A Phase III Clinical Trial of AK105 Injection Combined With Anlotinib Hydrochloride Capsules Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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This is a randomized, controlled, open-label, multicenter study to evaluate efficacy of AK105 injection combined with Anlotinib Hydrochloride Capsules versus Sorafenib. Patients are treated with AK105 injection combined with Anlotinib Hydrochloride Capsules or Sorafenib, with 2:1 random ratio. Every 21 days is a treatment cycle.

Official Title
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A Randomized, Controlled, Open-label, Multicenter Phase III Clinical Trial of AK105 Injection Combined With Anlotinib Hydrochloride Capsules Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma (HCC)

Conditions
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Advanced Hepatocellular Carcinoma (HCC)

Intervention / Treatment
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* Drug: AK105 Injection
* Drug: Anlotinib Hydrochloride Capsules
* Drug: Sorafenib Tosylate Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. 18-75 years old; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; Life expectancy ≥ 3 months. 2. Histopathology or cytology confirmed as HCC. 3. Has not received any systematic treatment for HCC. 4. Stage B or C in the Barcelona Clinic Liver Cancer (BCLC) classification, and is not suitable for surgery or local treatment, or progress after surgery or local treatment. 5. Child-Pugh liver function classification : A or B (≤7 points). 6. Central nervous system metastasis has no clinical symptoms or is stable at least 4 weeks after treatment. 7. Quantification of HBV DNA <500IU/ml or 2500 Copys/ml, and anti-HBV therapy should be given for at least 2 weeks before the first administration; Quantification of HCV RNA is positive must complete antiviral therapy at least 1 month before the first administration. 8. Patients who progress after local treatment should be at least 4 weeks after the end of local treatment. 9. Radiotherapy for bone metastases accompanied by clinical symptoms must be completed at least 2 weeks before the first administration. 10. Has at least one measurable lesion. 11. Adequate organ function. 12. Male or female subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study (such as intrauterine devices , contraceptives or condoms) ；No pregnant or breastfeeding women, and a negative pregnancy test are received within 7 days before the randomization. 13.Understood and signed an informed consent form. Exclusion Criteria: 1. Histopathology or cytology confirmed as fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, hepatobiliary cell carcinoma, mixed liver cancer, etc. 2. Has used anti-angiogenic drugs such as anlotinib, apatinib, lenvatinib, sorafenib, sunitinib, bevacizumab, or related immunotherapy drugs for PD-1, PD-L1, etc. 3. Has received systemic treatment such as chemotherapy and biological therapy. 4. Has a history of hepatic encephalopathy. 5. According to imaging examination, the portal vein has invasion of cancer embolus, inferior vena cava or heart involvement. 6. Hepatitis B with hepatitis C or hepatitis D infection. 7. Has received or planned to receive organ transplantation. 8. Has other malignant tumors within 5 years. 9. Has multiple factors affecting oral medication. 10. Has uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage. 11. Has any bleeding or bleeding events ≥grade 3 in the first 4 weeks before the first administration. 12. Has unhealed wounds, fractures, active gastric and duodenal ulcers, positive continuous fecal occult blood, ulcerative colitis in the first 4 weeks before the first administration. 13. Has adverse events caused by previous therapy except alopecia that did not recover to ≤grade 1. 14. Has received surgery, or unhealed wounds within 4 weeks before the first administration. 15. Has drug abuse history that unable to abstain from or mental disorders. 16. Has any serious and / or uncontrolled disease. 17. Has received vaccination or attenuated vaccine within 4 weeks prior to the first administration. 18. Has received anti-tumor Traditional Chinese Medicine within 2 weeks before the first administration. 19. Severe hypersensitivity after administration of other monoclonal antibodies. 20. Has any active autoimmune disease or history of autoimmune disease. 21.Immunosuppressant or systemic or absorbable local hormone therapy is required to achieve the aim of immunosuppression (dose &gt; 10mg/ day prednisone or other therapeutic hormones) and is still used within 2 weeks after the first administration. 22.Has participated in other anticancer drug clinical trials within 4 weeks. 23.Portal hypertension with high risk of hemorrhage, or have red sign confirmed by gastroscopy. 24.According to the judgement of the investigators, there are other factors that may lead to the termination of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK105 combined with Anlotinib<br>AK105 200mg intravenously (IV) on day 1 of each 21-day cycle plus Anlotinib capsules 10mg given orally in fasting conditions , once daily in 21-day cycle (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21). | Drug: AK105 Injection<br>* AK105 200mg intravenously (IV) on day 1 of each 21-day cycle.<br>Drug: Anlotinib Hydrochloride Capsules<br>* Anlotinib capsules 10mg given orally in fasting conditions , once daily in 21-day cycle (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).<br>|
| Active Comparator: Sorafenib Tosylate Tablets<br>Sorafenib Tosylate Tablets 400mg given orally, twice daily in 21-day cycle. | Drug: Sorafenib Tosylate Tablets<br>* Sorafenib Tosylate Tablets 400mg given orally, twice daily in 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS defined as the time from the first dose to death from any cause. Subjects who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. | Up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS defined as the time from randomization until the first documented progressive disease (PD) or death from any cause. | Up to 96 weeks | 
| Overall response rate（ORR） | Percentage of subjects achieving complete response (CR) and partial response (PR). | Up to 96 weeks | 
| Disease control rate（DCR） | Percentage of subjects achieving complete response (CR) and partial response (PR) and stable disease (SD). | Up to 96 weeks | 
| Duration of Response (DOR) | DOR defined as time from earliest date of disease response to earliest date of disease progression based on radiographic assessment. | Up to 96 weeks |