A Randomized Controlled Multicentered Phase 2/3 Study to Evaluate SHR-1210 (PD-1 Antibody) in Subjects With Advanced Hepatocellular Carcinoma (HCC) Who Failed or Intolerable to Prior Systemic Treatment
Phase: PHASE2
Conditions: Hepatocellular Carcinoma Non-Resectable
Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Title: A Randomized, Parallel-Controlled, Multicenter Phase II/III Clinical Study 
Evaluating Anti-PD-1 Antibody SHR-1210 in Patients with Advanced Hepatocellular 
Carcinoma (HCC) Who Have Previously Received Systemic Therapy   
Clinical trial registration number: NCT02989922  
Version Date: 3 Apr., 2018 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
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Translated from Original Document 
 
A RANDOMIZED, PARALLEL-CONTROLLED, 
MULTICENTER PHASE II/III CLINICAL STUDY 
EVALUATING ANTI-PD-1 ANTIBODY SHR-1210 IN 
PATIENTS WITH ADVANCED 
HEPATOCELLULAR CARCINOMA (HCC) WHO 
HAVE PREVIOUSLY RECEIVED SYSTEMIC 
THERAPY 
Study Protocol 
Protocol Number: 
SHR-1210-II/III-HCC 
Version No.: 
5.0 
Version Date: 
3 Apr., 2018 
Principal Investigator: 
 
Leading Site of Clinical Study: 
 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
Confidentiality statement 
This document contains important confidential information that is the property of Jiangsu 
Hengrui Pharmaceuticals Co., Ltd., and may not be disclosed unless required by current laws or 
regulations. In any event, persons to whom the information is disclosed must be informed that 
the information is privileged or confidential and may not be disclosed further. These restrictions 
on disclosure will apply equally to all future information supplied to you which is indicated as 
privileged or confidential. 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
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Version Number: 5.0 
Version Date: 3 Apr., 2018  
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VERSION HISTORY/REVISION HISTORY 
Version No. 
Version Date 
Amendment Rationale and Summary of Changes 
1.0 
13 Oct., 2016 
NA 
2.0 
28 Dec., 2016 
See separate document: Protocol Version 2.0 Amendment 
3.0 
22 Jun., 2017 
See separate document: Protocol Version 3.0 Amendment 
4.0 
25 Aug., 2017 
See separate document: Protocol Version 4.0 Amendment 
5.0 
3 Apr., 2018 
See separate document: Protocol Version 5.0 Amendment 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
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Version Date: 3 Apr., 2018  
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Sponsor’s Signature Page 
 
I have read and confirmed this clinical study protocol (protocol number: SHR-1210-II/III-HCC; 
version number: 5.0; version date: 3 Apr., 2018). I agree that relevant responsibilities must be 
fulfilled in accordance with Chinese laws, Helsinki Declaration, Chinese GCP and this study 
protocol. 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Sponsor's Medical Director: ____________________ (print) 
____________________ (signature) 
Date of Signature: ____________________________ 
Contact Number: _____________________________ 
 
 
     

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
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Version Date: 3 Apr., 2018  
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Principal Investigator's Signature Page (Leading Site) 
 
I will fulfill the investigator’s responsibilities carefully in accordance with Chinese GCP, 
participate or directly instruct this clinical study by myself. I have received the investigator’s 
brochure of the investigational drug for this clinical study; I have known and read the preclinical 
data of the investigational drug and the protocol of this clinical study. I agree that relevant 
responsibilities must be conducted in accordance with Chinese laws, Helsinki Declaration, 
Chinese GCP and this study protocol. Unless for the purpose of protection of subject’s safety, 
rights and benefits, I will amend the protocol only after informing the sponsor and obtaining the 
consent, and put into effect upon agreement by the ethics committee. I am responsible for 
making medical decisions related with clinical practice, so as to ensure prompt and appropriate 
treatment for subjects when any adverse event occurs during the study, and record and report 
these adverse events in accordance with national relevant regulations. I will ensure the authentic, 
accurate, complete and prompt entry of the data into the study medical record. I will accept the 
monitoring and auditing by monitors and auditors appointed by the sponsor, and inspection by 
the drug regulatory authority, so as to guarantee the quality of the clinical trial. I commit to the 
confidentiality on subject’s personal information and relevant affairs. I agree to publicize my full 
name and occupation to the sponsor as well as own expenditure related with the clinical study as 
requested, and prohibit any commercial or economic behavior related with the study. I agree 
upon the use of study results for the drug registration and publication. I will provide a curriculum 
vitae of the principal investigator to the ethics committee, and submit to the drug regulatory 
agency for filing prior to the start of the study. 
 
Study Site: ______________________ 
Principal Investigators: ______________________ (print) 
______________________ (signature) 
Date of Signature: 
Contact Number:___________________________ 
Address: __________________________________ 
Zip code: __________________________________ 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
Hengrui Confidential 
 
Version Number: 5.0 
Version Date: 3 Apr., 2018  
5 / 81 
 
Principal Investigator's Signature Page (Participating Site) 
 
I will fulfill the investigator’s responsibilities carefully in accordance with Chinese GCP, 
participate or directly instruct this clinical study by myself. I have received the investigator’s 
brochure of the investigational drug for this clinical study; I have known and read the preclinical 
data of the investigational drug and the protocol of this clinical study. I agree that relevant 
responsibilities must be conducted in accordance with Chinese laws, Helsinki Declaration, 
Chinese GCP and this study protocol. Unless for the purpose of protection of subject’s safety, 
rights and benefits, I will amend the protocol only after informing the sponsor and obtaining the 
consent, and put into effect upon agreement by the ethics committee. I am responsible for 
making medical decisions related with clinical practice, so as to ensure prompt and appropriate 
treatment for subjects when any adverse event occurs during the study, and record and report 
these adverse events in accordance with national relevant regulations. I will ensure the authentic, 
accurate, complete and prompt entry of the data into the study medical record. I will accept the 
monitoring and auditing by monitors and auditors appointed by the sponsor, and inspection by 
the drug regulatory authority, so as to guarantee the quality of the clinical trial. I commit to the 
confidentiality on subject’s personal information and relevant affairs. I agree to publicize my full 
name and occupation to the sponsor as well as own expenditure related with the clinical study as 
requested, and prohibit any commercial or economic behavior related with the study. I agree 
upon the use of study results for the drug registration and publication. I will provide a curriculum 
vitae of the principal investigator to the ethics committee, and submit to the drug regulatory 
agency for filing prior to the start of the study. 
 
Study Site: ______________________ 
Principal Investigators: ______________________ (print) 
______________________ (signature) 
Date of Signature: 
Contact Number:____________________________ 
Address: ___________________________________ 
Zip code: __________________________________ 
 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
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Version Number: 5.0 
Version Date: 3 Apr., 2018  
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TABLE OF CONTENTS 
VERSION HISTORY/REVISION HISTORY ........................................................................... 2 
TABLE OF CONTENTS .............................................................................................................. 6 
LIST OF TABLES ......................................................................................................................... 8 
LIST OF FIGURES ...................................................................................................................... 8 
SYNOPSIS ..................................................................................................................................... 9 
STUDY PROCEDURES............................................................................................................. 15 
ABBREVIATIONS AND DEFINITIONS ................................................................................ 22 
1. 
STUDY BACKGROUND ................................................................................................. 24 
1.1 
Epidemiology and Current Treatment Status of Hepatocellular Carcinoma ........... 24 
1.2 
Advances in the Treatment of Hepatocellular Carcinoma ....................................... 24 
1.3. 
Background of Immunotherapy ............................................................................... 25 
1.4 
Background on Development of Anti-PD-1 Antibody SHR-1210 .......................... 26 
1.5 
Preclinical Studies Result of SHR-1210 .................................................................. 27 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 30 
2.1 
Study Objectives ...................................................................................................... 30 
2.2 
Primary Study Endpoints ......................................................................................... 30 
2.3 
Secondary Study Endpoints ..................................................................................... 30 
2.4 
Exploratory Study Endpoints ................................................................................... 30 
3 
STUDY PLAN .................................................................................................................... 30 
3.1 
Study Design ............................................................................................................ 30 
3.2. 
Study Procedures ..................................................................................................... 31 
4. 
RANDOMIZATION AND BLINDING ........................................................................... 35 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 35 
5.1 
Inclusion Criteria ..................................................................................................... 35 
5.2 
Exclusion Criteria .................................................................................................... 37 
5.3 
Concomitant Medications and Treatments .............................................................. 39 
5.4 
Criteria for Re-screening of Subjects ...................................................................... 40 
5.5 
Criteria for Subjects’ Withdrawal from the Study or Termination of Study  
Treatment ................................................................................................................. 41 
5.6 
Criteria for Termination of Study Treatment ........................................................... 41 
5.7 
Subject ID ................................................................................................................ 42 
6 
STUDY TREATMENT ..................................................................................................... 42 
6.1 
Information of Investigational Drug ........................................................................ 42 
6.2 
Drug Dispensation ................................................................................................... 42 
6.3 
Drug Storage and Management ............................................................................... 43 
6.4 
Disposal of Remaining Drugs .................................................................................. 43 

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6.5 
Dose Regimen .......................................................................................................... 43 
6.6 
Common Recommendations on Safety Management ............................................. 43 
7 
DOSE ADJUSTMENT AND SAFETY MANAGEMENT ............................................. 46 
7.1 
Dose Level and Regimen ......................................................................................... 46 
7.2 
Dose Modification ................................................................................................... 46 
8 
EFFICACY EVALUATION ............................................................................................. 50 
8.1 
Primary Endpoints and Observation Method .......................................................... 50 
8.2 
Secondary Endpoints and Observation Method ...................................................... 51 
8.3 
Independent Tumor Imaging Evaluation ................................................................. 51 
9. 
SAFETY EVALUATION .................................................................................................. 51 
9.1 
Adverse Events ........................................................................................................ 51 
9.2 
Serious Adverse Event (SAE) .................................................................................. 53 
9.3 
Pregnancy ................................................................................................................ 55 
9.4 
AEs of Special Interest ............................................................................................ 56 
9.5 
Emergency Unblinding ............................................................................................ 56 
10 
DATA MANAGEMENT ................................................................................................... 56 
10.1 
Material Collection and Data Management ............................................................. 56 
11 
DATA ANALYSIS AND STATISTICAL METHODS .................................................... 58 
11.1 
Determination of Sample Size ................................................................................. 58 
11.2 
Analysis Populations ............................................................................................... 58 
11.3 
Statistical Analysis ................................................................................................... 59 
12 
INFORMED CONSENT AND ETHICS ......................................................................... 60 
12.1 
Informed Consent .................................................................................................... 60 
12.2 
Ethical Principles ..................................................................................................... 60 
12.3 
Regulatory Considerations ...................................................................................... 61 
12.4 
Security Measures of Subject Information .............................................................. 61 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 61 
14 
PUBLICATION OF STUDY RESULTS ......................................................................... 62 
15 
SCHEDULE OF THE TRIAL .......................................................................................... 62 
16 
PROTOCOL COMPLIANCE .......................................................................................... 62 
17 
STUDY SITE AND PARTICIPATING PERSONNEL .................................................. 63 
17.1 
Leading Site ............................................................................................................. 63 
17.2 
Sponsor .................................................................................................................... 63 
17.3 
Other Study Participating Personnel ........................................................................ 63 
18 
REFERENCES .................................................................................................................. 64 
Annex 1 
Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 ........ 66 
Annex 2 
Child-Pugh Classification on Hepatic Function ........................................ 76 

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Annex 3 
Criteria for ECOG Performance Status ...................................................... 76 
Annex 4 
Recommended Rules for Management of Immune-related  
Adverse Events .......................................................................................... 77 
 
LIST OF TABLES 
Table 1 
The binding affinity of antibody SHR-1210 to human, monkey, and  
mouse PD1 antigens .................................................................................................. 27 
Table 2 
The binding affinity of antibody SHR-1210, Nivolumab and MK3475 to  
PD-1 antigen ............................................................................................................. 28 
Table 3 
Pharmacokinetic parameters of cynomolgus monkeys after single  
intravenous infusion of SHR-1210 at different doses ............................................... 29 
Table 4 
Recommendations on management of immune related adverse reactions ............... 44 
Table 5 
Recommendations on management of immune-related adverse events ................... 45 
 
LIST OF FIGURES 
Figure 1 
SHR-1210 and Pembrolizumab blocking the binding of PD-1 / PD-L1 .................. 28 
Figure 2 
SHR-1210 and Nivolumab blocking the binding of PD-1 / PD-L1 .......................... 28 
Figure 3 
The schematic diagram for phase II study ................................................................ 31 
 
 

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SYNOPSIS 
Study Title 
A Randomized, Parallel-Controlled, Multicenter Phase II/III Clinical Study 
Evaluating Anti-PD-1 Antibody SHR-1210 in Patients with Advanced Hepatocellular 
Carcinoma (HCC) Who Have Previously Received Systemic Therapy 
Protocol Number 
SHR-1210-II/III-HCC 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Population 
Patients with advanced hepatocellular carcinoma (HCC) who have failed systematic 
therapy 
Study Objectives 
To evaluate the efficacy and safety of SHR-1210 in subjects with advanced HCC 
who have previously received systematic therapy 
Study Design 
The master study comprises of a randomized, parallel-controlled, multicenter, phase 
II clinical study and a randomized, double-blind, placebo-controlled, phase III 
clinical study, aiming at evaluating the efficacy and safety of anti-PD-1 antibody 
SHR-1210 in subjects with advanced hepatocellular carcinoma (HCC) who have 
received systematic therapy previously. 
This study will be conducted in several sites throughout the country. The whole 
study includes two parts, i.e., the first stage (phase II) and the second stage (phase 
III). The first stage (phase II) will be elucidated in the study protocol.  
The first stage: a phase II clinical study with the primary objective to investigate the 
efficacy and safety of SHR-1210 in subjects with advanced HCC who have 
previously failed systematic therapy. Sixty subjects are planned to be enrolled 
initially in the study and randomized in a 1:1 ratio to receive SHR-1210 3 mg/kg, 
I.V, q2W (once every two weeks) or SHR-1210 3 mg/kg, I.V, q3W (once every three 
weeks) in 42-day cycles.  
In order to observe the treatment effect of this investigational drug in a larger sample 
size, the sample size is increased according to the protocol treatment (Version 4.0,  
25 Aug., 2017), i.e., a total of 220 subjects are needed in the study.  
The second stage (phase III study) will not be included in the protocol temporarily, 
but using a separate protocol. 
Study Endpoints 
Primary Endpoints: 
1) Objective response rate (ORR) 
2) 6-month overall survival rate (6-month OS rate) 
Secondary Endpoints: 
1) Duration of response (DoR) 
2) Disease control rate (DCR) 
3) Safety of SHR-1210 
4) Time to progression (TTP) 
5) Progression-free survival (PFS) 
6) Overall survival (OS) 
Exploratory Endpoint: 
The relationship between PD-L1 expression level and efficacy. 

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Sample Size 
Determination 
This is a single-arm, open-label phase II study to observe the objective response rate 
(ORR) and survival rate at 6 months simultaneously.  
Referring to the study results on similar products, assuming the ORR is 15% for 
SHR-1210 in treatment of target population of this study, and the lower limit of 95% 
confidential interval of ORR obtained from this study is >7%, it can be considered as 
effective. 154 subjects need to be enrolled to obtain 90% power at a one-sided 
significance level of 0.025. Further assuming evaluable cases accounting for 80% of 
the enrolled subjects, 194 subjects are required to be enrolled.  
Assuming the survival rate at 6 months is 80% for SHR-1210 in treatment of target 
population, and the lower limit of 95% confidential interval is >70%, this therapy 
can be considered to have advantage in efficacy. 200 subjects need to be enrolled to 
obtain 90% power at a one-sided significance level of 0.025. Considering the drop-
out rate of 10%, a total of 220 subjects are required to be enrolled.  
Therefore, the planned sample size of this study is 220. 
Screening Criteria 
Inclusion Criteria: 
1. 
Age: 18 years old or older; male or female;   
2. 
Had a histological or cytological diagnosis of advanced HCC, not amenable for 
surgical or local therapy, and having at least one measurable lesion as defined 
by RECIST v1.1 (major diameter of the measurable lesion ≥10 mm or minor 
diameter of malignant lymph node ≥15 mm in spiral CT scan in accordance 
with RECIST v1.1);  
3. 
Failure of or intolerant to at least one systematic treatment for HCC: 1) the 
previous systematic treatment must be chemotherapy or sorafenib; 2) if not, the 
patient must be adequately informed by the treating physician that current 
therapeutic options include sorafenib and chemotherapy and should have 
refused these options, as recorded by investigator in a written form;  
a. 
Failure of treatment is defined as disease progression during treatment or 
recurrence after the end of treatment (the systematic chemotherapy must 
be ≥ 1 cycle, duration of sorafenib treatment must be ≥ 14 day); 
b. 
Intolerance to chemotherapy is defined as ≥ Grade 4 hematological 
toxicity or ≥ Grade 3 non-hematological toxicity or ≥ Grade 2 cardiac, 
hepatic or renal impairment during treatment;  
c. 
Intolerance to sorafenib is defined as: continuation or recurrence of 
CTCAE Grade 2 treatment-related adverse event (AE) after sufficient 
supportive treatment according to local standard, and dose interruption 
for at least 7 days and reduction of one dose level (until 400 mg qd); 
continuation or recurrence of CTCAE ≥ Grade 3 treatment-related 
adverse event after sufficient supportive treatment according to 
institutional standard, or dose interruption for at least 7 days and 
reduction of one dose level (until 400 mg qd);  
4. 
The end of previous systematic treatment was ≥ 2 weeks from the start of the 
study (at least reaching drug elution period, i.e., 5 times of drug half-life) and 
treatment related AE recovered to NCI-CTCAE ≤  Grade 1 (except Grade 2 
alopecia); 

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5. 
Child-Pugh scores of 7 or less (Child-Pugh A or B7); 
6. 
ECOG PS before enrollment: 0–1;  
7. 
With a life expectancy of ≥ 12 weeks;  
8. 
Patients with chronic hepatitis B (HBV) infection: HBV- deoxyribonucleic acid 
(DNA) must be < 500 IU/ml; and the patients with positive hepatitis B surface 
antigen must receive antiviral therapy according to the treatment guideline; the 
patients with positive hepatitis C (HCV) must receive antiviral therapy 
according to the treatment guideline and have ≤ CTCAE Grade 1 elevated 
hepatic function;  
9. 
Have adequate main organ function, which meets the following criterion:  
(1) Hematology: Complete blood cell count: (no blood transfusion, no use of 
granulocyte colony-stimulating factor (G-CSF) or corrective drug within 
14 days prior to screening) 
a. 
Hemoglobin (HB) ≥ 90 g/L 
b. 
Absolute neutrophil count (ANC) ≥ 1.5×109/L 
c. 
Platelet count (PLT) ≥ 60×109 /L 
(2) Blood biochemistry: (no infusion of albumin (ALB) within 14 days) 
a. 
ALB ≥ 29 g/L 
b. 
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) < 5  ULN 
c. 
Total bilirubin (TBIL) ≤ 1.5  ULN 
d. 
Creatinine ≤ 1.5  ULN 
(3) Pro-thrombin time (PT)- International normalized ratio (INR) ≤ 2.3 or PT 
≤ 6 seconds exceeding the range of normal control; 
(4) Urine protein < 2+ or 24 hours urine protein quantification < 1.0 g; 
10. Women of childbearing potential must receive serum pregnancy test within  
72 hours prior to start dose of investigational drug, and have negative result, 
willing to use at least two highly effective contraceptive methods during the 
trial and 60 days after the last dose of investigational drug (about 5 drug half-
lives + menstrual cycle). The male patients whose partner are women of 
childbearing potential should use at least two highly effective contraceptive 
methods during the trial and 120 days after the last dose of investigational drug 
(about 5 drug half-lives + sperm emptying cycle);  
11. The patients are voluntary to participate in the study and sign the informed 
consent form, with good compliance and willingness to cooperate with  
follow-up. 
Exclusion Criteria: 
1. 
Patients with known hepatocholangiocarcinoma, mixed cell carcinoma and 
lamellar cell carcinoma; other active malignant tumor within 5 years or 
simultaneously. Cured localized tumor, for example, basal cell carcinoma of 
skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in 
situ of prostate, carcinoma in situ of cervix, breast cancer in situ may be 
enrolled; 

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2. 
Plan to receive or previously received organ or bone marrow transplantation; 
3. 
Ascites with clinical symptoms, i.e., requiring therapeutic abdominal puncture 
or drainage, or Child-Pugh score > 2;  
4. 
History of gastrointestinal hemorrhage within 6 months prior to the start of 
study treatment or clear tendency of gastrointestinal hemorrhage, for example, 
esophageal varices with hemorrhagic risk, locally active ulcer, persistent fecal 
occult blood (+);  
5. 
Abdominal fistula, gastrointestinal perforation or abdominal abscess within  
28 days prior to the start of study treatment;  
6. 
Previous or current presence of metastases to central nervous system; 
7. 
Grade 2 or higher myocardial ischemia, myocardial infarction, or poorly 
controlled arrhythmia (including QTc interval ≥ 450 ms for man and ≥ 470 ms 
for woman) (QTc interval is calculated using Fridericia formula);  
8. 
Grade 3−4 cardiac insufficiency in accordance with New York Heart 
Association (NYHA) or color Doppler echocardiography: left ventricular 
ejection fraction (LVEF) < 50%;  
9. 
History of hepatic encephalopathy;  
10. Untreated active hepatitis (hepatitis B: HBsAg positive and HBV-DNA  
≥ 500 IU/mL; hepatitis C: HCV-RNA positive and obviously abnormal hepatic 
function); hepatitis B and hepatitis C co-infection;  
11. Human immunodeficiency virus (HIV) infection; 
12. Previous and current history of pulmonary fibrosis, interstitial pneumonia, 
pneumoconiosis, radiation pneumonitis, treatment-related pneumonia, serious 
pulmonary impairment that may interfere with the detection and management 
of suspected treatment-related pulmonary toxicity; 
13. Known active or suspected autoimmune disease. Patients who have stable 
disease and do not require systemic immunosuppressive therapy can be 
enrolled;  
14. Within 14 days prior to any dose of the investigational drug, use of 
corticosteroid (prednisone at the therapeutic dose > 10 mg/day) or other 
immunosuppressant for systematic treatment. With no active autoimmune 
disease, inhaled or local use of steroids and adrenaline equivalent to  
> 10 mg/day prednisone therapeutic dose is allowed for replacement;  
15. Use of any local therapy for the hepatic lesion (including but not limited to 
surgery, radiotherapy, hepatic artery embolism, TACE, hepatic artery perfusion, 
radiofrequency ablation, cryoablation or percutaneous ethanol injection) within 
4 weeks prior to participation in the study;  
16. Palliative radiotherapy to control symptoms is allowed, and must be completed 
at least 2 weeks prior to the start of study treatment, and no additional 
radiotherapy for the same lesion is planned; adverse event (AE) induced by 
radiotherapy haven’t recovered to ≤ CTCAE Grade 1;  
17. Patients may receive other anti-cancer therapies during the study, such as 
chemotherapy, targeted therapy, or radiation therapy; Patients have previously 
received other anti–PD-1 antibodies or other immunotherapies against  
PD-1/PD-L1;  

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18. Known history of serious allergy to any monoclonal antibody; 
19. Pregnant or breast-feeding women; 
20. Known to have a history of psychiatric substance abuse or drug abuse; Patients 
who have stopped drinking can be enrolled;  
21. Other factors that may affect the study results or lead to forced early 
termination of the study as judged by investigators, such as other serious 
illnesses, with serious laboratory examination abnormalities which may affect 
patient’s safety, or with family or social factors which may affect the collection 
of trial data and samples.  
22. Patients who had participated in “the randomized, double-blind, parallel-
controlled, multi-center, phase III clinical study on apatinib sulfonate tablets as 
the second line therapy for patients with advanced HCC” previously and been 
randomized to any medication cannot be enrolled before the primary study 
endpoint is reached in this study.  
Criteria for Termination of Study Treatment 
1. Subjects withdraw informed consent and require to withdraw from the study. 
2. Medical imaging examination shows progression of disease, unless the subjects 
meet the criteria on post-progression continuation of therapy (see Section 3.2.4); 
3. Occurrence of clinical adverse events, abnormal laboratory examination or  
co-morbidities, and continued participation in the study is judged by 
investigators as violating the subjects’ optimal benefit; 
4. Other reasons for inability to continue study treatment, as considered by 
investigators, for example, loss of the ability to express freely due to custody or 
isolation; 
5. Pregnancy in female subject;  
6. Termination of study by sponsor. 
Investigational Drug and 
Dose Regimen 
Group A: SHR-1210, 3 mg/kg, i.v., q2w, in a 42-day cycle;  
Group B: SHR-1210, 3 mg/kg, i.v., q3w, in a 42-day cycle;  
Data Analysis and 
Statistical Methods 
General analysis 
The following methods will be used for descriptive statistics summary in this study, 
unless otherwise noted. 
The continuous variables will be summarized with mean, standard deviation, 
median, maximum, and minimum value; the categorical variables will be 
summarized with frequency and percentage; Kaplan-Meier method will be used to 
estimate the survival rate and median survival time for time to event data. The 
corresponding 95% confidential interval will be provided for the above analyses, if 
necessary. 
Efficacy analysis 
The 95% confidential interval of overall percentage for ORR and DCR will be 
calculated by Clopper-Pearson method.  
 
 

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Safety analysis 
The safety analysis will be based on descriptive summary statistics. The AE, serious 
adverse event (SAE), treatment-related AE, AE leading to dose modification, AE 
leading to withdrawal from the trial, and laboratory data will be summarized 
according to CTCAE 4.0. The above AEs, laboratory tests, vital signs, and ECG will 
be analyzed and summarized using the existing criteria for clinical trial report from 
Hengrui. The criteria include but not limited to the following analyses and 
summaries: 
AEs (all-causality and treatment-related);  
The incidence and severity of AEs (all-causality and treatment-related);  
Summary of SAEs; Analysis of causality between AE and investigational drug;  
Laboratory parameters, vital signs, and changes from baseline;  
Number and percentage of “normal to abnormal” or “exacerbation of abnormal” in 
laboratory parameters and vital signs after the trial. 
Exploratory analysis 
The relationship between PD-L1 expression level and efficacy will be analyzed 
based on descriptive statistics.  
Version No. 
5.0 
Expected Study Period 
Oct. 2016 to May 2018 (primary endpoint analysis) 

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STUDY PROCEDURES 
1. 
Screening Period 
Items 
Screening period 
(baseline[1], Day -28) 
Comment 
Enrollment assessment 
 
 
Signing of informed consent 
form 
√ 
The signed informed consent form for subjects’ enrollment in this study needs to be completed during 
screening period. Any screening procedure specified in this study cannot be performed without the 
written informed consent form: there is a special provision on the radiological examination of tumors at 
baseline. Refer to the note in the radiological evaluation of tumors in the flow chart for details. The 
subjects with failure of screening prior to treatment are permitted to be given another chance for  
re-screening in this study[2], must re-perform the informed consent and re-register so as to obtain a new 
subject number at the re-screening group. 
Verification of eligibility 
√ 
Evaluated in screening period (including the re-screening period) 
Demographics 
√ 
 
Medical history 
√ 
Including previous medical history, tumor history (initial diagnosis, course of treatment, etc.) 
Child-Pugh score 
√ 
It will be completed within 14 days prior to the first dose 
Safety assessments 
 
 
ECOG PS 
√ 
It will be completed within 14 days prior to the first dose 
Physical examination 
√ 
It will be completed within 14 days prior to the first dose 
Vital signs 
√ 
Including blood pressure, heart rate, body temperature, and respiratory rate. Conducting at screening 
visit and within 72 hours prior to the first dose. If the assessment is completed within 72 hours prior to 
the first dose during screening period, no additional detection is required prior to the first dose.  
Concomitant 
medications/treatments 
√ 
Including the concomitant therapies information within one month prior to signing informed consent 
form 
Collection of AE 
√ 
Including symptoms, body signs 
12-Lead ECG 
√ 
It will be completed within 14 days prior to the first dose 
Echocardiography 
√ 
Including LVEF evaluation, performed within 14 days prior to the first dose 

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Items 
Screening period 
(baseline[1], Day -28) 
Comment 
Hematology 
√ 
Including complete blood cell count and category (white blood cell, red blood cell, lymphocyte, 
monocyte, neutrophil, basophil, eosinophil, hemoglobin), platelet count. The test will be conducted 
within 14 days prior to the first dose. If the test is completed within 72 hours prior to the first dose 
during screening period, no additional detection is required prior to the first dose.  
Urinalysis  
√ 
Including white blood cell, red blood cell, and urine protein. The test will be conducted within 14 days 
prior to the first dose. If urine protein is ≥ 2+ at screening period, 24 hours urine protein quantification 
must be detected additionally. If the test is completed within 72 hours prior to the first dose during 
screening period, no additional detection is required prior to the first dose.  
Fecal occult blood 
√ 
The test will be conducted within 14 days prior to the first dose. 
Blood biochemistry 
√ 
Including hepatic function (ALT, AST, TBIL, ALP), renal function [blood urea nitrogen (BUN) or 
serum urea level], albumin, creatinine, amylase (lipase must be detected additionally if amylase is 
abnormal and clinically significant), blood glucose, LDH. The test will be conducted within 14 days 
prior to the first dose. If the test is completed within 72 hours prior to the first dose during screening 
period, no additional detection is required prior to the first dose.  
Blood electrolytes 
√ 
Including K+, Na+, Ca++, Mg++, Cl-. The test will be conducted within 14 days prior to the first dose. If 
the test is completed within 72 hours prior to the first dose during screening period, no additional 
detection is required prior to the first dose.  
Coagulation function  
√ 
INR and/or PT (if INR cannot be collected, PT will be used as judgment basis). The test will be 
conducted within 14 days prior to the first dose. 
Alpha fetoprotein 
√ 
The test will be conducted within 14 days prior to the first dose. 
Thyroid function 
√ 
Including TSH, FT3, and FT4. The test will be conducted within 14 days prior to the first dose. 
Virology 
√ 
Including HIV-Ab, HBV and HCV infection test. Requirement for HBV test: HBsAg will be detected 
during screening period to determine the presence of HBV infection, HBsAg (quantitative), HBsAb 
(qualitative), HBcAb (qualitative), HBeAg (qualitative), HBeAb (qualitative) and HBV-DNA 
(qualitative, quantitation needed additionally if positive) will be detected in case it is positive. 
Requirement for HCV test: HCV-Ab will be detected in screening period to determine HCV infection, 
HCV-RNA (qualitative, quantitation needed additionally if positive) will be quantified in case of 
positive result. The test will be conducted within 14 days prior to the first dose 
Blood HCG test 
√ 
Only for women of childbearing potential (WOCBP). The test will be conducted within 72 hours prior 
to the first dose. 

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Items 
Screening period 
(baseline[1], Day -28) 
Comment 
Efficacy assessments 
 
 
Tumor imaging evaluation 
√ 
The radiological evaluation at baseline must be performed in accordance with RECIST v1.1, including 
the enhanced computed tomography (CT) scan of chest, abdomen, pelvis and site of lesions. In case of 
allergy to the contrast agent for enhanced CT scan, thoracic plain CT scan + abdominal and pelvic 
magnetic resonance imaging (MRI) can be performed. Bone scan will be performed only when 
clinically indicated. If the routine radiological tumor evaluation has been performed before signing the 
informed consent form, CT or MRI does not need to be repeated during screening period as long as 
they are completed within 28 days prior to the start of investigational drug (42 days prior to the first 
administration is acceptable for bone scan). Brain MRI or enhanced CT Scan will be conducted during 
screening period. 
Others 
 
 
Tumor tissue sample 
√ 
When applicable. For detection of PD-L1 expression, also see Laboratory Manual.  
2. 
Treatment Period 
Items 
Treatment period 
(One treatment cycle is 42 days) 
Comment 
D1[3] 
(±3 days) 
D15 
(±3 days) 
(Group A) 
D22 
(±3 days) 
(Group B) 
D29 
(±3 days) 
(Group A) 
Randomization 
√ 
 
 
 
It will be completed only within 3 days prior to the first dose. 
Child-Pugh score 
√ 
 
 
 
It will start from Cycle 2, and it will be finished at D1 of each cycle.  
Safety assessments 
 
 
 
 
 
ECOG PS 
√ 
√ 
√ 
√ 
It will be completed within 72 hours prior to each dose. 
Physical examination 
√ 
√ 
√ 
√ 
The physical examination will be performed for the target sites within 72 hours 
prior to each dose, at least include heart, lungs, abdomen, and skin.  
Vital signs 
√ 
√ 
√ 
√ 
Including blood pressure, heart rate, body temperature, respiratory rate. It will be 
conducted within 72 hours prior to each administration. 

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Items 
Treatment period 
(One treatment cycle is 42 days) 
Comment 
D1[3] 
(±3 days) 
D15 
(±3 days) 
(Group A) 
D22 
(±3 days) 
(Group B) 
D29 
(±3 days) 
(Group A) 
Concomitant 
medications/treatments 
√ 
√ 
√ 
√ 
 
Collection of AE 
√ 
√ 
√ 
√ 
Including symptoms and signs. 
12-Lead ECG 
 
 
 
 
Performed according to local standard during the study, when clinically indicated.  
Echocardiography 
 
 
 
 
Performed according to local standard during the study, when clinically indicated.  
Hematology 
√ 
√ 
√ 
√ 
Including complete blood cell count and category (white blood cell, red blood cell, 
lymphocyte, monocyte, neutrophil, basophil, eosinophil, hemoglobin), platelet 
count. The test will be conducted within 72 hours prior to each administration. 
Urinalysis 
√ 
√ 
√ 
√ 
Including white blood cell, red blood cell, and urine protein. The test will be 
conducted within 72 hours prior to each administration. If urine protein is ≥ 2+,  
24 hours urine protein quantification must be detected additionally. 
Blood biochemistry 
√ 
√ 
√ 
√ 
Including hepatic function (ALT, AST, TBIL, ALP), renal function (BUN or serum 
urea level), albumin, creatinine, amylase (lipase must be detected additionally if 
amylase is abnormal and clinically significant), blood glucose, and LDH. The test 
will be conducted within 72 hours prior to each administration. 
Blood electrolytes 
√ 
√ 
√ 
√ 
Including K+, Na+, Ca++, Mg++, Cl-. The test will be conducted within 72 hours prior 
to each administration. 
Coagulation function[4] 
√ 
 
 
 
INR and/or PT (if INR cannot be collected, PT will be used as judgment basis). The 
test will start from Cycle 2, and will be finished at D1 of each cycle. 
Alpha fetoprotein[4] 
√ 
 
 
 
The teat will start from Cycle 2, and will be finished at D1 of each cycle. 
Thyroid function[[4] 
√ 
 
 
 
TSH, FT4 and FT3 will be detected on D1 of each cycle from Cycle 2.  
Virology [4] 
√ 
 
 
 
The teat will start from Cycle 2, and will be finished at D1 of each cycle. HBV-
DNA (PCR) will be detected for those with HBV infection; HCV-RNA will be 
detected for those with HCV infection.  

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Items 
Treatment period 
(One treatment cycle is 42 days) 
Comment 
D1[3] 
(±3 days) 
D15 
(±3 days) 
(Group A) 
D22 
(±3 days) 
(Group B) 
D29 
(±3 days) 
(Group A) 
Efficacy assessments 
 
 
 
 
 
Tumor imaging 
evaluation 
√ 
 
 
 
Tumor radiological evaluation must be performed in accordance with RECIST v1.1. 
The first imaging evaluation after initiation of treatment will be performed at week 
8 (± 7 days). Once every 6 weeks afterwards, regardless of dose delay. Imagine 
evaluation will be performed once every 12 weeks (±14 days) for the subjects more 
than 12 months after the first dose of investigational drug, if tumor evaluation still 
needs to be continued. 
Including the enhanced CT scan at thorax, abdomen, pelvis and site of lesions. In 
case of allergy to the contrast agent for enhanced CT scan, thoracic plain CT scan + 
abdominal and pelvic MRI can be performed. Bone scan is only performed when 
clinically indicated. 
Study treatment 
 
 
 
 
 
Intravenous infusion 
of SHR-1210 
√ 
√ 
√ 
√ 
 
3. 
End-of-Treatment and Follow-up Period 
Items 
End-of-
Treatment[5] 
Follow-up period 
Comment 
Safety  
follow-up[6] 
Survival  
follow-up[7] 
Child-Pugh score 
√ 
√ 
 
 
Safety assessments 
 
 
 
 
ECOG PS 
√ 
√ 
 
 
Physical examination 
√ 
√ 
 
 
Vital signs 
√ 
√ 
 
Including blood pressure, heart rate, body temperature, and respiratory rate. 

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Items 
End-of-
Treatment[5] 
Follow-up period 
Comment 
Safety  
follow-up[6] 
Survival  
follow-up[7] 
Concomitant 
medications/treatments 
√ 
√ 
 
 
Collection of AE 
√ 
√ 
 
Including symptoms and signs. 
Hematology 
√ 
√ 
 
Including full blood count and classification, platelet count. 
Urinalysis 
√ 
√ 
 
If urine protein is ≥ 2+, 24 hours urine protein quantification must be detected 
additionally. 
Blood biochemistry 
√ 
√ 
 
Including hepatic function (ALT, AST, total bilirubin, ALP), renal function (BUN or 
serum urea level), albumin, creatinine, amylase (lipase must be detected 
additionally if amylase is abnormal and clinically significant), blood glucose, LDH. 
Blood electrolytes 
√ 
√ 
 
Including K+, Na+, Ca++, Mg++, Cl-.  
Coagulation function 
√ 
√ 
 
INR and/or PT (if INR cannot be collected, PT will be used as judgment basis).  
Alpha fetoprotein 
√ 
√ 
 
 
Thyroid function 
√ 
√ 
 
TSH, FT4 and FT3 will be detected.  
Virology 
√ 
√ 
 
HBV-DNA will be detected for those with HBV infection; HCV-RNA will be 
detected for those with HCV infection.  
Blood HCG test 
√ 
 
 
Only for WOCBP 
Efficacy assessments 
 
 
 
 
Tumor imaging 
evaluation 
√ 
√ 
√ 
If the subject has no progression of disease when withdrawal from the study, the 
tumor still has to be evaluated once every 6 weeks according to RECIST v1.1, until 
progression of disease or start of subsequent anti-cancer therapy.  
Including the enhanced CT scan at thorax, abdomen, pelvis and site of lesions. In 
case of allergy to the contrast agent for enhanced CT scan, thoracic plain CT scan + 
abdominal and pelvic MRI can be performed. Bone scan is only performed when 
clinically indicated. 

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Items 
End-of-
Treatment[5] 
Follow-up period 
Comment 
Safety  
follow-up[6] 
Survival  
follow-up[7] 
Others 
 
 
 
 
Survival information 
 
√ 
√ 
 
Subsequent anti-
cancer therapy 
 
√ 
√ 
 
Note: [1] All the baseline data will be based on the value closest to the study dose. 
[2] For the subjects who have failed screening and are enrolled during re-screening period, if the visit procedures completed at the initial screening, and meet 
the required time limit for this procedure prior to start dose of the investigational drug and meet the inclusion criteria, they do not need to repeat the 
procedure during the re-screening period.  
[3] There’s no ± 3 days window period for Day 1 of Cycle 1. 
[4] Starting from Cycle 2, the test will be performed on D1 ± 3 of each cycle or at least once every 42 days, and more frequently when clinically indicated.  
[5] End of Study Treatment/Withdrawal from Study: If these tests/procedures have been completed within 7 days after withdrawal from the study, no further 
repetition is required.  
[6] Safety follow-up: until 90 days after last dose. During this period, one visit will be performed once every 30 days (± 7 days). The first (30 days after the last 
dose) and third (90 days after the last dose) safety visit after receiving drugs must be performed at the study center, the second visit (60 days after the last 
dose) is telephone visit, and only survival data, concomitant medication/therapy, AE need to be collected. 
[7] Survival follow-up: The subjects will enter the survival follow-up period after the end of safety follow-up period. During this period, the subjects will be 
followed up by telephone once every 30 days (± 7 days) for collection of survival data and subsequent therapies. 

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ABBREVIATIONS AND DEFINITIONS 
The following abbreviations and special terms will be used in the study protocol.  
Abbreviation and specific terms Definition 
AE 
Adverse event 
AFP 
Alpha fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
B-ultrasonography  
B-mode ultrasound examination 
bFGF 
Basic fibroblast growth factor 
Ca 
Calcium 
Cl 
Chlorine  
Cr 
Creatinine 
CR 
Complete response 
CRC 
Clinical research coordinator 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T lymphocyte antigen 4 
DCR 
Disease control rate 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
FAS 
Full analysis set 
Hb 
Hemoglobin 
HCC 
Hepatocellular carcinoma 
INR 
International normalized ratio 
ITT 
Intention-to-treat  
i.v. 
Intravenous injection 
K 
Potassium 
Mg 
Magnesium 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Na 
Sodium 

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Abbreviation and specific terms Definition 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PFS 
Progression-free survival 
PI 
Principal investigator 
PLT 
Platelets 
PR 
Partial response 
PT 
Prothrombin time 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 

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1. 
STUDY BACKGROUND 
1.1 
Epidemiology and Current Treatment Status of Hepatocellular Carcinoma 
Primary carcinoma of the liver is a common malignant tumor worldwide, with about 748,300 
new cases per year according to the statistics in 2008, accounting for 6% of the new cases of all 
the cancers and ranking the fifth 1, 2. Up to 695,900 persons die per year due to its very poor 
prognosis, thus it has become the third cause of cancer death. China is a high-risk area for liver 
carcinoma, the number of cases accounting for about 55% of the world, the number of deaths 
accounting for 50%; it is the second most common tumor follows lung cancer. The high incidence 
age is 35−45 years for liver carcinoma, male cases more than females, at the ratio of 2−5:1 for 
male to female. Male patients account for higher proportion in the area with higher incidence. 
Hepatocellular carcinoma (HCC) is the most common type in primary carcinoma of liver and 
accounting for 90%. The main risk factors for HCC are infection with hepatitis B virus (HBV) 
and hepatitis C virus (HCV) infection, water pollution (blue-green algae toxins), alcoholism and 
aflatoxin. HCC mostly occurs based on hepatitis virus infection and liver cirrhosis, 
approximately 10−20 years after primary hepatic damage. 
Most HCC are asymptomatic in the early stage, most patients have reached locally advanced 
stage or had distant metastasis when diagnosis. There is no standard therapeutic method for 
advanced HCC currently. Its clinical treatment is facing severe challenges. The survival time is 
usually 3–6 months in the patients with advanced HCC in our country, and no longer than one 
year worldwide, which is greatly related with the lack of effective systematic treatment in these 
patients. HCC is resistant to common chemotherapy, its therapeutic methods basically include 
surgery (hepatectomy, transplantation and palliative surgery), non-surgical therapy (local therapy, 
arterial chemoembolization, chemotherapy, radiotherapy, biotherapy and molecular targeted 
therapy) and other therapeutic methods (including participation in clinical studies). 
1.2 
Advances in the Treatment of Hepatocellular Carcinoma  
1.2.1 
Advances of targeted therapy in the treatment of hepatocellular carcinoma  
In December 2007, sorafenib became the first drug approved by US FDA for the treatment of 
HCC, which is based on the result of significant survival benefits from SHARP trial, in which 
sorafenib increased progression-free survival (medians: 5.5 months and 2.8 months, respectively) 
by 73% and overall survival (medians: 10.7 months and 7.9 months, respectively) by 44% 
compared with placebo. Thus, it opened up a new era of targeted therapy for HCC. Sorafenib 
was approved for treatment of HCC in China in 2008, providing a new therapeutic option for 
numerous patients with HCC, however, its high cost (about 50,000 RMB per month for each 
patient) limits its further use. 

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In addition, a variety of multikinase inhibitors under development have been frustrated in the 
clinical study versus sorafenib: the phase III clinical trial of sunitinib (developed by Pfizer) 
versus sorafenib was terminated in advance in April 2010, because sunitinib did not improve the 
survival time compared with sorafenib, and the incidence of serious adverse events (SAE) in 
sunitinib group was higher than that in sorafenib group. The multikinase inhibitor ABT-869 
(linifanib, developed by Abbott) has no advantage compared with sorafenib. The phase III 
clinical trial of ABT-869 was terminated according to the advice by the independent data 
monitoring committee. A clinical study with 731 patients showed that the epidermal growth 
factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (Tarceva, developed by Roche) faced 
failure for no increase of additional benefit as compared with sorafenib. Brivanib is a tyrosine 
kinase inhibitor targeted VEGF receptor and basic fibroblast growth factor (bFGF, FGF-2) 
receptor, in the phase II clinical trial in patients with advanced HCC who are unsuitable for 
surgery, or have locally advanced or distant metastatic, the 6-month progression-free survival 
rate reached 18.2%, median progression-free survival was 2.7 months, median survival was 
10 months, the adverse effects were mild and mainly included fatigue, hypertension and diarrhea. 
However, it encountered failure in the phase III non-inferiority clinical trial in comparison with 
sorafenib, its overall survival was not satisfactory. 
In summary, no targeted drug is superior to sorafenib in the overall efficacy and safety in 
treatment of HCC. 
1.3. Background of Immunotherapy 
Tumor immunotherapy remains a hot spot in the field of tumor therapy for a long time, among 
which T-cell tumor immunotherapy lies in an essential position. Tumor immunotherapy is to take 
full advantage of and mobilize cytotoxic T-cell in the body, so as to kill tumors, which may be 
the most effective and safe way to treat cancer. However, tumor immunotherapy also has a huge 
obstacle, tumor escape, i.e. tumor cells can inhibit the immune system resulting in unlimited 
proliferation. There exists an extremely complicated relationship between the tumor immune 
escape mechanism and the body's immune response to tumor. In the early stage, tumor-specific 
cytotoxic T-cells are biologically active, but it loses its activity along with tumor growth at late 
stages. So, tumor immunotherapy is to maximize the patient's own immune response to tumors, 
not only to activate the original immune system response in the body, but also to maintain a 
longer and higher immune system response, which is the key in tumor immunotherapy. 
Recently, with a deeper understanding of the molecular mechanism of the response to tumor 
cells, the study on the identification of signaling pathways that limit the antitumor immune 
response have been further clarified. Programmed cell death protein-1 (PD-1) pathway, one of 
the most important pathways responsible for the regulation of tumor-induced 

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immunosuppression, has been confirmed. PD-1 is a protein receptor expressed on the T-cell 
surface that was discovered in 1992, and be involved in the process of apoptosis. PD-1 belongs 
to the CD28 family, possessing 23% amino acid homology with cytotoxic T lymphocyte antigen 
(CTLA) 4, but it mainly expresses on activated T cells, B cells, and myeloid cells, which is 
different from that of CTLA. PD-1 has two ligands, PD-1 ligand (PD-L) 1 and PD-L2. PD-L1 
mainly expresses on T cells, B cells, macrophages, and dendritic cells (DCs), and can be up-
regulated in activated cells. Many human solid tumors express PD-L1, which is often associated 
with poor prognosis . The tumor-infiltrating lymphocytes in cancer patients typically express 
PD-1, with a damage to their antitumor function. Several antibodies that block PD-1 or PD-L1 
have been shown to enhance T-cell function and facilitate tumor cell lysis in preclinical studies. 
A number of multinational pharmaceutical companies are developing PD-1 monoclonal 
antibodies which block the binding of PD-L1 and PD-1, and improve the patient's own immune 
response to tumors as much as possible, so as to kill tumors . PD-1 monoclonal antibodies 
developed by BMS and Merck, are currently the most advanced PD-1 antibody drugs. In 
accordance with the results of the completed pivotal studies, BMS’s antibody nivolumab and 
Merck’s antibody pembrolizumab have been approved by FDA for multiple indications. 
In July 2014, nivoluamb was approved by Japan's Ministry of Health and Welfare for treatment 
of advanced melanoma, and approved by FDA for treatment of melanoma (December 2014), 
non-small cell lung cancer (March 2015), renal cell carcinoma (November 2015), and classical 
Hodgkin's lymphoma (2016) . 
Pembrolizumab was approved by FDA for treatment of advanced melanoma (September 2014) 
and non-small cell lung cancer (October 2015). 
Except the above indications, the two companies are conducting large phase III studies for 
treatment of gastric cancer, bladder cancer, breast cancer, head and neck tumors and lymphoma, 
and are expected to bring new choices and shocks in the treatment of multiple tumors. 
1.4 
Background on Development of Anti-PD-1 Antibody SHR-1210 
Hengrui obtained a series of anti-PD-1 antibodies in mouse using PD-1 recombinant protein as 
antigen through a large number of in vitro binding assays, in vitro ligand blocking experiments, 
T-cell proliferation assays, animal experiments and antibody-based drug assays. Precursor 
antibody was selected, and then humanized PD-1 monoclonal antibody was further synthesized 
by computer simulation of the mouse-derived antibody, among them, we focused on the 
development of the most active antibody SHR-1210. Since 2015, Hengrui has started phase 1 
clinical trials in Australia and mainland China, and several studies are ongoing. 

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1.5 
Preclinical Studies Result of SHR-1210 
1.5.1 
Drug name and physicochemical properties 
[Generic name]: SHR-1210 for Injection 
[English name]: SHR-1210 for injection 
[Molecular weight]: about 146.3 kDa 
1.5.2 
Pharmacological class and mechanism of action 
PD-1 is a protein receptor expressed on the T-cell surface that was discovered in 1992 and 
involved in the process of apoptosis. PD-1 belongs to the CD28 family, possessing 23% amino 
acid homology with CTLA-4, but it mainly expresses on activated T cells, B cells and myeloid 
cells, which is different from that of CTLA. PD-1 has two ligands, PD-L1 and PD-L2, 
respectively. PD-L1 is mainly expressed on T cells, B cells, macrophages and DCs, and can be 
up-regulated on activated cells. The expression of PD-L2 is relatively limited, mainly on antigen-
presenting cells, such as activated macrophages and DCs. 
The humanized anti-PD-1 monoclonal antibody specifically binds to PD-1 and blocks the 
interaction of PD-1 with its ligand, allowing T-cell to recover immune respond against the tumor 
cells. 
1.5.3 
Pharmacodynamic studies 
1.5.3.1 
Affinity of antibody 
We tested the binding affinity of antibody SHR-1210 to human, monkey, and mouse antigens. 
For the results see Table 1. 
Table 1 
The binding affinity of antibody SHR-1210 to human, monkey, and mouse PD1 
antigens 
Stationary phase 
Mobile phase 
Binding affinity (nM) 
SHR-1210 
Human PD1 antigen 
6.9 
SHR-1210 
Mouse PD1 antigen 
Very weak signals, no detectable binding 
Monkey PD1 antigen (-hFc) 
SHR-1210 
4.1 
The results showed that the affinity of antibody SHR-1210 to human and monkey PD1 antigens 
was very close, 6.9 nM and 4.1 nM, respectively, while no binding was detected to mouse PD1 
antigen. 
From the detection of the binding affinity of antibody SHR-1210 against human antigen PD-1, 
the affinity of SHR-1210 against antigen (human PD-1) was 3.0 nM, which was comparable to 
that of control antibodies Nivolumab and MK3475. For the results see Table 2. 

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Table 2 
The binding affinity of antibody SHR-1210, Nivolumab and MK3475 to PD-1 
antigen 
Antibody 
Antigen 
Binding affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
MK3475 
Human PD-1 antigen 
3.2 
1.5.3.2 
Experiment on antibody SHR-1210 blocking the binding of PD-1/PD-L1 
The experimental results (see Figure 1 and Figure 2) showed that the antibody SHR-1210, 
Nivolumab and Pembrolizumab were comparable in blocking the binding of PD-1 / PD-L1 in 
vitro. The blocking activity IC50 of the antibodies SHR-1210, Nivolumab and Pembrolizumab 
was 0.70 nM / 0.79 nM, 0.79 nM / 0.77 nM, respectively.  
PD1 antibody blocking
-2
-1
0
1
2
3
0.0
0.5
1.0
1.5
2.0
2.5
HR301210
lambrolizumab
IC50
HR301210
0.7007
lambrolizumab
0.7864
negative control
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 1 SHR-1210 and Pembrolizumab blocking the binding of PD-1 / PD-L1 
PD1 antibody blocking
-2
-1
0
1
2
3
0
1
2
3
4
HR301210
Nivolumab
IC50
HR301210
0.7913
Nivolumab
0.7745
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 2 SHR-1210 and Nivolumab blocking the binding of PD-1 / PD-L1 
 

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1.5.4 
Toxicology studies 
Eight cynomolgus monkeys (half males and half females) were randomly divided into two 
groups in pre-clinical study of acute toxicity in cynomolgus monkeys. SHR1210 was 
intravenously injected at 200, 400 and 800 mg / kg for animals in Group 2 every other day in a 
dose-escalation manner. No changes in clinical signs, weight, food intake and blood clotting 
associated with SHR-1210 were observed. When dose ≥ 200mg / kg, lymphopenia was observed 
in male and female animals; when dose ≥ 400 mg / kg, increased serum globulin and decreased 
albumin were observed in male and female animals. For the range of the above changes was 
small, so it was not considered harmful. Maximum tolerated dose (MTD) of SHR-1210 ≥ 800 mg/kg. 
In the completed pre-clinical study of acute toxicity in cynomolgus monkeys, male and female 
cynomolgus monkeys were well tolerated when SHR-1210 intravenously injected at 20, 50 and 
100 mg / kg for 4 weeks (5 times) once a week. No changes in clinical signs associated with 
SHR-1210 were observed, including injection site irritation, or body weight, food consumption, 
body temperature, ECG, blood pressure, heart rate and respiratory parameters; No changes in B 
and T lymphocyte typing, cytokine, immunoglobulin and complement parameters were 
observed; No changes in organ weights, gross lesions and histopathological changes associated 
with SHR-1210 were observed. 
1.5.5 
Pharmacokinetic studies 
Pharmacokinetic parameters of cynomolgus monkeys after single intravenous infusion of SHR-
1210 are shown in Table 3 
Pharmacokinetic parameters of cynomolgus monkeys after single 
intravenous infusion of SHR-1210 at different doses. 
Table 3 
Pharmacokinetic parameters of cynomolgus monkeys after single intravenous 
infusion of SHR-1210 at different doses 
Dose 
(mg/kg) Gender 
T1/2 
Tmax 
Cmax 
AUClast 
Vz 
Cl 
MRTlast 
(hr) 
(hr) 
(ug/mL) 
(hr*ug/mL) 
(mL/kg) 
(mL/hr/kg) 
(hr) 
1 
Female 
76.06±32.93 
0.83±0.29 
31.16±11.25 
1716.12±453 
54.09±14.85 
0.57±0.17 
80.95±18.58 
Male 
91.72±25.26 
0.83±0.29 
35.96±13.09 
2359.7±684.07 
55.15±20.51 
0.37±0.06 
102.23±38.56 
Overall 83.89 ±27.62 0.83 ±0.26 33.56± 11.23 
2037.91± 627.32 
54.62± 16.02 0.47± 0.15 
91.59 ±29.47 
3 
Female 
92.95±22.60 
0.83±0.29 
81.09±12.66 
6896.79±1673.36 
40.75±12.66 
0.44±0.11 
120.92±49.96 
Male 
113.54±8.26 
1.67±0.58 
71.65±10.85 
6380.25±2062.85 
47.05±27.05 
0.47±0.12 
127.10±59.25 
Overall 103.25±18.94 1.25 ±0.61 76.37 ±11.74 
6638.51 ±1703.60 43.91 ±19.21 0.46 ±0.11 125.01±49.13 
10 
Female 169.70±38.96 2.17±1.76 217.46±20.22 31357.28±9338.28 41.25±25.76 
0.33±0.1 
179.68±73.6 
Male 
128.94±35.93 0.67±0.29 
251.88±6.49 
26779.98±7205.43 
30.9±30.2 
0.31±0.05 
113.25±44.39 
Overall 149.32±40.28 1.42±1.39 234.67±23.15 29068.63±7869.83 36.07±25.34 
0.32±0.07 
146.46±65.42 
 

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1.5.6 
Clinical studies results  
In 2015, Hengrui successfully carried out a phase 1 clinical trial in Australia, and achieved the 
expected clinical effect. Up to January 2016, 10 subjects had been enrolled, and 3 subjects had 
the first imaging data for 8 weeks. There was one case of PR in head and neck squamous 
carcinoma, two cases of SD in gastric/esophageal cancer and leiomyosarcoma of uterus. The 
domestic phase 1 clinical trials on SHR-1210 antibody, SHR-1210-101, SHR-1210-102 and 
SHR-1210-103, have also been conducted in multiple clinical centers in China and will provide 
more clinical data.  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
To evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 in subjects with advanced 
hepatocellular carcinoma (HCC) who had received previous systematic treatment. 
2.2 
Primary Study Endpoints 
1) Objective response rate (ORR)  
2) 6-month overall survival rate (6-month OS rate)  
2.3 
Secondary Study Endpoints 
1).  Duration of response (DoR) 
2).  Disease control rate (DCR) 
3).  Safety of SHR-1210 
4).  Time to progression (TTP) 
5).  Progression-free survival (PFS) 
6).  Overall survival (OS) 
2.4 
Exploratory Study Endpoints 
The relationship between PD-L1 expression level and efficacy. 
3 
STUDY PLAN 
3.1 
Study Design 
The whole study project includes two parts, i.e., the first stage (phase II) and the second stage 
(phase III). The subjects enrolled should be patients with inoperable advanced hepatocellular 
carcinoma (HCC) who have received at least one systematic treatment. 

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The first stage: an open-label, randomized controlled phase II clinical study. Sixty subjects are 
planned to be enrolled initially in the study and 1:1 randomized into SHR-1210 3mg/kg, I.V, 
q2W (once every two weeks) or SHR-1210 3mg/kg, I.V, q3W (once every three weeks), on a 
42-day cycle, until progression of disease, unacceptable toxicity, withdrawal of informed consent 
or the end of study, whichever comes first.  
The study design of the phase II study is illustrated in In the phase II study, . 
Figure 3 The schematic diagram for phase II study 
 
In the phase II study, enrollment will be implemented on a continuous basis until approximately 
220 subjects are randomized. 
The second stage will not be included in the protocol temporarily, but using a separate protocol. 
3.2. Study Procedures 
3.2.1 
Screening period 
The screening period starts from the signing of informed consent form and ends with the start of 
dosing or screening failure. 
Subjects must sign the informed consent form before performing any screening procedure 
specified in this study. 
Unless otherwise noted, the following screening should be completed within 28 days prior to the 
first dose of investigational drug: 
 
Signing of informed consent form. 
 
Assignment of subject ID. 
 
Collection of medical history, including prior treatment history, current medical history, 
history of drug allergy, and concomitant diseases. 
 
Collection of adverse events and concomitant medications. 
 
Providing pathological specimens (if applicable). Pathological tissue samples are transported 
to a central laboratory for PD-L1 expression test. 

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 
Tumor imaging evaluation according to RECIST v1.1. 
The following information will be collected within 14 days prior to the first dose of 
investigational drug: 
 
Physical examination: height, weight, vital signs (performed after sitting still for 5 minutes): 
including temperature, blood pressure, heart rate, and respiratory rate. 
 
ECOG PS. 
 
Hematology, urinalysis, and fecal occult blood test. 
 
Blood biochemistry, including ALT, AST, total bilirubin (TBIL), ALP, LDH, albumin, urea 
nitrogen/serum urea, creatinine, blood glucose, amylase/lipase. 
 
Blood electrolyte: including potassium, sodium, chlorine, calcium, and magnesium. 
 
Coagulation parameters: PT or INR. 
 
Child-Pugh class. 
 
Serum pregnancy test (only for women of childbearing potential, within 72 hours before the 
first dose). 
 
Virology (including HBV, HCV, and HIV markers). 
 
Serum AFP test. 
 
Thyroid function (TSH, FT3, FT4). 
 
Color Doppler echocardiography (mainly observe LVEF). 
 
12-Lead ECG (QTc interval time need to be noted, and QTc interval is calculated using 
Fridericia formula).  
3.2.2 
Treatment period 
The treatment period starts from randomization, and the investigational drug must be given 
within 3 days after randomization. 
A cycle is defined as 6 weeks. SHR-1210 3 mg/kg will be given i.v. drip over half an hour, no 
less than 20 minutes and no more than 60 minutes, including rinsing period, on D1, D15 and D29 
of each cycle in Group A, and on D1 and D22 of each cycle in Group B. Physical examination 
and laboratory examinations will be conducted during treatment, AE and concomitant 
medications information will be collected. 
The following evaluation will be completed within 72 hours prior to each administration of 
investigational drug in each cycle of therapy:  

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ECOG PS, physical examination (at least including heart, lungs, abdomen, skin), vital signs, 
hematology, urinalysis, blood biochemistry, and blood electrolytes examination. The 
investigational drug can be given only after investigators have reviewed the laboratory test 
results.  
Since the second treatment cycles, the following assessment will be completed at D1 of each 
cycle:  
Coagulation function, alpha fetoprotein, thyroid function (TSH, FT3, FT4), virology (HBV 
markers or HCV markers), and Child-Pugh class. 
In accordance with RECIST v1.1, the initial tumor imaging evaluation is assessed at 8 weeks 
(± 7 days), and then every 6 weeks (± 7 days), with or without dosing. After 12 months of dosing 
(i.e., the first dose), if tumor assessment is still required, it should be performed every 12 weeks 
(± 14 days) until the disease progresses or end of the study (whichever happens later). 
The subjects who are evaluated as progressive disease can continue to receive treatment if they 
meet the criteria defined in Section 3.2.4. 
The treatment period will end and proceed to follow-up period when the subjects terminate the 
study (see Section 5.5).  
Note: the specific study procedures during the treatment period are shown in the study flowcharts. 
3.2.3 
Follow-up period 
Follow up period is initiated when the end-of-treatment decision is made.  
Within 90 days after the last dose of investigational drug, follow-up visit will be performed once 
every 30 days (±7 days), the first and third follow-up must be face-to-face visit, and the required 
safety evaluation must be completed (see study flowchart), the second follow-up is telephone 
visit (only collect partial data).  
After the end of the safety follow-up period, the subjects will enter survival follow-up period. 
Investigators must follow up subject’s survival every 30 days (±7 days), until death, lost to 
follow-up, termination of study by the sponsor. Investigators can inquire the subject, his/her 
family members or local physician via phone, collect subject’s survival information (death and 
reason of death) and data on other tumor therapies after the end of study treatment. The data on 
each survival follow-up needs to be recorded in detail in the original medical record. 
Subjects who end study treatment for toxicity or other reasons with no radiological progression 
observed still need to receive radiological evaluation according to the same frequency, until 
progression of disease or start of other anti-cancer therapy, the radiological evidence on PD 
should be obtained from such subjects as much as possible. 

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The subject withdrawing from study treatment should also continue the safety follow-up and 
survival follow-up as required by protocol. Adverse effects of the investigational drug may occur 
after end of treatment; safety follow-up should be conducted as far as possible. Survival is one 
primary endpoint in this study, the study center should do their best to obtain the survival follow-
up information.  
3.2.4 
Criteria for continuing treatment beyond progression 
Some subjects receiving immunotherapy can still clinically benefit following radiological 
progression. After progression of disease as defined by RECIST v1.1, subjects meeting all of the 
following criteria may continue with the study treatment: 
 
Investigators judge continuation of study treatment meets the best benefit for the subject, 
and the subject does not need to start other anti-cancer therapy immediately;  
 
The subject can tolerate study treatment; 
 
No obvious decrease in the physical performance, no obvious exacerbation in tumor 
related symptoms;  
 
The subject must sign the informed consent form before continuation of the study treatment. 
Possible risks, discomfort and other therapeutic choices will be described in the informed 
consent form;  
 
The study treatment continued upon must be approved by the sponsor and principal 
investigator of the study.  
The evaluation of clinical benefit must take clinical exacerbation, continued benefit from the 
treatment into consideration. It is advisable to discuss with the sponsor about the decision on 
post-progression continuation of treatment, as judged by investigators.  
If a decision of continued study treatment is made following progression, the subject should be 
treated, evaluated and followed up as required in the protocol. Subjects who continue treatment 
after imaging progress need to assess the tumor and track each target lesion, non-target lesion, 
and new lesion according to protocol. The overall assessment is recorded as PD as long as the 
new lesion did not disappear.  
If further progression occurs in the next tumor evaluation, the subject should be withdrawn from 
the study. The initial date of progression will be used for statistical analysis which including all 
progression data, regardless of the continuation of study treatment following progression. 
If the subject terminates the treatment for systemic condition exacerbation and no objective 
evidence of disease progression is shown, the progression will be reported as systemic 
exacerbation. Every effort should be made to obtain the objective evidence on progression in 
these subjects after termination of the study (e.g., radiological confirmation). 

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Subjects withdrawn from study for unacceptable toxicity and haven’t observed radiological 
progression still need to receive radiological assessment according to the original frequency, until 
disease progression or start of other anti-cancer therapy, the radiological evidence on PD should 
be obtained from such subjects as far as possible.  
4. 
RANDOMIZATION AND BLINDING 
Eligible subjects will be randomized at a 1:1 ratio to receive SHR-1210 3 mg/kg as q2w or q3w. 
No drug number will be produced in this period. 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS  
5.1 
Inclusion Criteria 
1. Age: 18 years old or older; male or female;   
2. Had a histological or cytological diagnosis of advanced HCC, not amenable for surgical or 
local therapy, and having at least one measurable lesion (≥ 10 mm in long axis when 
assessed by spiral CT scan or ≥15 mm in short axis for malignant lymph nodes as per 
RECIST v1.1); 
3. Failure of or intolerant to at least one systematic treatment for HCC: 1) the previous 
systematic treatment must be chemotherapy or sorafenib; 2) if not, the patient must be 
adequately informed by the treating physician that current therapeutic options include 
sorafenib and chemotherapy and need to refuse these options, which is recorded by 
investigator in a written form;  
a. Failure of treatment is defined as disease progression during treatment or recurrence 
after the end of treatment (the systematic chemotherapy must be ≥ 1 cycle, duration of 
sorafenib treatment must be ≥ 14 day) 
b. Intolerance to chemotherapy is defined as ≥ Grade 4 hematological toxicity or ≥ Grade 3 
non-hematological toxicity or ≥ Grade 2 cardiac, hepatic or renal impairment during 
treatment;  
c. Intolerance to sorafenib is defined as: continuation or recurrence of CTCAE Grade 2 
treatment-related adverse event (AE) after sufficient supportive treatment according to 
local standard, and dose interruption for at least 7 days and reduction of one dose level 
(until 400 mg qd); continuation or recurrence of CTCAE ≥ Grade 3 treatment-related 
adverse event after sufficient supportive treatment according to institutional standard, or 
dose interruption for at least 7 days and reduction of one dose level (until 400 mg qd);  

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4. The end of previous systematic treatment was ≥ 2 weeks from the start of the study (at least 
reaching drug elution period, i.e., 5 times of drug half-life) and treatment related AE 
recovered to NCI-CTCAE ≤  Grade 1 (except Grade 2 alopecia); 
5. Child-Pugh scores of grade A and the better part of grade B (≤7); 
6. ECOG PS: 0–1;  
7. With a life expectancy of ≥ 12 weeks;  
8. Subjects with chronic hepatitis B (HBV) infection: HBV- deoxyribonucleic acid (DNA) must 
be < 500 IU/ml; and the patients with positive hepatitis B surface antigen must receive 
antiviral therapy according to the treatment guideline; the patients with positive hepatitis C 
(HCV) must receive antiviral therapy according to the treatment guideline and have ≤ CTCAE 
Grade 1 elevated hepatic function;  
9. Have adequate main organ function, which meets the following criterion:  
(1) Hematology Complete blood cell count: (no blood transfusion, no use of granulocyte 
colony-stimulating factor (G-CSF), no use of drug correction within 14 days prior to 
screening) 
d. Hemoglobin (HB) ≥ 90 g/L 
e. Absolute neutrophil count (ANC) ≥ 1.5×109/L 
f. 
Platelet count (PLT) ≥ 60×109 /L 
(2) Blood biochemistry: (no infusion of albumin (ALB) within 14 days) 
e. ALB ≥ 29 g/L 
f. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5  
ULN 
g. Total bilirubin (TBIL) ≤ 1.5  ULN 
h. Creatinine ≤ 1.5  ULN 
(3) Pro-thrombin time (PT)- International normalized ratio (INR) ≤ 2.3 or PT ≤ 6 seconds 
exceeding the range of normal control; 
(4) Urine protein < 2+ or 24 hours urine protein quantification < 1.0 g; 
10. Women of childbearing potential must receive serum pregnancy test within 72 hours prior to 
start dose of investigational drug, and have negative result, willing to use at least two highly 
effective contraceptive methods during the trial and 60 days after the last dose of 

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investigational drug (about 5 drug half-lives + menstrual cycle). The male subjects whose 
partner are women of childbearing potential should use at least two highly effective 
contraceptive methods during the trial and 120 days after the last dose of investigational drug 
(about 5 drug half-lives + sperm emptying cycle);  
11. The subjects are voluntary to participate in the study, signing the informed consent form, 
with good compliance and willingness to cooperate with follow-up. 
5.2 
Exclusion Criteria 
1. Known hepatocholangiocarcinoma, mixed cell carcinoma, and lamellar cell carcinoma; other 
active malignant tumor except HCC within 5 years or simultaneously. Cured localized 
tumor, for example, basal cell carcinoma of skin, squamous cell carcinoma of skin, 
superficial bladder cancer, carcinoma in situ of prostate, carcinoma in situ of cervix, breast 
cancer in situ may be enrolled; 
2. Be ready for or previously received organ or bone marrow transplantation; 
3. Ascites with clinical symptoms, i.e., requiring therapeutic abdominal puncture or drainage, 
or Child-Pugh score > 2;  
4. History of gastrointestinal hemorrhage within 6 months prior to the start of study treatment 
or clear tendency of gastrointestinal hemorrhage, for example, esophageal varices with 
hemorrhagic risk, locally active peptic ulcer, persistent fecal occult blood (+);  
5. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 28 days prior to 
the start of study treatment;  
6. Previous or current presence of metastases to central nervous system; 
7. Grade 2 or higher myocardial ischemia, myocardial infarction, or poorly controlled 
arrhythmia (including QTc interval ≥ 450 ms for man and ≥ 470 ms for woman) (QTc 
interval is calculated using Fridericia formula);  
8. Grade III−IV myocardial insufficiency in accordance with New York Heart Association 
(NYHA) criteria or color Doppler echocardiography: LVEF (left ventricular ejection 
fraction) < 50%;  
9. History of hepatic encephalopathy;  
10. Untreated active hepatitis (hepatitis B: HBsAg positive and HBV-DNA ≥ 500 IU/mL; 
hepatitis C: HCV-RNA positive and obviously abnormal hepatic function); combined 
hepatitis B and hepatitis C co-infection;  
11. Human immunodeficiency virus (HIV) infection; 

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12. Previous and current history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, 
radiation pneumonitis, treatment-related pneumonia, serious pulmonary impairment that 
may interfere with the detection and management of suspected treatment-related pulmonary 
toxicity; 
13. Known active or suspected autoimmune disease. Subjects who have stable disease state and 
do not require systemic immunosuppressive therapy can be enrolled;  
14. Within 14 days prior to any dose of the investigational drug, use of corticosteroid 
(prednisone at the therapeutic dose of >10 mg/day) or other immunosuppressant for 
systematic treatment. With no active autoimmune disease, inhaled or local use of steroids 
and adrenaline equivalent to > 10 mg/day prednisone therapeutic dose are allowed for 
replacement;  
15. Use of any local therapy for the hepatic lesion (including but not limited to surgery, 
radiotherapy, hepatic artery embolism, TACE, hepatic artery perfusion, radiofrequency 
ablation, cryoablation or percutaneous ethanol injection) within 4 weeks prior to 
participation in the study;  
16. Palliative radiotherapy to control symptoms is allowed, and must be completed at least 2 weeks 
prior to the start of study treatment, and no additional radiotherapy for the same lesion is 
planned; radiotherapy induced adverse events haven’t recovered to ≤ CTCAE Grade 1;  
17. Patients may receive other anti-cancer therapies during the study, such as chemotherapy, 
targeted therapy, or radiation therapy; previous treatment with other anti–PD-1 antibodies or 
other immunotherapy against PD-1/PD-L1;  
18. Known history of serious allergy to any monoclonal antibody; 
19. Pregnant or breastfeeding women; 
20. Known to have a history of psychiatric substance abuse or drug abuse; Patients who have 
stopped drinking can be enrolled;  
21. Other factors that may affect the study results or lead to forced termination of the study early 
as judged by investigators, such as other serious diseases, with serious laboratory 
examination abnormalities which may affect patient’s safety, or with family or social factors, 
which may affect the collection of trial data and samples.  
22. Patients who have participated in “the randomized, double-blind, parallel-controlled, 
multicenter, phase III clinical study on apatinib sulfonate tablets as the second line therapy 
for advanced hepatocellular carcinoma” previously and been randomized to any medication 
cannot be enrolled before the primary study endpoint is reached in this study.  

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5.3 
Concomitant Medications and Treatments  
All treatments and drugs used within 1 month prior to signing the informed consent form and in 
the course of the study should be recorded in the eCRF strictly in accordance with the GCP 
guideline. If adverse events occur, the subject should be closely observed, as well as given active 
symptomatic treatment if necessary, and the drug used shall be recorded and specified in the 
eCRF. 
5.3.1 
Drugs and therapies prohibited during the study 
Subjects are prohibited from using modern traditional Chinese medicines that have been 
approved by the NMPA (including but not limited to Delisheng Injection, Kanglaite Injection, 
Aidi Injection, Huaier Granule and Ganfule Tablet) and immunomodulators (including but not 
limited to interferon, interleukin-2, thymosin, etc.) during the study. 
During the treatment period of this study, subjects are not allowed to receive any local therapies 
against liver lesion and targeted lesion, and other systemic anti-cancer therapies, such as 
chemotherapy, molecular targeted therapy, hormone therapy, immunotherapies, traditional 
Chinese medicine therapy (as mentioned above) and radiotherapy. 
Subjects are not allowed to receive other immunosuppressive therapy simultaneously during the 
treatment period of this study (except management on the treatment-related AE). 
Investigational drugs for cancer treatment 
5.3.2 
Permitted concomitant medications and treatments during the study 
1. Antiviral treatment 
Subjects infected with HBV and HCV must receive antiviral therapy according to local 
standards, and the antiviral therapy is recommended as below: 
Subjects with HBV infection can continue the original antiviral therapy if HBV-DNA is positive 
and they have started antiviral therapy and achieved satisfactory control of virus (HBV-DNA 
< 500 IU/mL) prior to inclusion in the study; the drug must be replaced by Entecavir if the virus 
is not satisfactorily controlled, and subjects can be enrolled when HBV-DNA is < 500 IU/mL; 
subjects with newly discovered HBV infection in screening period can start Entecavir therapy 
immediately and can be enrolled when HBV-DNA is < 500 IU/mL. 
Subjects with HCV infection, if HCV-RNA is positive, subjects must receive antiviral therapy in 
accordance with the local standard guideline on diagnosis and treatment of hepatitis C. 

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2. Steroids 
Local use of steroids is allowed, for example, topically external use, eye, nasal cavity, intra-joint 
and inhalation; corticosteroids for epinephrine replacement therapy are allowed; corticosteroids 
for treatment of adverse reactions are allowed; transient use of steroids for prevention and 
treatment of allergic reactions (prevention of allergy to contrast agent, or treatment of other 
allergic reactions) is allowed. 
3. Vaccines 
Vaccines for preventing infectious disease are allowed, for example, pneumonia or influenza 
vaccines. It must be discussed with the sponsor before using other vaccines.  
4. Other systemic therapies 
During the treatment period, subjects should be given the best supportive treatment. The original 
hormone replacement therapy is allowed. Bisphosphonate for treatment of bone metastasis is 
permitted. 
5. Palliative local treatment 
Palliative therapy for local lesions causing obvious symptoms is allowed, for example, bone 
pain; local radiotherapies or surgery can be considered, however, the following conditions must 
be met: 
Progression of disease must be judged by investigators for subjects who need local therapy due 
to deterioration of symptoms during the study; 
Subjects with disease progression must meet the criteria for treatment beyond progression (see 
Section 3.2.4); 
The lesions for local therapy cannot be target lesions. 
It is advisable to discuss with the sponsor prior to the start of palliative local therapy. The content 
of palliative therapy should be recorded carefully in eCRF and medical record, including the 
date, site of treatment, therapeutic method and dosage, adverse reactions, and so on. 
5.4 
Criteria for Re-screening of Subjects 
Rescreening is allowed in this study, i.e., subjects who have entered screening process but do not 
meet randomization criteria, and have not been randomized or treated, can be re-enrolled. They 
must sign the informed consent form again, and obtain a new subject number at the time of 
re-screening. 

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5.5 
Criteria for Subjects’ Withdrawal from the Study or Termination of Study Treatment 
Subjects must terminate study treatment when any of the following conditions occurs: 
1. Subject withdraws informed consent and requires to withdraw from the study. 
2. Medical imaging examination shows progression of disease, unless the subject meets the 
criteria on post-progression continuation of therapy (see Section 3.2.4); 
3. Occurrence of clinical adverse events, abnormal laboratory examination or co-morbidities 
occur, when continued participation in the study is judged by investigators as violating the 
subject’s optimal benefit; 
4. Other reasons for inability to continue study treatment, as considered by investigators, for 
example, loss of the ability to express wills freely for custody or isolation; 
5. Pregnancy in female subject occurs during the study; 
6. Termination of study by sponsor. 
5.6 
Criteria for Termination of Study Treatment  
The criteria for study termination are as follows: 
(1) Criteria for terminating treatment at study site: 
If the sponsor discovers a serious or persistent non-compliance with the protocol and other trial 
procedures in study sites, the sponsor will have the right to suspend the trial conducting at the 
study site. In this case, the sponsor will immediately inform the investigator and the regulatory 
authorities of the termination information. The investigator must immediately report this 
termination information to the ethics committee and provide corresponding reasons.  
If the investigators terminate or suspend the trial in study site, they must inform subjects 
immediately and report the written decision to the sponsor and the regulatory authority, as 
required by regulations, and state the reason. The investigator should also report promptly to the 
ethics committee and the clinical trial institution, and state the reason. 
(2) Criteria for terminating the entire study: 
The study can be terminated or interrupted prematurely if the reason is sufficient. If the study is 
terminated or interrupted in advance, the sponsor shall provide a written notice which records the 
reasons for early termination or interruption to investigators, the National Medical Products 
Administration and relevant departments. The principal investigator should notify the ethics 
committee and the sponsor immediately, and provide relevant reasons. 

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The reasons for premature termination or interruption of the study may include (but not limited): 
 
Discovery of unexpected, significant or unacceptable risk; 
 
Major mistakes in the protocol are found during the trial; 
 
Ineffective investigational drug/trial therapy, or meaningless to continue the study;  
 
The enrollment of subjects is seriously prolonged or having frequent protocol deviation, 
which makes it extremely difficult in completing the study. 
5.7 
Subject ID 
Subjects will be assigned a unique number in the study with five digits: 
 
The first 2 digits = Site number. 
 
The last 3 digits = Subject number in the same site. The subjects will be numbered in 
accordance with the sequence in which the subjects sign the informed consent form, for 
example: 001, 002, 003, etc.  
6 
STUDY TREATMENT 
6.1 
Information of Investigational Drug 
Investigational drug: SHR-1210 for injection 
Manufacturer: Shanghai Hengrui Pharmaceutical Co., Ltd., Suzhou Shengdia Biological 
Medicine Co., Ltd. 
Dosage form: lyophilized powder 
Specification: tentatively set as 200 mg and packed in 20 ml vials. The batch number is provided 
in the drug inspection report in detail; 
Administration: intravenous infusion; 
Shelf life: 2 years (tentative) from the date of manufacture;  
Storage: Stored in sealed, protected from light, stored in a medical refrigerator at 2–8℃, must 
not be frozen.  
6.2 
Drug Dispensation 
Management, dispensation and return of the investigational drugs in this study will be performed 
by a special person, investigators must make sure all the investigational drugs are only used for 
the subjects in this clinical trial, the dosage and administration method should be in accordance 
with the protocol, the residual investigational drugs will be returned to the sponsor and must not 
be transferred to any non-clinical trial participant. 

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The investigational drugs are stored in a medical refrigerator at 2–8 °C. When the drug is 
dispensed to the study site, a drug receipt form must be signed by two persons in duplicate, one 
for clinical study site and the other for sponsor. At the end of the study, the remaining drugs and 
empty boxes will be returned, and the two sides need to sign a drug return form. The 
dispensation and return of each drug shall be recorded on a specific record sheet in time. 
Monitors are responsible for monitoring supply, use, storage of the investigational drugs and 
treatment of the remaining drugs. 
6.3 
Drug Storage and Management 
In accordance with the requirement of the GCP, the investigational drugs are uniformly stored, 
dispensed and returned by the participating study site. The investigational drugs should be sealed 
and protected from light, stored in a medical refrigerator at 2−8 °C, and must not be frozen.  
SHR-1210 is not permitted to be used in the treatment outside of this study.  
6.4 
Disposal of Remaining Drugs 
Investigators should record the date and dose of the drug administered for each subject. The total 
amount of investigational drugs is 110% of the designed amount, and the residual investigational 
drugs will be returned to the sponsor regularly for destruction after being counted. If the 
remaining drugs should be destroyed at study sites, the written certification of the destruction of 
residual investigational drugs needs to be obtained and stored as well.  
6.5 
Dose Regimen 
The subjects randomized to Group A will receive SHR-1210 3 mg/kg intravenous infusion over 
30 minutes (no less than 20 minutes and no more than 60 minutes, including a wash-out period) 
once every two weeks. The subjects randomized to Group B will receive the same dose once 
every three weeks.  
The interval between two doses cannot be less than 12 days for once every two weeks. The 
interval between two doses cannot be less than 18 days for once every three weeks.  
6.6 
Common Recommendations on Safety Management  
6.6.1 
Infusion reaction 
As SHR-1210 is a fully humanized monoclonal antibody, the possibility of infusion or allergic 
reaction is low, and preventive medication is not needed prior to infusion. Allergic reaction is 
most likely to occur within 24 hours after infusion. Once the allergic reactions occur, the infusion 
should be slowed down or interrupted based on the condition, and clinical supportive treatment is 
needed, and after that, the preventive medication should be given prior to the subsequent doses. 

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The allergic reactions are possibly characterized by fever, intolerance of cold, chills, headache, 
rash, pruritus, joint pain, low or high blood pressure, or bronchospasm. All the Grade 3 or 4 
infusion reactions should be reported to the sponsor within 24 hours, and reported as SAE in case 
of meeting the criteria for SAE. See detailed reporting method in Section 9.2. 
Response to allergic reactions should be based on the medical practice and guidelines of the 
study site. The following is the recommendations for the treatment of infusion reaction for 
reference. 
Table 4 
Recommendations on management of immune related adverse reactions 
CTCAE 
Grade 
Clinical symptoms 
Clinical treatments 
SHR-1210 treatment 
Grade 1 
Mild transient reactions 
Bedside monitor, close monitoring till 
recovery. 
Preventive medication is recommended 
prior to the infusion afterwards: 
Diphenhydramine 50 mg, or equivalent 
and/or Acetaminophen 325–1000 mg, 
administered at least 30 minutes before the 
infusion of SHR-1210. 
Continue. 
 
Grade 2 
Moderate reaction 
requiring treatment or 
dose interruption that can 
be rapidly relieved after 
symptomatic treatment 
(e.g., antihistamine drugs, 
non-steroid anti-
inflammatory drugs, 
anaesthetics, 
bronchodilator, 
intravenous infusion, etc.) 
Normal saline i.v. infusion, 
Diphenhydramine 50 mg i.v. or equivalent 
and/or Acetaminophen 325–1000 mg; 
bedside observation, close monitoring till 
recovery. 
Corticosteroid or bronchodilator can be 
considered if clinically required; 
The dose of investigational drug 
administered will be recorded in the source 
documents; 
Preventive medications are recommended 
prior to the infusion afterwards: 
Diphenhydramine 50 mg, or equivalent 
and/or Acetaminophen 325–1000 mg, 
administered at least 30 minutes before the 
infusion of SHR-1210. Cortisol (equivalent 
to 25 mg hydrocortisone), can be used if 
necessary. 
Interrupted temporarily. 
Resuming the medication 
after symptoms 
disappear at 50% of the 
initial infusion rate. If 
there is no complication 
within 30 minutes, 
increase to the original 
100% infusion rate. 
Closely monitor. If 
relapse, the current dose 
of SHR-1210 cannot be 
given again. 
Grade ≥ 3 
Grade 3: serious reaction, 
no rapid relief after 
treatment and/or dose 
interruption; or relapse 
after remission; sequela 
occurred requiring 
hospitalization. 
Grade 4: life threatening 
The infusion of SHR-1210 shall be 
immediately discontinued; 
And normal saline i.v. infusion should be 
started. 
 
Bronchodilator, 0.2–1 mg 1:1000 
epinephrine solution (s.c.) , or 0.1–
0.25 mg 1:10000 epinephrine solution 
(i.v.), and/or diphenhydramine 50 mg 
combined with methylprednisolone 
100 mg or equivalent drugs (i.v.) is/are 
recommended; 
Discontinued 
permanently. 

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CTCAE 
Grade 
Clinical symptoms 
Clinical treatments 
SHR-1210 treatment 
 
Comply with guidelines for allergic 
reactions of the study site; 
Bedside monitor, close monitoring, till 
recovery.  
6.6.2 
Principles of management for immune-related adverse events 
In overall principle, according to the severity of adverse reaction, interruption of SHR-1210 is 
taken as the main measure, resumption of SHR-1210 can be considered when the severity of 
adverse event has recovered to Grade 1 or below, and SHR-1210 should be discontinued 
permanently when serious Grade 3 or life-threatening Grade 4 adverse events occur. 
Management of immune-related adverse events should base on the medical practice of the study 
site and the guidelines. The following provides the recommendations on management of 
immune-related adverse events (see Table 5), for reference. Recommended treatment procedures 
for common immune-related adverse events are detailed in Appendix 4. 
Table 5 
Recommendations on management of immune-related adverse events 
CTCAE Grade 
Clinical Treatment* 
SHR-1210 Treatment 
Grade 1 (Mild) 
Close observation; symptomatic and supportive 
treatment. 
Continue 
Grade 2 (moderate) 
Close monitoring; 
Symptomatic and supportive treatment; 
Local or systemic steroids treatment,  
0.5–1 mg/kg/day, Prednisone or equivalent 
drugs. 
Interrupted temporarily, resume the 
medication when adverse reactions  
≤ Grade 1; 
Resuming the medication, except 
cutaneous and endocrine disorders. 
Grade 3 (severe) 
Hospitalization is recommended; 
1–2 mg/kg/day, prednisone or equivalent drugs 
(i.v. or p.o.); 
If failed after steroids treatment for 3–5 days, 
consider addition of other immunosuppressants; 
Specialized consultation is recommended.  
Interrupted temporarily; dose 
resumption must comprehensively 
consider risk/benefit ratio and be 
decided after discussion. 
Grade 4 (life threatening) Intravenous 1–2 mg/kg Methylprednisolone; 
If failed after steroids treatment for 3–5 days, 
consider addition of other immunosuppressants; 
Specialized consultation is recommended. 
Discontinued permanently. 
（S. Champiat, O. Lambotte, E. Barreau, er al. Management of immune checkpoint blockade 
dysimmune toxicities: a collaborative position paper. Annals of Oncology 27: 559–574, 2016） 
 

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7 
DOSE ADJUSTMENT AND SAFETY MANAGEMENT 
7.1 
Dose Level and Regimen 
The dose level in trial is 3 mg/kg, q2w or q3w, intravenously infusion over 30 minutes (no less 
than 20 minutes and no more than 60 minutes, including a wash-out period), until progression of 
disease, unacceptable toxicity, withdrawal of informed consent or the end of study, whichever 
comes first.  
The administration interval cannot be less than 12 days at the frequency of once every two 
weeks. The administration interval cannot be less than 18 days at the frequency of once every 
three weeks. Dosing 3 days post the intended date of administration will be considered as 
delayed dose. The subsequent time of administration will be calculated on the actual date of the 
previous dose.  
7.2 
Dose Modification 
7.2.1 
Criteria for dose modification 
Dose modification is not allowed.  
7.2.2 
Criteria for dose delay 
The dose should be delayed if the following conditions occur: 
 
Any  Grade 2 treatment-related non-cutaneous AE, except Grade 2 treatment-related 
fatigue or laboratory abnormalities; 
 
Any Grade 3 treatment-related cutaneous AE; 
 
Any Grade 3 treatment-related laboratory abnormalities, except Grade 3 abnormal 
amylase or lipase unrelated with the symptoms and clinical manifestations of 
pancreatitis; 
 
The administration will be delayed if the following AST or ALT abnormalities occurs: 
- 
AST and ALT at baseline are within normal range, and Grade 2 treatment-related 
adverse events occur ; 
- 
AST or ALT at baseline elevates no greater than Grade 1, and Grade 3 treatment-
related adverse events occur; 
- 
AST or ALT at baseline elevates no greater than Grade 2, and treatment-related 
elevated AST or ALT reaches > 2 times the baseline or either AST or ALT 
reaches > 8×ULN (whichever is lower). 

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 
The administration needs to be delayed for any AE, laboratory examination 
abnormalities or complications, as judged by investigators; 
Subjects who need delayed dose should be monitored every week, and the frequency of 
monitoring can be increased when clinically indicated. It is recommended to monitor liver 
function every three days, until the highest value of AST or ALT starts to decrease. When 
meeting the criteria for resumption of medication (see Section 7.2.3), the investigational drug can 
be resumed. 
Tumor evaluation still needs to proceed for all the subjects as required in the protocol, regardless 
of dose delay. 
7.2.3 
Criteria for dose resumption 
When treatment-related AEs recover to ≤ Grade 1 or baseline level, the dose can be resumed, 
except the following: 
 
The therapy can be resumed for the subjects with Grade 2 fatigue that has not been 
recovered; 
 
The therapy can be continued for Grade 2 cutaneous AE; 
 
For subjects with AST, ALT or TBIL Grade 1 elevation at baseline who delay SHR-
1210 for reasons other than treatment-related hepatic AE, the therapy can be resumed in 
the presence of AST, ALT or TBIL Grade 2 elevations; 
 
For subjects who delay the dose for treatment-related AST, ALT or TBIL elevation, 
when these parameters are recovered to baseline CTCAE Grade or normal (see Section 
7.2.4) and have not reached the criteria for permanent discontinuation of the treatment, 
the investigational drugs can be resumed; 
 
In the case that the treatment-related endocrine disorder can be sufficiently controlled 
only with hormone replacement at physiological dose, the treatment can be resumed. 
The study medication is allowed to be delayed for up to 6 weeks, as calculated from the last 
dose. If the subject still does not reach the criteria for dose resumption after delay for 6 weeks, 
the study treatment need to be discontinued permanently, except the exceptions mentioned in 
Section 7.2.4. The guideline on management of adverse reactions is seen in Appendix 4 in detail. 
7.2.4 
Criteria for permanent treatment discontinuation 
The study medication must be discontinued permanently when the following conditions occur: 
 
Any Grade 2 treatment-related uveitis, ophthalmodynia, and blurred vision, that has no 
response to local therapy and is not recovered to Grade 1 after delayed dose; or the 
above AE requiring systemic therapy. 

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 
Any Grade 3 treatment-related non-cutaneous AE, lasting for > 7 days, except the 
following: 
- 
When any Grade 3 treatment-related uveitis, pneumonia, bronchospasm, 
hypersensitivity, or infusion reaction occurs, the study treatment must be 
terminated; 
- 
In case the Grade 3 treatment-related endocrine disorder can be sufficiently 
controlled only with hormone replacement therapy at physiological dose, the 
treatment does not need to be terminated; 
- 
The treatment does not need to be terminated for Grade 3 treatment-related 
laboratory abnormality, however, the study medication must be terminated for 
Grade 3 thrombocytopenia > 7 days or related with hemorrhage. 
 
Hepatotoxicity meeting the following: 
- 
AST or ALT > 10 times of ULN for over two weeks; 
- 
ALT or AST > 15 × ULN; 
- 
TBIL > 8 times of ULN for subjects with elevated TBIL at baseline, > 5 times of 
ULN for subjects with normal TBIL at baseline; 
 
Any Grade 4 treatment-related AE or abnormal laboratory examination, except the 
following: 
- 
Grade 4 granulocyte decrease lasts less than 7 days; 
- 
Grade 4 lymphopenia or leukopenia; 
- 
Isolated Grade 4 elevated amylase or lipase, without symptoms or clinical 
manifestations of pancreatitis. The sponsor needs to be informed in case of Grade 4 
elevated amylase or lipase occurs; 
- 
Isolated Grade 4 electrolyte imbalance/abnormality without clinical sequela that 
could be corrected through supplement/appropriate management within 72 hours 
after occurrence; 
- 
Grade 4 treatment-related endocrine disorder that can be sufficiently controlled 
only with hormone replacement therapy at physiological dose, the treatment does 
not need to be terminated. 

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 
The study treatment must be terminated in case dose delay > 6 weeks is required, 
except the following:  
- 
After the use of cortisol for management of treatment-related AEs, the study 
medication is allowed to be delayed for > 6 weeks due to the need for dose 
tapering. Discussion with the sponsor must be made before resuming the dose. 
During the dose delay, the tumor assessment should continue as required by the 
protocol. Safety visits and laboratory tests should also be performed at the original 
frequency (at least once every 6 weeks, window period ± 7 days) or more 
frequently when clinically indicated; 
- 
The dose delay for > 6 weeks due to non-related reasons must be discussed with 
the sponsor prior to resuming administration. During dose delay, the tumor 
evaluation should still proceed as required in the protocol. Safety visits and 
laboratory examinations should also be performed at the original frequency (at 
least once every 6 weeks, window period ± 7 days), or more frequently when 
clinically indicated; 
 
Clinical AE, laboratory abnormality, or complications may bring major risk to subjects 
who continue taking the study medication, as judged by investigators. 
 
Progression of disease evaluated by investigators in accordance with RECIST v1.1 
(unless the subject meets the criteria in Section 3.2.4). 
Even though the study medication is terminated, subjects must continue to perform tumor 
evaluation as required in the protocol. 
7.3 
Safety Management of Immuno-Oncology Drugs 
7.3.1 
Rules for safety management of immuno-oncology drugs 
The AEs induced by Immuno-Oncology (I-O) drugs vary from other types of anti-cancer drugs, 
the severity and duration are special. SHR-1210 belongs to this type of drugs, thus it is required 
to achieve early identification and management of the AE induced by it, in order to reduce the 
incidence of serious toxicities. The investigator may refer to the rules for safety management of 
similar products in overseas markets to facilitate evaluation and management of I-O treatment-
related AEs occurring in the following systems: 
 
Gastrointestinal tract 
 
Lung 
 
liver 

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 
Endocrine 
 
Skin 
Rules for safety management are provided in Appendix 4 in detail. 
7.3.2 
Rules for management on hepatic adverse events 
Below are suggestions on management of hepatic AEs during the treatment period of this study: 
 
The criteria on dose delay resulted from hepatic AE are listed in Appendix 4. If the dose 
is delayed for 3−5 days and AST or ALT level is not improved but even exacerbated, 
cortisol, i.e., methylprednisolone 0.5−2 mg/kg/day or equivalent oral drugs will be 
given. 
 
In case of AST or ALT > 8 times of ULN, cortisol, i.e., methylprednisolone 
0.5−2 mg/kg/day or equivalent oral drug will be given immediately. 
 
The sponsor must be informed within 24 hours when cortisol treatment starts. At the 
same time, a gastroenterology consultation is advised. 
 
If AST or ALT level is not improved but even exacerbated 3−5 days after the start of 
corticosteroids treatment, it must be discussed with the sponsor, and other 
immunosuppressants may need to be added, such as mycophenolate 1g BID. 
 
Once AST or ALT is decreased by CTCAE Grade, the dose can be decreased gradually 
in no less than one month. 
The study medication can be resumed when AST or ALT is recovered to baseline level, unless 
the criteria on permanent discontinuation is reached. 
8 
EFFICACY EVALUATION 
8.1 
Primary Endpoints and Observation Method 
1) 6-month survival rate (6-month OS%): defined as the percentage of non-death cases in the 
evaluable subjects from the start of the trial to 6 months.  
2) Objective response rate (ORR):  
Defined as objective tumor response evaluated based on RECIST v1.1, including CR and PR 
cases.  
Definition of evaluable population: all the subjects meeting the following criteria, i.e., 
having received at least one dose of SHR-1210 treatment and at least one tumor evaluation 
after the start of study treatment. If the efficacy reaches CR or PR, subjects must receive 
repeated test for confirmation in no less than 4 weeks (28 days) after the first evaluation. 

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8.2 
Secondary Endpoints and Observation Method 
1).  Duration of response (DoR): defined as the time from the date of first record of objective 
response (CR or PR) to the first occurrence of progression or death.  
2).  Time to progression (TTP): defined as the time from the date of randomization to any 
documented radiological tumor progression.  
3).  Disease control rate (DCR): defined as the percentage of subjects with CR, PR and SD 
( 6 weeks) in the evaluable population.  
4).  Progression-free survival (PFS): defined as the time from randomization to any documented 
radiological tumor progression or death.  
5).  Overall survival (OS): defined as the time from randomization to death from any cause. 
8.3 
Independent Tumor Imaging Evaluation 
In order to provide objective, neutral and reproducible efficacy data except investigators’ 
evaluation, the 3rd-party Independent Radiology Review Committee (IRC) will be set up for 
tumor response evaluation in this study.  
All the images (including unscheduled scan, possibly including bone scan or brain scan) obtained 
from each center will be centrally reviewed by IRC, and tumor evaluation will be performed in 
accordance with RECIST v1.1. The central evaluated data will be used for analysis of ORR, TTP, 
DoR and DCR. The clinical decisions related with response evaluation will be based on 
investigator’s evaluation.  
The detailed procedures and standard for central evaluation will be defined in the additional 
"Radiology Manual for Study Center".  
9. 
SAFETY EVALUATION 
The safety evaluation of investigational drug includes vital signs, laboratory parameters, AE, 
SAE, treatment-related AE and SAE, which will be evaluated according to NCI-CTC AE v4.03 
criteria.  
9.1 
Adverse Events 
9.1.1 
Definition of AE 
AE is defined as adverse medical event that occurs after the subject who receives a drug in 
clinical trial, but do not necessarily have a causal relationship with the treatment. Any AE from 
the signature of informed consent form to 90 days after the last dose will be collected. AE can be 
any undesirable and unexpected symptom, sign, laboratory abnormal or disease, including at 
least the following conditions: 

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1) Aggravation of existing (prior to enrollment of clinical trial) medical condition/disease 
(including exacerbation of symptoms, signs, abnormal laboratories); 
2) Any new occurrence of AE: any adverse medical condition newly occurs (including 
symptom, signs, newly diagnosed diseases); 
3) Abnormal laboratory test or result of clinical significance. 
The investigators should carefully record any AE occurs in the subjects, including: description of 
adverse event and relevant symptoms, time of onset, severity, causality with investigational drug, 
duration, actions taken, final outcomes and prognosis. 
9.1.2 
Judgment standard on severity of AE  
Refer to NCI-CTC AE v4.03 grading criteria for AE related drugs. If any AE is unlisted in NCI-
CTC AE v4.03, refer to the following criteria: 
Grade 
Clinical description of severity 
1 
Mild; without clinical symptoms or mild clinical symptoms; only with clinical or laboratory 
abnormalities; no treatment is required. 
2 
Moderate, requiring minimal, local or non-invasive treatment; age-appropriate limits activities of daily 
living (ADL); involving tools refer to cooking, shopping, calls and counting money, etc. 
3 
Severe conditions or serious medical symptoms but not life-threatening; leading to hospitalization or 
hospitalization prolonged; leading to disability; limited in self-care ADL. Daily self-care includes 
bathing, dressing, undressing, eating, going to the bathroom, medication, and so on, non-bedridden. 
4 
Life-threatening, emergency treatment is required. 
5 
Leading to death. 
9.1.3 
Judgment standard on causality assessment  
Collection of AE starts from the signing of informed consent form to 90 days after the last dose 
of investigational drug, records are collected regardless of whether the event is related to the 
investigational drug, whether the subject is assigned to the experimental arm, or even whether 
the drug is used or not. Any discomfort or abnormal change in objective laboratory tests during 
the treatment should be recorded accurately, and the severity, duration, actions taken and 
outcome of the AE should be recorded. The study doctor should determine the relationship 
between AE and investigational drug, such as whether the occurrence of AE has relationship with 
a reasonable medication order, the properties of investigational drug, toxicological and 
pharmacological effects of investigational drug, subjects' use of other concomitant drugs, 
subjects' underlying diseases, medical history, family history and provocative and re-provocative 
reactions, etc. The causality between AE and investigational drug will be assessed using the 
following 5 categories: "definitely related", "possibly related", "unlikely related", "not related", 
and "unassessable". Among them, AEs with a causality of "definitely related", "possibly related", 
"unlikely related" and "unassessable" will be listed as adverse drug reactions. 

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9.1.4 
Follow-up of AE 
An AE will be followed up until it is resolved, returns to the baseline level or ≤ Grade 1, or 
reaches a stable state, or until other reasonable time points (e.g., lost to follow-up, death).  
9.2 
Serious Adverse Event (SAE) 
9.2.1 
Definition of SAE 
Serious adverse events (SAE) is defined as the medical events that require hospitalization or 
prolonged hospitalization, disability, limiting working ability, life-threatening or death, and 
leading to congenital malformation during the clinical trial. Including the following medical 
events: 
 
Events leading to death; 
 
Life-threatening events (defined as the subject has a risk of immediate death); 
 
Events requiring hospitalization or prolonged hospitalization; 
 
Events that result in persistent or severe disability/dysfunction/limiting working ability; 
 
Congenital abnormalities or birth defect; 
 
Other significant medical events (defined as the event threatens the safety of the subject, or 
requires intervention measures for the prevention of any of the above conditions). 
9.2.2 
Disease progression 
Disease progression is defined as the exacerbation of the subject caused by indications of the 
investigational drug, including radiological progression and progression of clinical symptom and 
sign. New metastases relative to the primary tumor and the progression of the original metastases 
are both considered to be progressive disease. Events that are life-threatening, requiring initial or 
prolonged hospitalization due to symptoms and signs of disease progression, which can lead to 
permanent or severe disability/dysfunction/limiting work ability, congenital abnormalities or 
birth defects are not reported as SAEs in expedition. Death caused by symptoms and signs of 
disease progression is reported as SAE. 
9.2.3 
Hepatic enzyme abnormalities 
Hepatic enzyme abnormalities with abnormal values in AST and/or ALT and meet the laboratory 
abnormalities in the following table should be reported as SAE. Additional follow-up of subjects 
will be required until the hepatic enzyme returns to the baseline level.  

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Baseline 
period 
Normal (AST, ALT, and TBIL) 
Abnormal (AST, ALT, or TBIL, any of them) 
Treatment 
period 
ALT ≥ 3× ULN 
AST ≥ 3× ULN 
ALT ≥ 8× ULN 
AST ≥ 8× ULN 
Meeting one of the above two criteria, with 
TBIL ≥ 2× ULN and alkaline phosphatase 
≤ 2×ULN with no hemolysis 
Meeting one of the above two criteria, 
with TBIL ≥ 3×ULN or increase ≥ 1× baseline value 
 
9.2.4 
Other anti-cancer therapy 
The record of AE starts from the signing of informed consent form until 90 days after the last 
dose of investigational drug. SAEs occurring within 90 days after the last dose also need to be 
reported even if the subject has started to use other anti-cancer drugs.  
9.2.5 
Hospitalization 
AEs that result in hospitalization or prolonged hospitalization should be considered as SAEs. 
Any initial hospitalization meets the criteria. 
Hospitalization does not include the following situations: 
 
Rehabilitation facilities 
 
Nursing homes 
 
Routine emergency room admissions 
 
Surgeries at the same day (as outpatient/same day/ambulatory procedures) 
Hospitalization or prolongation of hospitalization which are unrelated to the exacerbation of AEs 
will not be considered as SAEs. For example, 
 
Admission for treatment of a preexisting condition without the development of new 
adverse events or worsening of the preexisting condition (e.g., for check of persistent 
pre-trial laboratory test abnormality); 
 
Administrative admission (e.g., for yearly physical exam); 
 
Hospitalization as per the trial protocol during the study (e.g., as required by the 
protocol); 
 
Elective admission not associated with the aggravation of adverse events (e.g., elective 
surgery); 
 
Predefined treatments or surgical procedures should be documented throughout the study 
program and/or in the baseline data of individual subject. 

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 
A subject is hospitalized due to only use of blood products. 
Diagnostic or therapeutic invasive (e.g., operation) and non-invasive procedures should not be 
reported as AE, but if the disease condition leading to the operation, it should be reported as long 
as it conforms to the definition of AE, e.g., acute appendicitis during the AE reporting period 
should be reported as AE; therefore, the appendectomy should be recorded as the treatment of AE. 
9.2.6 
Reporting procedures of SAE 
The reporting of SAEs starts from the signing of informed consent form to 90 days (inclusive the 
90th day) after the last dose of investigational drug. In case of SAE, regardless of first report or 
follow-up report, the investigators must fill in the “serious adverse event report form” 
immediately, sign and date it, report it to the sponsor within 24 hours after learning of it, and 
report it to relevant organizations in time as required by regulations. 
The sponsor’s email to receive SAE report in this study: hengrui_drug_safety@shhrp.com  
The SAEs occurring 90 days after the last dose of investigational drug will generally not be 
reported, unless it is suspected to be related to the investigational drug. The detailed record 
content of SAE should include symptoms, severity, and causality with investigational drug, time 
of onset, time of treatment, actions taken, follow-up time and method as well as outcome. If the 
investigator considers that an SAE is not related to investigational drug while potentially related 
to the study conditions (e.g., termination of the original treatment or complications during the 
trial), the relationship should be described in detail in the narrative section of SAE report form. 
If there is a change in the severity of an ongoing serious adverse event or its relationship with the 
investigational drug, follow-up reports should be submitted immediately. If misinformation is 
considered to be present in the previously reported SAE, it can be corrected, withdraw or 
degraded in the follow-up report, and reported in accordance with the SAE reporting procedure. 
9.2.7 
Follow-up of SAE 
An SAE should be followed up until it is resolved, returns to the baseline level ≤ Grade 1, or 
reaches a stable state, or until other reasonable time points (e.g., lost to follow-up, death). 
9.3 
Pregnancy 
If a female subject is pregnant during the clinical study, the subject will be withdrawn from the 
group, investigators should fill in “Pregnancy Report/Follow-up Form in Hengrui Clinical 
Study”, and report to the sponsor within 24 hours after investigator awareness. 
If the partner of male subject becomes pregnant during the clinical study, the subject can 
continue the clinical trial, investigators should fill in “Pregnancy Report/Follow-up Form in 
Hengrui Clinical Study”, and report to the sponsor within 24 hours after investigator awareness. 

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The investigator should follow up the pregnancy result, until one month after delivery, and will 
report the result to sponsor. 
If the outcome of pregnancy is stillbirth, spontaneous abortion, or fetal malformations, it should 
be considered as an SAE and be reported in accordance with SAE reporting requirements. 
If an SAE occurs during pregnancy, the investigator is required to complete the “Serious Adverse 
Event Report Form” and report this SAE according to the reporting procedures. 
9.4 
AEs of Special Interest 
For the AE of special interest specified in the clinical study protocol, investigators need to fill in 
the “Adverse Event of Special Interest Report Form in Hengrui Clinical Study” within 24 hours 
after awareness, and report to the sponsor. 
If it is SAE at the same time, please also fill in “Serious Adverse Event Report Form” and report 
to the relevant department in accordance with SAE procedure.  
 
≥ Grade 3 infusion reaction 
 
≥ Grade 2 diarrhea/colitis, uveitis, or interstitial pneumonia 
 
≥ Grade 3 other immune-associated adverse events 
 
Any possible event of abnormal hepatic enzyme (see Section 9.2.3, whilst lacking other 
related causes, for example, progression of disease, acute viral hepatitis, cholestasis, 
concomitant medication, pre-existing hepatopathy, etc.) 
 
Grade 4 increased amylase or lipase 
9.5 
Emergency Unblinding 
Not applicable. 
10 DATA MANAGEMENT 
10.1 Material Collection and Data Management 
Electronic case report form (eCRF) will be used for collection and management of the study data 
in this study. 
10.1.1 
Collection of data 
eCRF is used for acquisition of study data in this study; the electronic data collection (EDC) 
system will be provided by Jiangsu Hengrui Pharmaceuticals Co., Ltd. to study institutions. The 
company’s staff will train on EDC system for the designated personnel at the study institutions. 
The personnel at the study institutions can login EDC system only after the training. PI or 
specialized person for data entry (qualified investigator and/or CRC) should enter the data into 

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EDC system in accordance with the requirement for visit procedure and the guideline on filling 
in eCRF. The system logic verification program will check the completeness and logicality of the 
clinical trial data entered in EDC system, and generate error message for the problem data, 
allowing PI, investigator or CRC to modify or explain the data. After the database is locked, 
investigators will receive one CD-ROM or hard copy of the data, for archival at the study 
institution. 
10.1.2 
Data management and quality control 
In order to ensure the clinical data are true and reliable, improve the quality of clinical data, 
clinical monitors will review the completeness, consistency and accuracy of the trial data in 
clinical database in accordance with monitoring plan during the trial, and discuss with the study 
staff on the problem data, and the study staff should make supplement or correction when 
necessary. The clinical monitor or data management professionals will propose their queries on 
the questionable data to PI, investigator or CRC in a form of electronic query table, PI, 
investigator or CRC must respond to the queries and make correction or explanation to the 
problem data, the query can be proposed for multiple times until the problem data are solved, if 
necessary. The person in charge of medical affairs, drug safety affairs and data management 
professionals will conduct consistency comparison for SAE on a regular basis. 
At the end of the trial, the data management professionals and medical staff will do the final 
quality control of all the data in the database, summarize all the protocol deviations and 
violations appeared in the trial, and convene data verification meeting. After the data in the 
database meet the requirement for quality, the database will be locked, the data management 
professionals will export data for analysis by statistical department. 
10.1.3 
Data review and monitoring of study institution 
At the initiation of the trial, the representatives from Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
will introduce the protocol and eCRF together with investigators and working staff at the first 
visit to study institutions or in the investigator’s meeting. During the trial, the monitor will visit 
study centers on a regular basis, check the completeness of record and accuracy of the content on 
eCRF, compliance with the protocol and Good Clinical Practice, progress in enrollment, and 
make sure the investigational drug is stored, dispensed and counted in accordance with the 
provisions. During these visits, the key study staff must be able to assist the monitors. 
Investigators must keep the original documents of each subject participating in the trial, 
including the study medical records and visit records (hospitalization or outpatient medical 
record), which include demographic parameters and medical information, laboratory data, ECG 
and results of any other examination or evaluation. All the information on eCRF must be sourced 
from the original document in the subject’s archives. Investigators also have to keep the 
informed consent forms signed by subjects. 

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Investigators must confirm all the relevant original documents can be monitored, so as to verify 
the consistency with that on eCRF. The monitoring standard by Jiangsu Hengrui Pharmaceuticals 
Co., Ltd. requires a 100% monitoring for study-related original documents, including but not 
limited to informed consent form signed by the subject, compliance with inclusion/exclusion 
criteria, visit record, AE/SAE record, and all the data required for evaluation of the main efficacy 
and safety parameters. Any information on subject’s identity in the original documents will not 
be disclosed. 
11 DATA ANALYSIS AND STATISTICAL METHODS 
The detailed summary of the data collected in this study and the statistical analysis method will 
be recorded in the statistical analysis plan (SAP), and will be finalized and put on record by the 
sponsor. If any change to the study protocol is judged by the sponsor or the principal investigator 
to have an impact on the statistical analysis plan, the SAP needed to be re-modified so as to keep 
consistency with the study protocol. 
11.1 Determination of Sample Size 
This is a single-arm, open-label phase II study to observe the objective response rate (ORR) and 
survival rate at 6 months simultaneously.  
Referring to the study results on similar products, assuming the ORR is 15% for SHR-1210 in 
treatment of target population of this study, and the lower limit of 95% confidential interval of 
ORR obtained from this study is >7%, it can be considered as effective. 154 subjects need to be 
enrolled to obtain 90% power at a one-sided significance level of 0.025. Further assuming 
evaluable cases accounting for 80% of the enrolled subjects, 194 subjects are required to be 
enrolled.  
Assuming the survival rate at 6 months is 80% for SHR-1210 in treatment of target population, 
and the lower limit of 95% confidential interval is >70%, this therapy can be considered to have 
advantage in efficacy. 200 subjects need to be enrolled to obtain 90% power at a one-sided 
significance level of 0.025. Considering the drop-out rate of 10%, a total of 220 subjects are 
required to be enrolled.  
Therefore, the planned sample size of this study is 220. 
11.2 Analysis Populations 
Full analysis set (FAS): an analysis set determined in accordance with intention-to-treat 
principle. All the subjects who are randomized and have documented at least one dose of 
investigational drug will be included in this analysis set. The full analysis set is the primary 
efficacy analysis set.  

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Per protocol set (PPS): one subset of full analysis set. The subjects with protocol violation which 
has important influence on efficacy will be excluded from this set. The list of subjects who are 
included or excluded from PPS needs to be determined through review by the sponsor and 
investigators prior to lock of database.  
Safety analysis set (SS): all the subjects who are randomized and have documented at least one 
dose of investigational drug will be included in the safety analysis set.  
PD-L1 analysis set: PD-L1 expression analysis set of this trial comprise of all the subjects who 
have been randomized and enrolled and have received at least one dose of the investigational 
drug, and have provided tumor biopsy samples.  
11.3 Statistical Analysis 
11.3.1 
General analysis 
Unless otherwise specified, the continuous variables in this study will be summarized with mean, 
standard deviation, median, maximum and minimum; the categorical variables will be 
summarized with frequency and percentage; Kaplan-Meier method will be used to estimate the 
survival rate and plot survival curve for time-event data. 
11.3.2 
Efficacy analysis 
The tumor evaluation will be performed by the investigators based on RECIST v1.1. This 
evaluation data will be based on following responding parameters: complete response (CR), 
partial response (PR), stable disease (SD), progression of disease (PD), and not evaluable (NE). 
All the efficacy analysis will be based on the full-analysis set. 
The survival distribution of OS will be estimated based on Kaplan-Meier (KM) method, median 
OS and two-sided 95% confidential interval will be calculated. In addition, KM method will be 
used to estimate the probability of survival at different time points (at month 6/9/12), and the 
corresponding 95% confidential interval will be calculated. Moreover, the subgroup analysis of 
OS will be performed by the predefined factors, the analytical method will be based on the 
aforementioned method.  
The survival distribution of time to progression (TTP) will be estimated based on Kaplan-Meier 
(KM) method, median TTP and two-sided 95% confidential interval will be calculated. 
The survival distribution of progression-free survival (PFS) will be estimated based on Kaplan-
Meier (KM) method, median PFS and two-sided 95% confidential interval will be calculated. 
Objective response rate (ORR) and disease control rate (DCR): Clopper-Pearson method will be 
used to calculate the 95% confidential interval of overall percentage.  

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11.3.3 
Safety analysis 
Analysis of adverse events will be based on the safety analysis set. The data for analysis will 
include but not limited to the calculation of the incidence of adverse reactions by group; 
incidences and frequencies of adverse reactions by system; calculation of the percentage and 
detailed listing of a variety of adverse events, and the specific analysis will be presented in the 
statistical analysis plan.  
Number of “normal to abnormal” or “exacerbation of abnormal” laboratory parameters, ECG, 
physical examinations and the abnormality conversion rate after the trial, the number of 
abnormal laboratory parameters, ECG, physical examinations and the clinical explanation would 
be presented. 
11.3.4 
Exploratory analyses 
PD-L1 expression will be analyzed using descriptive statistics. PD-L1 analysis set is the analysis 
data set.  
12 INFORMED CONSENT AND ETHICS 
12.1 Informed Consent 
The clinical research physician must fulfill the obligation of full disclosure to the subjects, and 
explain to subjects that they are voluntary to participate in the clinical trial, and have the right to 
withdraw from the trial without discrimination and retaliation at any time during the trial, their 
medical treatment and benefits would not be affected at all and they could still continue other 
treatment. The subjects must be made aware that the participation in the trial and the personal 
data in the trial are kept confidential. The property, objective, expected possible benefit and 
possible risks and inconvenience of the trial are also needed to be informed to the subjects, the 
available other therapies, rights and obligations for subjects in compliance with the Helsinki 
Declaration should be informed to the subjects, allowing subjects to have adequate time to 
consider whether they are willing to participate in the trial and sign the informed consent form.  
12.2 Ethical Principles 
This trial protocol needs to be approved by the hospital ethics committee prior to its conduct with 
written approval. The study protocol, amendments, informed consent form and other relevant 
documents, e.g., recruitment advertisement, should be provided to the ethics committee. This 
study shall be conducted strictly in accordance with the Declaration of Helsinki and Good 
Clinical Practice (GCP) and relevant regulations issued by NMPA. Prior to the start of the trial, 
the approval from the ethics committee must be obtained, the study could be initiated then. 

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The sponsor and investigator must not amend this study protocol unilaterally without mutual 
agreement. Only limited to eliminate the direct and immediate injury to subjects, investigators 
can change or deviate from the study protocol prior to approval by the ethics 
committee/institutional review board. At the same time, all the deviations or changes made, their 
reasons, and the recommended amendment to the protocol should be submitted to the ethics 
committee/institutional review board for review as soon as possible, and communicate with the 
sponsor. Investigators must explain and record any deviation from the protocol. 
During the clinical study, any amendment made to the study protocol should be submitted to the 
ethics committee, corresponding amendment should also be made to other study documents 
when necessary and submitted and/or approved as required by the ethics committee. 
Investigators are responsible for periodic submission of the in-trial report to the ethics committee 
in accordance with relevant requirement, and should inform the ethics committee that the trial 
has ended after the end of trial. 
12.3 Regulatory Considerations 
SHR-1210 for injection, innovatively developed and submitted for approval by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd., has been approved by NMPA, and given the clinical trial approval for 
national Class I new drugs. Now, the nationwide, multi-center, phase II/III clinical trial on SHR-
1210 for injection in the subjects with advanced hepatocellular carcinoma who had received 
systematic treatment previously is conducted in accordance with Drug Registration Regulation 
and GCP, led and organized by National Drug Clinical Research Institute of the 81st Hospital of 
PLA (Nanjing).  
12.4 Security Measures of Subject Information 
Every effort will be made to protect subject's personal privacy during the study. Subject's name 
and other personal privacy information must not be included in the study related documents, 
study report, publications and any other public materials, unless required by the law. Collection, 
transmission, process and maintenance of subject's information will be in accordance with the 
provisions in relevant laws and regulations, so as to protect subject's personal data from 
disclosure. 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
 
The clinical trial institution must be the base of drug clinical trials determined by NMPA 
with clinical study conditions; 
 
The study staff must be the qualified persons who have been trained on clinical trials, and 
conduct their work under the guidance of highly specialized personnel.  

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 
The clinical ward must be in accordance with the standardized requirement before the trial, 
so as to ensure complete rescue equipment; 
 
The dose will be given by healthcare professionals, intake of the drug will be carefully 
understood, so as to ensure subject’s compliance; 
 
Each study center must conduct it strictly in accordance with the study protocol and fill in 
the eCRF truthfully; 
 
The monitor should follow the standard operating procedure to supervise the conduct of the 
clinical trial, confirm proper and complete record and report of all the data, accurate filling 
of all the eCRFs and consistency with the original data, and ensure the trial is conducted in 
accordance with the protocol; 
 
Once SAE occurs, the sponsor must inform each study unit promptly, the study needs to be 
discontinued temporarily if necessary; 
 
Each center participating in the trial should receive the audit from the sponsor and Food and 
Drug Administrations, it is particularly important for the investigators and relevant staff to 
provide convenience and time for the monitoring and audit. 
14 PUBLICATION OF STUDY RESULTS 
Hengrui does not restrict the investigators to publish any information collected or produced, 
despite whether this result favors for the investigational drug. However, in order to make sure no 
unintentional leakage of the confidential information or unprotected invention, the investigators 
must give an opportunity for sponsor to review any proposed publication or publication in other 
forms in advance prior to submission or publication of the documents. If the study is one part of 
one multi-center study, the investigators need to agree on the first publication of the 
comprehensive results from all the study centers. However, if the manuscript of the 
comprehensive analysis has not been submitted for publication within 12 months after 
completion or termination of the study at all the study sites, investigators can request 
independent publication of the results in accordance with other requirement in this section. 
15 SCHEDULE OF THE TRIAL 
Expected Oct. 2016 to May 2018 (primary endpoint analysis) 
16 PROTOCOL COMPLIANCE 
Investigators will guarantee that every effort will be made to avoid violations from the protocol. 
Investigators cannot contact with Jiangsu Hengrui Pharmaceuticals Co., Ltd. to request approval 
of the violation from the protocol at any time, as no any authorized violation of the protocol shall 

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be allowed. If investigators consider some deviation from the protocol can improve the 
implementation of the trial, amendment to the protocol must be considered, however, it can be 
conducted only when the amendment is agreed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
and approved by the medical ethics committee. All the major violations from the protocol will be 
recorded and reported on the clinical trial report.  
17 STUDY SITE AND PARTICIPATING PERSONNEL 
17.1 Leading Site 
Name: the 81st Hospital of PLA  
Address: No. 34, Yanggongjing 34, Qinhuai District, Nanjing, Jiangsu 
Study Team Leader: Shukui Qin, Professor  
17.2 Sponsor 
Name of sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Sponsor’s person responsible for the project: See signature page 
Address: No. 7 Kunlunshan Road, Economic and Technological Development Zone, 
Lianyungang City, Jiangsu Province 
Telephone: See signature page 
E-mail: See signature page 
17.3 Other Study Participating Personnel 
 
 

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2. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in 
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3. Josep ML, Sergio R, Vincenzo M, et al. Sorafenib in Advanced Hepatocellular Carcinoma. 
N Engl J Med, 2008, 359:378-90. 
4. Park J W, Finn R S, Kim J S et al. Phase II, open-label study of brivanib as first-line therapy 
in patients with advanced hepatocellular carcinoma. Clin Cancer Res, 2011, 17(7) : 1973-
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5. Sun W, Sohal D, Haller D G, et al. Phase II trial of bevacizumab, capecitabine, and 
oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer, 2011, 117(14) :3187-
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6. Eisenhauer, EA, Therasse P, Boqaerts J, et al., New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009, 45(2) : 228-257. 
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Immunol Immunother (2007) 56:739–745. 
8. Julie R. Brahmer, Charles G. Drake, Ira Wollner, et al. Phase I Study of Single-Agent Anti-
Programmed Death-1(MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, 
Pharmacodynamics, and Immunologic Correlates. J Clin Oncol 2010 Jul. 28:3167-3175. 
9. David F. McDermott, Michael B Atkins. PD-1 as a potential target in cancer therapy. Cancer 
Medicine 2013; 2(5): 662–673. 
10. Omid Hamid, Caroline Robert, Adil Daud, et al. Safety and Tumor Responses with 
Lambrolizumab （Anti-PD-1）in Melanoma. N Engl J Med 2013. DOI: 
10.1056/NEJMoa1305133. 
11. Suzanne L. Topalian, F Stephen Hodi, Julie R, Brahmer, et al. Safety, Activity, and Immune 
Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012;366:2443-54. 
12. C. Zielinski, S. Knapp, C. Mascaus, et al. Rationale for targeting the immune system through 
checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Annals of 
Oncology 2013. 24: 1170–1179. 

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13. Omid Hamid, Richard D Carvajal. Anti-programmed death-1 and anti-programmed death-
ligand 1 antibodies in cancer therapy. Expert Opin. Biol. Ther. (2013)13(6):847-861 
14. Caroline Robert, Antoni Ribas, Jedd D Wolchok. Anti-programmed-death-receptor-1 
treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a phase 1 trial. http://dx.doi.org/10.1016/S0140-6736(14)60958-2 
15. Chuan-Yong Mu, Jian-An Huang, Ying Chen.High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
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16. Qiang Gao, Xiao-Ying Wang, Shuang-Jian Qiu. Overexpression of PD-L1 Significantly 
Associates with Tumor Aggressiveness and Postoperative Recurrence in Human 
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17. China Food and Drug Administration, Provisions for Drug Registration. 2007. 
18. China Food and Drug Administration, Good Clinical Practice. 2003 
 
 

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Annex 1 Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 
1 
Measurability of Tumor at Baseline Level 
1.1 
Definition 
At baseline level, tumor lesions/lymph nodes can be divided as measurable and non-measurable 
according to the definitions below: 
Measurable Lesions 
Tumor lesions: at least one diameter that could be precisely measured (recorded as maximum 
diameter), its minimum length is as below: 
 
10 mm for CT scan (thickness of CT scan is no more than 5 mm) 
 
10 mm for clinical routine instrument (tumor lesion that could not be accurately measured 
by diameter-measuring instrument should be recorded as non-measurable) 
 
20 mm for chest X-ray 
 
Malignant lymph nodes: pathologically enlarged and measurable, and short axis ≥ 15 mm for 
single lymph node in CT scan (thickness of CT scan recommended no more than 5 mm). 
Only the short axis is measured and followed up at baseline and during follow-up. 
Non-measurable Lesions 
All the other lesions, including small lesions (maximum diameter < 10 mm or short axis of 
pathological lymph node ≥ 10 mm and < 15 mm) and non-measurable lesions. Non-measurable 
lesions include: meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
cancer, skin/pulmonary cancerous lymphatic inflammation, abdominal mass that cannot be 
diagnosed and followed up by radiology, as well as cystic lesion. 
Special Considerations on the Measurement of Lesions 
Osseous lesion, cystic lesion and the lesion previously given topical therapy needed to be 
specially noted: 
Osseous lesion: 
 
Bone scan, PET scan or plain X-ray are inappropriate for measurement of osseous lesions, 
however, they can be used for confirmation of the presence or disappearance of osseous 
lesions; 
 
If the osteolytic lesion or mixed osteolytic/osteogenic lesion with determined soft tissue 
component could be evaluated with tomographic imaging technique, such as CT or MRI, 
when the soft tissue component meets the above definition on measurability, these lesions 
can be regarded as measurable lesion; 

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 
Osteoblastic lesions belong to non-measurable lesions. 
Cystic lesions: 
 
The lesions meeting the definition of radiologically simple cyst should not be considered as 
malignant foci as they are simple cysts in terms of the definition; they are neither measurable 
lesions nor the non-measurable lesions. 
 
Cystic metastatic lesions that meet the above definition on measurability can be considered 
as measurable lesions. However, if non-cystic lesions are present in the same patient, the 
non-cystic lesions should be preferably selected as the target lesion. 
Lesions treated topically: 
 
The lesions located at the site once radiated or treated with other topical therapies are 
generally considered as non-measurable lesions, unless clear progression occurred in these 
lesions. The study protocol should describe the conditions for these lesions to become 
measurable lesions in detail. 
1.2 
Description of Measurement Method 
Measurement of Lesions 
Measurement of all the tumors is recorded in meter in the clinical evaluation. All the baseline 
evaluations in terms of the size of tumor foci should be completed as close as possible to the start 
of treatment, and must be completed within 28 days (4 weeks) prior to the start of treatment. 
Methods of Evaluation 
Baseline evaluation and subsequent measurements of a lesion should be carried out by the same 
techniques and methods. All the lesions must be radiologically evaluated except those that cannot 
be radiologically evaluated but only be evaluated with clinical examinations. 
Clinical lesion: only the superficial clinical lesions with diameter ≥ 10 mm measured could be 
considered as measurable lesions (e.g., cutaneous nodule). For patients with cutaneous lesions, it 
is advised to use the color image containing one ruler to measure the size of lesion for 
documentation. When the lesion is evaluated with radiology and clinical examination 
simultaneously, the radiological evaluation should be used as much as possible as it is more 
objective and can be reviewed repeatedly at the end of the study. 
Chest X-ray: when the progression of tumor is used as the important endpoint, chest CT should 
be used preferably, as it is more sensitive than X-ray, in particular for new lesions. Breast X-ray 
are only suitable when the lesion measured has a clear border and pulmonary ventilation is 
patent. 

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CT, MRI: CT is currently the best reproducible method for evaluation of efficacy. The definition 
of measurability in this guideline is based on the thickness of CT scan ≤ 5 mm. If the thickness 
of CT scan is more than 5 mm, the measurable lesion should be at least 2 times of the thickness. 
MRI could also be accepted in some circumstances (e.g., systemic scan). 
Ultrasound: ultrasound should not be used as one method for measurement of the size of lesion. 
Ultrasonography is not reproducible due to its dependency on the operation, thus could not 
ensure the technical and measurement consistency between different measurements. If one new 
lesion is found in ultrasound during the trial, CT or MRI should be used for confirmation. If the 
exposure to the radiation from CT scan is considered, alternative MRI can be used. 
Endoscopic and laparoscopic examination: these techniques are not recommended for the 
objective evaluation of tumors, however, these methods can be used for confirmation of CR 
when biopsy specimen is obtained, and for confirmation of recurrence in the trial while 
recurrence after CR or surgical resection are taken as the study endpoint. 
Tumor marker: tumor marker cannot be used independently to evaluate the objective response of 
tumors. However, if the marker level exceeds the upper limit of normal at baseline, it must return 
to the normal level when it is used to evaluate complete response. As the tumor marker varies for 
disease, it is needed to be considered when including this measurement criterion in the protocol. 
The specific criteria on CA-125 response (recurrent ovarian cancer) and PSA response (recurrent 
prostate cancer) have been published. The criteria on CA-125 progression have been established 
by the international organization of gynecological cancers, i.e., it will be added in the evaluation 
criteria on the objective response of tumors in the 1st-line therapy for ovarian cancer. 
Cytological /histological technology: in the specific situations specified in the protocol, these 
techniques can be used to differentiate PR and CR (e.g., residual benign tumor tissue is usually 
present in the lesions of germline cell tumors). When exudation is possibly one potential side 
effect of one therapy (e.g., Taxanes or angiogenesis inhibitor), and the measurable lesion met the 
criteria on response or stable disease; cytological technique could be used to differentiate 
response (or stable disease) and progression of disease when tumor related exudation occurred or 
became exacerbated during the treatment. 
2 
Tumor Response Evaluation 
2.1 
Evaluation of Target Lesions 
Complete response (CR): all target lesions disappear, and the minimum diameter of all pathological 
lymph nodes must decrease to < 10 mm (including target nodes and non-target nodes). 
Partial response (PR): The sum of diameter of target lesion decreases by at least 30% from the 
baseline level. 

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Progressive disease (PD): The sum of diameter of all measurable target lesions increases by at 
least 20% over the minimum value of such sum or over the baseline measured value (whichever 
is smaller), and the absolute value of such sum should increase by at least 5 mm. Or there are one 
or more new lesions. 
Stable disease (SD): The target lesion does not decrease in a degree of PR or increase by an 
intensity of PD, but changes in the intensity between PR and PD (the minimum sum of diameter 
is used as reference). 
2.2 
Considerations on Target Lesion Evaluation 
Lymph node: Even when the lymph node of target lesion decreases to less than 10 mm, the 
corresponding actual value of minimum diameter should be recorded at each examination (same 
as dissection plane at baseline examination). That means if lymph node is considered as target 
lesion, the lesion cannot be regarded as complete disappearance despite meeting the requirements 
of CR, because the minimum diameter of normal lymph node is defined as < 10 mm. In eCRF or 
other record ways, the lesion of target lymph node should be recorded in specific position: in 
case of CR, the minimum diameter of all lymph nodes should be <10 mm; and in case of PR, SD 
and PD, the actual measured value of minimum diameter of target lymph node will be included 
into the sum of diameter of target lesion. 
Target lesion too small to be measured: In clinical study, for all lesions recorded at baseline 
(including nodular or non-nodular lesion), the actual measured value should be recorded again at 
the subsequent assessment even if the lesion is very small (e.g., 2 mm). However, the lesion may 
sometimes be so small that the image of CT scanning is so obscure that it is very difficult to 
determine a definite value even by the radiologists, and then such lesion may be reported as too 
small to be measured. In this case, it is very important to record a value in eCRF. If the 
radiologists think that the lesion may disappear, such lesion should also be recorded as 0 mm. If 
the lesion exists really but is too obscure to be measured accurately, the default value can be 
regarded as 5 mm. (note: such case is improbable to appear in the lymph nodes, because they are 
generally of measurable dimension under the normal conditions or they are often wrapped with 
fat tissue just like those in the retro peritoneum. However, if the accurate examination is 
impossible just as mentioned above, the default value can also be regarded as 5 mm). The default 
value of 5 mm is obtained from the cutting depth of CT scanning, but does not change with such 
depth. Since the same measured value is improbable to reappear, this default value is offered so 
as to reduce the risk for wrong assessment. However, to be reaffirmed, if the radiologists cannot 
offer a precise value for size of lesion, the actual value should be recorded even if the diameter of 
lesion is less than 5 mm. 

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When the non-nodular lesion is split into fragment, the maximum diameter of each separated part 
is added up as the sum of diameter of lesion. Likewise, the merged lesion is first distinguished 
through the plane between each merged part, and then the maximum diameter of each merged 
part is calculated; but if the merging is too tight to be split, the overall maximum diameter of 
merged lesion should be regarded as maximum diameter of lesion. 
2.3 
Evaluation of Non-target Lesions 
The criteria of response are defined as follows for the tumor of non-target lesion. If some non-
target lesions are actually measurable but need not be measured, only a qualitative assessment 
needs to be made at the time point stipulated in the protocol. 
Complete response (CR): All non-target lesions disappear, and the level of tumor marker becomes 
normal. All lymph nodes are of non-pathological dimension (minimum diameter < 10 mm). 
Non-complete Response or non-progressive Disease-Persistence: 1 or more non-target lesion(s) 
and/or maintenance tumor marker level above normal limits. 
Progressive disease (PD): a definite progress appears in the existing non-target lesion. Note: PD 
is also regarded if there is one or more new lesion. 
2.4 
Special Precautions for Evaluation of Non-target Lesion Progression 
Supplementary explanation for defining the progression of non-target lesion: For measurable 
non-target lesions, a definite progress can be judged on the basis of non-target lesion only when 
the non-target lesion has deteriorated in an overall intensity necessary for treatment termination, 
even if the target lesion is assessed as SD or PR. However, the ordinary increase in the 
dimension of one or more non-target lesions is often insufficient to reach the criteria of PD. 
Therefore, when the target lesion is assessed as SD or PR, it is nearly very rare to judge overall 
progression only according to the change of non-target lesion 
When all non-target lesions are unmeasurable, such condition will appear in some Phase III 
studies if the necessary existence of measurable lesion is not stipulated in the inclusion criteria, 
and the overall assessment is still made by referring to the above-mentioned criteria because 
there are unmeasurable data of lesions in this case. Since the deterioration of non-target lesions is 
difficult to assess (as defined, all non-target lesions should be really unmeasurable), a definite 
progress is judged according to the non-target lesion and an effective examination method should 
be established for assessment if the change of non-target lesion increases the overall load of 
disease in an intensity equivalent to the PD of target lesion. e.g. the increase in tumor load is 
equivalent to the additional increase of 73% in volume (i.e. equivalent to an increase of 20% in 
the diameter of measurable lesion); the peritoneal exudates change from trace to massive, with a 
change in the lesion of lymph duct from localized to extensive (or enough to change the 

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therapeutic method as described in the protocol); or pleural exudates change from trace to 
massive, with a spreading of involved lymph from original position to distal position (or 
necessary to change the therapeutic method as described in the protocol). In case of definite 
progress, PD should be overall judged for this patient at that time point. The objective 
assessment criteria had better be established for unmeasurable lesion (note: the added criteria 
should be reliable). 
2.5 
New Lesions 
Since the emergence of new malignant lesions predicts a PD, it is very important to make some 
assessment of such new lesions. At present, there are no concrete criteria for imaging 
examination of lesions, but a new lesion can be found only in a definite way. E.g., PD shall not 
be based on the difference in imaging technique, the change in imaging morphology or the 
lesions other than tumor (e.g. some so-called new bone lesions are only the cure of original 
lesions or the recurrence of original lesions). When the baseline lesion is judged as PR or CR, 
such treatment is very important, e.g., the necrosis in one liver lesion may be judged as new 
cystic lesion in the CT report, which does not actually appear. 
If a lesion is found during the follow-up but not found at the baseline examination, a new lesion 
should be identified, and PD is indicated. E.g., when a metastatic lesion is found at skull CT or 
MRI in the patients with visceral lesion found at baseline examination, such intracranial 
metastatic lesion is regarded as the basis for PD even though the skull examination is not made at 
baseline examination. 
If a new lesion is not definite for some reasons (e.g., due to small dimension), a further treatment 
and follow-up evaluation should be made to determine whether this lesion is new. If a new lesion 
is verified through the repeated examination, the time of PD should be calculated by starting 
from the time of its preliminary finding. 
For FDG-PET assessment of lesions, an additional examination is generally required for 
supplementary confirmation, and it is rational to evaluate the conditions of progress by 
combining the results of FDG-PET examination and supplementary CT examination (especially 
for new suspicious disease). A new lesion can be definitely judged through the FDG-PET 
examination according to the following criteria: 
The results of baseline FDG-PET examination are negative but the results of subsequent FDG-PET 
examination are positive at follow-up, indicating a PD; 
The baseline FDG-PET examination is not made and the results of subsequent FDG-PET 
examination are positive; 

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The new lesion is shown by the positive results of FDG-PET examination at follow-up, which 
consists with the results of CT examination, verifying a PD. 
If the new lesion indicated by the positive results of FDG-PET examination at follow-up is not 
confirmed by the results of CT examination, CT examination should be made again for 
confirmation (if such new lesion is confirmed, the time of PD should be calculated by starting 
from the time of abnormal finding at previous FDG-PET examination). 
If the lesion indicated by the positive results of FDG-PET examination at follow-up does not 
consist with that confirmed by the results of CT examination and the imaging showed no 
progression of such lesion, PD is not judged. 
2.6 
Explanation for Absence of Evaluation or Non-evaluation 
If the imaging or examination of lesions cannot be made at a specific time point, this patient is 
judged as unevaluable at this time point. If only some lesions are evaluated at an evaluation, this 
patient is generally judged as unevaluable at this time point, unless the lesions of missing 
evaluation are verified through some evidences as no influence on the evaluation of efficacy 
response at a specified time point. 
2.7 
Special Hints for Efficacy Evaluation 
When the nodular lesion is included into overall assessment of target lesion and this node is 
shrunk to normal size (< 10 mm), there should still be scanning report on the size of lesions. To 
avoid overestimation of the condition reflected on the basis of node size, the measurement results 
will be recorded, even though the node is normal. Just as mentioned above, for the patients 
judged as CR, 0 is not recorded in the eCRF. 
If it is required to confirm response during trial, optimal efficacy evaluation will be complicated 
by repeated “immeasurable” time points. The analytical plan of study should specify that: while 
judging the efficacy, such missing data/evaluation can be clearly explained. E.g., in most studies, 
the response of PR-NE-PR in a certain patient can reflect that the efficacy is confirmed. 
When the treatment has to be terminated after the overall deterioration of health conditions but 
not verified disease progression through the objective evidence, a symptomatic progress should 
be reported. Even after the termination of treatment, the conditions of objective progress should 
also be assessed as far as possible. The symptomatic deterioration is not the assessment 
description of objective response, but the reason for termination of treatment. The conditions of 
objective response in such patients will be assessed through the conditions of target and non-target 
lesions as stipulated in attached Table 1−3. 

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In special case, an early progress, early death and unevaluable condition can be judged, which 
should be definitely described in each protocol (according to the interval and cycle of treatment). 
In some cases, it is very difficult to distinguish the localized lesions from normal tissues. When 
complete response is judged on the basis of such definition, a biopsy is recommended to be 
performed before the localized lesion is judged as CR. When a lesion fibrosis or scar formation is 
considered according to the abnormal results of imaging examination on localized lesions in 
some patients, FDG-PET is used as assessment criteria similar to biopsy for confirming the 
efficacy of CR. In this case, the application of FDG-PET should be described prospectively in 
the protocol, which is supported through the report on the specialty medical literatures for such 
conditions. However, to be noteworthy, a false positive result of CR judgment can be caused by 
the limitation of FDG-PET and biopsy (including their resolution and sensitivity). 
Table 1 
Time Point Response-Patients with Target Lesions (Including Non-target Lesions 
or Not) 
Target lesion 
Non-target lesion 
New lesions 
Overall response 
CR 
CR 
None 
CR 
CR 
Non CR/non PD 
None 
PR 
CR 
Unevaluable 
None 
PR 
PR 
Non-progress or incomplete 
assessment 
None 
PR 
SD 
Non-progress or incomplete 
assessment 
None 
SD 
Incomplete assessment 
Non-progress 
None 
NE 
PD 
Any conditions 
Any conditions 
Any conditions 
PD 
Any conditions 
Y or N 
Y or N 
Yes 
PD 
PD 
PD 
Note: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NE= non-
evaluable. 
Table 2 
Time Point Response-Patients with Only Non-target Lesions 
Non-target lesion 
New lesions 
Overall response 
CR 
None 
CR 
Non-CR or non-PD 
None 
Non CR/Non PD 
Incomplete assessment 
None 
Unevaluable 
Indefinite PD 
Y or N 
PD 
Any conditions 
Yes 
PD 
Note: For the non-target lesions, “non-CR or non-PD” means an efficacy superior to SD. Since SD becomes more 
and more as endpoint index of efficacy evaluation, the efficacy of non-CR or non-PD is stipulated when the 
conditions of no measurable lesions are not specified.  

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In case of indefinite progress finding (e.g., very small uncertain new lesions and cystic 
degeneration or necrotic lesion of original lesions), the treatment can continue until the next 
assessment of efficacy. If PD is verified at the next assessment, the date of progression should be 
the date of previous suspicious progression. 
Table 3 
Best Overall Response for Which It Is Required to Confirm CR and PR 
Overall response at the 
first time point 
Overall response at the 
subsequent time points 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
If SD lasts for a sufficient time, SD is judged; 
otherwise PD is judged 
CR 
PD 
If SD lasts for a sufficient time, SD is judged; 
otherwise PD is judged 
CR 
NE 
If SD lasts for a sufficient time, SD is judged; 
otherwise NE is judged 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
If SD lasts for a sufficient time, SD is judged; 
otherwise PD is judged 
PR 
NE 
If SD lasts for a sufficient time, SD is judged; 
otherwise NE is judged 
NE 
NE 
NE 
Note: CR is complete response, PR is partial response, SD is stable disease, PD is progressive 
disease, and NE is non-evaluable. Superscript “a”: If actual CR occurs at the first time point, 
then for any disease occurs at subsequent time points, its response evaluation is PD at subsequent 
time points (as the disease occurs again after CR), even though the response evaluation of the 
patient meets the PR criteria. The best response depends on whether SD appears within the 
minimum treatment interval. However, although CR is judged at the first time point, a small 
lesion sometimes seems to still appear under the scanning at the subsequent time points; and 
therefore, the efficacy at the first time point is actually judged as PR but not as CR. In this case, 
PR (but not CR) should be judged at the first time point, and PR is considered as the best 
response. 
 

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2.8 
Confirmation of Efficacy Evaluation/Response Period 
Efficacy Confirmation 
In the non-randomized clinical study with tumor response as primary study endpoint, the efficacy 
of PR and CR should be confirmed to ensure that the efficacy is not caused by error in 
evaluation. However, in the studies with SD or PD as primary study endpoint, the efficacy should 
not be confirmed again, because such efficacy confirmation is useless for explaining the study 
results. In case of SD, at least one measurement complies with the SD criteria specified in the 
protocol at the minimum time interval (generally not less than 6−8 weeks) after start of the trial.  
Duration of response 
The overall duration of response is calculated as time duration from first conformance with the 
criteria of CR or PR (whichever is earlier) to first actual recording with recurrence or progression 
of disease (the minimum measured value recorded in the studies will be used as reference for the 
calculation of PD). The overall response time is the period from the time when the measurement 
first meets the CR criteria to the time when disease or progressive disease is first recorded. 
Duration of stable disease 
The duration of SD is calculated as time duration from start of treatment to PD (or from 
randomization in the randomized trial), with the minimum sum in the trial as reference value 
(and the sum of baseline level will be used as reference for the calculation of PD, if it is the 
minimum). The clinical relevance during stable disease varies in different studies and for 
different diseases. If, in a certain trial, the proportion of patients maintaining the minimum stable 
disease time is used as research endpoint, then the protocol shall describe particularly the 
minimum time interval between two measurements in the definition of SD. 
Notes: The response period, the stable disease period and PFS are impacted by follow-up 
frequency after baseline evaluation. This guideline is not applicable to define the standard 
frequency of follow-up. The frequency of follow-up should be determined by various factors, 
including type/stage of disease, treatment cycle and standard specifications. However, if a 
comparison needs to be made between studies, the limitation in the accuracy of these 
measurement endpoints should be considered. 
2.9 
PFS/TTP 
PFS or TTP is used as the primary endpoint in many trials for advanced tumors. If all the patients 
are required to have measurable lesions in the protocol, evaluation of progression will be 
relatively simple. More and more trials allow patients with or without measurable lesions to be 
enrolled. In such circumstance, the clinical finding of progression of disease must be described 

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carefully and clearly for patients without measurable lesions. As the date of progression often has 
a deviation in its determination, the time point for observation should be the same for each test 
group.  
Annex 2 Child-Pugh Classification on Hepatic Function 
Indicators 
Score 
 
1 
2 
3 
Hepatic encephalopathy 
None 
Grade 1−2 
Grade 3−4 
Ascites 
None 
Mild 
Moderate and above 
Prolonged prothrombin time or INR 
1−3 seconds 
4−6 seconds 
> 6 seconds 
< 1.7 
1.7−2.3 
> 2.3 
Total bilirubin (μmol/L) 
< 34 
34−51 
> 51 
Serum albumin (g/L) 
> 35 
28−35 
< 28 
Note: 5−6 for Grade A; 7−9 for Grade B and 10−15 for Grade C;  
Grade A and the better part of Grade B (i.e., score 7) can be enrolled.  
Annex 3 Criteria for ECOG Performance Status 
ECOG PS 
Standard 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work 
2 
Being capable of free walking and self-care, but loss of working ability, can get up for activities 
in no less than half time of a day.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Loss of self-care. Totally confined to bed or chair 
5 
Death 

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Annex 4 Recommended Rules for Management of Immune-related Adverse Events 
1. Rules for management of gastrointestinal adverse event 
 
Non-inflammatory etiology should be excluded. Opioids/anesthetic may cover the symptom of perforation. 
Infliximab cannot be used in case of perforation/sepsis. 
Diarrhea/colitis Grade 
Treatment 
Follow-up 
Grade 1 
Diarrhea: defecation frequency  
< 4 times/day beyond baseline  
Colitis: no symptom 
Grade 2 
Diarrhea: defecation frequency  
4−6 times/day beyond baseline; 
requiring intravenous infusion  
< 24 hours; no effect on daily living 
Colitis: abdominal pain; 
hematochezia 
Grade 3-4 
Diarrhea (Grade 3): defecation 
frequency ≥ 7 times/day beyond 
baseline; fecal incontinence; 
requiring intravenous infusion  
≥ 24 hours; affect daily life 
Colitis (Grade 3): severe abdominal 
pain; indicative of medical 
intervention; peritoneal sign 
Grade 4: life-threatening, perforation 
Continue I-O therapy 
according to the study 
protocol 
Symptomatic treatment 
Delay I-O therapy according 
to the study protocol 
Symptomatic treatment 
Stop I-O therapy according to 
the study protocol 
1.0−2.0 mg/kg/day 
Methylprednisolone iv or 
equivalent dose iv drip 
Addition of preventive 
antibiotics for prevention of 
opportunistic infection 
Endoscopy of lower digestive 
tract considered 
Close monitoring of symptoms exacerbated 
Educate patients to report immediately in case of 
exacerbation 
If exacerbated:  
Treat with the method for Grade 2 or 3/4 
If improved to Grade 1: 
Resume I-O therapy according to study protocol 
If lasting for > 5−7 days or recurrence:  
0.5−1.0 mg/kg/day Methylprednisolone iv or 
equivalent dose orally 
When the symptom is improved to Grade 1, 
reduce dose of steroids for at least one month, 
and consider preventive use of antibiotics for 
If improved: 
Continue steroid treatment until recovery to 
Grade 1, then gradually reduce the dose of 
steroids for at least one month 
If lasting for > 3−5 days or recurrence post 
improvement:  
Add Infliximab 5 mg/kg (in case of no 
contraindications). Note: Infliximab cannot be 
used in case of perforation or sepsis.  
Once continuous clinical improvement is observed, the patients receiving intravenous steroids can switch to equivalent dose of oral 
corticosteroid (e.g., prednisone) at the same time or earlier than the dose is reduced gradually. When switching to the equivalent dose 
of oral corticosteroid, low bioavailability of oral corticosteroid should be considered.  

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2. Rules for management of pulmonary adverse events 
 
Once continuous clinical improvement is observed, the patients receiving intravenous steroids can switch to equivalent dose of oral 
corticosteroid (e.g., Prednisone) at the same time or earlier than the dose is reduced gradually. When switching to the equivalent 
dose of oral corticosteroid, low bioavailability of oral corticosteroid should be considered.  
Pneumonia grading 
Treatment 
Follow-up 
Grade 1 
Only radiological change 
Grade 2 
Mild-to moderate new 
symptom 
Grade 3-4 
Severe new symptom; 
new/exacerbated hypoxia; 
life-threatening 
Consider delayed I-O therapy 
Monitor symptoms every 2−3 days 
Consider consultation from the 
department of respiratory medicine and 
infectious diseases 
Delay I-O therapy according to study protocol 
Request consultation from the department of 
respiratory medicine and infectious diseases 
Monitor symptoms daily, consider 
hospitalization 
1.0 mg/kg/day Methylprednisolone iv or 
equivalent dose orally 
Consider bronchoscopy and pulmonary biopsy 
Discontinue I-O therapy according to study 
protocol 
hospitalization 
Request consultation from the department of 
respiratory medicine and infectious diseases 
2−4 mg/kg/day Methylprednisolone iv or 
equivalent dose iv 
Add preventive antibiotics for preventing 
opportunistic infection 
Consider bronchoscopy and pulmonary biopsy 
Radiological examination at least every three weeks 
If exacerbated:  
Treat with the method for Grade 2 or 3−4 
Radiological examination at least every 2−3 days 
If improved:  
When the symptom is recovered close to baseline, 
reduce the dose of steroids for at least one month, then 
resume I-O therapy according to study protocol and 
consider preventive use of antibiotics 
If not improved or exacerbated two weeks later:  
Treat with the method for Grade 3 or 4 
If improved to baseline:  
Reduce the dose of steroids gradually for at least 6 
weeks 
If not improved or exacerbated 48 hours later: 
Add other immunosuppressants (e.g., Infliximab, 
cyclophosphamide, intravenous immunoglobulin or 
Mycophenolate mofetil) 
Non-inflammatory etiology should be excluded. Symptomatic treatment should be given and I-O 
therapy should be continued in case of non-inflammatory etiology. Radiological evaluation will be 
performed and a consultation from the department of respiratory will be requested. 

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3. Rules for management of hepatic adverse events 
 
Once continuous clinical improvement is observed, the patients receiving intravenous steroids can switch to equivalent dose of oral 
corticosteroid (e.g., Prednisone) at the same time or earlier than the dose is reduced gradually. When switching to the equivalent dose of oral 
corticosteroid, low bioavailability of oral corticosteroid should be considered.  
*In case of AST/ALT ≤ 8×ULN and T.bili ≤ 5×ULN, I-O therapy can be delayed rather than discontinued.  
**For Grade 4 hepatitis, the recommended initial dose of Methylprednisolone iv drip is 2 mg/kg/day.  
Treatment 
Follow-up 
Elevated hepatic 
function Grade 
Non-inflammatory etiology should be excluded. Symptomatic treatment should be given and I-O therapy 
should be continued in case of non-inflammatory etiology. Radiological evaluation will be considered to 
exclude obstruction/progression of tumor. 
Grade 3-4 
AST or ALT > 5×ULN 
and/or T.bili > 3×ULN 
Continue I-O therapy according to 
study protocol 
Delay I-O therapy according to study 
protocol 
Increase monitoring frequency to once 
every three days 
Discontinue I-O therapy* 
Increase monitoring frequency to once 
every 1−2 days 
1.0−2.0 mg/kg/day Methylprednisolone 
iv or equivalent dose iv 
Add preventive antibiotics for 
prevention of opportunistic infection 
Request a consultation from the 
department of gastroenterology 
Continue monitoring of hepatic function according to study 
protocol 
If exacerbated:  
Treat with the method for Grade 2 or 3/4 
If returned to baseline:  
Resume routine monitoring, and I-O therapy according to study 
protocol 
If elevated for > 5−7 days or exacerbated:  
0.5−1 mg/kg/day Methylprednisolone iv or equivalent dose 
orally, if LFT is recovered to Grade 1 or baseline, reduce the 
dose of steroids for at least one month, use antibiotics for 
prevention of opportunistic infection, then resume I-O therapy 
according to study protocol 
If returned to Grade 2:  
Reduce the dose of steroids for at least one month 
If not improved, exacerbated or rebound > 3−5 days:  
Add Mycophenolate mofetil 1g bid 
If not relieved within 3−5 days, consider other 
immunosuppressants according to local guideline 
Grade 2 
AST or ALT > 3.0 to  
≤ 5×ULN and/or T.bili 
> 1.5 to ≤ 3×ULN 
 
Grade 1 
AST or ALT > ULN-
3.0×ULN and/or 
T.bili >ULN-1.5×ULN 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
 
Hengrui Confidential 
 
Version Number: 5.0 
Date of Version: 3 Apr., 2018  
80 / 81 
 
4. Rules for management of endocrine adverse event 
 
Once continuous clinical improvement is observed, the patients receiving intravenous steroids can switch to equivalent dose of oral 
corticosteroid (e.g., Prednisone) at the same time or earlier than the dose is reduced gradually. When switching to the equivalent dose of 
oral corticosteroid, low bioavailability of oral corticosteroid should be considered.  
Non-inflammatory etiology should be excluded. Symptomatic treatment should be given and I-O therapy 
should be continued in case of non-inflammatory etiology. Perimetry, consultation from the department of 
endocrinology and radiological examination will be considered. 
Asymptomatic 
elevation of TSH 
Symptomatic 
endocrine change 
Suspected adrenal 
crisis (e.g., serious 
dehydration, 
hypotension, shock not 
in accordance with the 
intensity of the disease) 
Continue I-O therapy according to study protocol 
If TSH <  0.5*LLN or TSH > 2*ULN, or continuously beyond the range in subsequently two 
consecutive measurements: detect free T4 in subsequent cycles according to clinical indication; 
consider consultation from the department of endocrinology 
Evaluate endocrine function 
Consider pituitary scanning 
Symptom and abnormal laboratory examination/pituitary 
scanning: 
Delay I-O therapy according to study protocol 
1−2 mg/kg/day Methylprednisolone iv or equivalent dose orally 
Start corresponding hormone therapy 
No abnormality in laboratory examination/pituitary MRI but 
symptom persists:  
Repeat the laboratory examination in 1−3 weeks, repeat 
pituitary MRI one month later 
Delay or discontinue I-O therapy according to study 
protocol 
Exclude sepsis 
Steroids containing mineralocorticoid component iv at 
stress dose 
Intravenous infusion 
Consult endocrinologist  
Treat symptomatic endocrine change according to the above 
method if adrenal crisis is excluded 
If improved (with or without 
hormone replacement):  
Reduce the dose of steroids for 
at least one month, and consider 
preventive use of antibiotics to 
prevent opportunistic infection 
Resume I-O therapy according 
to study protocol 
Patients with adrenal insufficiency 
may need continuous use of the 
steroids containing 
mineralocorticoid component 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Number: SHR-1210-II/III-HCC 
Study Protocol 
 
 
 
Hengrui Confidential 
 
Version Number: 5.0 
Date of Version: 3 Apr., 2018  
81 / 81 
 
5. Rules for management of cutaneous adverse events 
 
(Weber JS, Postow M, Lao CD, Schadendorf D. Management of Adverse Events Following Treatment With Anti-Programmed Death-1 
Agents. Oncologist. 2016 Jul 8: 2016-0055.) 
Once continuous clinical improvement is observed, the patients receiving intravenous steroids can switch to equivalent dose of oral corticosteroid (e.g., Prednisone) at 
the same time or earlier than the dose is reduced gradually. When switching to the equivalent dose of oral corticosteroid, low bioavailability of oral corticosteroid 
should be considered.  
Treatment 
Follow-up 
Rash Grade 
If improved to Grade 1: 
Reduce the dose of steroids for at least one month, and add 
preventive antibiotics to prevent opportunistic infection 
Resume I-O therapy according to study protocol 
If lasting for > 1−2 weeks or recurrence:  
Consider skin biopsy 
Delay I-O therapy according to study protocol 
0.5−1.0 mg/kg/day Methylprednisolone iv or equivalent 
dose orally 
Once improved, reduce the dose of steroids for at least one 
month, consider preventive antibiotics to prevent 
opportunistic infection, and resume I-O therapy according to 
study protocol 
If exacerbated:  
Treat with the method for Grade 3−4 
Symptomatic treatment (e.g., antihistamine 
drug, topical steroids) 
Continue I-O therapy according to study 
protocol 
Delay or discontinue I-O therapy according to 
study protocol 
Consider skin biopsy 
Request a consultation from the department of 
dermatology 
1.0−2.0 mg/kg/day Methylprednisolone iv or 
equivalent dose iv 
 
Grade 1−2 
Coverage ≤ 30% body 
surface area 
 
Grade 3−4 
Coverage > 30% body 
surface area (BSA); or 
life-threatening result