A Study of SHR-1210 in Combination With Apatinib or Chemotherapy in Subjects With Advanced PLC or BTC

Study Overview
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Brief Summary
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This an open-label，Non-Randominzed Phase 2 study to evaluate the Safety and Tolerability of SHR-1210 in combination with Apatinib or chemotherapy (FOLFOX4 or GEMOX regimen) in subjects with Advanced PLC.or BTC Participants with advanced PLC who failed or intolerable to prior systemic therapy will be treated with SHR-1210 plus Apatinib; Participants with advanced PLC or BTC who have never received prior systemic therapy will be treated with SHR-1210 plus FOLFOX4 or GEMOX regimen.

Official Title
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A Phase 2 Study of SHR-1210 (PD-1 Antibody) in Combination With Apatinib or Chemotherapy (FOLFOX4 or GEMOX) in Subjects With Advanced Primary Liver Cancer（PLC）or Biliary Tract Carcinoma (BTC)

Conditions
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Advanced Primary Liver Cancer, Advanced Biliary Tract Carcinoma

Intervention / Treatment
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* Biological: SHR-1210
* Drug: Apatinib
* Drug: FOLFOX4
* Drug: GEMOX


Participation Criteria
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Eligibility Criteria
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Histologically confirmed advanced PLC or advanced BTC (including bile duct carcinoma and gallbladder carcinoma) ; not suitable to surgery or local regional treatment; with at least one measurable lesion per RECIST 1.1. Arm A:Failed or intolerable to at least one prior systemic treatment for advanced PLC. Arm B:No previous systemic treatment for advanced PLC or BTC ECOG Performance Status of 0 or1. Child-Pugh Class A or B with 7 points . Life Expectancy of at least 12 weeks. Has controlled infection by Hepatitis B Virus (HBV DNA<500 IU/ml) or Hepatitis C Virus. Adequate organ function. Male or female participants of childbearing potential must be willing to use an adequate method of contraception starting with the first dose of study drug through 60 days for female subjects and 120 days for male subjects after the last dose of study drug. Patient has given written informed consent. Exclusion Criteria: Known fibrolamellar HCC; Prior malignancy active with the previous 5 years except for locally curable cancers that have been apparently cured. Known or occurrence of central nervous system (CNS) metastases. Ascites with clinical symptoms. Known or evidence of GI hemorrhage within the past 6 months. Known or occurrence of hemorrhage/ thrombus. Known or evidence of abdomen fistula, gastrointestinal perforation, or abdominal abscess within the past 2 months. Suffered from grade II or above myocardial ischemia or myocardial infarction, uncontrolled arrhythmias. Grade III IV cardiac insufficiency, according to NYHA criteria or echocardiography check: LVEF<50%. Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents (systolic blood pressure > 140mmHg, diastolic blood pressure > 90 mmHg). Factors to affect oral administration (such as patients unable to swallow oral medications, chronic diarrhea and ileus etc. situations evidently affect drug oral medication and absorption). History of hepatic encephalopathy. Known history of human immunodeficiency virus (HIV) infection. Active infection or an unexplained fever > 38.5°C during screening visits. Has received a live vaccine within 30 days. Prior or planning to organ transplantation including liver transplantation. Interstitial lung disease that is symptomatic or may interfere with the detection and management of suspected drug-related pulmonary toxicity. Proteinuria≥ 2+ or 24 hours total urine protein > 1.0 g. Active known, or suspected autoimmune disease. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first administration of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily. prednisone equivalent, are permitted in the absence of active autoimmune disease Any loco-regional therapy to liver (included but not limited: resection, radiotherapy, TAE, TACE, TAI, RFA or PEI) within 4 weeks prior to study. Prior therapy with anti-PD-1 or other anti-PD-1/anti-PD-L1 immunotherapy. Known history of hypersensitivity to monoclonal antibodies or any components of the study drugs. Treatment with anti-coagulation therapy(Warfarin or heparin) or anti-platelet therapy(aspirin at dose≥300mg/day, clopidogrel at dose≥75mg/day). Pregnant or breast-feeding women. According to the investigator, other conditions that may lead to stop the research.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-1210+Apatinib(Arm A）<br> | Biological: SHR-1210<br>* Subjects receive SHR-1210 intravenous at the dose 3mg/kg on Day 1 every 2 weeks<br>Drug: Apatinib<br>* Subjects receive Apatinib orally every day with a dose escalation<br>|
| Experimental: SHR-1210+FOLFOX4 or GEMOX regimen(Arm B）<br> | Biological: SHR-1210<br>* Subjects receive SHR-1210 intravenous at the dose 3mg/kg on Day 1 every 2 weeks<br>Drug: FOLFOX4<br>* Subjects receive FOLFOX4 treatment every 2 weeks<br>Drug: GEMOX<br>* Subjects receive GEMOX treatment every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability | The incidence and grade of adverse events (AEs) and Serious adverse events (SAEs) assessed by NCI-CTCAE v4.03 | Up to approximately 2years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 2 years | 
| Duration of Response (DoR) | Duration of Response (DoR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 2 years | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 6 months2 years | 
| Time to Progression (TTP) | Time to Progression (TTP) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 2 years | 
| Overall Survival | Overal Survial will be calculated based on Kaplan-Meier estimates | Up to approximately 2 years |