A Study to Evaluate SHR-1210 in Combination With Apatinib as First-Line Therapy in Patients With Advanced HCC

Study Overview
=================
Brief Summary
-----------------
This is a randomized, open-label, international, multi-center, phase III trial to evaluate the efficacy and safety of SHR-1210 plus apatinib mesylate versus sorafenib as first-line therapy in patients with advanced HCC.

Official Title
-----------------
A Randomized, Open-Label, International, Multi-Center, Phase 3 Clinical Study of PD-1 Antibody SHR-1210 Plus Apatinib Mesylate Versus Sorafenib as First-Line Therapy in Patients With Advanced Hepatocellular Carcinoma (HCC) Who Have Not Previously Received Systemic Therapy

Conditions
-----------------
Locally Advanced or Metastatic and Unresectable HCC

Intervention / Treatment
-----------------
* Drug: SHR-1210
* Drug: Apatinib
* Drug: Sorafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histopathologically or cytologically confirmed advanced HCC No previous systematic treatment for HCC Have at least one measurable lesion (in accordance with RECIST v1.1) BCLC stage B or C, and not suitable for surgical or local therapy, or has progressed following surgical and/or local therapy ECOG-PS score 0 or 1 Child-Pugh Class: Grade A Life Expectancy of at least 12 weeks Subjects with HBV infection: HBV DNA<500 IU/ml or < 2500 copy/mL, and have received anti-HBV therapy for at least 14 days prior to enrollment in the study Subjects with HCV-RNA(+) must receive antiviral therapy Adequate organ function Exclusion Criteria: Known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma and lamellar cell carcinoma; other active malignant tumor except HCC within 5 years or simultaneously Moderate-to-severe ascites with clinical symptoms History of gastrointestinal hemorrhage within 6 months prior to the start of study treatment or clear tendency of gastrointestinal hemorrhage Abdominal fistula, gastrointestinal perforation or intraperitoneal abscess within 6 months prior to the start of study treatment Known genetic or acquired hemorrhage or thrombotic tendency Thrombosis or thromboembolic event within 6 months prior to the start of study treatment Cardiac clinical symptom or disease that is not well controlled Hypertension that can not be well controlled through antihypertensive drugs Factors to affect oral administration History of hepatic encephalopathy Previous or current presence of metastasis to central nervous system HIV infection Combined hepatitis B and hepatitis C co-infection Be ready for or previously received organ or allogenic bone marrow transplantation Interstitial lung disease that is symptomatic or may interfere with the detection and management of suspected drug-related pulmonary toxicity Active known, or suspected autoimmune disease Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of first administration of study treatment Use of potent CYP3A4 inducers or inhibitors within 2 weeks prior to the signature of ICF Known history of serious allergy to any monoclonal antibody or targeted anti-angiogenic drug Severe infection within 4 weeks prior to the start of study treatment Palliative radiotherapy for non-target lesions to control symptoms is allowed, but it must be completed at least 2 weeks prior to the start of study treatment Treatment of other investigational product(s) within 28 days prior to the start of study treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-1210<br>SHR-1210+Apatinib | Drug: SHR-1210<br>* Subjects receive SHR-1210 intravenously, Dosage form: lyophilised powder, Strength: 200 mg /vial<br>Drug: Apatinib<br>* Subjects receive Apatinib orally, Dosage form: tablet, Strength: 250 mg/tablet<br>|
| Active Comparator: Control<br>Sorafenib | Drug: Sorafenib<br>* Subjects receive Sorafenib orally, Dosage form: tablet, Strength: 0.2 g/tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the overall survival (OS) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 
| To compare the progression-free survival (PFS) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the time to progression (TTP) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 
| To compare objective response rate (ORR) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 
| To compare disease control rate (DCR) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 
| To compare duration of response (DoR) of SHR-1210 plus apatinib with sorafenib |  | Up to approximately 3 years | 
| The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) of SHR-1210 plus apatinib versus sorafenib as assessed by CTCAE v4.03 |  | Up to approximately 3 years | 
| Serum concentration of SHR-1210 and plasma concentration of apatinib |  | Up to approximately 3 years | 
| Proportion of anti-SHR-1210 antibody (ADA) and neutralizing antibody (Nab) formed during the study from baseline |  | Up to approximately 3 years |