The Phase III Study of Icaritin Versus Sorafenib in PD-L1 Positive Advanced Hepatocellular Carcinoma Subjects

Inclusion Criteria:

• Patients who meet any of the following criteria are not allowed to enter the test:

1. Aged between 18 and 75 years old, no gender restriction;
2. According to "Primary Liver Cancer Diagnosis and Treatment Standard." (2011Edition) issued by the National Health and Family Planning Commission, advancedor metastatic hepatocellular carcinoma patients who diagnosed by pathology /cytology fail to undergo liver surgery and/or other local treatment (ablation orhepatic artery intervention), or have recurrence and progression after surgeryand/or other local treatment;
3. Not previously accepted first-line system therapy (systemic chemotherapy,molecular targeting, immunotherapy and research medication, etc.) for advanced ormetastatic HCC, including but not limited to systematic chemotherapy withoxaliplatin, sorafenib, PD-1/PD-L1 antibody and Icaritin, etc.;
4. The central laboratory must receive specimen of tumor tissue (wax block or whiteslice) at first, and detect the PD-L1of tumor tissues by immunohistochemistry,only positive expression of PD-L1 in immune cells can be enrolled;
5. According to the evaluation criteria of solid tumor reaction (RECIST 1.1), it hasat least one measurable target lesion (Non-lymph node lesions with the longestdiameter larger than 10mm, lymph node lesions with the short diameter larger than 15mm); the lesions previously received local treatment such as ablation orhepatic artery interventional therapy should be detected by computed tomography (CT) / magnetic resonance imaging (MRI) and according to RECIST1.1, It's surethat disease progression has occurred and the longest diameter is more than 1.0cm,it can be used as a measurable target lesions;
6. Liver surgery was performed more than 3 months ago, ablation or interventionaltreatment of hepatic artery was performed more than 4 weeks ago, and the adversereactions returned to normal; After surgery or other local treatment, if patientshave gone beyond the norm for systemic adjuvant chemotherapy or sorafenib, itwill need more than 6 months after the chemotherapy or sorafenib, and diseaseprogression and / or metastasis have occurred;
7. The Child-Pugh score of liver function is grade A or better grade B (score≤7);
8. The ECOG score of physical condition is 0-1;
9. Expected survival time≥12 weeks;
10. 2 weeks before the first medication of the trial, there is no use of modernChinese medicine preparation with liver cancer indication, including Delishenginjection, Kanglaite injection/soft capsule, Aidi injection or Cotside injection,elemene injection/oral liquid, Huaier granule, cinobufotalin and GanFuLe capsule / tablet and so on.
11. The function of the main organs is basically normal and meets the followingrequirements: ① Marrow: Absolute neutrophil count≥1.5×109/L, platelet≥80×109/L,hemoglobin≥90g/L; ② Liver: Total bilirubin≤1.5 times of the upper limit of normal(ULN), Aspartateaminotransferase (AST) and alanine aminotransferase (ALT)≤5 × ULN; albumin≥29g/L; ③ Kidney: Serum creatinine≤ 1.5 x ULN, or creatinine clearance rate≥ 50ml/min;
12. If HBV-DNA≥104 copies/ml(2000IU/ml), antiviral therapy must be done first, thepatient can be included in the group until HBV-DNA<104 copies /ml(2000IU/ml); andcontinue to take antiviral drugs, monitor liver function and hepatitis B virusload;
13. Women of childbearing age must receive pregnancy tests 14 days before treatmentand the results are negative; Men and women must take effective contraceptivemeasures during the trial (from signing an informed consent to 3 months after thelast medication);
14. Patients volunteered to join the study, sign the informed consent, have goodcompliance and cooperate with follow-up;
15. The subjects do not participate in other clinical trials within 4 weeks beforescreening; If the subject fails in other test screening, but meets therequirements of this test, then can be enrolled.

Exclusion Criteria:

• Patients who meet any of the following criteria are not allowed to enter the test:

1. Imaging examination shows that HCC liver tumors are huge (≥60% of the livervolume), or cancer embolus of portal trunk (occupying ≥50% of the vasculardiameter), or cancer embolus invading mesenteric vein or inferior vena cava;
2. Middle or higher ascites which is clinically significant, it requires therapeuticabdominal paracentesis /drainage, or the Child-Pugh score > 2;
3. Local anticancer therapy (including surgery, ablation, hepatic arterialchemotherapy, embolization or radiotherapy) or major surgery was performed 28days prior to randomization;
4. Hepatocholangiocarcinoma and fibrolamellar cell carcinoma; In the past or at thesame time, there were other cancers whose primary site or histology are entirelydifferent from hepatocellular carcinoma, except cervical carcinoma in situ,previously treated basal cell carcinoma and superficial bladder tumor (Ta, Tis,T1); Patients with other malignancies who have been cured for >5 years prior toenrollment may be admitted to the group;
5. Pregnant or lactating women;
6. Patients who have high blood pressure and failed to receive good control withantihypertensive drugs (systolic blood pressure >140mmHg, diastolic pressure >100mmHg); Patients suffer from CTCAE classification type II or above myocardialischemia or myocardial infarction, poorly controlled arrhythmia; and/or New YorkHeart Association(NYHA) grade III to IV cardiac dysfunction.
7. Allograft transplants including liver transplantation were performed previously,or a liver transplant was planned during the trial;
8. Hepatic encephalopathy and / or hepatic nephropathy occurred within 6 months;
9. Patient with active hepatitis C, that is, anti -HCV positive or HCV-RNA positiveand abnormal liver function;
10. Human immunodeficiency virus (HIV) tests are positive or severe infectionrequiring systemic treatment with antibiotics;
11. Inability to swallow, chronic diarrhea or intestinal obstruction thatsignificantly affecting medication intake and absorption;
12. Having a history of digestive tract bleeding within 6 months, or with a cleargastrointestinal bleeding tendency, including local active ulcerative lesions,positive fecal occult blood;
13. The patient has or is suspected to have known active autoimmune disease;
14. If a central nervous system metastasis is known and a metastasis of the centralnervous system is suspected, the cranial MRI examination should be performed toexclude it;
15. Abnormal coagulation function: prothrombin time (PT) >16S or internationalnormalized ratio (INR) >1.5;
16. There is a history of schizophrenia or psychotropic substance abuse;
17. Known to be allergic or intolerant to Icaritin or sorafenib and excipients;
18. Other conditions that researchers believe discourage patients from participatingin trials.