14 days before the first dose): Absolute neutrophil count ≥ 1.5 × 109 / L; Platelets ≥ 50 × 109 / L; Hemoglobin ≥ 80 g / L; Biochemical examination shall meet the following standards: TBIL < 1.5 × ULN； ALTand AST < 5 × ULN； Bun and Cr ≤ 1 × The clearance rate of ULN or endogenous creatinine ≥ 50ml / min (Cockcroft Gault formula). Stable coagulation function: INR ≤ 1.5, PTT < 1.2 times the upper limit of normalvalue (except for tumor related anticoagulant therapy).
13. Anti HBV therapy should be initiated before enrollment for patients with detectableHBV DNA.

Exclusion Criteria:

1. Accepted any systematic treatment before (excluding traditional Chinese medicine andtraditional Chinese medicine preparations);
2. Existed Hepatobiliary carcinoma, sarcomatoid HCC, mixed cell carcinoma and fibrouslamellar cell carcinoma; Active malignant tumors other than HCC within 5 years or atthe same time. Limited localized tumors, such as basal cell carcinoma of the skin,squamous cell carcinoma of the skin, superficial bladder cancer, prostate cancer insitu, in situ carcinoma of the cervix, and breast cancer in situ, can be included.
3. History of organ allograft;
4. Moderate and severe ascites with clinical symptoms, i.e. those who need therapeuticpuncture and drainage, or child Pugh score > 2 (except those who only show a smallamount of ascites on imaging but are not accompanied by clinical symptoms);Uncontrolled or moderate pleural effusion and pericardial effusion;
5. With a history of gastrointestinal bleeding or definite tendency of gastrointestinalbleeding within 6 months before enrollment, such as bleeding risk or severe esophagealand gastric varices, local active gastrointestinal ulcer lesions, and positivecontinuous fecal occult blood, shall not be included in the group (if fecal occultblood is positive in the baseline period, it can be rechecked. If it is still positiveafter recheck, gastroduodenoscopy is required (EGD), if EGD indicates the risk ofbleeding, esophageal and gastric varices cannot be included in the group);
6. Abdominal fistula, gastrointestinal perforation or abdominal abscess occurred within 6months before the start of the study drug;
7. Events of arterial/venous thrombosis occurring within the first 6 months ofenrollment, such as cerebrovascular accidents (including transient ischemic attacks,cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonaryembolism;
8. Aspirin (> 325 mg / day (maximum antiplatelet dose) or dipyridamole, ticlopidine,clopidogrel and cilostazol were currently or recently used (within 10 days before thestart of study treatment);
9. hrombosis or embolism events occurred within 6 months before the start of the studydrug, such as cerebrovascular accidents (including transient ischemic attack,intracerebral hemorrhage, cerebral infarction), pulmonary embolism, etc;
10. Suffering heart diseases with clinical symptoms or those not well controlled, such as: (1) heart failure in NYHA class 2 or higher; (2) unstable angina; (3) myocardialinfarction occurred within 1 year; (4) clinically symptomatic supraventricular orventricular arrhythmia requiring treatment or intervention; (5) Tc > 450ms (male); QTc > 470ms (female);
11. Suffering from hypertension, and cannot be well controlled by antihypertensive drugs (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥90 mmHg);
12. Major vascular diseases (e.g., aortic aneurysms requiring surgical repair or recentperipheral arterial thrombosis) occurred within 6 months before the start of the studydrug;
13. Severe, unhealed or cracked wounds and active ulcers or untreated fractures;
14. Major surgical treatment (except diagnosis) within 4 weeks before the start of studytreatment or major surgical treatment is expected during the study period;
15. Inability to swallow tablets, malabsorption syndrome, or any condition affectinggastrointestinal absorption;
16. Clinical signs or symptoms of intestinal obstruction and / or gastrointestinalobstruction within 6 months before the start of study treatment, including incompleteobstruction related to original disease or requiring routine parenteral hydration,parenteral nutrition or tube feeding:
17. At the initial diagnosis, patients with incomplete obstruction / obstruction syndrome / signs / symptoms of intestinal obstruction may be admitted to the study if theyreceive definite (surgical) treatment to subside the symptoms;
18. There is evidence of intraabdominal pneumatosis that cannot be explained by punctureor recent surgery;
19. Known central nervous system tumors including metastatic brain disease;
20. Metastatic diseases involving major airways or blood vessels (such as portal veintrunk or vena cava completely occluded due to tumor invasion, which refers to theconfluence of splenic vein and superior mesenteric vein and the branches of hepaticportal vein divided into left and right branches) or large mediastinal tumor mass inthe center (less than 30 mm from the ridge);
21. With a history of hepatic encephalopathy;
22. Present with interstitial pneumonia or interstitial lung disease, or previous historyof interstitial pneumonia or interstitial lung disease requiring hormone treatment, orother pulmonary fibrosis, organic pneumonia (e.g., bronchiolitis obliterans),pneumoconiosis, drug-related pneumonia, idiopathic pneumonia or chest computedtomography in the screening period that may interfere with the judgment and treatmentof immune-related pulmonary toxicity (CT) subjects with evidence of active pneumoniaor severely impaired pulmonary function on the figure, allowed radiation field to haveradiation pneumonia; active tuberculosis;
23. The patient has any active auto-immune disease or a history of autoimmune disease;
24. immunosuppressive treatment with immunosuppressants or systemic hormones within 14days before the start of study treatment (dose > 10mg / day prednisone or otherequivalent hormones);
25. Applying strong CYP3A4 / CYP2C19 inducers including rifampicin (and its analogues) andHypericum perforatum or strong CYP3A4 / CYP2C19 inhibitors within 14 days before thestart of study treatment;
26. Severe infection within 4 weeks before the start of study treatment, including but notlimited to hospitalization due to complications of infection, bacteremia or severepneumonia; oral or intravenous administration of therapeutic antibiotics within 2weeks before the start of study treatment (patients receiving prophylactic antibiotics (e.g. prevention of urinary tract infection or exacerbation of chronic obstructivepulmonary disease are eligible to participate in the study);
27. Known history of HIV;
28. Co-infection of hepatitis B and HCV.
29. Patients have previously received other anti-PD-1 antibody therapy or otherimmunotherapy against PD-1/PD-L1, or have received apatinib before;
30. Palliative radiotherapy for non target lesions allowed to control symptoms must becompleted at least 2 weeks before the start of study treatment, and the adverse eventscaused by radiotherapy have not recovered to ≤ CTCAE level 1.