A Phase 2 Study of SHR-1210 (PD-1 Antibody) in Combination With Apatinib or Chemotherapy (FOLFOX4 or GEMOX) in Subjects With Advanced Primary Liver Cancer（PLC）or Biliary Tract Carcinoma (BTC)
Phase: PHASE2
Conditions: Advanced Primary Liver Cancer, Advanced Biliary Tract Carcinoma
Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Title: A Phase II Clinical Study of PD-1 Antibody SHR-1210 in Combination with 
Apatinib Mesylate or Chemotherapy in the Treatment of Advanced Primary Liver 
Cancer or Extrahepatic Cholangiocarcinoma  
Clinical trial registration number: NCT03092895  
Version Date: 12 May., 2018 

Translated from Original Document 
Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
Confidentiality Statement 
This document contains important confidential business information proprietary to Jiangsu Hengrui Pharmaceuticals 
Co., Ltd., and should not be disclosed unless required by current laws or regulations. In any case, all personnel 
receiving this document should be notified of this confidential requirement and should not further disclose this 
information. This disclosure restriction also applies to all future confidential documents provided by the company. 
 
 
 
 
A Phase II Clinical Study of PD-1 Antibody 
SHR-1210 in Combination with Apatinib 
Mesylate or Chemotherapy in the Treatment 
of Advanced Primary Liver Cancer or 
Extrahepatic Cholangiocarcinoma 
 
 
Protocol No.: 
SHR-1210-APTN-II-203-PLC 
Version No. 
2.0 
Version Date: 
12 May, 2018 
 
 
 
 
 
 
 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Version No.: 2.0 
Version Date: 12 May 2018                Page 2 of 132 
Version History/Revision History 
Document 
Version Date 
Amendment Rationale and Summary of Changes 
1.0 
17 Feb., 2017 
Not applicable 
2.0 
12 May 2018 
Increased the number of subjects with extrahepatic 
cholangiocarcinoma in group B; added the study basis of 
immunotherapy combined with oxaliplatin plus gemcitabine 
chemotherapy in malignant bile duct tumors; adjusted the 
number of cases in group B due to changes in the study 
population; revised the section of statistics for group B; 
revised articles 3 and 5 of the inclusion criteria; added 
relevant contents of the investigational drug gemcitabine; 
 
 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 3 
Sponsor's Signature Page 
I have read and confirmed this study protocol (study no.: SHR-1210-APTN-II-203-PLC, 
version no.: 2.0, version date: 12 May 2018). I agree to fulfill my duties in accordance 
with Chinese laws, the Declaration of Helsinki, the Chinese GCP, and this study protocol. 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Sponsor's Medical Director: _____________________ (print)  
 
_____________________(signature) 
Signature Date: ______________________ 
Telephone: __________________________ 
 
   
       
 
 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
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Principal Investigator's Signature Page (Coordinating Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, 
and personally participate in or directly lead this clinical study. I have received the 
Investigator's Brochure for the investigational drugs; I have read the materials of 
preclinical studies of the investigational drugs and the protocol for this clinical trial. 
I agree to fulfill my duties in accordance with Chinese laws, the Declaration of Helsinki, 
the Chinese GCP, and this study protocol. I agree that any modifications to the protocol 
must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the Ethics Committee, unless measures must be taken to protect the safety, 
rights and interests of the subjects. It is my responsibility to make clinically relevant 
medical decisions to ensure appropriate and timely treatments in subjects experiencing 
adverse events during the study period, and to document and report such adverse events 
in accordance with relevant state regulations. I will document all data in medical records 
in a truthful, accurate, complete and timely manner. I agree to be monitored and audited 
by the clinical research associate or auditor assigned by the sponsor, and to be inspected 
by the drug regulatory authorities, to ensure the quality of the clinical trial. I will keep the 
personal information of and matters related to the subjects confidential. I agree to 
disclose my full name and occupation to the sponsor, and the expenses related to the 
clinical study upon request. I agree not to engage in any commercial and economic 
activities related to this study. I agree for the study results to be used for drug registration 
and publication. I will provide a resume before the start of the study, submit it to the 
ethics committee, and to the drug regulatory authority for filing purposes. 
 
Study Site: 
 
 
 
Principal Investigator:_____________________(print)  
 
_____________________(signature)  
Signature Date:______________________ 
Telephone: __________________________ 
Address:____________________________ 
Postal Code:_________________________ 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 5 
Principal Investigator's Signature Page (Participating Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, 
and personally participate in or directly lead this clinical study. I have received the 
Investigator's Brochure for the investigational drugs; I have read the materials of 
preclinical studies of the investigational drugs and the protocol for this clinical trial. 
I agree to fulfill my duties in accordance with Chinese laws, the Declaration of Helsinki, 
the Chinese GCP, and this study protocol. I agree that any modifications to the protocol 
must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the ethics committee, unless measures must be taken to protect the safety, 
rights and interests of the subjects. It is my responsibility to make clinically relevant 
medical decisions to ensure appropriate and timely treatments in subjects experiencing 
adverse events during the study period, and to document and report such adverse events 
in accordance with relevant state regulations. I will document all data in medical records 
in a truthful, accurate, complete and timely manner. I agree to be monitored and audited 
by the clinical research associate or auditor assigned by the sponsor, and to be inspected 
by the drug regulatory authorities, to ensure the quality of the clinical trial. I will keep the 
personal information of and matters related to the subjects confidential. I agree to 
disclose my full name and occupation to the sponsor, and the expenses related to the 
clinical study upon request. I agree not to engage in any commercial and economic 
activities related to this study. I agree for the study results to be used for drug registration 
and publication. I will provide a resume before the start of the study, submit it to the 
ethics committee, and to the drug regulatory authority for filing purposes. 
 
Study Site: _______________________________ 
Principal Investigator:_____________________(print) 
 
_____________________(signature) 
Signature Date: __________________________ 
Telephone: ______________________________ 
Address:________________________________ 
Postal Code: ____________________________ 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
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TABLE OF CONTENTS 
Version History/Revision History ................................................................................................ 2 
Sponsor's Signature Page ............................................................................................................. 3 
Principal Investigator's Signature Page (Coordinating Center) .............................................. 4 
TABLE OF CONTENTS .............................................................................................................. 1 
LIST OF TABLES ......................................................................................................................... 3 
LIST OF FIGURES ...................................................................................................................... 4 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
SCHEDULE OF ACTIVITIES .................................................................................................. 13 
ABBREVIATIONS AND DEFINITIONS ................................................................................ 21 
1 
BACKGROUND .................................................................................................................. 23 
1.1 Epidemiology and Current Treatment Status of Liver Cancer ............................................. 23 
1.2 Research Developments in Targeted Therapies for Liver Cancer ........................................ 24 
1.3 Background of Immunotherapy in Liver Cancer .................................................................. 25 
1.4 Study Basis of Combined Immunotherapy in Hepatobiliary Malignancies ........................ 28 
1.5 Scientific Basis ....................................................................................................................... 31 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 41 
2.1 Study Objectives .................................................................................................................... 41 
3 
STUDY DESIGN .................................................................................................................. 42 
3.1 Study Design .......................................................................................................................... 42 
3.2 Study Procedures ................................................................................................................... 46 
4 
RANDOMIZATION AND BLINDING ............................................................................. 51 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................... 51 
5.1 Inclusion Criteria ................................................................................................................... 51 
5.2 Exclusion Criteria .................................................................................................................. 53 
5.3 Concomitant Medications/Treatments .................................................................................. 55 
5.4 Re-screening Criteria for Subjects......................................................................................... 57 
5.5 Criteria of Study Medication Discontinuation or Study Withdrawal for Subjects .............. 58 
5.6 Subject Number ..................................................................................................................... 58 
 
 

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6 
STUDY DRUGS ................................................................................................................... 58 
6.1 Information ............................................................................................................................. 58 
6.2 Packaging and Labeling of Study Drugs ............................................................................... 60 
6.3 Drug Dispensation ................................................................................................................. 60 
6.4 Drug Storage and Management ............................................................................................. 60 
6.5 Disposal of Remaining Drugs ............................................................................................... 61 
6.6 Method of Administration ..................................................................................................... 61 
7 
DOSE MODIFICATION AND SAFETY MANAGEMENT ........................................... 62 
7.1 Dose Modification ................................................................................................................. 62 
7.2 Common Recommendations on Safety Management .......................................................... 70 
8 
SAFETY EVALUATION..................................................................................................... 78 
8.1 Adverse Event (AE) ............................................................................................................... 78 
8.2 Serious Adverse Event (SAE) ............................................................................................... 79 
8.3 Pregnancy ............................................................................................................................... 83 
8.4 Adverse Events of Special Interest ........................................................................................ 83 
8.5 Emergency Unblinding .......................................................................................................... 83 
9 
DATA MANAGEMENT ...................................................................................................... 84 
9.1. Data Collection ..................................................................................................................... 84 
9.2 Data Management and Quality Control ................................................................................ 84 
9.3 Data Review and Study Site Monitoring .............................................................................. 84 
10 DATA ANALYSIS AND STATISTICAL METHOD......................................................... 85 
10.1 Determination of Sample Size ............................................................................................. 85 
10.2 Analysis Population ............................................................................................................. 86 
10.3 Statistical Analysis ............................................................................................................... 86 
10.4 Bayesian Logistic Regression Model (BLRM) .................................................................. 87 
11 INFORMED CONSENT AND ETHICS REGULATION ............................................... 88 
11.1 Informed Consent ................................................................................................................. 88 
11.2 Ethics .................................................................................................................................... 88 
11.3 Regulatory Considerations................................................................................................... 89 
11.4 Confidentiality of Subject Information ............................................................................... 89 
 
 

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12 QUALITY CONTROL AND ASSURANCE ..................................................................... 89 
13 PUBLICATION OF STUDY RESULTS ............................................................................ 90 
14 TRIAL PROGRESS ............................................................................................................ 91 
15 TRIAL PROTOCOL COMPLIANCE ............................................................................... 91 
16 STUDY SITES AND TRIAL STAFF ................................................................................. 91 
16.1 Coordinating Center ............................................................................................................. 91 
16.2 Sponsor ................................................................................................................................. 91 
16.3 Other Participants ................................................................................................................ 91 
17 REFERENCES ..................................................................................................................... 92 
Appendix 1. Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) ..................... 96 
Appendix 2. Child-Pugh Score of Liver Function ....................................................................... 110 
Appendix 3. ECOG Performance Status Scoring Criteria ........................................................... 110 
Appendix 4. Management Principles for Immune Related Adverse Events ................................ 111 
Appendix 5. Definition of the prior probability distribution f(θ) of the  
unknown parameter vector θ in the BLRM ............................................................ 116 
Appendix 6. Packaging and Labeling of Study Drugs. ................................................................ 118 
LIST OF TABLES 
Table 1. Binding affinity of SHR-1210 to human, monkey, and rat PD-1 antigens ..................... 32 
Table 2. Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigens .................. 33 
Table 3. PK parameters after a single intravenous infusion at different doses of  
SHR-1210 in cynomolgus monkeys ............................................................................. 34 
Table 4. Comparison of efficacy results of the subjects in the two groups (FAS) ........................ 36 
Table 5. Comparison of incidences of adverse events and adverse drug  
reactions of the subjects in the two groups (SS) ........................................................... 37 
Table 6. Common AEs (incidence ≥ 10%) in both groups............................................................ 38 
Table 7. Efficacy of medication with the antibody and the compound on  
xenograft in MC38 (PD-L1) tumor-bearing mice ......................................................... 39 
Table 8. Dose levels for group A .................................................................................................. 44 
Table 9. Dose levels for group B .................................................................................................. 45 
Table 10. Rules for dose modification of apatinib mesylate (applicable to group A). .................. 66 

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Table 11. Rules for dose modification of chemotherapy (applicable to group B). ....................... 68 
Table 12. Rules for dose modification of oxaliplatin in the chemotherapy  
regimen when sensory neuropathy occurs (applicable to group B). .......................... 69 
Table 13. Treatment recommendations for immune-related adverse drug reactions. ................... 72 
 
LIST OF FIGURES 
Figure 1. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab ........................ 33 
Figure 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab ................................ 33 
Figure 3. Effects of medication with the antibody and the compound on the 
 relative volume of xenograft in MC38 (PD-L1) tumor-bearing mice ....................... 40 
Figure 4. Efficacy of medication with the antibody and the compound on  
xenograft in MC38 (PD-L1) tumor-bearing mice - tumor weight .............................. 40 
Figure 5. Effects of medication with the antibody and the compound on the  
weight of xengraft in MC38 (PD-L1) tumor-bearing mice ......................................... 41 
 
 

Investigational Drug No.: SHR-1210 
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PROTOCOL SYNOPSIS 
Study Title 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in Combination with Apatinib 
Mesylate or Chemotherapy in the Treatment of Advanced Primary Liver Cancer or 
Extrahepatic Cholangiocarcinoma 
Protocol No. 
SHR-1210-APTN-II-203-PLC 
Version No. 
2.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
 
 
Study Population 
Patients with advanced primary liver cancer (PLC)/extrahepatic cholangiocarcinoma 
Study Objective 
Primary Objectives: 
 
The safety and tolerability of PD-1 antibody SHR-1210 in combination with apatinib 
mesylate or the FOLFOX4 or GEMOX regimen in the treatment of advanced primary 
liver cancer or extrahepatic cholangiocarcinoma. 
Secondary Objectives: 
 
To preliminarily observe the efficacy of PD-1 antibody SHR-1210 in combination with 
apatinib mesylate or the FOLFOX4 or GEMOX regimen in the treatment of advanced 
primary liver cancer or extrahepatic cholangiocarcinoma. 
Study Endpoints 
Primary Endpoints: 
 
The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
(per the NCI-CTCAE V4.03 criteria). 
Secondary Endpoints: (per the RECIST 1.1 criteria) 
 
Objective response rate (ORR) 
 
Duration of response (DoR) 
 
Disease control rate (DCR) 
 
Time to progression (TTP) 
 
Overall survival (OS) 

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Study Design 
This study is an open-label phase II study, and 152 patients with advanced primary liver 
cancer or extrahepatic cholangiocarcinoma are intended to be enrolled. Subjects will be 
enrolled into treatment group A or B based on whether they have received systemic treatment 
before. 
Subjects in group A will receive treatment of SHR-1210 in combination with apatinib 
mesylate (APTN) for exploring the optimal dose first. The objective is to determine the 
optimal dose of SHR-1210 combined with APTN in patients with advanced primary liver 
cancer. After the determination of the optimal dose of the combined medication, the case 
extension stage was proceeded for collecting sufficient safety data of the combination of 
immunotherapy and targeted therapy. 
Subjects in group B will receive treatment of SHR-1210 in combination with the FOLFOX4 
or GEMOX regimen. The objective is to explore the safety and tolerability of the 
immunotherapy combined with systemic chemotherapy. 
Subjects in group A will be given dose level 1 as the starting dose. The subjects will be 
enrolled in the group in sequence (see Table 1) from low dose to high dose to explore the 
optimal dose. The first cycle (28 days) of continuous medication is the tolerability 
observation period. After the tolerability observation period, if none of the 3 subjects 
experienced clinically significant toxicity, the next group of dose may be explored. If 1 of the 
3 subjects developed clinically significant toxicity, another 3 subjects will be enrolled. If no 
clinically significant toxicity was observed in the later-enrolled 3 subjects, the next group of 
dose may be explored. If ≥ 1 of the 3 later-enrolled subjects developed clinically significant 
toxicity again, the dose exploration will be terminated. The dose prior to the current one is 
the tolerable dose. 
Also, the Bayesian logistic regression model (BLRM) was used as an auxiliary analysis to 
help explore the probability of clinically significant toxicity at different doses. 
Finally, the optimal dose level for case extension is determined through dose exploration, 
with 8-12 subjects enrolled, to collect sufficient safety data for the combination therapy. 
The dose levels for group A are as follows: 
Dose 
Level 
SHR-1210 
Apatinib Mesylate 
(APTN) 
Number of 
Enrolled Subjects 
1 
3 mg/kg Q2W 
125 mg QD (once daily) 
3-6 
2 
3 mg/kg Q2W 
250 mg QD 
3-6 
3 
3 mg/kg Q2W 
375 mg QD 
3-6 
4 
3 mg/kg Q2W 
500 mg QD 
3-6 
A regimen will be selected by the investigator for the subjects in group B according to Table 
2. Six (6) subjects are first enrolled to receive treatment at dose level 1. If the proportion of 
subjects showing clinically significant toxicity in the 6 subjects is < 0.33, some other 122 
subjects will be enrolled to receive treatment at the same dose level. The dose levels for 
group B are as follows: 
 

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Dose 
Level 
SHR-1210 
FOLFOX4 
Number of 
Enrolled 
Subjects 
1 
3 mg/kg 
Q2W 
D1: Oxaliplatin (OXA) 85 mg/m2 
(2-h infusion) + levoleucovorin 
(LV) 200 mg/m2 (2-h infusion), 
followed by fluorouracil 400 mg/m2 
(bolus injection), and fluorouracil 
600 mg/m2 (22-h infusion) 
D2: Levoleucovorin (LV) 200 
mg/m2 (2-h infusion), followed by 
fluorouracil 400 mg/m2 (bolus 
injection), and fluorouracil 
600 mg/m2 (22-h infusion) 
Q2W 
Approximately 
122 subjects 
GEMOX 
D1: Gemcitabine 800 mg/m2 
(80-min infusion) 
D2: Oxaliplatin (OXA) 85 mg/m2 
(2-h infusion) 
Q2W 
During the study period, imaging tumor assessments are performed every 8 weeks (± 7 days) 
until disease progression or the subject's initiation of other anti-tumor treatments. 
Screening Criteria 
Inclusion Criteria: 
1. 
Male and female subjects aged 18-70 years old. 
2. 
Patients with histologically or cytologically confirmed advanced primary liver cancer or 
extrahepatic cholangiocarcinoma (only applicable to group B, including gallbladder 
cancer and common bile duct cancer) who are not suitable for surgery or local 
treatment, and have at least one measurable lesion (RECIST 1.1 criteria). 
3. 
Group A: Patients who have previously undergone systemic therapy for advanced 
primary liver cancer, molecular targeted therapy (sorafenib, etc.) and/or systemic 
chemotherapy (monotherapy or combination therapy) but have failed or become 
intolerable; 
Group B: Patients who have not previously undergone systemic treatment (molecular 
targeted therapy or chemotherapy) of advanced primary liver cancer or extrahepatic 
cholangiocarcinoma. 
4. 
There must have been at least a 2-week interval between the completion of previous 
anti-tumor treatment and the start of the investigational drug, or have reached the drug 
wash-out period (that is, 5 times the half-life of the drug), and treatment-related AE 
resolved to NCI-CTCAE Grade ≤ 1. 
5. 
Subjects with primary liver cancer or a history of liver cirrhosis must meet the 

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Child-Pugh score: Class A and Class B (≤ 7 points). 
6. 
ECOG PS: 0-1. 
7. 
Expected survival ≥ 12 weeks. 
8. 
Subjects with chronic HBV infection must have HBV-DNA < 500 IU/mL, and patients 
with positive HBsAg must receive antiviral treatment in accordance with the 2015 
"Guidelines for the Prevention and Control of Chronic Hepatitis B". Patients with 
positive HCV-RNA must receive antiviral treatment in accordance with the 2015 
"Guidelines for the Prevention and Control of Chronic Hepatitis C" and hepatic function 
tests must be within the normal range. 
9. 
Major organs must function normally, meeting the following criteria: 
(1) Hematology: (no blood transfusion or use of hematopoietic stimulating factors 
within 14 days before screening) 
1) 
HB ≥ 90 g/L; 
2) 
ANC ≥ 1.5 × 109/L; 
3) 
PLT ≥ 80 × 109/L; 
(2) Biochemistry: (no blood transfusion or use of blood products within 14 days prior 
to screening) 
1) 
ALB ≥ 29 g/L; 
2) 
ALT and AST < 2.5  ULN; 
3) 
TBIL ≤ 1.5  ULN; 
4) 
Creatinine ≤ 1.5  ULN; 
(3) Prothrombin time (PT) - International Normalized Ratio (INR) ≤ 2.3 or 
prothrombin time (PT) ≤ 6 seconds from normal 
10. Female subjects of childbearing potential must have a negative serum or urine 
pregnancy results within 14 days prior to the start of the study treatment, and be willing 
to take effective contraceptive measures during the study period and within 60 days 
after the last dose of the investigational drug. Male subjects with partners of 
childbearing potential must have undergone surgical sterilization or agree to take 
effective contraceptive measures during the course of the study until 120 days after the 
last dose of the investigational drug. 
11. Subjects must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 
Exclusion Criteria: 
1. 
Known fibrolamellar hepatocellular carcinoma; other uncured malignancies in the past 
(within 5 years) or concurrently. Except for localized tumors that have been cured, such 
as basal cell carcinoma, squamous cell carcinoma, superficial bladder cancer, prostate 
carcinoma in situ, cervical carcinoma in situ, and breast carcinoma in situ. 
2. 
Current or past metastasis to the central nervous system. 

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3. 
Symptomatic ascites requiring therapeutic paracentesis or drainage, or with a 
Child-Pugh score > 2. 
4. 
History of gastrointestinal bleeding within the past 6 months or a high risk of bleeding 
such as esophageal varices with bleeding risk, active ulcers, and persistent positive fecal 
occult blood. 
5. 
Known hereditary or acquired hemorrhage and thrombophilia, such as hemophilia 
patients. 
6. 
Abdominal fistula, gastrointestinal perforation, or abdominal abscess within 2 months 
prior to the study. 
7. 
Grade II or higher myocardial ischemia or myocardial infarction, uncontrolled 
arrhythmias (including QTcF interval ≥ 450 ms in males and ≥ 470 ms in females) (QTc 
interval calculated using Fridericia's Formula). 
8. 
NYHA Class III-IV cardiac insufficiency or LVEF (left ventricular ejection fraction) < 
50% by echocardiography. 
9. 
Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
10. Thromboembolism events that have occurred in the past 6 months, such as 
cerebrovascular events (including transient ischemia attacks) and pulmonary embolism. 
11. Dysphagia, chronic diarrhea, or intestinal obstruction, which significantly affect drug 
intake and absorption. 
12. History of hepatic encephalopathy. 
13. Untreated active hepatitis (Hepatitis B: positive HBsAg with abnormal liver function 
and HBV-DNA ≥ 500 IU/ mL; Hepatitis C: positive HCV-RNA with abnormal liver 
function). 
14. Infection with human immunodeficiency virus (HIV). 
15. Subjects with active infection or unexplained fever (body temperature > 38.5 °C) during 
screening or prior to the first dose. 
16. Received any vaccine treatment within 30 days prior to enrollment. 
17. Patients planning to receive or previously received allogeneic organ or allogeneic bone 
marrow transplants, including liver transplant. 
18. Subjects with previous or current pulmonary fibrosis, interstitial pneumonia, 
pneumoconiosis, radiation-induced pneumonitis, drug-induced pneumonitis, severe lung 
function impairment or other conditions that may interfere with the detection and 
management of suspected treatment-related pulmonary toxicities. 
19. Urine protein ≥ 2+ and 24-h urine protein > 1.0 g as indicated by urinalysis. 
20. Subjects with active, known, or suspected autoimmune diseases; subjects who are stable 
and do not require systemic immunosuppressive treatment may be enrolled. 

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21. Subjects requiring systemic treatment with corticosteroids (> 10 mg/day of prednisone 
or equivalent) or other immunosuppressive medications within 14 days prior to the 
administration of the investigational drug; in the absence of active autoimmune disease, 
inhaled or topical use of corticosteroids and an equivalent dose to > 10 mg/day of 
prednisone for adrenal hormone replacement are permitted. 
22. Received local treatment for liver within 4 weeks prior to participating in this study 
(including but not limited to surgery, radiation, hepatic artery embolization, TACE, 
hepatic arterial infusion, radiofrequency ablation, cryoablation, or percutaneous ethanol 
injection). 
23. Palliative radiotherapy for symptomatic control of non-target lesions is permitted but 
must be completed at least 2 weeks prior to the start of the investigational drug, and no 
additional radiotherapy should be scheduled for the same lesion; radiation-induced 
adverse events that have not resolved to CTCAE grade ≤ 1; 
24. Subjects who have previously received other PD-1 antibody treatment or other 
immunotherapies targeting PD-1/PD-L1. 
25. Known history of severe allergies to any monoclonal antibodies, anti-angiogenesis 
targeted drugs, platinums, fluorouracils and other components of the investigational 
drug. 
26. Requiring long-term anticoagulant therapy with warfarin or heparin; requiring 
long-term antiplatelet therapy (aspirin ≥ 300 mg/day, clopidogrel ≥ 75 mg/day). 
27. Subjects with a known history of psychotropic substance abuse or drug abuse. 
28. Pregnant or breastfeeding women. 
29. Patients with any other potential factors that may result in the premature termination of 
the study as determined by the investigator, such as other serious illnesses or serious 
laboratory abnormalities or family or social factors that could affect the safety of the 
subject, or study data and sample collection 
Method of 
Administration 
Group A: SHR-1210, 3 mg/kg, I.V. on D1, once every 14 days; apatinib mesylate 125-500 mg 
orally, once daily (QD); 
Group B: SHR-1210, 3 mg/kg, I.V. on D1, once every 14 days; FOLFOX4, on D1-D2, once 
every 14 days. 
Or SHR-1210, 3 mg/kg, I.V. on D1, once every 14 days; GEMOX, on D1-D2, once every 14 
days. 
The study treatment will continue until disease progression, intolerable toxicity, or subject 
withdrawal. Every 4-week is a treatment cycle. 

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Clinically 
Significant Toxicity 
Any of the following toxicities that may or are definitely related to the investigational drug 
will be considered clinically significant toxicity: 
Significant hepatotoxicity: 
 
ALT or AST > 10 × ULN for > 14 days; 
 
ALT or AST > 15 × ULN regardless of the duration; 
 
TBIL > 5 × ULN (> 8 × ULN for subjects with increased TBIL at baseline). 
Significant hematological toxicity: 
 
Grade 3 treatment-related thrombocytopenia with bleeding; 
 
Grade 3 treatment-related neutropenia with fever; 
 
Grade 4 treatment-related neutropenia for > 5 days; 
 
Grade 4 treatment-related thrombocytopenia. 
Significant non-hematological toxicity: 
 
Grade 2 or above treatment-related eye pain or decreased vision that are not 
responsive to local treatment (not resolved to grade ≤ 1 within 14 days), and 
requiring systemic treatment; 
 
Grade 3 or above treatment-related, non-skin AEs, except for the following: 
- 
Endocrine diseases that can be adequately controlled by replacement 
therapy; 
- 
Isolated laboratory abnormalities of no clinical significance; 
- 
Gastrointestinal AEs persistent for < 48 h; 
- 
Fatigue; 
- 
Fever persistent for < 72 h, without neutropenia or impairment of other 
organ functions; 
- 
Hypertension that can be controlled within the normal range after 
medication (systolic pressure ≤ 140 mmHg, diastolic pressure ≤ 80 mmHg) 
 
Grade 4 treatment-related AEs, including laboratory abnormalities. 
Criteria for 
Discontinuing the 
Study or Treatment 
1. 
Subject withdraws informed consent and requests to withdraw from the study; 
2. 
Imaging evaluations show disease progression, unless the subject meets the criteria for 
continuation of treatment beyond progression (see Section 3.2.4 for details);  
3. 
Continuing the participation in the study is not in the best interests of the subject if still 
intolerable to the toxicity or due to adverse events, laboratory abnormalities, or 
concurrent diseases after dose modification per the investigator's judgment. 
4. 
Other reasons for which the investigator considers a withdrawal necessary; 
5. 
The subject becomes pregnant; 
6. 
The study is terminated by the sponsor. 

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Statistical Methods 
Trial results are mainly analyzed using descriptive statistics. Numerical data will be 
summarized in means, standard deviations, medians, maximums, and minimums. Categorical 
data will be summarized in frequencies (proportions), percentages, and confidence intervals. 
All statistical analyses will be performed using SAS 9.2 or above. 
Safety Analysis: 
Subjects will be observed for any adverse event during the clinical trial, including clinical 
symptoms and abnormal vital signs, and laboratory abnormalities. The clinical 
manifestations, characteristics, severity, time of onset, duration, treatment, and prognosis will 
be recorded. In addition, the correlation of the adverse event with the investigational drug 
will be assessed. NCI-CTC AE (4.03) criteria will be used to evaluate drug safety. 
Efficacy Analysis: 
Point estimates of efficacy endpoints such as objective response rate (ORR) and disease 
control rate (DCR) are provided with 95% confidence interval. The median survival time, 
time to progression (TTP), duration of response (DoR), and corresponding 95% confidence 
intervals are calculated using the Kaplan-Meier method, and overall survival curves are 
plotted. 
Study Period 
Feb. 2017 to Mar. 2019 

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SCHEDULE OF ACTIVITIES 
1. Procedures during Screening Period 
Item 
Screening Period 
(baseline[1],  
-28 days) 
Note 
Enrollment Assessment 
 
 
Signing of Informed 
Consent 
√ 
Activities during the screening period must be carried out after the signing of the informed consent form. 
In this study, subjects who have failed the pre-treatment screening may be enrolled. The informed consent 
form should be re-signed and a new subject number should be given for re-enrollment. 
Verification of 
inclusion/exclusion 
criteria 
√ 
Evaluated during the screening period (including re-screening). 
Demographics 
√ 
 
Medical History 
√ 
Including past history, tumor history (initial diagnosis and treatments), and allergy history. 
Child-Pugh Score 
√ 
Performed within 14 days prior to the first dose. 
Safety Assessments 
 
 
ECOG PS 
√ 
Performed within 14 days prior to the first dose. 
Physical Examination 
√ 
Performed within 14 days prior to the first dose. Must include: height, weight, head and face, skin system, 
lymph nodes, eyes, ears, nose and throat, oral cavity, respiratory system, cardiovascular system, abdomen, 
urogenital system (when necessary), musculoskeletal system, nervous system, and mental state. 
Vital Signs 
√ 
Including blood pressure, heart rate, body temperature, and respiratory rate. Performed during screening 
visit. 

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Item 
Screening Period 
(baseline[1],  
-28 days) 
Note 
Collecting information 
on concomitant 
medications/treatment 
√ 
Including concomitant treatment within 28 days prior to the signing of informed consent form. 
Collecting information on 
adverse events 
√ 
Including symptoms, signs, complaints of discomfort, and abnormal laboratory results. 
12-Lead ECG[2] 
√ 
Performed within 14 days prior to the first dose. The QTc interval must be indicated, which was calculated 
by Fridericia's formula. 
Echocardiography 
√ 
Including LVEF assessment 14 days prior to the first dose. 
Hematology 
√ 
Including complete blood count with differential (white blood cells, red blood cells, lymphocytes, 
monocytes, neutrophils, basophils, and eosinophils), hemoglobin, and platelet count. Tested within 14 days 
prior to the first dose. If the screening tests were done within 72 h prior to the first dose, a retest was not 
required before the first dose. 
Urinalysis 
√ 
Including white blood cells, red blood cells, and urine protein. Tested within 14 days prior to the first dose. 
In case of a urine protein ≥ 2+ at screening, a 24-h urine protein quantitation should be added. If the 
screening tests were done within 72 h prior to the first dose, a retest was not required before the first dose. 
Fecal occult blood 
√ 
Tested within 14 days prior to the first dose. 
Blood biochemistry 
√ 
Including liver function measurements (ALT, AST, total bilirubin, ALP), renal function measurements 
(BUN or serum urea level, creatinine), albumin, amylase (a lipase test should be added in case of an 
abnormal amylase level), blood glucose, and LDH. Tested within 14 days prior to the first dose. If the 
screening tests were done within 72 h prior to the first dose, a retest was not required before the first dose. 
Electrolytes 
√ 
Including potassium, sodium, calcium, phosphorus, magnesium, and chlorine. Tested within 14 days prior 
to the first dose. If the screening tests were done within 72 h prior to the first dose, a retest was not required 
before the first dose. 
Coagulation Function 
√ 
International normalized ratio (INR) and/or prothrombin time (PT). Tested within 14 days prior to the first 
dose. If the screening tests were done within 72 h prior to the first dose, a retest was not required before the 
first dose. 

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Item 
Screening Period 
(baseline[1],  
-28 days) 
Note 
Alpha-Fetoprotein 
√ 
Tested within 14 days prior to the first dose. 
Thyroid function 
√ 
Including TSH, FT3, and FT4. Tested within 14 days prior to the first dose. 
Virological Examination 
√ 
Including HIV-Ab, HBV and HCV infection tests. HBV testing requirements: HBsAg is tested at screening 
to determine the presence of HBV infection. If positive, HBsAg (quantitative), HBsAb (qualitative), 
HBcAb (qualitative), HBeAg (qualitative), HBeAb (qualitative) and HBV-DNA (qualitative, and if 
positive, quantitatively) are tested. Requirements for HCV testing: HCV-Ab is tested at screening to 
determine the presence of HCV infection. If positive, HCV-RNA will be tested (qualitative, and if positive, 
quantitatively). Performed within 14 days prior to the first dose. 
Blood or urine HCG test 
√ 
For women of childbearing potential (WOCBP) only. Must be tested within 14 days prior to the first dose. 
Efficacy Assessment 
 
 
Tumor imaging 
assessment 
√ 
Baseline imaging assessment must be performed as per the RECIST 1.1 criteria, including enhanced CT 
scans of the chest, abdomen, pelvis, and lesions. If subject was allergic to the contrast agents used in 
enhanced CT, non-enhanced chest CT and abdominal and pelvic MRI scans were done. Brain MRI or 
enhanced CT scan. Bone scans were only performed when clinically indicated, and must be within 42 days 
prior to the first dose. If routine tumor imaging assessment was performed prior to the signing of informed 
consent form, as long as the CT or MRI scan was done within 28 days prior to the first dose, a repeat CT or 
MRI during the screening period was not required. 

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2. Procedures during Treatment Period 
Item 
Treatment Period 
(28 days/cycle) 
Note 
D1[3] 
(± 3 days) 
D15 
(± 3 days) 
Child-Pugh score 
√ 
 
Completed on D1 of each cycle. 
Safety Assessments 
 
 
 
ECOG PS 
√ 
√ 
Conducted before dosing on the day of each visit. 
Physical Examination 
√ 
√ 
Conducted before dosing on the day of each visit, must include: body weight, skin system, respiratory 
system, cardiovascular system, and abdomen. 
Vital Signs 
√ 
√ 
Including blood pressure, heart rate, body temperature, and respiratory rate. Conducted before dosing 
on the day of each visit (after sitting for 5 min). 
Collecting information on 
concomitant 
medications/treatment 
√ 
√ 
 
Collecting information on 
adverse events 
√ 
√ 
Including symptoms, signs, complaints of discomfort, and abnormal laboratory results. 
12-Lead ECG 
√ 
√ 
Conducted within 72 h before dosing of each visit. The QTc interval must be indicated, which was 
calculated by Fridericia's formula. 
Echocardiography 
 
 
This is performed according to local standard practice when clinically indicated. 
Hematology 
√ 
√ 
Including complete blood count with differential (white blood cells, red blood cells, lymphocytes, 
monocytes, neutrophils, basophils, and eosinophils), hemoglobin, and platelet count. Tested within 72 
h before dosing of each visit. 
Urinalysis 
√ 
√ 
Including white blood cells, red blood cells, and urine protein. Tested within 72 h before dosing of each 
visit. In case of a urine protein ≥ 2+, a 24-h urine protein test should be added. 

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Item 
Treatment Period 
(28 days/cycle) 
Note 
D1[3] 
(± 3 days) 
D15 
(± 3 days) 
Blood Biochemistry 
√ 
√ 
Including liver function measurements (ALT, AST, total bilirubin, ALP), renal function measurements 
(BUN or serum urea level, creatinine), albumin, amylase (a lipase test should be added in case of an 
abnormal amylase level), blood glucose, and LDH. Tested within 72 h before dosing of each visit. 
Electrolytes 
√ 
√ 
Including potassium, sodium, calcium, phosphorus, magnesium, and chlorine. Tested within 72 h 
before dosing of each visit. 
Coagulation Function 
√ 
 
International normalized ratio (INR) and/or prothrombin time (PT). Tested on D1 of each cycle starting 
from cycle 2. 
Alpha-Fetoprotein 
√ 
 
Tested on D1 of each cycle starting from cycle 2. 
Thyroid Function 
√ 
 
Completed on D1 of each cycle starting from Cycle 2. Including: TSH, FT4, and FT3. 
Virological examination 
√ 
 
Completed on D1 of each cycle starting from Cycle 2. Including: HBV-DNA qualitative + quantitative 
assay (quantitative assay using PCR). HCV-RNA qualitative + quantitative assay (quantitative assay 
using PCR). 
EFFICACY 
ASSESSMENT 
 
 
 
Tumor imaging 
assessment 
√ 
 
Tumor imaging assessments must be performed as per the RECIST 1.1 criteria. Once every 8 weeks 
(± 7 days), regardless of any medication delays. Including enhanced CT scans of the chest, abdomen, 
pelvis, and lesions. If subject was allergic to the contrast agents used in enhanced CT, non-enhanced 
chest CT and abdominal and pelvic MRI scans were done. Brain MRI or enhanced CT and bone scans 
were performed only when clinically indicated. 
Study Treatment 
 
 
 
Injection of SHR-1210 
√ 
√ 
 
Apatinib Mesylate 
√ 
√ 
Only applicable to the subjects in group A. Orally administered daily starting from D1 of cycle 1. 
FOLFOX4/GEOX 
Chemotherapy 
√ 
√ 
Only applicable to the subjects in group B. 

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Item 
Treatment Period 
(28 days/cycle) 
Note 
D1[3] 
(± 3 days) 
D15 
(± 3 days) 
Distribution, Validation, 
and Recovery of Subject 
Diary Card 
√ 
√ 
Only applicable to the subjects in group A administered with apatinib mesylate. 
3. End of Treatment and Follow-Up Period 
Item 
End of 
treatment [4] 
Follow-Up Period 
Note 
Safety 
follow-up [5] 
Survival 
follow-up [6] 
Child-Pugh score 
√ 
√ 
 
 
Safety 
Assessments 
 
 
 
 
ECOG PS 
√ 
√ 
 
 
Physical 
Examination 
√ 
√ 
 
 
Vital Signs 
√ 
√ 
 
Including blood pressure, heart rate, body temperature, and respiratory rate (after 
sitting for 5 min). 
Collecting 
information on 
concomitant 
medications/ 
treatment 
√ 
√ 
 
 
Collecting 
information on 
√ 
√ 
 
Including symptoms, signs, complaints of discomfort, and abnormal laboratory results. 

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Item 
End of 
treatment [4] 
Follow-Up Period 
Note 
Safety 
follow-up [5] 
Survival 
follow-up [6] 
adverse events 
12-Lead ECG 
√ 
√ 
 
The QTc interval must be indicated, which was calculated by Fridericia's formula. 
Echocardiography 
√ 
 
 
 
Hematology 
√ 
√ 
 
Including complete blood count with differential, platelet count, and hemoglobin. 
Urinalysis 
√ 
√ 
 
In case of a urine protein ≥ 2+, a 24-h urine protein test should be added. 
Blood 
Biochemistry 
√ 
√ 
 
Including liver function measurements (ALT, AST, total bilirubin, ALP), renal function 
measurements (BUN or serum urea level, creatinine), albumin, amylase (a lipase test 
should be added in case of an abnormal amylase level), blood glucose, and LDH. 
Electrolytes 
√ 
√ 
 
Including potassium, sodium, calcium, phosphorus, magnesium, and chlorine. 
Coagulation 
Function 
√ 
√ 
 
International normalized ratio (INR) and/or prothrombin time (PT). 
Alpha-Fetoprotein 
√ 
√ 
 
 
Thyroid Function 
√ 
√ 
 
TSH, FT4, and FT3. 
Virological 
examination 
√ 
√ 
 
Including: HBV-DNA qualitative + quantitative assay (quantitative assay using PCR). 
HCV-RNA qualitative + quantitative assay (quantitative assay using PCR). 
Blood or urine 
HCG test 
√ 
 
 
For women of childbearing potential (WOCBP) only. 

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Item 
End of 
treatment [4] 
Follow-Up Period 
Note 
Safety 
follow-up [5] 
Survival 
follow-up [6] 
EFFICACY 
ASSESSMENT 
 
 
 
 
Tumor imaging 
assessment 
√ 
√ 
√ 
If the subject did not have tumor progression when withdrawing from the study 
treatment, tumor assessments were still required every 8 weeks (± 7 days) as per the 
RECIST 1.1 criteria until disease progression or initiation of new anti-tumor treatment. 
Including enhanced CT scans of the chest, abdomen, pelvis, and lesions. If subject was 
allergic to the contrast agents used in enhanced CT, non-enhanced chest CT and 
abdominal and pelvic MRI scans were done. Brain MRI or enhanced CT and bone 
scans were performed only when clinically indicated. 
Others 
 
 
 
 
Survival 
information 
 
√ 
√ 
 
Subsequent 
anti-tumor 
treatment 
 
√ 
√ 
 
Note: 
[1] Baseline measurements obtained closest to the first dose were used. 
[2] Fridericia's formula: QTcF = QT/(RR^0.33), where RR is the standardized heart rate value, obtained by dividing 60 by the heart rate. 
[3] There was no ±3-day window for Day 1 of Cycle 1. 
[4] End of treatment/withdrawal: These examinations/procedures were not repeated if they were completed within 7 days from withdrawal. 
[5] Safety follow-up period: 90 days after the last dose. During this period, follow-up visits were conducted once every 30 days (± 7 days). The first safety follow-up (30 days 
after the last dose) and the third safety follow-up (90 days after the last dose) must be conducted at the study site. The safety follow-up in between (60 days after the last dose) 
was a telephone interview, and only survival information, concomitant medications/treatments, and adverse events were collected. 
[6] Survival follow-up period: the survival follow-up period started after the end of the safety follow-up period. During this period, a telephone follow-up was conducted every 
30 days (±7 days) to collect information about subject survival and about subsequent treatments. 

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ABBREVIATIONS AND DEFINITIONS 
Abbreviations and Special 
Terms 
Definitions 
AE 
Adverse event 
AFP 
Alpha-Fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTN 
Apatinib mesylate 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BLRM 
Bayesian logistic regression model 
BUN 
Blood urea nitrogen 
B-Scan 
B-mode ultrasound 
CIV 
Continuous intravenous infusion 
CR 
Complete response 
CT 
Computed tomography 
DCR 
DoR 
Disease control rate 
Duration of response 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
FAS 
Full analysis set 
FT3 
Free triiodothyonine 
FT4 
Free thyroxine 
Glu 
Glucose 
Hb 
HCC 
Hemoglobin 
Hepatocellular carcinoma 
HSF 
Hand-and-Foot Syndrome 
INR 
International normalized ratio 
ITT 
Intention to Treat 
LDH 
Lactate dehydrogenase 
I.V. 
Intravenous injection 
LV 
Levoleucovorin 

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Abbreviations and Special 
Terms 
Definitions 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
NHYA 
New York Heart Association 
OB 
Occult blood 
ORR 
Objective response rate 
OS 
Overall survival 
OXA 
Oxaliplatin 
PD 
Progressive disease 
PFS 
Progression free survival 
PI 
PLC 
Principal Investigator 
Primary liver cancer 
PLT 
PO 
Platelet 
Oral administration 
PR 
Partial response 
PT 
Prothrombin time 
QD 
Quaque die 
Q2W 
Once every 2 weeks 
RECIST 
Response evaluation criteria in solid tumors 
RTKs 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SD 
Stable disease 
TBIL 
Total bilirubin 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
5-Fu 
5-fluorouracil 

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1 BACKGROUND 
1.1 Epidemiology and Current Treatment Status of Liver Cancer 
Primary hepatocellular carcinoma ranked fifth among common malignant tumors in the world in 
2012, with about 782,500 new cases, accounting for 6% of all new cancer cases. Due to the poor 
prognosis of this disease, it is responsible for up to 745,500 deaths per year, hence making it the 
third leading cause of cancer deaths [1]. China has a high incidence of liver cancer. In 2016, 
statistics showed there were approximately 466,100 new cases per year, accounting for 10.8% of 
all new cancer cases, ranking fourth. The annual number of deaths from liver cancer was 422,100, 
second only to lung cancer and gastric cancer in tumor-related deaths, ranking third [2]. Liver 
cancer is more prevalent in men than in women, with male-to-female ratio of 2.8:1, and is most 
common in the age group of 45-59 years old. A higher proportion of male patients has been 
observed in areas with higher incidence [2]. 
Primary liver cancer mainly includes different pathological types such as hepatocellular 
carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and mixed hepatocellular 
carcinoma-intrahepatic cholangiocarcinoma. HCC is the most common type of primary liver 
cancer, accounting for 90% of patients with primary liver cancer [3]. The main risk factors are 
infection with hepatitis B and C virus and non-alcoholic fatty liver; in addition, rare causes 
include hereditary hemochromatosis, α-antitrypsin deficiency, and autoimmune hepatitis [3]. 
HCC occurs mostly in patients with hepatitis and liver cirrhosis, at approximately 10-20 years 
after primary hepatic damage. 
Most early-stage liver cancers are asymptomatic, and majority of the patients have reached a 
locally advanced stage or distant metastasis at the time of diagnosis, with clinical treatment 
facing severe challenges. The survival times of patients with advanced primary liver cancer in 
China fall within the range of 3-6 months, and the longest survival time among patients 
worldwide is not more than 1 year [4]. The overall 5-year survival rate of liver cancer is 5-6%. 
The treatment challenge mainly comes from the high heterogeneity of the disease, the diversified 
etiology, and the different diagnostic and treatment standards. Patients are also often 
accompanied by impaired liver function. Thus, the treatment is more complicated and the 
efficacy thereof varies [5-7]. 
Due to its insensitivity to conventional chemotherapy, liver cancer is usually treated through 
surgical operations (hepatectomy, liver transplantation, and palliative treatment), non-surgical 
approaches (locoregional treatment, arterial chemoembolization, chemotherapy, radiotherapy, 
biological therapy, and molecular targeted therapy), and other therapies (including participation 

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in clinical studies). The treatment method is usually selected according to the stage of the disease, 
the extent of tumor invasion, and the physical status of the patient, while in patients with liver 
cancer, the liver function status should also be considered. Approximately 90% of patients with 
liver cancer also have liver cirrhosis, which should be treated at the same time as tumor treatment. 
1.2 Research Developments in Targeted Therapies for Liver Cancer 
In December 2007, sorafenib became the first FDA-approved drug for the treatment of HCC. 
Sorafenib is a multi-target tyrosine kinase inhibitor. Its approval was based on the results of its 
remarkable benefits in terms of survival as demonstrated in the SHARP and Oriental trials. 
The SHARP study was a randomized phase III study in the western population. Sorafenib, in 
comparison with the placebo, the progression-free survival (median of 5.5 months and 2.8 months, 
respectively) was increased by 73% and the overall survival (median of 10.7 months and 
7.9 months, respectively) was increased by 44%. Oriential, another randomized phase III study 
conducted in Asian populations with a study design similar to those of SHARP, also yielded the 
same results, with the overall survival increased by 2.3 months (median OS of 6.5 months and 
4.2 months, respectively) [8, 9]. 
In 2008, sorafenib was approved in China for the treatment of HCC, hence offering a new 
treatment option to numerous liver cancer patients in China. 
Several multi-kinase inhibitors have suffered setbacks in head-to-head comparisons with 
sorafenib. The phase III clinical trial of sunitinib (Pfizer) in patients with advanced liver cancer 
was terminated prematurely in April 2010 due to the failure of sunitinib to improve survival in 
comparison to sorafenib, and the incidence of serious adverse events (SAEs) was higher in the 
sunitinib group than in the sorafenib group [10]. The multi-kinase inhibitor ABT-869 (Linifanib) 
developed by Abbott had also failed to demonstrate any advantages over sorafenib. As such, the 
phase III clinical trial of ABT-869 was terminated based on the recommendation of the 
independent data monitoring committee (IDMC) [11]. A study involving 731 patients showed 
that Roche's Tarceva (erlotinib), an epidermal growth factor receptor tyrosine kinase inhibitor, 
also failed to provide additional benefits, as compared with sorafenib [12]. Brivanib is a tyrosine 
kinase inhibitor targeting VEGF receptor and basic fibroblast growth factor (bFGF, FGF-2) 
receptor. The phase II trial of brivanib in patients with unresectable, locally advanced or distant 
metastatic liver cancer showed that 6-month PFS reached 18.2%, median PFS was 2.7 months, 
and median survival was 10 months, with relatively mild side effects, mainly including fatigue, 
hypertension, and diarrhea [13]. However, brivanib failed in the comparison with sorafenib in the 
phase III non-inferiority clinical trial, because the overall survival for brivanib treatment was not 
superior to sorafenib [14]. Even the main exploration in the population after sorafenib treatment 

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cannot demonstrate the superiority of other targeted drugs relative to the best supportive 
treatment in terms of overall survival. The primary endpoints of 2 phase III studies of brivanib 
and everolimus in patients with advanced HCC who failed or were intolerant after sorafenib 
treatment were not reached, with a median OS of 9.4 months vs. 8.2 months (HR 0.89, P = 0.33) 
[15] and 7.6 months vs. 7.3 months (HR 1.05) [16] compared with the best supportive treatment. 
In summary, sorafenib remains the most superior targeted drug in terms of overall efficacy and 
safety in the treatment of HCC. The median survival of sorafenib in patients with advanced HCC 
was not more one year, and new treatments that improve patients' survival were still expected 
clinically. 
1.3 Background of Immunotherapy in Liver Cancer 
Contrary to chemotherapy or molecular targeted therapy that directly acts on cancer cells, tumor 
immunomodulatory therapy not only kills cancer cells directly, but, more importantly, also 
enhances the immune response of the body by acting on the immune system and ultimately 
prolonging the survival of patient. Molecular targeted therapy may result in significant clinical 
response for numerous types of tumors. However, the duration of response is short, and the initial 
responses are usually accompanied by tumor resistance and clinical recurrence within a few 
months. Tumor immunomodulatory therapy can be applied to a various types of tumors, and can 
also produce a long-lasting response in some patients. 
Cancer immunotherapy is a long-time hot spot in the field of cancer treatment, in which the 
cancer immunotherapy using T cells is at the core position. Cancer immunotherapy fully utilizes 
and mobilizes killer T cells in cancer patients to kill tumors, and may be the most effective and 
safest way to treat cancer. Also, tumor immune escape is a great challenge in cancer 
immunotherapy. Cancer cells' suppressive effect on the immune system promotes uncontrolled 
tumor growth. There is an extremely complex relationship between the immune escape 
mechanism of tumors and the body's anti-tumor immune response. Tumor-specific killer T cells 
have certain biological activities in the early stage of the cancer immunotherapy, but they lose 
their cytotoxicity in the late stage of tumor growth. Therefore, the cancer immunotherapy aims to 
maximize a patient's own immune response against the tumor. It not only activates the original 
immune response in the body, but also maintains the duration and intensity of the immune 
responses which is the key to the cancer immunotherapy. 
Programmed death-1 (PD-1) is a protein receptor expressed on the surface of T cells discovered 
in 1992 and is involved in the process of cell apoptosis. PD-1 is a member of the CD28 family 
and has a 23% consistency in amino acid sequence with cytotoxic T lymphocyte antigen 4 
(CTLA-4). However, its expression is different from CTLA. It is primarily expressed by 

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activated T cells, B cells, and myeloid cells. PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is 
primarily expressed on T cells, B cells, macrophages, and dendritic cells (DCs), and is 
up-regulated on activated cells. Many human solid tumors have expression of the PD-1 ligand 
(PD-L1), which is often associated with a poor prognosis. Tumor-infiltrating lymphocytes in 
patients with cancers usually express PD-1 and their anti-tumor function is impaired. Pre-clinical 
trials of several antibodies that block PD-1 or PD-L1 have proven that they can enhance T-cell 
function and promote tumor cell lysis. 
A number of pharmaceutical companies are currently developing monoclonal antibodies 
targeting PD-1. By blocking the binding of PD-L1/PD-1, these monoclonal antibodies maximize 
a patient’s own immune response against the tumor, thereby achieving the purpose of killing 
tumor cells. BMS and Merck's PD-1 monoclonal antibodies are currently the most advanced 
PD-1 antibody drugs. Based on the results of key studies that have been completed, the FDA has 
approved nivolumab from BMS and pembrolizumab from Merk for multiple indications: 
nivoluamb has been approved by the FDA for the treatment of melanoma, non-small cell lung 
cancer, renal cell carcinoma, Hodgkin lymphoma, and squamous cell carcinoma on the head and 
neck; pembrolizumab has been approved by the FDA for the treatment of advanced melanoma, 
non-small cell lung cancer, and squamous cell carcinoma in the head and neck. 
Currently, multiple antibody drugs against PD-1 are undergoing clinical study in advanced 
hepatocellular carcinoma. A phase I/II study of nivolumab in the treatment of patients with 
advanced hepatocellular carcinoma (HCC) was reported at the ASCO meeting in 2015. The 
preliminary results of the dose escalation part of the study were announced. Fourty-seven (47) 
patients with HCC were enrolled; among them, 51% were not accompanied with viral infection, 
25.5% had HCV coinfection, 23.4% had HBV coinfection, and 98% had Child-Pugh score of 
class A; 75% received systemic therapy; 68% received previous treatment with sorafenib. The 
patients received nivolumab at different doses (0.1-10 mg/kg, once every 2 weeks). The results 
showed that nivolumab was safe and tolerable. Only one patient withdrew from treatment due to 
treatment-related hepatitis. The incidence of Grade 3 increased transaminase was not high, with 
11% of patients experienced Grade 3 AST elevation and 9% of patients experienced Grade 3 
ALT elevation. Among the 42 evaluable patients, 8 patients (19%) showed objective response 
(CR + PR, RECIST 1.1), and 6 patients had a duration of response of more than 12 months (2 
patients with CR discontinued the medication). The one-year overall survival rate was 62%. In 
patients with HCV coinfection, transient reduction of HCV-RNA in some patients was observed. 
The preliminary results of this study suggested that the immune checkpoint inhibitor PD-1 
antibody was safe and tolerable in the treatment of advanced HCC, and it was also very safe in 
patients with hepatitis B or hepatitis C infection. The preliminary efficacy results were 

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encouraging [17]. At the 2016 ASCO annual meeting, the interim analysis data, as the 
subsequent extension of the study in 214 patients with HCC, was announced. All the enrolled 
patients had Child-Pugh score of class A. Among them, 66% had previously received sorafenib 
treatment. The numbers of patients with HCV infection, HBV infection, and non-viral infection 
were 51, 51, and 112, respectively. Nivolumab was given at 3 mg/kg, once every 2 weeks. As of 
the analysis (15 Mar., 2016), the median number of administrations was 10, and 8 patients 
withdrew from treatment due to treatment-related toxicity. Elevated transaminase was the most 
common laboratory abnormality. The incidences of elevated ALT and AST were 7% and 6%, 
respectively, of which 3% and 4%, respectively, were of Grade 3-4. Most were asymptomatic 
and more common in patients with HCV infection. The tumor objective response rate (ORR) was 
16% (35/214). The ORR in patients with PD-L1 expression of  1% and < 1% was 19% (5/26) 
and 20% (20/102), respectively. The majority (29/35) of tumor objective response was observed 
within 3 months at the start of treatment, and the majority response (30/35) continued. The 6- 
and 9-month OS rates were 82.5% and 70.8%, respectively. Viral reactions were observed in 
some patients with viral infections (6% of patients with HBV infection showed HBsAg 
quantitative decrease, and 20% of patients with HCV infection experienced HCV-RNA transient 
decrease) [18]. At the ESMO meeting in October 2016 and the ASCO GI meeting in January 
2017, the updated follow-up results of the study were further reported. A total of 262 patients in 
the dose-escalation group and subsequent extension group received treatment, with 48 in the 
dose-escalation group and 214 in the subsequent extension group. Asian patients accounted for 
45%. Patients treated with sorafenib accounted for 67%. The safety results showed that the 
incidence of Grade 3/4 treatment-emergent adverse events was 19%, and the incidence rates of 
Grade 3/4 elevated ALT and elevated AST were 5% and 3%, respectively. The efficacy results 
showed, in the extension group, that the ORR was 20%, the median duration of response (DoR) 
was 9.9 months, the 9-month OS rate was 74%, and the median OS was 13.2 months. Nivolumab 
was safe and controllable in the treatment of advanced HCC and showed long duration of 
response and long-term survival benefits. Its efficacy was not associated with whether 
accompanied with HBV/HCV infection, whether treated with sorafenib, and the expression status 
of PD-L1 [19, 20]. 
A global phase III study of nivolumab vs. sorafenib in the first-line treatment of patients with 
advanced HCC is currently underway, the results of which are worth looking forward to [21]. 

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1.4 Study Basis of Combined Immunotherapy in Hepatobiliary Malignancies 
1.4.1 Application of immunotherapy combined with targeted therapy in tumor treatment 
Tumor immunotherapy has received more and more attention and affirmation. The duration of 
response of this therapy is long in patients, and the incidence and severity of adverse drug 
reactions are low. However, no or late responses to this therapy exist in a large number of 
patients, causing a considerable number of patients to abandon the treatment due to early disease 
progression. On the other hand, although tumor-targeted therapy results in responses in the early 
stage of treatment, but the duration of response is short and drug resistance is prone to appear. 
Combining the respective characteristics of the above two therapies, tumor immunotherapy 
combined with targeted therapy has a good development prospect. It not only improves the 
response rate but also result in sustained clinical benefits [22, 23]. In addition, studies have 
shown that small molecule targeted drugs can induce tumor cell death. Dead tumor cells can 
release tumor autoantigens, which are taken up by antigen-presenting cells and presented to 
tumor-specific T lymphocytes. PD-1 antibody inhibits the PD-1/PD-L1 signaling pathway by 
binding to PD-1 on T lymphocytes, thereby activating the specific killing effect of T 
lymphocytes on tumor cells. In addition, the release of tumor autoantigens caused by targeted 
therapy reduces attacks of T lymphocytes on non-tumor antigens, thereby reducing 
immunotherapy-related adverse drug reactions [24]. This provides a strong basis for tumor 
immunotherapy combined with targeted therapy. 
At present, some clinical trials of the combination of targeted therapy and immunotherapy are 
being actively carried out. For example, Merck's Keynote-022 study (NCT02130466) aims to 
study the safety and efficacy of PD-1 monoclonal antibody, pembrolizumab, combined with 
trametinib and dabrafenib in patients with advanced melanoma. Merck's Keynote-426 study 
(NCT02853331) is a study on the efficacy and safety of pembrolizumab combined with axitinib 
vs. sunitinib monotherapy in renal cancer. The preliminary study results showed that the 
objective response rate (ORR) was 40%-50% [25], showing a good response rate. Therefore, the 
combination of immunotherapy and targeted therapy will be one of the inevitable trends in tumor 
treatment in the future. How to carry out the combination medication is a problem that needs to 
be solved by the medical community. 
This clinical trial involves recombinant humanized anti-PD-1 monoclonal antibody injection 
(SHR-1210), a new class 1 therapeutic biological product developed by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. that has not been marketed both in China and abroad. Preclinical trial 
data show that SHR-1210 has comparable in vivo efficacy and safety with those of similar drugs 
abroad. Phase I clinical studies have been conducted by Hengrui in Australia and China since 
2015. Several clinical studies are currently underway. 

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This study also involves apatinib mesylate (trade name: Aitan), which was launched in 2014 by 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. Apatinib mesylate is a small molecule targeted drug, 
which is a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. It 
exerts its anti-angiogenic effect mainly by inhibiting VEGFR. Preclinical studies have shown 
that it is superior to similar product in anti-tumor effect. In 2014, apatinib mesylate was approved 
for patients with refractory or relapsed advanced gastric adenocarcinoma or gastroesophageal 
junction adenocarcinoma who have previously been treated with at least 2 systemic 
chemotherapies. The completed phase II clinical trial of apatinib mesylate in the treatment of 
advanced HCC showed good efficacy (mTTP of the 850 mg group and 750 mg group was 4.2 
months and 3.3 months, respectively; and mOS of the 850 mg group and 750 mg group was 9.7 
months and 9.8 months, respectively). Currently, a randomized (2:1), double-blind, 
placebo-controlled, multi-center phase III clinical trial evaluating the efficacy and safety of 
apatinib mesylate as second-line treatment of advanced HCC is underway. Patients with 
advanced HCC who failed sorafenib or systemic chemotherapy, had relapse, or intolerant to 
sorafenib were recruited. 
This study intends to use drugs that target the VEGF-VEGFR signaling pathway combined with 
PD-1 monoclonal antibody in the treatment of advanced liver cancer as an exploratory study, 
aiming to provide guidance and experience for new combination therapies urgently needed in 
clinical practice, and laying a foundation for subsequent studies. Thus, it has important 
significance in scientific studies and clinical value. 
1.4.2 Study basis of immunotherapy combined with oxaliplatin chemotherapy in liver cancer 
Oxaliplatin (OXA) is a third-generation platinum anti-tumor drug. In addition to its cytotoxic 
effect on DNA, several studies in recent years have shown that the anti-tumor activity of OXA is 
more related to its immune effect [26, 27]. The immunological mechanism of OXA's anti-tumor 
effect mainly includes its ability to induce immunogenic cell death (ICD), regulate the STAT 
signal pathway, and regulate the immune microenvironment of tumor [26-33]. 
Since OXA has an immunomodulatory effect against tumors, it may produce synergistic 
anti-tumor activity when combined with immunotherapy drugs [26, 27]. Current researches on 
immunotherapy focus on the development of immune checkpoint inhibitors, the main targets 
being T cell surface receptors CTLA-4 and PD-1. The expression level of these receptors can 
regulate the proliferation and activation of T cells [26]. Platinum enhances the effect of immune 
checkpoint inhibitors by inducing ICD production, enhancing the sensitivity of tumor cells to 
cytotoxic lymphocyte (CTL) lysis, and stimulating the proliferation of T cells. Recently, data of 
multiple clinical studies have shown that the effect of platinum combined with anti-PD-1 
monoclonal antibody exhibited good anti-tumor effects [34, 35]. 

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In recent years, many progresses have been made in systemic chemotherapies for HCC. A 
prospective, randomized, controlled, international multicenter phase III clinical study (EACH 
study) [36] compared the efficacy and safety of the FOLFOX4 regimen containing OXA with 
doxorubicin monotherapy in the treatment of Asian patients with advanced HCC. The results 
showed that the PFS, OS, and RR of the FOLFOX4 group were better than those of the 
doxorubicin group (PFS: 2.93 months vs. 1.77 months; OS: 6.40 months vs. 4.9 months; RR: 
8.15% vs. 2.67%). Further analyses showed that [37]: In the main target population, i.e., Chinese 
patients, the mOS of the FOLFOX4 group vs. the doxorubicin group was prolonged (5.9 months 
vs. 4.3 months, P = 0.0281); also, the mPFS, RR and DCR showed significant superiority (2.4 
months vs. 1.7 months, 8.6% vs. 1.4%, and 44.0% vs. 30.8%, respectively); the OS and PFS 
benefits of patients in the FOLFOX4 group remained consistent in each subgroup. The EACH 
study showed that the OXA-based FOLFOX4 regimen is effective and safe for the treatment of 
patients with HCC in the Asia-Pacific region, especially in China. Based on the above study 
results and other clinical observation data, in 2013, the China Food and Drug Administration 
(now National Medical Products Administration, or NMPA) approved the indication of systemic 
chemotherapy with OXA for the treatment of advanced HCC [38]. Also, the "Guideline for the 
Diagnosis and Treatment for HCC" formulated by the Chinese Ministry of Health (now National 
Health Commission) also listed the OXA-based FOLFOX4 regimen as a first-line treatment for 
advanced HCC [39]. In view of the results of the large-scale phase III study of OXA in HCC, the 
approval of the NMPA, and the recommendations of the Chinese guidelines, the immunotherapy 
of immune checkpoint inhibitors combined with OXA-based systemic chemotherapy can 
hopefully improve clinical outcomes for patients with advanced liver cancer. 
Therefore, this study intends to carry out an exploratory study on FOLFOX4 regimen combined 
with PD-1 monoclonal antibody SHR-1210 in the treatment of advanced primary liver cancer 
simultaneously. It is expected to provide guidance and experience for the new combination of 
immunotherapy and chemotherapy in the future as well as effectively improve the anti-tumor 
efficacy of monotherapy while minimizing the toxic side effects as much as possible, and 
ultimately bringing better survival benefits for patients. 
1.4.3 Study basis of immunotherapy combined with oxaliplatin chemotherapy in bile duct 
malignancies 
Malignant tumors of the bile duct originate from epithelia of intrahepatic and extrahepatic bile 
ducts or of the gallbladder, including cholangiocarcinoma and gallbladder cancer, of which 
gallbladder cancer is more common, accounting for approximately 2/3. Cholangiocarcinoma 
consists of intrahepatic cholangiocarcinoma (20-25%), hilar cholangiocarcinoma (50-60%), and 

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distal cholangiocarcinoma (20-25%) according to anatomical location. Malignant tumors of the 
bile duct are not common in clinical practice, accounting for approximately 2% of all malignant 
tumors and ranking fifth among malignant tumors of the gastrointestinal tract. The etiology is not 
yet clear, and may be related to high-risk factors such as chronic inflammation of the bile duct, 
cholelithiasis, ulcerative colitis, cystic malformation of the bile duct, sclerosing cholangitis, 
K-ras mutation, liver flukes, and hepatitis B. Malignant tumors of the bile duct have high 
malignancy, poor prognosis, and insidious onset, most of which are advanced at the time of 
diagnosis [40-42]. 
The recommended chemotherapy regimen for advanced patients is the two-drug combination 
regimen based on gemcitabine or fluorouracil. Commonly used regimens include: gemcitabine + 
cisplatin, gemcitabine + carboplatin, gemcitabine + oxaliplatin, capecitabine + oxaliplatin, 
capecitabine + cisplatin, and fluorouracil + cisplatin. In multiple phase II studies, the response 
rates were 9-40% and the median survivals were 5-13 months. In UKABC-02, the only phase III 
study with positive results in bile duct malignancies, gemcitabine combined with cisplatin vs. 
gemcitabine monotherapy in the treatment of 410 patients with advanced or metastatic 
cholangiocarcinoma, gallbladder cancer, or ampullary cancer showed a median OS of 11.7 
months and 8.1 months, and a PFS of 8 months and 5 months, respectively [43-45]. 
The chemotherapy regimen based on gemcitabine is the recommended treatment regimen for 
advanced biliary tract tumors. Among them, the GEMOX regimen combined with oxaliplatin has 
been used in multiple single-arm phase II studies and randomized controlled phase II studies, 
showing good activity and safety characteristics. In consideration of the proven efficacy of 
gemcitabine in biliary tract tumors and the possible immunomodulatory effect of oxaliplatin, the 
GEMOX regimen combined with PD-1 monoclonal antibody SHR-1210 is selected for this study 
to treat patients with advanced cholangiocarcinoma and is expected to improve the treatment 
efficacy in such a refractory population [46-48]. 
1.5 Scientific Basis 
1.5.1 Preclinical study results of SHR-1210 
1.5.1.1 Product name and physicochemical properties 
[Generic Name]: SHR-1210 Injection 
[English Name]: SHR-1210 Injection 
[Molecular Weight]: approx. 146.3 kDa 

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1.5.1.2 Pharmacology and mechanism of action 
Programmed death-1 (PD-1) is a protein receptor expressed on the surface of T cells discovered 
in 1992 and is involved in the process of cell apoptosis. PD-1 is a member of the CD28 family 
and has a 23% consistency in amino acid sequence with cytotoxic T lymphocyte antigen 4 
(CTLA-4). However, its expression is different from that of CTLA-4. It is primarily expressed by 
activated T cells, B cells, and myeloid cells. PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is 
primarily expressed on T cells, B cells, macrophages, and dendritic cells (DCs), and is 
up-regulated on activated cells. In contrast, the expression of PD-L2 is mainly restricted to 
antigen presenting cells, such as activated macrophages and dendritic cells. Humanized 
anti-PD-1 monoclonal antibody can specifically bind to PD-1, blocking the interaction between 
PD-1 and its ligands, and restore T cell immune response to tumor cells. 
1.5.1.3 Pharmacodynamic studies 
1) Antibody affinity 
The binding affinity of antibody SHR-1210 to human, monkey, and rat antigens was assayed. 
The results are shown in Table 1. 
Table 1. Binding affinity of SHR-1210 to human, monkey, and rat PD-1 antigens. 
Stationary Phase 
Mobile Phase 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
6.9 
SHR-1210 
Rat PD-1 antigen 
Extremely weak signals, no binding 
detected 
Monkey PD-1 antigen (-hFc) 
SHR-1210 
4.1 
Results from affinity assays showed that the affinity of SHR-1210 to human and monkey PD-1 
antigens were quite close at 6.9 nM and 4.1 nM, respectively, but no binding was detected with 
rat PD-1 antigens. Results from the binding affinity assay involving SHR-1210 and human PD-1 
antigen showed that the binding affinity of SHR-1210 to human PD-1 antigen was 3.0 nM, which 
was similar to those of the control antibodies nivolumab and MK3475. The results are shown in 
Table 2. 

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Table 2. Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigens. 
Antibody 
Antigen 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
MK3475 
Human PD-1 antigen 
3.2 
2) Inhibition of PD-1/PD-L1 binding by SHR-1210 
The experimental results (see Figure 1 and Figure 2) showed that the in vitro activity of 
SHR-1210 in blocking the binding of PD-1/PD-L1 was comparable to that of nivolumab and 
pembrolizumab. The IC50 of inhibition activities of SHR-1210 antibody, nivolumab, and 
pembrolizumab was 0.70 nM/0.79 nM and 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. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab. 
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. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab. 

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1.5.1.4 Toxicology studies 
In an acute toxicity study in cynomolgus monkeys, 8 monkeys (half male and half female) were 
randomized to 2 groups. The animals in group 2 were given an intravenous injection of 
SHR-1210 once every other day at doses of 200, 400 and 800 mg/kg, respectively, in a dose 
escalation manner. No changes in clinical symptoms, weight, food intake, and coagulation 
related to SHR-1210 were observed. Lymphocytes decreased for both sexes at doses ≥ 200mg/kg. 
Serum globulin increased and albumin decreased at doses ≥ 400 mg/kg. Since the magnitude of 
these changes were small, they were not considered harmful effects. The maximum tolerated 
dose (MTD) of SHR-1210 was ≥ 800 mg/kg. 
In a completed preclinical long term toxicity study in cynomolgus monkeys, continuous 
intravenous injection of SHR-1210 at 20, 50, and 100 mg/kg/dose once a week for 4 weeks 
(5 doses in total) were well-tolerated in both sexes. Clinical symptoms, including injection site 
irritation, or changes in body weight, food intake, body temperature, ECG, blood pressure, heart 
rate and respiratory measurements related to SHR-1210 were not observed. No changes in B and 
T cell differentiation, cytokines, immunoglobulins, and complements were observed. No changes 
in organ weight, gross lesions, or histopathological changes associated with SHR-1210 were 
observed. 
1.5.1.5 Pharmacokinetic studies 
For SHR-1210 PK parameters after a single intravenous infusion in cynomolgus monkeys, see 
Table 3. 
Table 3. PK parameters after a single intravenous infusion at different doses of 
SHR-1210 in cynomolgus monkeys. 
Dose 
(mg/kg) Gender 
T1/2 
(hr) 
Tmax 
(hr) 
Cmax 
(μg/mL) 
AUClast 
(hr•μg/mL) 
Vz 
(mL/kg) 
Cl 
(mL/hr/kg) 
MRTlast 
(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 
6380.24 ± 2062.85 
47.05 ± 27.05 
0.47 ± 0.12 
127.10 ± 59.24 
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 
124.01 ± 49.13 
10 
Female 
169.70 ± 38.96 
2.17 ± 1.76 
217.46 ± 20.22 
31357.28 ± 9338.28 
41.24 ± 24.76 
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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1.5.2 Progress in the clinical studies of SHR-1210 
After SHR-1210 was approved for clinical trials in 2016, three phase I clinical studies have been 
carried out in China, all of which were studies on the safety and tolerability in patients with 
advanced solid tumors. As of 28 Feb., 2018, a total of 258 patients with advanced solid tumors 
who failed standard treatment were included in the 3 phase I studies. The safety was summarized 
and analyzed as follows: 
All 258 subjects (100.0%) had at least one AE. AEs with an incidence of ≥ 10% mainly included: 
Skin and subcutaneous tissue diseases: skin capillary hyperplasia (81.8%), pruritus (22.5%), rash 
(16.3%); abnormal liver function: aspartate aminotransferase increased (22.1%), alanine 
aminotransferase increased (19.0%), bilirubin conjugated increased (17.8%), blood bilirubin 
increased (13.2%); hematological toxicity: anemia (29.5 %), white blood cell count decreased 
(17.1%), neutrophil count decreased (10.5%); systemic symptoms: asthenia (38.4%), fever 
(22.1%); gastrointestinal AEs: nausea (12.0%), diarrhea (11.6%); respiratory, thoracic, and 
mediastinal disorders: cough (21.3%), upper respiratory tract infection (10.9%); metabolism and 
nutrition disorders: hypoproteinemia (22.1%), blood sodium decreased (18.2%), appetite 
decreased (12.0%); renal and urinary disorders: proteinuria (22.5%); endocrine disorders: 
hypothyroidism (20.9%). A total of 98 subjects (38.0%) experienced at least one Grade 3 or 
higher AE. Grade 3 or higher AEs with an incidence of ≥ 2% mainly included anemia (7.0%), 
lung infection (6.6%), blood sodium decreased (4.3%), bilirubin conjugated increased (3.9%), 
tumor progression (3.5%), death (3.1%), aspartate aminotransferase increased (2.7%), alanine 
aminotransferase increased (2.3%), and blood bilirubin increased (2.3%). 
Of the 258 subjects, 256 (99.2%) experienced at least one treatment-related AE. 
Treatment-related AEs with an incidence of ≥ 10% mainly included: Skin and subcutaneous 
tissue diseases: skin capillary hyperplasia (81.8%), pruritus (22.1%), rash (16.3%); systemic 
symptoms: asthenia (37.6%), fever (20.9%); abnormal liver function: aspartate aminotransferase 
increased (21.7%), alanine aminotransferase increased (18.6%), bilirubin conjugated increased 
(16.7%), blood bilirubin increased (12.0%); hematological toxicity: anemia (27.5%), white blood 
cell count decreased (14.7%); gastrointestinal disorders: diarrhea (11.2%), nausea (10.5%); 
respiratory, thoracic, and mediastinal disorders: cough (19.0%), upper respiratory tract infection 
(10.1%); metabolism and nutrition disorders: hypoalbuminemia (19.4%), blood sodium 
decreased (14.3%); renal and urinary disorders: proteinuria (22.1) %); endocrine disorders: 
hypothyroidism (19.8%). A total of 82 subjects (31.8%) experienced at least one Grade 3 or 
higher drug-related AE. Grade 3 or higher treatment-related AEs with an incidence of ≥ 2% 
mainly included anemia (6.2%), lung infection ( 5.8%), bilirubin conjugated increased (3.9%), 

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blood sodium decreased (3.5%), death (3.1%), aspartate aminotransferase increased (2.7%), 
alanine aminotransferase increased (2.3%), and blood bilirubin increased (2.3%). 
Of the 258 subjects, Grade 3 or higher AEs with an incidence of ≥ 2% mainly included anemia 
(7.0%), lung infection (6.6%), blood sodium decreased (4.3%), bilirubin conjugated increased 
(3.9%), tumor progression (3.5%), death (3.1%), aspartate aminotransferase increased (2.7%), 
alanine aminotransferase increased (2.3%), and blood bilirubin increased (2.3%). 
In general, in patients with advanced solid tumors, AEs of SHR-1210 other than skin capillary 
hyperplasia were similar to those of similar drugs on the market. Skin capillary hyperplasia 
mostly occurred within 1-2 months after the start of medication. The earlier ones appeared within 
a few days after the medication while the later ones appeared approximately 5 months after the 
medication. It mainly occurred on the trunk or limbs. Most (99.5%) were Grade 1-2 as per 
CTCAE, with only one subject reported as Grade 3. The subject was hospitalized due to surgical 
resection and was assessed as a Grade 3 AE. No patient discontinued medication due to this AE. 
A small number of subjects with bleeding symptoms received local symptomatic treatment. The 
symptoms gradually disappeared after the interruption of SHR-1210 treatment. Overall, 
SHR-1210 has good safety and tolerability. See the investigator's manual for more safety 
information. 
1.5.3 Phase II clinical study results of apatinib mesylate in the treatment of advanced liver 
cancer 
A randomized, open-label, multi-center phase II clinical trial evaluating apatinib mesylate in 
advanced HCC was conducted from 2010 to 2013 by the 81st Hospital of the Chinese People's 
Liberation Army and other sites. A total of 121 subjects were enrolled in this study. The trial 
involved two treatment groups: the 850 mg group and the 750 mg group. Primary endpoint: TTP; 
secondary endpoints: OS, ORR, DCR, AFP, QoL, and safety. Efficacy results showed that in the 
FAS (ITT population), mTTP values in the 850 mg and 750 mg groups were 4.2 and 3.3 months, 
and mOS values were 9.7 and 9.8 months, respectively. ORRs were 8.6% and 0.0%, and DCRs 
were 48.6% and 37.3%, respectively. See Table 4 for the comparison of efficacy results of the 
subjects in the two groups. 
Table 4. Comparison of efficacy results of the subjects in the two groups (FAS). 
Group 
mTTP (month) 
mOS (month) 
ORR (%) 
DCR (%) 
850 mg 
4.2 
9.7 
8.6 
48.6 
750 mg 
3.3 
9.8 
0.0 
37.3 

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Safety results: The incidences of AEs in the 850 mg and 750 mg groups were 98.6% and 94.1%, 
respectively; the incidences of severe AEs (NCI CTCAE Grade III-V) were 67.1% and 72.6%, 
respectively. The incidences of adverse drug reactions in the 850 mg and 750 mg groups were 
95.7% and 90.2%, respectively; the incidences of severe adverse reactions (NCI CTCAE Grade 
III-V) were 58.6% and 58.8%, respectively. The incidences of SAEs were 18.6% and 23.5%, 
respectively; and the incidences of serious ADRs were 4.3% and 5.9%, respectively. See Table 5 
for the comparison of incidences of adverse events and adverse drug reactions of the subjects in 
the two groups . 
Table 5. Comparison of incidences of adverse events and adverse drug reactions of the 
subjects in the two groups (SS). 
 
Group 
Yes 
None 
Total 
Incidence 
(%) 
Inter-group 
comparison 
P 
Adverse event 
(n) 
850 mg group 
69 
1 
70 
98.57 
0.3090 
750 mg group 
48 
3 
51 
94.12 
 
Grade III-V Adverse Events 
(n) 
850 mg group 
47 
23 
70 
67.14 
0.5551 
750 mg group 
37 
14 
51 
72.55 
 
Adverse drug reaction 
(n) 
850 mg group 
67 
3 
70 
95.71 
0.2790 
750 mg group 
46 
5 
51 
90.20 
 
Grade III-V Adverse Drug 
Reactions 
(n) 
850 mg group 
41 
29 
70 
58.57 
1.0000 
750 mg group 
30 
21 
51 
58.82 
 
Serious adverse event 
(n) 
850 mg group 
13 
57 
70 
18.57 
0.5060 
750 mg group 
12 
39 
51 
23.53 
 
Serious adverse drug reaction 
(n) 
850 mg group 
3 
67 
70 
4.29 
0.6960 
750 mg group 
3 
48 
51 
5.88 
 
Common adverse events (incidence ≥ 10%) mainly included: transaminases increased, 
hypertension, proteinuria, hand-and-foot syndrome, etc., most of which were mild to moderate, 
and all were controllable. Refer to Table 6 for details: 

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Table 6. Common AEs (incidence ≥ 10%) in both groups. 
Adverse event 
Group 
Total 
Adverse event 
n (%) 
Grade III-V Adverse Events 
n (%) 
Transaminases increased 
850 mg 
70 
44 (62.9) 
8 (11.4) 
750 mg 
51 
25 (49.0) 
7 (13.7) 
Bilirubin increased 
850 mg 
70 
44 (62.9) 
8 (11.4) 
750 mg 
51 
24 (47.1) 
8 (15.7) 
Hypertension 
850 mg 
70 
36 (51.4) 
3 (4.3) 
750 mg 
51 
25 (49.0) 
7 (13.7) 
Proteinuria 
850 mg 
70 
33 (47.1) 
1 (1.4) 
750 mg 
51 
24 (47.1) 
2 (3.9) 
Gamma-Glutamyltransferase increased 
850 mg 
70 
30 (42.9) 
13 (18.6) 
750 mg 
51 
6 (31.4) 
5 (9.8) 
Hand-and-Foot syndrome 
850 mg 
70 
29 (41.4) 
4 (5.7) 
750 mg 
51 
15 (29.4) 
4 (7.8) 
Platelet count decreased 
850 mg 
70 
27 (38.6) 
6 (8.6) 
750 mg 
51 
23 (45.1) 
7 (13.7) 
White blood cell count decreased 
850 mg 
70 
21 (30.0) 
3 (4.3) 
750 mg 
51 
17 (33.3) 
2 (3.9) 
Lactate dehydrogenase increased 
850 mg 
70 
19 (27.1) 
2 (2.9) 
750 mg 
51 
6 (11.8) 
2 (3.9) 
Neutrophil count decreased 
850 mg 
70 
18 (25.7) 
4 (5.7) 
750 mg 
51 
16 (31.4) 
3 (5.9) 
Abdominal pain 
850 mg 
70 
18 (25.7) 
4 (5.7) 
750 mg 
51 
7 (13.7) 
0 (0.0) 
Asthenia 
850 mg 
70 
17 (24.3) 
3 (4.3) 
750 mg 
51 
9 (17.7) 
2 (3.9) 
The 850 mg and 750 mg groups had comparable efficacy. In terms of safety, the types and 
incidence of AEs and adverse drug reactions observed in both groups were also similar. 

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1.5.4 Phase III clinical study results of apatinib mesylate in the treatment of advanced liver 
cancer 
A randomized (2:1), double-blind, placebo-controlled, multi-center, phase III clinical trial 
evaluating the efficacy and safety of apatinib mesylate as second-line treatment of advanced 
HCC is currently underway. Patients with advanced HCC who failed sorafenib or systemic 
chemotherapy or patients with relapse or unacceptable toxicity were recruited. As of 31 Oct., 
2017, a total of 400 subjects were enrolled, including 7 randomized patients who have not 
received the medication and 393 patients who took at least one dose of medication. Adverse 
events that have been observed included proteinuria, blood pressure increased, thrombocytopenia, 
aspartate aminotransferase increased, hand-and-foot syndrome, total bilirubin increased, asthenia, 
diarrhea, leukopenia, neutropenia, headache/dizziness, alanine aminotransferase increased, 
vomiting, direct bilirubin increased, abdominal pain, decreased appetite, nausea, and 
glutamyltransferase increased. 
1.5.5 Experimental report on the efficacy of SHR-1210 combined with apatinib mesylate in 
human PD-1 transgenic mice 
With human PD-1 transgenic mice as the test subject, the efficacy of the combination of PD-1 
antibody SHR1210 and VEGFR-2 compound apatinib on C57 human PD-1 transgenic mice with 
mouse colon cancer cell MC-38 (PD-L1) xenograft transfered with PD-L1 gene. In the 
experiment, antibody SHR1210 was injected intraperitoneally, Q2D × 7. Compound apatinib was 
administered through oral gavage, QD × 14. On day 21 of observation, the tumor inhibition rate 
of SHR1210 (3 mg/kg) reached 20.40%, the tumor inhibition rate of apatinib (200 mg/kg) 
monotherapy group reached 35.67%; The tumor inhibition rate of the combination of SHR1210 
(3 mg/kg) + apatinib (200 mg/kg) reached 63.07% (significantly different from the HIgG control 
group), and the other monotherapy groups showed no significant difference from the HIgG 
control group. See Table 7 and Figure 3 for details. 
Table 7. Efficacy of medication with the antibody and the compound on xenograft in 
MC38 (PD-L1) tumor-bearing mice. 
Group 
Administration 
Route 
Average Tumor 
Volume (mm3) 
Relative Tumor 
Volume 
Relative Tumor 
Volume 
Tumor 
Inhibition 
Rate% 
p 
(vs blank) 
Number of 
Animals 
per Group 
D0 
SEM 
D21 
SEM 
D21 
SEM 
HIgG(3mg/kg） 
Q2D*7 
ip 
141.46 
13.23 
1,983.55 
292.09 
14.41 
2.07 
- 
- 
8 
SHR1210(3mg/kg) 
Q2D*7 
ip 
141.40 
12.68 
1,652.93 
309.61 
11.47 
2.49 
20.40% 
 
0.379164 
8 
SHR1210(3mpk)+Ap
atinib(200mg/kg) 
Q2D*7/QD(14D) 
ip/po 
146.11 
11.69 
771.98 
73.42 
5.32 
0.73 
63.07%** 
0.001007 
8 
Apatinib(200mg/kg) 
QD(14D) 
po 
139.70 
7.59 
1,263.86 
206.54 
9.27 
1.58 
35.67% 
0.068923 
8 
**: p < 0.01, vs. blank 

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Figure 3. Effects of medication with the antibody and the compound on the relative 
volume of xenograft in MC38 (PD-L1) tumor-bearing mice. 
The experimental results showed that the efficacy of the combination of SHR1210 (3 mg/kg) + 
apatinib (200 mg/kg) was superior to that of SHR1210 and apatinib monotherapy (Table 7, 
Figure 3, and Figure 4). The weight of the mice in each treatment group was normal, indicating 
that the drug had no significant toxic adverse effects. See Figure 6 for details. 
 
Figure 5. Efficacy of medication with the antibody and the compound on xenograft in 
MC38 (PD-L1) tumor-bearing mice - tumor weight. 

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*: p < 0.05, vs. blank 
Figure 6. Effects of medication with the antibody and the compound on the 
weight of xengraft in MC38 (PD-L1) tumor-bearing mice. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary objectives 
 
To observe and evaluate the safety and tolerability of PD-1 antibody SHR-1210 in 
combination with apatinib mesylate or the FOLFOX4 regimen or GEMOX regimen in 
the treatment of advanced primary liver cancer or extrahepatic cholangiocarcinoma. 
2.1.2 Secondary objectives 
 
To preliminary observe the efficacy of PD-1 antibody SHR-1210 in combination with 
apatinib mesylate or the FOLFOX4 regimen or GEMOX regimen in the treatment of 
advanced primary liver cancer or extrahepatic cholangiocarcinoma. 
2.2 Study Endpoints 
2.2.1 Primary endpoints (per the NCI-CTCAE V4.03 criteria) 
 
The incidence and severity of adverse events (AEs) and serious adverse events (SAEs), 
including laboratory tests, vital signs, physical examinations, ECOG PS, and 
electrocardiography. 

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2.2.2 Secondary endpoints (per the RECIST 1.1 criteria) 
 
Objective response rate (ORR) 
 
Duration of response (DoR) 
 
Time to progression (TTP) 
 
Refers to the time from the start of treatment to any documentation of radiologic tumor 
progression. 
 
Disease control rate (DCR) 
 
Overall survival (OS): Refers to the time from the start of treatment to death due to any 
cause. 
3 STUDY DESIGN 
3.1 Study Design 
This study is an open-label phase II study, and 152 patients with advanced primary liver cancer 
or extrahepatic cholangiocarcinoma are intended to be enrolled. Subjects will be enrolled into 
treatment group A or B based on whether they have received systemic treatment for advanced 
liver cancer or extrahepatic cholangiocarcinoma. 
Subjects in group A will receive treatment of SHR-1210 in combination with apatinib mesylate 
(APTN) for exploring the optimal dose first. The objective is to determine the optimal dose of 
SHR-1210 combined with apatinib mesylate in patients with advanced primary liver cancer and 
extrahepatic cholangiocarcinoma. After the determination of the optimal dose of the combined 
medication, the case extension stage was proceeded for collecting sufficient safety data of the 
combination of immunotherapy and targeted therapy. 
Subjects in group B will receive treatment of SHR-1210 in combination with the FOLFOX4 
regimen or GEMOX regimen. The objective is to explore the safety and tolerability of the 
immunotherapy combined with systemic chemotherapy. 
This study will consist of a screening period, a treatment period, and a follow-up period. The 
study treatment will continue until disease progression, intolerable toxicity, or subject 
withdrawal. Every 4-week is a treatment cycle. 
 

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Study Design Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approximately 152 subjects are intended to be enrolled in this study (group A + group B). 
Subjects in group A will be given dose level 1 as the starting dose. The subjects will be enrolled 
in the group in sequence (see Table 10) from low dose to high dose to explore the optimal dose. 
The first cycle (28 days) of continuous administration is the tolerability observation period. After 
the tolerability observation period, if none of the 3 subjects experienced clinically significant 
Number of enrolled 
subjects: Approximately 
122 subjects 
SHR1210 3 mg/kg IV Q2W + 
FOLFOX4 or GEMOX (per the 
investigator's choice) Q2W 
Group A: Advanced PLC 
undergoing prior molecular 
targeted therapy and/or 
systemic chemotherapy 
Dose escalation:  
3-6 subjects/group 
SHR-1210 
3 mg/kg Q2W + 
APTN at dose level 1 
SHR-1210 
3 mg/kg Q2W + 
APTN at dose level 2 
Case expansion: 12 
subjects 
SHR-1210 3 mg/kg IV 
Q2W + APTN at a desired 
dose 
SHR-1210 
3 mg/kg Q2W + 
APTN at dose level 3 
SHR-1210 
3 mg/kg Q2W + 
APTN at dose level 4 
Dose 
Level 
Group B: Advanced PLC 
without previous systemic 
treatment 
Apatinib (APTN) 
125 mg QD  
(once a day) 

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toxicity, the next group of dose may be explored. If 1 of the 3 subjects developed clinically 
significant toxicity, another 3 subjects will be enrolled. If no clinically significant toxicity was 
observed in the later-enrolled 3 subjects, the next group of dose may be explored. If ≥ 1 of the 3 
later-enrolled subjects developed clinically significant toxicity again, the dose exploration will be 
terminated. The dose prior to the current one is the tolerable dose. 
Also, the Bayesian logistic regression model (BLRM) was used as an auxiliary analysis to help 
explore the probability of clinically significant toxicity at different doses. 
Finally, the optimal dose level for case extension is determined through the above-mentioned 
dose exploration, with 8-12 subjects enrolled, to collect sufficient safety data for the combination 
therapy. The dose levels for group A are detailed in Table 8 below. 
Table 8. Dose levels for group A. 
Dose Level 
SHR-1210 
Apatinib mesylate (APTN) 
Number of Enrolled 
Subjects 
1 
3 mg/kg Q2W 
125 mg QD (once a day) 
3-6 
2 
3 mg/kg Q2W 
250 mg QD 
3-6 
3 
3 mg/kg Q2W 
375 mg QD 
3-6 
4 
3 mg/kg Q2W 
500 mg QD 
3-6 
The subjects in group B will receive treatment at dose level 1 according to Table 11, with 6 
subjects enrolled first. If the proportion of subjects showing clinically significant toxicity in the 6 
subjects is < 0.33, some other 122 subjects will be enrolled to receive treatment at the same dose 
level. The dose levels for group B are detailed in Table 9 below. 
 
 

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Table 9. Dose levels for group B. 
Dose Level 
SHR-1210 
FOLFOX4 
Number of Enrolled 
Subjects 
1 
3 mg/kg 
Q2W 
D1: Oxaliplatin (OXA 85 
mg/m2 (2-h infusion) + 
levoleucovorin (LV) 200 
mg/m2 (2-h infusion), 
followed by 5-Fu 400 mg/m2 
(bolus injection), and 5-Fu 
600 mg/m2 (22-h infusion) 
D2: Levoleucovorin (LV) 200 
mg/m2 (2-h infusion), 
followed by 5-Fu 400 mg/m2 
(bolus injection), and 5-Fu 
600 mg/m2 (22-h infusion) 
Q2W 
Approximately 122 
subjects 
GEMOX 
 
 
D1: Gemcitabine 800 
mg/m2(80-min infusion)  
D2: OXA 85 mg/m2 
(2-h infusion) 
Q2W 
 
3.1.1 Definition of clinically significant toxicity 
Any of the following toxicities that may or are definitely related to the investigational drug will 
be considered clinically significant toxicity: 
Significant hepatotoxicity: 
 
ALT or AST > 10 × ULN for > 14 days; 
 
ALT or AST > 15 × ULN regardless of the duration; 
 
TBIL > 5 × ULN (> 8 × ULN for subjects with increased TBIL at baseline) 
Significant hematological toxicity: 
 
Grade 3 treatment-related thrombocytopenia with bleeding; 
 
Grade 3 treatment-related neutropenia with fever; 
 
Grade 4 treatment-related neutropenia for > 5 days; 
 
Grade 4 treatment-related thrombocytopenia; 

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Significant non-hematological toxicity: 
 
Grade 2 or above treatment-related eye pain or decreased vision that are not responsive to 
local treatment (not resolved to grade ≤ 1 within 14 days), and requiring systemic treatment; 
 
Grade 3 treatment-related non-cutaneous AEs, except for the following: 
- 
Endocrine diseases that can be adequately controlled by replacement therapy; 
- 
Isolated laboratory abnormalities of no clinical significance 
- 
Gastrointestinal AEs persistent for < 48 h; 
- 
Fatigue; 
- 
Fever persistent for < 72 h, without neutropenia or impairment of other organ functions; 
- 
Hypertension that can be controlled within the normal range after medication (systolic 
pressure ≤ 140 mmHg, diastolic pressure ≤ 80 mmHg) 
 
Grade 4 treatment-related AEs, including laboratory abnormalities. 
3.1.2 Definition of subjects with uncompleted tolerability evaluation 
Subjects who have not completed the tolerability assessment refer to those who have not 
completed the tolerability observation period due to reasons other than clinically significant 
toxicity, and such subjects will be replaced. When a subject fails to complete the tolerability 
observation, the sponsor and the principal investigator of the coordinating center will jointly 
define the subject to be replaced. 
3.1.3 Subsequent treatment for subjects with clinically significant toxicity 
During the tolerability observation period, the subjects with clinically significant toxicity could 
receive a subsequent treatment of the investigational drug based on the investigator's judgment 
after they have recovered from toxicity. The dose of the investigational drug (SHR-1210 does not 
allow dose adjustment) can be adjusted according to the adjustment principle, or terminate the 
treatment. Subjects are also followed up and their data are collected according to the trial 
procedure. 
3.2 Study Procedures 
3.2.1 Screening period 
The screening period is the time from the signing of the informed consent form until the start of 
study treatment or screen failure. 

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Subjects must sign the informed consent form before undergoing any screening procedures. 
Unless otherwise stated, the following screening procedures should be completed within 28 days 
prior to the first dose: 
 
Signing of Informed Consent Form. 
 
Assigning subject number. 
 
Collection of demographics. 
 
Collection of medical history, including past treatment history, current medical history, drug 
allergies, and concurrent diseases. 
 
Collection of information on adverse events and concomitant medications. 
 
Tumor imaging assessment, the results of imaging assessment before the signing of 
informed consent form and within 28 days of the first dose are acceptable, per the RECIST 
1.1 criteria. 
The following information should be collected within 14 days prior to the first dose: 
 
Physical examination, height, weight, vital signs (including body temperature, blood 
pressure, heart rate, respiratory rate, to be taken after sitting for 5 minutes). 
 
ECOG PS. 
 
Routine blood test, routine urinalysis, and fecal occult blood. 
 
Blood biochemistry (ALT, AST, total bilirubin, ALP, LDH, albumin, urea nitrogen or serum 
urea, creatinine, blood sugar, amylase/lipase). 
 
Electrolytes (potassium, sodium, chlorine, calcium, magnesium, phosphorus). 
 
Coagulation function (PT-INR and/or PT). 
 
Child-Pugh score. 
 
Virologic tests (including HBV, HCV, and HIV markers). 
 
Test of serum AFP. 
 
Thyroid function (TSH, FT3, FT4). 
 
Echocardiography (including LVEF). 
 

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 
12-Lead ECG (the QTc interval must be indicated, which was calculated by Fridericia's 
formula). 
 
Blood or urine HCG test: For women of childbearing potential (WOCBP) only. 
The following information should be collected within 72 h prior to the first dose: 
 
Hematology and urinalysis. 
 
Blood biochemistry (ALT, AST, total bilirubin, ALP, LDH, albumin, urea nitrogen or serum 
urea, creatinine, blood sugar, amylase/lipase). 
 
Electrolytes (potassium, sodium, chlorine, calcium, magnesium, phosphorus). 
 
Coagulation function (PT-INR and/or PT) 
 
12-Lead ECG (the QTc interval must be indicated, which was calculated by Fridericia's 
formula). 
3.2.2 Treatment period 
The treatment period starts from the subject's first dose. 
Each cycle during the treatment period was 28 days. 
For subjects in group A, SHR-1210 at 3 mg/kg was intravenously infused within 30 min (not less 
than 20 min and not more than 60 min, including flushing time) on D1 and D15 of each 
treatment cycle; at the same time, apatinib mesylate was continuously administered (125 mg, 
250 mg, 375 mg, or 500 mg, orally administered, once daily) starting from D1 of cycle 1. 
For subjects in group B, SHR-1210 at 3 mg/kg was intravenously infused within 30 min (not less 
than 20 min and not more than 60 min, including flushing time) on D1 and D15 of each 
treatment cycle; at the same time, chemotherapy with FOLFOX4 was given: D1: oxaliplatin 
(85 mg/m2, 2-h infusion) + levoleucovorin (200 mg/m2, 2-h infusion), 5-Fu (400 mg/m2, bolus 
injection, followed by 5-Fu at 600 mg/m2, 22-h infusion); D2: levoleucovorin (200 mg/m2, 2-h 
infusion), 5-Fu (400 mg/m2, bolus injection, followed by 5-Fu at 600 mg/m2, 22-h infusion) ); 
or chemotherapy with GEMOX was given: D1: gemcitabine (800 mg/m2, 80-min infusion), 
D2: oxaliplatin (85 mg/m2, 2-h infusion); repeated once every two weeks. 
During the treatment period, relevant physical examinations and laboratory tests were performed, 
and information on AEs and concomitant medications were collected. 
The following assessments must be completed within 72 h before dosing of each visit: 

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For hematology, urinalysis, blood biochemistry, blood electrolytes, and 12-lead ECG, the 
investigator must review the laboratory results before dosing. 
The following assessments must be completed before dosing on the day of each visit: 
ECOG PS, physical examination, and vital signs. 
The following assessments should be completed on D1 of each cycle from cycle 2: 
Thyroid function, Child-Pugh score, alpha-fetoprotein, virological tests (HBV marker or HCV 
marker), and coagulation function. 
As per RECIST v1.1, tumor assessment is supposed to be performed every 8 weeks (± 7 days), 
regardless of drug administration. Until disease progression or initiation of subsequent 
anti-tumor therapy (whichever occurs later).  
Patients with progression may continue to use SHR-1210 monotherapy if they meet the criteria 
defined in 3.2.4. 
Note: The detailed study procedures during the treatment period are shown in the schedule of 
study procedures. 
3.2.3 Follow-up period 
The follow-up period begins when the decision is made to discontinue the study treatment. 
Within 90 days after the last study medication, subjects will undergo a follow-up visit every 30 
days (± 7 days). The first safety follow-up (30 days after the last dose) and the third safety 
follow-up (90 days after the last dose) must be conducted face-to-face at the study site, and the 
required safety assessments (see the schedule of study procedures) must be completed; the 
second follow-up (60 days after the last dose) will be a telephone interview, and only survival 
information, concomitant medications/treatments, and adverse events are required to be 
collected. 
The survival follow-up period starts after the end of the safety follow-up period on day 90. The 
investigator must conduct follow-ups every month until death, lost to follow-up, or the sponsor 
terminates the study. The investigator may phone the subject, his or her family, or a local 
physician to collect information about the subject's survival (date of death and cause of death) 
and any further anti-tumor treatments after the end of the study treatment. Each survival 
follow-up should be recorded in the original medical record. 

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For subjects who withdraw from the study due to toxicity or other reasons without radiographic 
disease progression observed, the imaging evaluation should be performed at the same frequency, 
until disease progression or initiation of other anti-tumor treatments. The radiographic evidence 
of progressive disease in these subjects must be obtained as much as possible. 
3.2.4 Criteria for continuing treatment beyond progression 
Some subjects receiving immunotherapy can still benefit clinically after radiographic progression. 
The tumor of some subjects may be enlarged, but remarkable necrosis or denaturation may occur 
inside the tumor, with CT showing decreased internal density of the tumor lesion. It is generally 
considered to be beneficial to subjects under this circumstance. Study treatment may be 
continued after disease progression defined per RECIST 1.1 for subjects who meet the criteria 
below: 
 
The investigator deems that it is in the best interest of the subject to continue treatment, and 
subject is not required to start other anti-tumor treatment immediately;  
 
The subject is able to tolerate continued study treatment; 
 
No significant deterioration in subject's performance status, and no significant worsening of 
cancer-related symptoms; 
 
Subjects must sign the informed consent form prior to continuing treatment, in which 
potential risks, discomforts, and other treatment options shall be included; 
 
Continued treatment must be reviewed and approved by the lead principal investigator. 
The assessment of clinical benefit must consider whether the subject has clinical exacerbations 
and whether the subject can benefit from continuing treatment. It is recommended that the 
investigator should discuss with the sponsor whether the subject should continue treatment after 
the disease progression. 
If it is decided that the subject will continue the study treatment after progression, the subject 
should continue to be treated, evaluated and followed up according to the protocol requirements. 
Subjects should withdraw from study treatment if further progression is observed at the next 
assessment. The initial date of investigator-assessed progression should be used for all statistics 
analyses involving progression, regardless of whether the subject continues the study treatment 
beyond progression. 
If the subject discontinues treatment due to deterioration of the general condition without 
objective evidence for disease progression, the progression will be reported as "general 

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deterioration". More objective evidences (such as imaging confirmation) of progression of these 
subjects should be obtained after treatment discontinuation. 
For subjects who withdraw from the study due to intolerable toxicity without radiographic 
disease progression observed, the imaging examination should be performed at the same 
frequency, until disease progression or initiation of other anti-tumor treatments. The radiographic 
evidence of PD of these subjects must be obtained whenever possible. 
4 RANDOMIZATION AND BLINDING 
Randomization and blinding are not involved in this study. 
5 SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Inclusion Criteria 
1. Male and female subjects aged 18-70 years old. 
2. Patients with advanced primary liver cancer or extrahepatic cholangiocarcinoma (only 
applicable to group B, including gallbladder cancer and common bile duct cancer) diagnosed 
by histopathological or cytological examinations are not suitable for surgery or local 
treatment and have at least one measurable lesion (RECIST 1.1 criteria). 
3. Group A: Patients who have previously undergone systemic therapy for advanced primary 
liver cancer, molecular targeted therapy (sorafenib, etc.) and/or systemic chemotherapy 
(monotherapy or combination therapy) but have failed or become intolerable; 
Group B: Patients who have not previously undergone systemic treatment (molecular 
targeted therapy or chemotherapy) of advanced primary liver cancer or extrahepatic 
cholangiocarcinoma. 
4. The end of the previous anti-tumor treatment must be ≥ 2 weeks from the start of medication 
in this study, or the drug washout period (that is, 5 times the drug half-life) is reached, and 
the AEs related to the previous treatment should resolve to NCI-CTCAE Grade ≤ 1. 
5. Subjects with primary liver cancer or a history of liver cirrhosis should meet the Child-Pugh 
liver function rating: grade A and better grade B (≤ 7 points). 
6. ECOG PS: 0-1. 
7. Expected survival ≥ 12 weeks. 

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8. Subjects with chronic HBV infection must have HBV-DNA < 500 IU/mL, and patients with 
positive HBsAg must receive antiviral treatment in accordance with the "Guidelines for the 
Prevention and Control of Chronic Hepatitis B, Version 2015". Patients with positive 
HCV-RNA must receive antiviral treatment in accordance with the 2015 "Guidelines for the 
Prevention and Control of Chronic Hepatitis C" and hepatic function tests must be within the 
normal range. 
9. Major organs must function normally, meeting the following criteria: 
(1) 
Hematology: (no blood transfusion or use of hematopoietic stimulating factors within 
14 days before screening) 
1) HB ≥ 90 g/L;  
2) ANC ≥ 1.5 × 109/L; 
3) PLT ≥ 80 × 109/L; 
(2) 
Biochemistry: (no blood transfusion or use of blood products within 14 days before 
screening) 
1) ALB ≥ 29 g/L;  
2) ALT and AST < 2.5  ULN; 
3) TBIL ≤ 1.5  ULN; 
4) Creatinine ≤ 1.5  ULN; 
(3) 
Prothrombin time (PT) - international normalized ratio (INR) ≤ 2.3 or prothrombin 
time (PT) ≤ 6 seconds from normal. 
10. Female subjects of childbearing potential must have a negative serum or urine pregnancy 
results within 14 days prior to the start of the study treatment, and be willing to take 
effective contraceptive measures during the study period and within 60 days after the last 
dose of the investigational drug. Male subjects with partners of childbearing potential must 
have undergone surgical sterilization or agree to take effective contraceptive measures 
during the course of the study until 120 days after the last dose of the investigational drug. 
11. Subject must participate voluntarily, sign the informed consent form, have good compliance, 
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5.2 Exclusion Criteria 
1. Known fibrolamellar cell carcinoma; having other uncured malignant tumors within the past 
5 years or concurrently, except for cured localized tumors, such as skin basal cell carcinoma, 
cutaneous squamous cell carcinoma, superficial bladder cancer, prostate carcinoma in situ, 
cervical carcinoma in situ, and breast carcinoma in situ. 
2. Current or past metastasis to the central nervous system. 
3. Symptomatic ascites requiring paracentesis or drainage, or with a Child-Pugh score > 2. 
4. History of gastrointestinal bleeding within the past 6 months or a high risk of bleeding such 
as esophageal varices with bleeding risk, active ulcers, and persistent positive fecal occult 
blood. 
5. Known hereditary or acquired hemorrhage and thrombophilia, such as hemophilia patients. 
6. Abdominal fistula, gastrointestinal perforation, or abdominal abscess within 2 months prior 
to the study. 
7. Grade II or higher myocardial ischemia or myocardial infarction, uncontrolled arrhythmias 
(including QTcF interval ≥ 450 ms in males and ≥ 470 ms in females) (QTcF interval 
calculated using Fridericia's Formula).  
8. NYHA Class III-IV cardiac insufficiency or LVEF (left ventricular ejection fraction) < 50% 
by echocardiography. 
9. Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or diastolic 
pressure > 90 mmHg). 
10. Thromboembolism events that have occurred in the past 6 months, such as cerebrovascular 
events (including transient ischemia attacks) and pulmonary embolism. 
11. Dysphagia, chronic diarrhea, or intestinal obstruction, which significantly affect drug intake 
and absorption. 
12. History of hepatic encephalopathy. 
13. Untreated active hepatitis (Hepatitis B: positive HBsAg with abnormal liver function and 
HBV DNA ≥ 500 IU/mL; Hepatitis C: positive HCV-RNA with abnormal liver function). 
14. Infection with human immunodeficiency virus (HIV). 

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15. Subjects with active infection or unexplained fever (body temperature > 38.5 °C) during 
screening or prior to the first dose. 
16. Received any vaccine treatment within 30 days prior to enrollment. 
17. Patients planning to receive or previously received allogeneic organ or allogeneic bone 
marrow transplants, including liver transplant. 
18. Subjects with previous or current pulmonary fibrosis, interstitial pneumonia, 
pneumoconiosis, radiation-induced pneumonitis, drug-induced pneumonitis, severe lung 
function impairment or other conditions that may interfere with the detection and 
management of suspected treatment-related pulmonary toxicities. 
19. Urine protein ≥ 2+ and confirmed 24-h urine protein quantitation > 1.0 g. 
20. Subjects with active, known, or suspected autoimmune diseases; subjects who are stable and 
do not require systemic immunosuppressive treatment may be enrolled. 
21. Subjects requiring systemic treatment with corticosteroids (> 10 mg/day of prednisone or 
equivalent) or other immunosuppressive medications within 14 days prior to the 
administration of the investigational drug; in the absence of active autoimmune disease, 
inhaled or topical use of corticosteroids and an equivalent dose to > 10 mg/day of prednisone 
for adrenal hormone replacement are permitted. 
22. Received any local treatment for liver within 4 weeks before participating in this study 
(including but not limited to surgery, radiation, hepatic artery embolization, TACE, hepatic 
arterial infusion, radiofrequency ablation, cryoablation, or percutaneous ethanol injection). 
23. Palliative radiotherapy for symptomatic control of non-target lesions is permitted but must 
be completed at least 2 weeks prior to the start of study treatment, and no additional 
radiotherapy should be scheduled for the same lesion; patients with radiation-induced 
adverse events that have not resolved to CTCAE grade ≤ 1; 
24. Subjects who have previously received other PD-1 antibody treatment or other 
immunotherapies targeting PD-1/PD-L1. 
25. Known history of severe allergies to any monoclonal antibodies, anti-angiogenesis targeted 
drugs, platinums, fluorouracils, or components of the study drug. 
26. Subjects requiring long-term anticoagulant therapy with warfarin or heparin; Subjects 
requiring long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day). 

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27. Subjects with a known history of psychotropic substance abuse or drug abuse. 
28. Pregnant or breastfeeding women. 
29. Patients with any other potential factors that may result in the premature termination of the 
study as determined by the investigator, such as other serious illnesses or serious laboratory 
abnormalities or family or social factors that could affect the safety of the subject, or 
collection of trial data. 
5.3 Concomitant Medications/Treatments 
All treatments and medications used in the 28 days before the signing of the informed consent 
form and during the study should be documented in the eCRF in strict accordance with the GCP 
regulations. Subjects should be monitored closely if an adverse event occurs. Symptomatic 
treatment will be provided when necessary and details will be documented in the eCRF. 
5.3.1 Drugs or treatments that are prohibited or used with caution during the study 
5.3.1.1 Drugs and treatments that must be prohibited or used with caution for all subjects 
during the study 
During the study period, subjects are prohibited from using NMPA-approved modern Chinese 
medicine preparations with indications for the treatment of liver cancer or extrahepatic 
cholangiocarcinoma (including but not limited to Delisheng injection, Kanglaite injection, Aidi 
injection, Huai'er granules, and Ganfule tablets) and immunomodulators (including but not 
limited to interferon, interleukin-2, and thymosin). 
During the study period, subjects are not allowed to receive any local treatment for liver lesions 
and target lesions. Other systemic anti-tumor therapies such as chemotherapy, molecular targeted 
therapy, hormone therapy, immunotherapy, and Chinese medicine therapy (above) are not 
allowed. 
During the study period, subjects are not allowed to receive immunosuppressive therapy 
concomitantly (except for the treatment of drug-related adverse events). 
During the study period, subjects are not allowed to use other study drugs for anti-tumor therapy. 
5.3.1.2 Drugs that must be used with caution for subjects in group A during the study 
 
Drugs that interfere with liver P450 enzymes: 
- 
CYP3A4 inducers: dexamethasone, phenytoin, carbamazepine, rifampicin, 
phenobarbital, and rifapentin; 

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- 
CYP3A4 inhibitors: itraconazole, clarithromycin, voriconazole, telithromycin, 
and saquinavir;  
- 
Drugs metabolized by CYP3A4: benzodiazepines, dihydropyridine, calcium ion 
antagonists nisodipine, and lercanidipine; 
- 
HMG-COA reductase inhibitors: simvastatin and midazolam;  
- 
Drugs metabolized by CYP2C9: warfarin, phenytoin, and certain sulfonylurea 
hypoglycemic agents such as glibenclamide; 
 
Drugs that prolong the QT interval: antibiotics, antiarrhythmic drugs, antipsychotics, 
antifungals, antimalarials, and antidepressants. 
5.3.1.3 Drugs that must be used with caution or prohibited for subjects in group B during 
the study 
 
For subjects using the FOLFOX4 regimen: Antiviral drug sorivudine or drugs with 
similar chemical structures, such as brivudine, are not allowed. Because the 
clinically significant drug-drug interaction between sorivudine and 5-Fu can lead to 
increased toxicity of 5-Fu, which is potentially lethal. Drugs to be used with caution: 
phenytoin and warfarin potassium. 
 
For subjects using the GEMOX regimen: Gemcitabine has a radiosensitization 
effect, and thus should be used at least 7 days before and after radiotherapy; drugs 
used with caution: yellow fever vaccine and other attenuated vaccines. 
In addition, for the drugs or treatments that are prohibited or used with caution for subjects in 
group B during the study period, the investigator may refer to the drug marketing instructions of 
oxaliplatin, 5-Fu, levoleucovorin calcium and gemcitabine in combination with clinical practice. 
5.3.2 Drugs and treatments allowed to be used concomitantly during the study 
1. Anti-viral therapy 
Subjects with HBV or HCV infections are required to receive anti-viral therapy according to 
local standard practices. Recommendations for antiviral therapy are as follows: 
Patients with HBV infection, e.g., HBsAg-positive, may continue the original antiviral therapy if 
they have started antiviral therapy before enrolled in the study with satisfactory virus control 
(HBV-DNA < 500 IU/mL). Those with unsatisfactory virus control should switch to entecavir, 
and be enrolled after HBV-DNA < 500 IU/mL. Patients with newly discovered HBV infection at 
screening should start entecavir treatment immediately, and may be enrolled after HBV-DNA < 
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Patients with HCV infection, e.g., HCV-RNA-positive, must receive antiviral treatment in 
accordance with the "Guidelines for the Prevention and Control of Hepatitis C, Version 2015". 
2. Corticosteroids 
Local application of steroid hormones, such as topical, eye, nasal, intra-articular, and inhalation, 
is allowed; corticosteroids for adrenal replacement therapy are allowed; corticosteroids for the 
treatment of adverse reactions are allowed; short-term use of corticosteroids for the prevention 
and treatment of allergic reactions (prevention of contrast agent allergy, or treatment of other 
allergic reactions) is allowed. 
3. Other systemic treatment 
Subjects should be given optimal supportive care during the treatment. Existing hormone 
replacement therapies are permitted. Bisphosphonate treatment for bone metastasis is permitted. 
4. Palliative local treatment 
Palliative treatment is allowed for local non-target lesions that cause evident symptoms, such as 
bone pain lesions. Local radiotherapy or surgery may be considered, but the following conditions 
must be met: 
1) The investigator must assess whether there was disease progression in subjects who required 
local treatment due to symptom exacerbations during the study; 
2) Subjects with disease progression must meet the criteria for continuing treatment after 
progression (see 3.2.4); 
3) The locally treated lesions should not be the target lesions. 
A discussion with the sponsor is recommended before starting palliative local treatment. The 
content of palliative treatment, including the treatment date, location, treatment method and 
dosage and adverse drug reactions, should be documented in the eCRF and medical records in 
detail. 
5.4 Re-screening Criteria for Subjects 
In this study, re-screening is allowed, i.e., subjects who have entered the screening process but 
have not met the enrollment conditions and have not started treatment may be re-enrolled. When 
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5.5 Criteria of Study Medication Discontinuation or Study Withdrawal for Subjects 
The study drug must be discontinued in any of the following cases: 
1. Subject withdraws informed consent and requests to withdraw from the study; 
2. Imaging evaluations show disease progression, unless the subject meets the criteria for 
continuation of treatment beyond progression (see Section 3.2.4 for details); 
3. Continuing the participation in the study is not in the best interests of the subject, due to 
intolerable toxicity, adverse events, laboratory abnormalities, or concurrent diseases after 
dose modification, as assessed by the investigator; 
4. Other reasons for which the investigator considers a withdrawal necessary; 
5. The subject becomes pregnant; 
6. The study is terminated by the sponsor. 
5.6 Subject Number 
Each subject will be given a 5-digit subject number: 
 
First 2 digits = Study site number 
 
Last 3 digits = Numbers for subjects from the same study site Subjects will be 
numbered 001, 002, 003, and so on, according to the order in which the informed 
consent form is signed . 
6 STUDY DRUGS 
6.1 Information 
Study drug: SHR-1210 for injection 
Manufacturer: Shanghai Hengrui Pharmaceutical Co., Ltd. 
Dosage form: lyophilized powder 
Strength: 200 mg (tentative)/20 mL vial. Please refer to the drug analysis certificate for the batch 
number; 
Route of administration: intravenous injection 
Shelf life: 2 years (tentative) from the date of manufacture. 
Storage conditions: sealed, away from light, stored at 2-8 °C in medical refrigerator. Do not freeze. 

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Investigational drug: apatinib mesylate tablets 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: tablet 
Strength: 250 mg/tablet or 375 mg/tablet 
Administration: oral administration after meals (best to take at the same time on each day) 
Shelf life: 2 years (tentative) 
Storage conditions: sealed, away from light, stored below 25 °C 
Study drug: Oxaliplatin for Injection 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: injection 
Strength: 50 mg/vial or 100 mg/vial 
Route of administration: intravenous injection 
Shelf life: 2 years (tentative) 
Storage conditions: sealed, away from light, stored below 25 °C. 
Study drug: Levoleucovorin calcium for injection  
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: injection 
Strength: 25 mg/vial 
Route of administration: intravenous injection 
Shelf life: 3 years (tentative) 
Storage conditions: sealed, away from light, stored in a dry place. 
Study drug: 5-fluorouracil (5-Fu) 
Manufacturer: Tianjin KingYork Pharmaceutical Co., Ltd. 
Dosage form: Small volume injection 
Strength: 10 mL: 0.25 g  

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Route of administration: intravenous injection 
Shelf life: 18 months 
Storage conditions: sealed, away from light. 
Study drug: Gemcitabine hydrochloride for injection 
Manufacturer: Jiangsu Hansoh Pharmaceutical Group Co., Ltd. 
Dosage form: lyophilized powder 
Strength: 1.0 g (gemcitabine-based)  
Administration: intravenous drip 
Shelf life: 36 months 
Storage conditions: sealed and stored in a dry place. 
6.2 Packaging and Labeling of Study Drugs 
See Appendix 6 for details 
6.3 Drug Dispensation  
The management, dispensing, and recovery of the study drugs of this study are in the charge of 
designated staff. The investigator must ensure that all the study drugs are only used for the 
subjects participating in this clinical trial. The dosage and administration should follow the trial 
protocol. The remaining drugs should be returned to the sponsor. The study drug should not be 
transferred to any non-clinical trial participant. 
The drug receipt forms must be signed by two people during drug dispensing at the study site. 
The form is in duplicate copies, of which one is for the study site and one for the sponsor. 
Remaining drugs and empty boxes will be retrieved at the end of the study and a retrieval form 
will also be signed by both parties. The dispensing and return of every drug should be 
immediately documented on designated forms. 
6.4 Drug Storage and Management 
In accordance with the Good Clinical Practice for Drug Clinical Trials (GCP), study drugs 
should be stored, dispensed, and recovered by the participating study site. The study drug, 
SHR-1210, should be sealed, away from light, and stored at 2-8 °C in medical refrigerator, and 
must not be frozen. 

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The study drug, apatinib mesylate, should be stored in a sealed container away from light below 
25 °C. 
The study drugs, oxaliplatin for injection and levoleucovorin calcium for injection, in the 
FOLFOX4 chemotherapy regimen will be supplied by Jiangsu Hengrui Pharmaceuticals Co., 
Ltd.; fluorouracil injection will be purchased from Tianjin KingYork Pharmaceutical Co., Ltd. 
The study drug, oxaliplatin for injection, in the GEMOX chemotherapy regimen will be supplied 
by Jiangsu Hengrui Pharmaceuticals Co., Ltd.; gemcitabine hydrochloride for injection will be 
purchased from Jiangsu Hansoh Pharmaceutical Group Co., Ltd. 
The study drug, oxaliplatin for injection, should be sealed, away from the light and stored below 
25 °C; the study drug, levoleucovorin calcium for injection, should be stored in a sealed 
container away from light in a dry environment; the study drug, fluorouracil injection, should be 
stored in a sealed container away from light; the study drug, gemcitabine hydrochloride for 
injection, should be sealed and stored in a dry place. 
The study drugs are not allowed to be used except for this study. 
6.5 Disposal of Remaining Drugs 
The investigator should record the date and dose of administration of each subject. The total 
amount of study drugs is 110% of the designed dosage. The remaining study drugs should be 
periodically returned to the sponsor for destruction after being counted. 
6.6 Method of Administration 
The preparation of SHR-1210 is detailed in the pharmacy manual. 
Refer to the instruction manuals for the preparation methods of the study drugs in the FOLFOX4 
and GEMOX regimens. 
The method of administration in this study is detailed in the following table: 
Group A 
SHR-1210 
3 mg/kg, intravenously infused within 30 min, not less than 20 min and not more than 
60 min (including flushing time), once every 2 weeks. The interval between two doses 
must not be less than 12 days 
Apatinib 
mesylate 
Orally administered, once daily, with four dose groups: 125 mg, 250 mg, 375 mg, and 
500 mg, for dose exploration from low dose to high dose 
Group B 
SHR-1210 
3 mg/kg, intravenously infused within 30 min, not less than 20 min and not more than 
60 min (including flushing time), once every 2 weeks. The interval between two doses 
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FOLFOX4 
regimen 
D1: OXA 85 mg/m2 (2 h infusion) + levoleucovorin calcium(LV) 200 mg/m2 (2 h infusion), 
followed by 5-Fu 400 mg/m2 (bolus injection), 5-Fu 600 mg/m2 (22 h infusion) 
D2: levoleucovorin calcium (LV) 200 mg/m2 (2 h infusion), followed by 5-Fu 
400 mg/m2 (bolus injection), 5-Fu 600 mg/m2 (22 h infusion) 
Once every 2 weeks 
GEMOX 
regimen 
D1: gemcitabine (800 mg/m2, 80 min infusion)  
D2: oxaliplatin (85 mg/m2, 2 h infusion) 
Once every 2 weeks. 
The subjects continue to use the investigational drugs until the criteria for treatment termination 
specified in the protocol are met. 
7 DOSE MODIFICATION AND SAFETY MANAGEMENT 
7.1 Dose Modification 
7.1.1 Criteria for SHR-1210 dose modification 
Dose modification of SHR-1210 is not allowed. Only dose interruption of SHR-1210 is allowed 
for up to 6 weeks. 
7.1.2 Criteria for SHR-1210 dose delay 
SHR-1210 administration should be delayed when any of the following occurs: 
 
Any Grade ≥ 2 treatment-related non-cutaneous AEs, except for Grade 2 treatment-related 
fatigue or laboratory abnormalities; 
 
Any Grade 3 treatment-related cutaneous AEs; 
 
Any Grade 3 treatment-related laboratory abnormalities, except for Grade 3 abnormalities in 
amylase or lipase not related to symptoms and clinical manifestations of pancreatitis; 
 
The administration should be delayed when the following AST or ALT abnormalities occur: 
- 
If the baseline AST/ALT of a subject is within the normal range and a Grade ≥ 2 
drug-related toxicity occurs, the administration should be delayed; 
- 
If the baseline AST/ALT of a subject is within a Grade 1 increase and a Grade ≥ 3 
drug-related toxicity occurs, the administration should be delayed; 
 
Any AEs, laboratory abnormalities, or accompanying diseases requiring that the 
administration be delayed as judged by the investigator. 

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Subjects who need delay of administration should be re-examined and monitored weekly. 
Monitoring frequency should be increased when clinically indicated. It is recommended to monitor 
once every three days until AST/ALT starts to decrease after reaching its maximum. Administration 
may be resumed when criteria for resuming administration are met (see Section 7.1.3). 
Tumor evaluation in all subjects will continue as required by the protocol, regardless of whether 
the administration is delayed. 
7.1.3 Criteria for resuming SHR-1210 administration 
SHR-1210 treatment may be resumed when drug-related AEs recover to Grade ≤ 1 or baseline 
status, except for: 
 
Subjects with Grade 2 fatigue that is not recovered may resume treatment; 
 
Treatment may be resumed when cutaneous AE is still of Grade 2; 
 
Subjects with Grade 1 increase in AST/ALT or total bilirubin at baseline who delay 
administration due to causes other than treatment-related hepatic AEs may resume study 
treatment in the presence of Grade 2 increase in AST/ALT or total bilirubin; 
 
Subjects who delay administration due to treatment-related increase in AST/ALT or total 
bilirubin may resume study treatment when these indicators recover to baseline CTCAE 
levels or normal and criteria for permanent treatment discontinuation are not met (see 
Section 7.1.4). 
 
Administration may be resumed if treatment-related endocrine illnesses are fully controlled 
with hormone replacement at only physiological doses. 
Dose delays up to 6 weeks from the previous dose are allowed. If, after a 6-week delay, the 
subject still does not meet criteria for resuming administration, study treatment should be 
discontinued permanently, except for conditions in 7.1.4. See Appendix 4 for the detailed 
treatment measures for adverse drug reactions. 

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7.1.4 Criteria for SHR-1210 permanent discontinuation 
SHR-1210 must be permanently discontinued under the conditions below: 
 
Any Grade 2 treatment-related uveitis, eye pain, and blurred vision that are not responsive to 
local treatment and have not recovered to Grade ≤ 1 after dose delay; or the aforementioned 
AEs that require systemic treatment. 
 
Any Grade 3 treatment-related non-cutaneous AEs persisting > 7 days, except for: 
- 
Study treatment must be discontinued if any Grade 3 treatment-related uveitis, 
pneumonia, bronchospasm, hypersensitivity, or infusion reaction occur; 
- 
Study treatment may not be discontinued if Grade 3 treatment-related endocrine 
illnesses are and the fully controlled with hormone replacement therapy at only 
physiological doses; 
- 
Study treatment may not be discontinued if Grade 3 treatment-related laboratory 
abnormalities occur, but must be discontinued if Grade 3 thrombocytopenia 
persists > 7 days or is related to bleeding. 
 
Hepatotoxicity that meets the criteria below: 
- 
AST/ALT > 10 × ULN for > 2 weeks; 
- 
AST/ALT > 15 × ULN; 
- 
TBIL > 8 × ULN for subjects with increased TBIL at baseline, and TBIL > 5 × ULN for 
subjects with normal TBIL at baseline; 
- 
AST/ALT > 3 × ULN and TBIL > 5 × ULN for subjects with normal TBIL at baseline, 
and AST/ALT > 3 × ULN and TBIL > 8 × ULN for subjects with increased TBIL at 
baseline; 
 
Any Grade 4 treatment-related AEs or laboratory abnormalities, except for: 
- 
Grade 4 neutropenia for < 7 days; 
- 
Grade 4 lymphopenia or leukopenia; 
- 
Solitary Grade 4 pancreatic enzymes or lipases elevated without pancreatitis symptoms 
or clinical manifestations. The sponsor should be notified when Grade 4 amylase or 
lipase elevation occurs; 
 

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- 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not accompanied by 
clinical sequelae and can be corrected with supplements/appropriate treatment within 
72 hours of their occurrence; 
- 
Study treatment may not be discontinued if Grade 4 treatment-related endocrine 
illnesses are fully controlled with hormone replacement therapy at only physiological 
doses. 
 
SHR-1210 treatment must be discontinued if dose delay of > 6 weeks is needed, except for: 
- 
Dose delays of > 6 weeks due to dose tapering of corticosteroids that are used for 
treatment-related AEs are permitted. Must discuss with the sponsor before resuming 
administration. Tumor evaluations should be continued as required by the protocol 
during dose delay. Safety follow-ups and laboratory tests should also be performed at 
the original frequency or more frequently when clinically indicated; 
- 
Must discuss with the sponsor before resuming administration for dose delays 
of > 6 weeks due to reasons unrelated to study drugs. Tumor evaluations should be 
continued as required by the protocol during dose delay. Safety follow-ups and 
laboratory tests should also be performed at the original frequency or more frequently 
when clinically indicated. 
 
Any AEs, laboratory abnormalities, or accompanying diseases that render the subject 
significant risks from continued treatment as judged by the investigator; 
 
Disease progression assessed by the investigator as per RECIST 1.1 criteria (unless the 
subject meets the criteria in Section 3.2.4). 
Tumor evaluations should be conducted for subjects who have discontinued SHR-1210 treatment 
as required by the protocol. 
7.1.5 Standards for dose modification of apatinib mesylate 
For the subjects in group A, dose modifications caused by apatinib mesylate-related toxicity 
include: dose interruption (not more than 28 days), dose reduction (except for the 125 mg dose 
group), and dose discontinuation (see Table 12 and Table 13). 
The dose should be interrupted and reduced in the case of Grade ≥ 3 hematological toxicity or 
Grade ≥ 2 non-hematological toxicity. Among the events of non-hematological toxicity, 
controllable nausea and vomiting as well as fever (under 38 °C) with a clear cause may be 
handled with active symptomatic treatments without the need for dose interruption and dose 
reduction. 

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During the medication period, changes in blood pressure should be routinely monitored. When a 
grade 3 increase in blood pressure occurs (systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg, or more than one antihypertensive medication required), it is recommended that 
the use of apatinib mesylate be interrupted and the patient be treated with antihypertensive 
treatment under the guidance of a specialist. When the blood pressure decreases to the normal 
range (systolic pressure ≤ 140 mmHg and diastolic pressure ≤ 90 mmHg), the medication of 
apatinib mesylate may be resumed. If hypertension persists, apatinib mesylate must be reduced 
by one dose level. For patients with hypertensive crisis (systolic pressure ≥ 180 mmHg or 
diastolic pressure ≥ 120 mmHg, and/or accompanied by manifestations of progressive target 
organ dysfunction), treatment should be interrupted immediately and active symptomatic 
treatment should be administered (hypertension, dehydration, and convulsion control). 
When apatinib mesylate-related toxic reactions occur, the dose should be interrupted first. 
Medication may be resumed after the toxicity recovers at the original dose or a dose level lower. 
The dose level may be lowered to 125 mg/d at minimum. If the toxic reaction still cannot be 
tolerated after lowering the dose to 125 mg/d, apatinib mesylate should be permanently 
discontinued (see Table 10). Dose increase for apatinib mesylate is not allowed during the study 
period. 
Table 10. Rules for dose modification of apatinib mesylate (applicable to group A). 
Apatinib 
Mesylate-Related 
Toxicities 
Grade 
Whether 
to Suspend 
Criteria for 
Dose 
Resumption 
Dose Modification 
Criteria for 
Dose 
Discontinuation 
Hematological 
Toxicity 
Grade 1 to 2 
No 
— 
— 
— 
Grade 3 
Yes 
Toxicity returns 
to 
Grade ≤ 2 
Resume at original 
dose 
Interruption of 
apatinib mesylate 
for more than 
28 days; 
Grade 4 
Yes 
Toxicity returns 
to  
Grade ≤ 2 
Reduce apatinib 
mesylate by a dose 
level (dose 
discontinuation for the 
125 mg/d dose group) 
Non-Hematological 
Toxicity 
Grade 1 
No 
— 
— 
— 
Grade 2 (lasts 
for ≥ 7 d) 
Yes 
Toxicity returns 
to 
Grade ≤ 1 
Resume at original 
dose 
Interruption of 
apatinib mesylate 
for more than 
28 days; 
Grade 3 
Yes 
Toxicity returns 
to 
Grade ≤ 1 
Apatinib mesylate was 
reduced by one dose 
level (dose 
discontinuation for the 
125 mg/d dose group) 

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Apatinib 
Mesylate-Related 
Toxicities 
Grade 
Whether 
to Suspend 
Criteria for 
Dose 
Resumption 
Dose Modification 
Criteria for 
Dose 
Discontinuation 
Hypertension 
Grade 3 
(after 
corrective 
treatment) 
Yes 
Toxicity returns 
to 
Grade ≤ 1 
Consider resuming 
medication at the 
original dose; reduce 
apatinib mesylate by a 
dose level if grade 3 
hypertension occurs 
again (dose 
discontinuation for the 
125 mg/d dose group) 
Interruption of 
apatinib mesylate 
for more than 
28 days 
Proteinuria 
(without significant 
increase in blood 
creatinine) 
Grade 3 
(24 h protein 
urine 
quantification
) 
Yes 
Toxicity returns 
to 
Grade ≤ 2 
Apatinib mesylate was 
reduced by one dose 
level (dose 
discontinuation for the 
125 mg/d dose group) 
Interruption of 
apatinib mesylate 
for more than 
28 days 
Hand-and-Foot 
syndrome 
Grade 3 
Yes 
Toxicity returns 
to 
Grade ≤ 1 
Apatinib mesylate was 
reduced by one dose 
level (dose 
discontinuation for the 
125 mg/d dose group) 
Interruption of 
apatinib mesylate 
for more than 
28 days 
Headache 
Grade 2 (last 
for ≥7 d) or 
Grade 3 
Yes 
Toxicity returns 
to 
Grade ≤ 1 
Apatinib mesylate was 
reduced by one dose 
level (dose 
discontinuation for the 
125 mg/d dose group) 
Interruption of 
apatinib mesylate 
for more than 
28 days 
7.1.6 Standards for dose modification of chemotherapy regimen in group B 
For the subjects in group B, dose modifications caused by the toxicity of chemotherapy drugs are 
shown in Table 11 and Table 12. If Grade ≥ 3 toxicity occurs repeatedly even the dose is reduced, 
chemotherapy must be interrupted. 
During the course of treatment, if the dose of the chemotherapy study drug is reduced due to 
toxicity, the dose will not be allowed to be increased during subsequent treatment. 

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Table 11. Rules for dose modification of chemotherapy (applicable to group B). 
Toxicity Type 
NCI-CTC 4.03 Grade 
(Except for sensory 
neurotoxicity) 
FOLFOX4 Initial Dose (mg/m2) 
5-Fu bolus injection 
5-Fu continuous 
intravenous drip 
Oxaliplatin 
400 × 2  
600 × 2  
85 
Dose modification of investigational drug (mg/m2) 
Hematological toxicity ≥ 
Grade 3-4 
Suspend the FOLFOX4 treatment until the toxicity returns to Grade ≤ 1, the dose 
may be modified as follows 
300 × 2 
500 × 2 
65 
Grade 3 nausea and/or 
vomiting (when antiemetics 
were administered) 
Repeat antiemetic treatment 
If still intolerable, discontinue FOLFOX4 treatment for the patient 
Grade 3 diarrhea 
Suspend the FOLFOX4 treatment until the toxicity returns to Grade ≤ 1, the dose 
may be modified as follows 
300 × 2 
500 × 2 
Not adjusted 
Grade 4 diarrhea* 
Suspend the FOLFOX4 treatment until the toxicity returns to Grade ≤ 1, the dose 
may be modified as follows 
300 × 2 
500 × 2 
65 
Grade 3 stomatitis 
300 × 2 
500 × 2 
Not adjusted 
Grade 4 stomatitis* 
300 × 2 
500 × 2 
65 
Grade ≥ 2 cardiotoxicity 
Discontinue the FOLFOX4 treatment 
Until toxicity returns to Grade ≤ 1, adjust the dose as follows 
Discontinue 
Discontinue 
65 
Grade 3 or 4 skin toxicity 
300 × 2 
500 × 2 
Not adjusted 
Grade ≥ 3 allergy 
Discontinue the FOLFOX4 treatment 
Cranial nerve 
Discontinue the FOLFOX4 treatment 
Sensory nerve: adjust according 
to symptoms 
Not adjusted 
Not adjusted 
As shown in Table 14 
Alopecia (any grade) 
Not adjusted 
Not adjusted 
Not adjusted 
Local symptoms (any grade) 
Not adjusted 
Not adjusted 
Not adjusted 
Other unequivocal 
treatment-related toxicities: 
 
- Grade 1 and 2 
 
- Grade 3 
 
- Grade 4 
 
Not adjusted 
300 × 2 
Discontinue 
 
Not adjusted 
500 × 2  
Discontinue 
 
Not adjusted 
65 
Discontinue 
*Or Grade 3 recurs after 5-FU dose modification. 

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Table 12. Rules for dose modification of oxaliplatin in the chemotherapy regimen when 
sensory neuropathy occurs (applicable to group B). 
Duration 
Toxicity Type 
Dose Modification of Oxaliplatin (mg/m2/course) 
≤ 7 days 
Does not last  
> 7 and < 14 days 
Course of treatment lasts 
≥ 14 days 
Cold-related Dullness 
Not adjusted 
Not adjusted 
Not adjusted 
Mild Paresthesia 
Not adjusted 
Not adjusted 
Not adjusted 
Paresthesia with Pain or 
Complaints 
Not adjusted 
 
Normal physical examination  
 
Decrease: 65 mg/m² 
 
Abnormal physical examination* 
 
Oxaliplatin was discontinued for one 
 
cycle, and then reduce to 65 mg/m2 
until the symptoms was 
improved; if the 
symptom improves, 
restart the dose at 
65 mg/m2 
Paresthesia with Functional 
Impairment 
Not adjusted 
 
Normal physical examination without 
daily activities affected 
Decrease: 65 mg/m² 
 
Abnormal physical examination* or 
with daily activities affected 
Oxaliplatin was discontinued for one 
cycle, 
and then reduced to 65 mg/m² 
until the symptoms 
was improved; if the 
symptom improves, 
restart the dose at 
65 mg/m2 
*Examination indicates neurological examination. If objective conditions are found, such as weakened tendon 
reflexes, it is considered abnormal. 
Toxicity Type 
NCI-CTC 4.03 Grade 
(Except for sensory 
neurotoxicity) 
GEMOX Initial Dose (mg/m2) 
Gemcitabine 
Oxaliplatin 
800 
85 
Dose modification of investigational drug (mg/m2) 
Hematological toxicity ≥ 
Grade 3-4 
Interrupt GEMOX treatment, until toxicity returns to Grade ≤ 1, adjust the dose as 
follows 
600 
65 
Grade 3 nausea and/or 
vomiting (when antiemetics 
were administered) 
Repeat antiemetic treatment 
If still intolerable, discontinue chemotherapy for the patient 
Other unequivocal 
treatment-related toxicities: 
 
- Grade 1 and 2 
 
- Grade 3 
 
- Grade 4 
 
 
Not adjusted 
600 
Discontinue 
 
 
Not adjusted 
65 
Discontinue 

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7.2 Common Recommendations on Safety Management 
7.2.1 Safety management procedures for immuno-oncological medications 
Adverse events caused by immuno-oncology (I-O) drugs are different from those of other 
anti-cancer drugs, especially in terms of severity and duration. SHR-1210 is one such drug, and 
therefore, early identification and management of adverse events is required to reduce the 
incidence of severe toxicities. The safety handling rules of similar approved drugs provide 
references to assist the investigator in assessing and dealing with adverse events involving the 
following systems: 
 
GI tract 
 
Lung 
 
Liver 
 
Endocrine 
 
Skin 
Refer to Appendix 4 for safety handling rules. 
7.2.2 Management procedures for hepatic adverse events of SHR-1210 
In this study, hepatic AEs of SHR-1210 are treated with the procedures below: 
 
Criteria for dose delays due to hepatic AEs are shown in section 7.1.2. Corticosteroids, 
methylprednisolone 0.5-2 mg/kg/day, or equivalent should be given if the AST/ALT 
level does not improve or even aggravates following a dose delay of 3-5 days. 
 
Corticosteroids, methylprednisolone 0.5-2 mg/kg/day or equivalent should be given 
immediately if AST/ALT > 8 × ULN. 
 
The sponsor shall be informed of the use of corticosteroids within 24 hours of its start. 
Consultation with the gastroenterology department is also recommended. 
 
The sponsor should be consulted for the use of other immunosuppressants such as 
mycophenolate 1 g BID if the AST/ALT level does not improve or even exacerbates 
following treatment with corticosteroids of 3-5 days. 
 
Dose tapering may start once AST/ALT decreases by 1 grade per CTCAE, with the 
dose reduction persisting no less than 1 month. 

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Study treatment may be resumed when AST/ALT recovers to baseline level, unless the criteria 
for permanent discontinuation are met. 
7.2.3 Recommendations on treatment for SHR-1210 infusion reactions 
SHR-1210 is a fully humanized monoclonal antibody, and thus the possibility of infusion or 
allergic reactions is small and there is no need for preventive medication before infusion. An 
allergic reaction is most likely to occur within 24 h after infusion. Once occurs, the infusion 
should be slowed or interrupted accordingly, and a supportive treatment should be given. Also, 
premedications should be given before further administrations. Possible allergic reactions include 
fever, chills, shiver, headache, rash, pruritus, joint pain, hypotension/hypertension, or 
bronchospasm. The sponsor should be notified of any Grade ≥ 3 infusion reaction within 24 h. 
The Hengrui Clinical Trial AE of Special Interest Report should be filled out and the CFDA SAE 
Report be filled out, and if the event meets the criteria for SAEs, an SAE report should also be 
filled. See section 8.2.6 for reporting methods in detail. 
Management of allergic reactions should be based on the medical practice and guidelines of the 
trial site. The treatment recommendations for infusion reactions are shown below for reference. 
CTCAE 
Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade 1 
Mild and transient 
reactions 
Bedside observation and close monitoring 
until recovery. 
Pre-dose prophylactics are recommended for 
subsequent administrations: 50 mg of 
diphenhydramine or equivalent, and/or 
325-1000 mg of acetaminophen, at least 
30 minutes before the administration of 
SHR-1210. 
Continuation. 
Grade 2 
 
Moderate reactions 
requiring treatment or 
interruption; rapidly 
resolve after 
symptomatic treatment 
(such as antihistamines, 
non-steroidal 
antiphlogistics, 
anesthetics, 
bronchodilators, 
intravenous fluids, etc.) 
Intravenous administration of normal saline: 
50 mg of diphenhydramine IV or equivalent 
and/or 325-1000 mg of acetaminophen; 
Bedside observation and close monitoring 
until recovery. 
Corticosteroids or bronchodilators can be 
considered based on clinical needs; 
The amount of study drug infused should be 
recorded in the original medical record; 
Pre-dose prophylactics are recommended for 
subsequent administrations: 50 mg of 
diphenhydramine or equivalent, and/or 
325-1000 mg of acetaminophen can be given 
at least 30 minutes before the administration 
of SHR-1210. Use corticosteroids (equivalent 
to 25 mg of hydrocortisone) when necessary. 
Interruption. 
Re-administer at 50% of 
the initial rate after 
symptoms resolve. Restore 
the original infusion rate 
(100%) if no 
complications occur 
within 30 minutes. Closely 
monitor. If symptoms 
return, the administration 
of the current SHR-1210 
dose will be terminated. 

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CTCAE 
Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade ≥ 3 
 
Grade 3: Severe 
reaction without rapid 
recovery with treatment 
and/or interruption; or 
symptoms recur after 
alleviation; or the 
subject develops 
sequelae that requires 
hospitalization. 
Grade 4: 
Life-threatening 
Immediately discontinue SHR-1210; 
Intravenous administer normal saline. 
•Bronchodilators are recommended. 
Subcutaneous injection of 0.2-1 mg of 1:1000 
adrenaline solution or slow intravenous 
infusion of 0.1-0.25 mg of 1:10000 adrenaline 
solution, and/or 50 mg of diphenhydramine 
plus 100 mg methylprednisolone or equivalent 
by intravenous injection if necessary; 
•Based on the guidelines for anaphylaxis of 
the study site; 
Bedside observation and close monitoring 
until recovery.  
Discontinuation 
7.2.4 Principles for handling immune-related adverse events 
In principle, interruption of SHR-1210 is preferred based on the severity of the adverse drug 
reaction. The study treatment may be considered to resume when AE recovers to Grade ≤ 1. The 
study treatment should be permanently discontinued if severe (Grade 3) or life-threatening 
(Grade 4) adverse drug reactions occur. 
The treatment of immune-related adverse drug reactions should be based on the medical practice 
and guidelines of the study site. The treatment recommendations for immune-related adverse 
drug reactions are as follows (see Table 13) for reference. See Appendix 4 for the management 
procedures for immune-related adverse drug reactions of common organ systems. 
Table 13. Treatment recommendations for immune-related adverse drug reactions. 
CTCAE Grade 
Clinical Management* 
SHR-1210 Treatment 
Grade 1 (mild) 
Close observation; symptomatic and supportive 
treatment 
Continuation 
Grade 2 (moderate) 
 
Closely monitoring; 
Symptomatic and supportive treatment 
Topical or systemic use of steroids at  
0.5-1 mg/kg/day, equivalent prednisone 
Interrupt medication; resume when 
recovering to Grade ≤ 1; 
Medication may be continued for 
skin and endocrine disorders 
Grade 3 (severe) 
Hospitalization recommended; 
Intravenous or oral use at 1-2 mg/kg/day, 
equivalent prednisone 
Consider adding other immunosuppressants if steroid 
treatments were not responsive after 3-5 days 
Consultation with specialists recommended 
Interrupt medication; whether to 
resume medication should be 
determined after comprehensive 
consideration of the risk/benefit ratio 
and discussion 

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Grade 4 
(life-threatening) 
Intravenous injection of methylprednisolone at 
1-2 mg/kg/day 
Consider adding other immunosuppressants if 
steroid treatments were not responsive after 
3-5 days 
Consultation with specialists recommended 
Permanent discontinuation 
(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) 
7.2.5 Principles for handling apatinib mesylate-related adverse drug reactions 
(1) Hand-and-foot syndrome  
Hand-and-foot syndrome is skin toxicity with palmar-plantar dysesthesia or acral erythema and 
manifests especially in areas under pressure or force. It may occur in patients with tumor during 
chemotherapy or molecular targeted therapy. Hand-and-foot syndrome is characterized by 
numbness, dysesthesia, paraesthesia, tingling, no pain or pain, skin swelling, or erythema, 
desquamation, chapping, scleroma-like blisters, and severe pain. 
Symptomatic treatment and management of hand-and-foot syndrome:  
Necessary symptomatic and supportive treatments must be taken, including: strengthen skin care, 
keep skin clean, and avoid secondary infections; avoid pressure or friction; use moisturizers or 
lubricants, topically use lotions or lubricants containing urea and corticosteroids; topically use 
antifungal or antibiotic treatment if necessary.  
Note: If hand-and-foot syndrome of Grade 3 or higher occurs for 3 consecutive times with an 
aggravating trend, the treatment with apatinib mesylate should be discontinued.  
(2) Hypertension  
Subjects should be strictly screened according to blood pressure requirements in the inclusion 
and exclusion criteria prior to enrollment. Subjects with hypertension can control the blood 
pressure by adjusting the dose of or adding new antihypertensive drugs before administering the 
investigational drug. The blood pressure must be under 140/90 mmHg (average of 2 blood 
pressure measurements taken at least 24 h apart).  
Monitoring and handling of hypertension: 
During the first 2 cycles of apatinib mesylate medication, blood pressure should be monitored at 
least 3 times per week.  

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Once hypertension occurs, the following standard treatments can be given: Angiotensin II 
receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), beta blocker, etc., or 
the combined application of above drugs.  
If hypertension occurs or aggravates during the administration: 
1) Adjust the study drug per the protocol (see 7.1.5); 
2) Start administering antihypertensive or adjust the dosage of medication. 
Subjects should record the daily blood pressure values in the subject diary card. If taking 
hypertensive drugs at the same time, the drug name, dose, method and frequency of 
administration, as well as relevant complaints or symptoms should be recorded. 
During the trial, the following antihypertensive drugs are recommended: 
1) Angiotensin converting enzyme inhibitors (ACEIs);  
2) Angiotensin II receptor antagonists (ARBs);  
3) Dihydropyridine calcium channel antagonists; 
4) Beta blockers.  
Diuretic antihypertensive drugs are not recommended. Antihypertensive drugs with inhibitory 
effects on CYP3A4, such as nicardipine, diltiazem and verapamil, are prohibited. For those with 
hypertensive crisis, the application of apatinib mesylate should be terminated.  
(3) Proteinuria  
All subjects should be closely monitored for proteinuria throughout the entire treatment period, 
especially for those with a history of hypertension. For those with a urine protein result of ≥ 2+ 
in 2 consecutive tests, a 24-h urine protein assay is required.  
Note: In case of nephrotic syndrome, apatinib mesylate should be discontinued. 
(4) Gastrointestinal bleeding  
Symptomatic treatment should be actively given for gastrointestinal hemorrhage, including 
persistently positive fecal occult blood, or bloody stool. Patients with upper gastrointestinal 
hemorrhage should be fasted and given acid suppression, gastric mucosal protection, hemostasis 
(transamin, reptilase, etc.), as well as octreotide if necessary; patients with lower gastrointestinal 
hemorrhage should be given hemostasis, blood transfusion and supportive care, etc.; for those 
whose bleeding cannot be controlled, assistance from the surgery department should be requested 
immediately. And adjust the dose following Section 7.1.5 of the protocol.  

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(5) Thrombosis  
If any arterial thrombosis (such as cerebral ischemia, stroke, angina pectoris, myocardial 
infarction, etc.) occurs, apatinib mesylate should be discontinued. In case of any symptomatic 
venous thrombosis, apatinib mesylate should be discontinued.  
Once the symptoms of thrombosis are observed, symptomatic treatment, surgery, or 
anticoagulants shall be immediately given.  
7.2.6 Rules for handling adverse drug reactions of FOLFOX4 chemotherapy 
Since the FOLFOX4 chemotherapy regimen has been approved by the CFDA (now NMPA) and 
the Ministry of Health (now National Health Commission) for the treatment of patients with 
advanced hepatocellular carcinoma and has accumulated much experience in the clinical 
application, the treatment of FOLFOX4 chemotherapy-related adverse drug reactions in this 
study protocol may be carried out based on clinical practice. The following suggestions are for 
reference. 
(1) Peripheral neuropathy 
Peripheral neuropathies of oxaliplatin include two types, symptoms of which include hand, foot, 
and perioral paresthesias and hypoesthesia. It is recommended that patients treated with 
oxaliplatin in the study keep warm, especially during the 3-5 days after the oxaliplatin 
medication, avoid cold drinks and exposure to cold water or cold air. For peripheral neuropathy, 
the dose of oxaliplatin may be modified following the methods in Table 12. 
(2) Throat paresthesia 
Occasionally, an acute paraesthetic reaction of the throat may be observed when using oxaliplatin. 
Patients may experience loss of respiratory sensation (acute respiratory depression) without 
objective signs of respiratory depression (such as hypoxia, laryngospasm, or bronchospasm). 
This reaction may be induced or exacerbated by cold stimulation. Therefore, patients who use 
oxaliplatin should avoid cold stimulation on the first day of each cycle, and must not drink cold 
drinks or eat cold food. 
If the patient develops acute throat paresthesia, the patient's blood oxygen saturation should be 
evaluated. If it is normal, the patient may be given comprehensive explanation and psychological 
support, and benzodiazepines or other anti-anxiety drugs may be considered. Whenever 
necessary, the infusion rate of oxaliplatin should be reduced, and the patient should be closely 
observed until the symptoms are completely relieved. 

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(3) Allergic reaction 
If Grade 1 or 2 allergic reactions occur, dexamethasone (20 mg intravenously), diphenhydramine 
(50 mg intravenously), or other drugs should be given prophylactically 30 min before the 
FOLFOX4 chemotherapy. 
For grade ≥ 3 allergic reactions, the FOLFOX4 treatment should be discontinued immediately. 
(4) Pulmonary fibrosis 
If respiratory symptoms, such as non-spontaneous coughing, dyspnea, crackles, rales, blisters, 
hypoxia, shortness of breath, or radiographic images showing lung exudate, suggest pulmonary 
fibrosis, the oxaliplatin medication should be interrupted for further investigation. If interstitial 
pulmonary fibrosis is diagnosed, the FOLFOX4 treatment should be permanently discontinued. 
(5) Nausea/vomiting 
It is recommended to use 5-HT3 antagonists (granisetron, ondansetron or isomers) and 
corticosteroids (such as dexamethasone) to prevent and treat oxaliplatin-induced vomiting. Oral 
administration of metoclopramide is recommended for nausea/vomiting caused by 5-Fu. If Grade 
≥3 nausea and/or vomiting occur, chemotherapy should be discontinued immediately until these 
symptoms are relieved or recovered to Grade ≤ 1. 
(6) Diarrhea 
Patients with severe diarrhea should be closely observed. If dehydration occurs, supportive 
treatment for rehydration should be given to supplement water and electrolytes. Follow Table 13 
for the dose modification of FOLFOX4 chemotherapy. 
(7) Hand-foot syndrome 
Necessary symptomatic and supportive treatments may be taken, including: strengthen skin care, 
keep skin clean, and avoid secondary infections; avoid pressure or friction; use moisturizers or 
lubricants, topically use lotions or lubricants containing urea and corticosteroids; topically use 
antifungal or antibiotic treatment if necessary. And adjust the dose of FOLFOX4 following Table 13. 
(8) Cardiotoxicity 
For patients with Grade ≥ 2 cardiotoxicity caused by 5-Fu, the FOLFOX4 treatment should be 
interrupted. The oxaliplatin treatment may be resumed when the toxicity returns to Grade ≤ 1. 

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7.2.7 Rules for handling adverse drug reactions of GEMOX chemotherapy 
The GEMOX chemotherapy regimen is a systemic treatment regimen recommended in the 
NCCN guidelines for advanced cholangiocarcinoma. The regimen has mature applications in 
non-small cell lung cancer and advanced metastatic breast cancer. In this study, the treatments of 
adverse drug reactions are as follows: 
(1) Oxaliplatin-related toxic and adverse effects are the same as those described in Section 
7.2.6. 
(2) Bone marrow suppression: Gemcitabine has a bone marrow suppression effect. 
Symptoms such as anemia, leukopenia, and thrombocytopenia may appear after 
medication. Febrile neutropenia has also been reported. If Grade 3 or higher 
hematological toxicity occurs, the treatment of GEMOX chemotherapy regimen should 
be suspended and symptomatic supportive treatment should be given. The medication 
should be discontinued for recurrent Grade 3-4 hematological toxicities that are not 
controllable. 
(3) Gastrointestinal reactions: Gastrointestinal reactions such as nausea, vomiting, and 
diarrhea may appear in approximately 1/3 of subjects but are generally of Grade 1-2 
and easy to control with symptomatic medication. For gastrointestinal reactions 
uncontrollable with drugs, the dose should be reduced or discontinued. 
(4) Abnormal liver function: More than half of the subjects may experience transient liver 
enzyme elevations, which are generally mild and do not require dose discontinuation. 
However, liver function should still be routinely monitored during medication, and if 
necessary, symptomatic liver protection treatment should be given. 
(5) Renal toxicity: Approximately half of the subjects may experience mild proteinuria and 
hematuria; if accompanied by abnormalities of creatinine and urea nitrogen, renal 
impairment should be alerted. The medication should be suspended immediately and 
symptomatic treatment should be given; more attention should be paid to changes in 
renal function for subjects with underlying renal insufficiency. 
(6) Allergic reactions: They are generally mild skin reactions such as rash and pruritus, 
but large-area rash, peeling, ulcers, and other rare severe skin reactions have also been 
reported. During and within a few hours after the use of gemcitabine, the subjects may 
experience bronchial spasm, manifested as mild, short-term and continuous dyspnea, 
most of which can stop without special treatment. Once severe and persistent dyspnea 
occurs, the following treatments are required: 1. Stop the chemotherapy; 
2. Intravenously administer anti-allergic drugs such as epinephrine or diphenhydramine; 
and 3. Administer oxygen inhalation and other emergency treatment in time. 

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(7) Edema: Mild to moderate local edema may occur in 30% of subjects, some of whom 
may experience local pain. A very small number of subjects may experience 
pulmonary edema. Severe edema generally recovers after dose interruption. 
(8) Oral mucositis: Attention should be paid whether the subjects experience symptoms of 
oral bleeding, erythema, and ulceration. The subjects should be educated to keep their 
oral cavity clean, adjust their diet reasonably, enhance supportive treatment, and, when 
necessary, symptomatic treatment should be given: If symptoms of fungal infection 
occur, antifungal drugs should be applied by mouthwash or oral administration, and 
appropriate local treatment of oral ulcers should be taken; 
(9) Other adverse drug reactions: Such as flu-like manifestations, alopecia, and drowsiness, 
which are generally mild, and will be relieved after the treatment. 
Refer to the drug instruction details. 
8 SAFETY EVALUATION 
8.1 Adverse Event (AE) 
8.1.1 Definition of AE 
AE refers to any untoward medical occurrence in a study subject administered a medicinal 
product, and which does not necessarily have a causality with this treatment. In this study, AEs 
should be documented from the signing of the informed consent form until 90 days after the last 
study dose or the start of new anti-tumor treatment (whichever comes first). AEs can include any 
unfavorable and unintended symptoms, signs, abnormal laboratory finding, or diseases, including 
the follows: 
1) Worsening of pre-existing (prior to entering clinical trial) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2) Any new AE: Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
3) Clinically significant abnormal laboratory findings. 
All AEs should be documented in detail by the investigators, including: the name of the AE and 
description of all relevant symptoms, onset time, severity, causality assessment, duration, 
measures taken, as well as final results and outcomes. 

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8.1.2 AE severity grading criteria 
The severity of AE is determined using NCI-CTCAE 4.03. Refer to the following criteria for 
AEs not listed in NCI-CTCAE 4.03: 
Grade 
Clinical Description of Severity 
1 
Mild; asymptomatic or mild clinical symptoms; clinical or laboratory test abnormality only; medical 
intervention not indicated. 
2 
Moderate; minimal, local, or non-invasive interventions required; limited age-appropriate instrumental 
activities of daily living (ADL), e.g., cooking, shopping, using the telephone, counting money, etc. 
3 
Severe or medically significant symptoms but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. Self-care ADL: refer to 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death due to AEs 
8.1.3 Causality assessment 
All discomforts complained by the subject and abnormal changes in laboratory tests during the 
treatment period should be documented truthfully. The severity, duration, measures taken, and 
outcome of the AE shall be noted. The research physician should assess the relationship between 
the AE and the investigational drugs, such as whether there is a plausible temporal relationship 
with the investigational drug, the characteristics of the investigational drug, the toxicological and 
pharmacological effects of the investigational drug, whether there are concomitant medications, 
the subject's underlying diseases, medical history, family history, as well as stimulation and 
re-stimulation reactions, etc. The potential relationship between the AE and the investigational 
drug should be assessed with 5 grades of causality: definitely related, possibly related, unlikely 
related, not related, and indeterminable. All "definitely related", "possibly related", and 
"indeterminable" events were listed as adverse drug reactions. 
8.2 Serious Adverse Event (SAE) 
8.2.1 Definition of SAE 
SAE refers to a medical occurrence during the clinical trial that results in hospitalization, 
prolonged hospitalization, disability, incapacity, life-threatening or death, or congenital 
malformation. The following unexpected medical events are included: 
 Events resulting in death; 

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 Life-threatening events (defined as the subject being at immediate risk of death at the 
time of the event if not medically treated, but does not mean that it may lead to death if 
the adverse events worsen); 
 Events resulting in hospitalization or prolonged hospitalization; 
 Permanent or serious disability/incapacity/impairment of work ability; 
 Congenital anomalies or birth defects; 
 Other important medical events (defined as events that may jeopardize the subject or 
require interventions to prevent any of the above). 
8.2.2 Progressive disease 
Progressive disease (PD) is defined as the deterioration of the subject's conditions caused by the 
primary tumor targeted by the investigational drug, including radiological progressions and 
progressions in clinical symptoms and signs. New metastases relative to the primary tumor, or 
progression of the previous metastases, are all recognized as PD. Life-threatening events, 
hospitalization or prolonged hospitalization, permanent or serious disability/incapacity/impairment 
of work ability, congenital anomalies or birth defects resulting from signs and symptoms of 
progressive disease should not be reported as SAEs on an expedited basis. Death caused by the 
symptoms and signs of PD should be reported as an SAE on an expedited basis. 
8.2.3 Events of hepatic enzyme abnormalities 
If the levels of AST and/or ALT are abnormal and meet the laboratory test abnormalities shown 
in the table below, such cases of hepatic enzyme abnormalities should be reported as SAEs. The 
investigator is required to strengthen the follow-up of the subjects, who should be followed up 
until their hepatic enzyme levels recover to the normal or baseline level. 
Baseline 
Period 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT/TBIL) 
Treatment 
Period 
ALT ≥ 3 × ULN 
AST ≥ 3 × ULN 
ALT ≥ 8 × ULN 
AST ≥ 8 × ULN 
Meet one of the two criteria above, 
with TBIL ≥ 2 × ULN 
and ALP ≤ 2 × ULN without hemolysis 
Meet one of the two criteria above, 
with 
TBIL ≥ 3× ULN or increase ≥ 1 × baseline value 

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8.2.4 Collection of SAEs after the start of new anti-tumor treatments 
SAEs are documented starting from the signing of consent form until the completion of the 
safety follow-up. SAEs that result in death during the safety follow-up period must be 
documented and followed up, regardless of whether the subject has started other anti-tumor 
treatments. If the subject has otherwise started other anti-tumor treatments, SAEs that do not 
result in death are not required to be documented and followed up. At the end of the safety 
follow-up period or when other anti-tumor treatments have been started, SAEs that are suspected 
to be study drug-related must still be reported. 
8.2.5 Hospitalization 
During the clinical study, adverse events resulting in hospitalization or prolonged hospitalization 
should be considered as SAEs, not including non-medical hospitalization. Hospitalization or 
prolonged hospitalization not related to the worsening of adverse events is not considered an 
SAE. For example: 
 
Hospitalization due to pre-existing disease without occurrence of new AEs or 
worsening of the pre-existing disease (e.g., for testing persistent laboratory 
abnormalities that started before the study); 
 
Hospitalization for management reasons (e.g., annual routine physical examination, 
patients having no place to stay, hospitalization due to medical insurance 
reimbursement); 
 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to the deterioration of an AE (e.g., elective cosmetic 
surgery); 
 
Scheduled treatment or surgery that should be documented in the entire study protocol 
and/or in subject's individual baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) or non-invasive procedures should not be 
reported as adverse events. However, the disease condition leading to such procedures should be 
reported if it meets the definition of an AE. For example, acute appendicitis during the AE 
reporting period should be reported as an AE, and the resulting appendectomy should be 
recorded as the treatment of the AE. 

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8.2.6 SAE reporting system 
The reporting period for SAE begins with the signing of the informed consent form until 90 
calendar days (inclusive) after the last study dose. In the event of an SAE, whether in the first 
report or a follow-up report, the investigator must complete the "Serious Adverse Event Report 
Form for New Drug Clinical Trials" immediately, with a signature and date. The SAE must be 
reported (via email) to the relevant regulatory authorities, the sponsor, and the ethics committee 
within 24 hours of knowing of the event. 
The email address of the sponsor for the safety information of this project: 
hengrui_drug_safety@shhrp.com 
SAEs that occur 90 days after the last study dose should also be reported if they are suspected to 
be related to the investigational drug. 
The symptoms, severity, relationship with the investigational drug, time of occurrence, treatment 
duration, measures taken, time and method of follow-up, and outcome should be documented in 
details in the SAE report. If the investigator believes that an SAE is not related to the study drug 
but potentially related to the study conditions (such as the termination of past treatment, or 
comorbidities during the trial), their relationship should be explained in the description section of 
the SAE report form. 
If the severity of an SAE or its relationship to the study drug changes, a follow-up report should 
be submitted immediately. If an error is found in a previously reported SAE, such SAE may be 
revised, revoked, or downgraded in follow-up reports and reported in accordance with the SAE 
reporting procedure. 
8.2.7 Follow-up of adverse events 
All AEs/SAEs should be followed until recovered, resolved to baseline level or Grade ≤ 1, or 
stabilized. If the event cannot be resolved to baseline level or stabilized, a reasonable explanation 
should be documented in the case report form (e.g., lost to follow-up, death). 
All SAEs, whether related to the study drug or not, should be properly handled, and the outcome 
and date of the SAE should be documented in the subject's case report form. 
The investigator should provide follow-up information in a timely manner based on the sponsor's 
request. 

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8.3 Pregnancy 
During the study, if a female subject becomes pregnant, she must discontinue the study drug 
immediately. The investigator must report to the sponsor within 24 hours and fill out the 
Pregnancy Report/Follow-up Form for Hengrui Clinical Studies. 
During the study, if the partner of a male subject becomes pregnant, the subject can continue in 
the study. The investigator must report to the sponsor within 24 hours and fill out the Pregnancy 
Report/Follow-up Form for Hengrui Clinical Studies. 
The investigator should follow up the pregnancy until 1 month after delivery, and report the 
results to the sponsor. 
Pregnancy outcomes such as stillbirth, spontaneous abortion and fetal malformation are 
considered SAEs and need to be reported according to the time requirements for SAEs. 
If a subject experiences any SAE during pregnancy, then "SAE Report Form for New Drug 
Clinical Trials" should be filled out and reported according to SAE reporting procedure. 
8.4 Adverse Events of Special Interest 
When an AE of special interest specified in the trial protocol occurs, the investigator must fill out 
the "Report of Adverse Event of Special Interest for Hengrui Clinical Studies" and report to the 
sponsor within 24 hours of event awareness. 
If an AE of special interest is also an SAE, the "NMPA Serious Adverse Event Report Form" 
must also be completed. 
 
Grade ≥ 3 infusion reaction 
 
Grade ≥ 2 diarrhea/colitis, uveitis, interstitial pneumonia 
 
Other ≥ Grade 3 immune-related AEs 
 
Any possible events of hepatic enzyme abnormalities (see 8.2.3, lacking other related 
causes of the abnormalities at the same time, e.g., PD, acute viral hepatitis, cholestasis, 
concomitant medication, previous concomitant liver disease, etc.) 
 
Grade 4 amylase or lipase increased 
8.5 Emergency Unblinding 
Not applicable. 

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9 DATA MANAGEMENT 
Data will be collected and managed using the electronic case report form (eCRF). 
9.1. Data Collection 
Data will be collected using the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. will provide 
an electronic data capture (EDC) system. Company staff will deliver EDC system training to the 
designated staff of study site. Access to EDC system will only be granted to the study site staff 
who have completed the training. The PI or dedicated data entry person (CRC) should input data 
into the EDC system in accordance with the requirements of the visit procedures and the eCRF 
completion guide. The logic verification program in the system will verify the integrity and logic 
of the clinical trial data entered into the EDC system and generate an error message prompt for 
questionable data. The PI or CRC is permitted to modify or explain the problematic data. After 
the database is locked, the investigator will receive a CD-ROM or hard copy of subject data to 
archive at the study site. 
9.2 Data Management and Quality Control 
To ensure authenticity and reliability and improve the quality of the clinical data, the CRA will 
monitor the integrity, consistency, and accuracy of the trial data in database following the 
monitoring protocol, and discuss problematic data with the investigator, if necessary, 
supplementation or correction will be made by the investigator. The CRA or data manager will 
send electronic query form to the PI or CRC for problematic data. The PI or CRC must respond 
and provide correction or explanation of the problematic data. Multiple queries may be raised 
when necessary until the problem is solved. The medical director, drug safety director, and data 
manager will perform consistency comparison of SAEs periodically. 
At the end of the study, the data manager and medical personnel will conduct a final quality 
control on all data in the database, summarize all protocol deviations and violations during the 
trial, and hold a data verification meeting. Database locking and unblinding will be carried out 
after the quality requirements have been met. The data manager will export the data to the 
statistics department for data analysis. 
9.3 Data Review and Study Site Monitoring 
Before the initiation of the study, a representative from Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. will introduce the study protocol and eCRF to the investigator and staff at the initial visit to 
the study site or at the researcher conference. During the study, the CRA will visit the study site 
routinely to monitor the integrity of the subjects' records and accuracy of the eCRF, compliance 

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with the study protocol and GCP, and progress of the enrollment, and to ensure that the storage, 
dispensing, and count of the investigational drug are performed according to the requirements. 
During these visits, the major research personnel are required to assist the work of CRA. 
The investigator must keep the source documents of each subject, including all medical records 
and visit records (outpatient or inpatient record), such as demographic indicators, medical 
information, lab results, ECGs, and result of other examinations and evaluations. All information 
in eCRF must come from the source document of the subject. The investigator must also keep the 
informed consent forms of all the subjects. 
The investigator must ensure all source documents are available for monitoring to verify the 
consistency with the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. requires complete 
monitoring of all original documents related to the study, including but not limited to the 
informed consent forms signed by the subjects, compliance with the inclusion/exclusion criteria, 
visit records, AE/SAE records, and all the data required for the evaluation of the primary efficacy 
and safety endpoints. No information referring to the subjects' identity in the source document 
will be disclosed. 
10 DATA ANALYSIS AND STATISTICAL METHOD 
Detailed summaries and methods of statistical analyses for the data collected from the study will 
be included in the statistical analysis plan (SAP), which will be finalized and filed by the sponsor. 
The SAP should be revised accordingly if there are any changes to the study protocol that may 
have a significant impact on the SAP, as determined by the sponsor or principal investigator. 
10.1 Determination of Sample Size 
10.1.1 Group A 
The sample size of group A depends on the number of dose groups and the decision made by the 
clinical department based on some results in the trial. According to the trial data of group A, 6-12 
subjects are enrolled in the tolerable dose group for the extension study. Approximately 24-36 
subjects need to be enrolled. 
10.1.2 Group B 
The sample size of the cholangiocarcinoma population is calculated as follows: 
With reference to previous study results, an unacceptable ORR of 6%, an expected ORR of 15%, 
a two-sided alpha of 0.05, and a power of 80% are assumed. The Simon two-stage minimax 
design is adopted. Fourty-five (45) subjects are enrolled in the first stage. If at least 3 subjects 

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show response, then proceed to the second stage. Thirty-seven (37) subjects are enrolled in the 
second stage. A total of 82 subjects will finally be enrolled. If 10 or more subjects show response, 
then proceed to the next step of the study. Considering a proportion of non-evaluable efficacy of 
10%, approximately 92 subjects with cholangiocarcinoma must be enrolled and treated. 
For the population with hepatocellular carcinoma, 20-30 subjects are intended to be enrolled for 
evaluating the safety of combination therapy and preliminarily evaluating the efficacy. 
Approximately 122 subjects are enrolled in group B. 
10.2 Analysis Population 
10.2.1 Full analysis set 
Full analysis set (FAS): All enrolled subjects who have taken at least one dose of the 
investigational drug will be included in this analysis set.  
10.2.2 Safety analysis set 
Safety Set (SS): including all enrolled subjects who have received at least one study dose and 
have at least one post-treatment safety assessment. 
10.3 Statistical Analysis 
10.3.1 General analysis 
Unless otherwise stated, continuous variables will be summarized by mean, standard deviation, 
median, maximum, and minimum; categorical variables will be summarized by frequencies and 
percentages; for time-event data, the median survival will be estimated using the Kaplan-Meier 
method. SAS 9.2 or above will be used for statistical analysis. 
Unless otherwise stated, the following analysis will be applied to both group A and group B. 
Different populations in group B will also be analyzed. 
10.3.2 Efficacy analysis 
Tumor evaluations will be conducted by the investigator as per RECIST 1.1. The evaluation data 
will be based on the following indicators: complete response (CR), partial response (PR), stable 
disease (SD), disease progression (PD), and not evaluable (NE). All efficacy analyses will be 
conducted based on the FAS. 
The median overall survival (OS), time to tumor progression (TTP), and duration of response 
(DOR) with their corresponding two-sided 95% confidence intervals are estimated using the 
Kaplan-Meier method, and the overall survival curves are plotted. 

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The objective response rate (ORR) and disease control rate (DCR) and their 95% CIs will be 
calculated using the Clopper-Pearson method. 
10.3.3 Safety analysis 
Safety analysis will be based on the SS. 
Adverse events will be coded per MedDRA, and graded using NCI-CTCAE4.03. Given the same 
SOC and/or PT, multiple cases of the same events occurred in one subject will be counted only 
once. For the same AE reported in one subject multiple times but varying in CTCAE grade, the 
greatest grade episode will be enumerated. 
The frequency and percentage of events will be described based on the system organ class (SOC) 
and/or preferred term (PT). Analysis of adverse events, serious adverse events, adverse drug 
reactions, severity of adverse events, and adverse events resulting in treatment discontinuation in 
each dose group will be analyzed. 
Adverse events of special interest will be described and summarized in SAP. 
The incidence and cause of death will be summarized and listed. 
Clinically significant toxicities will be summarized and listed using frequency and percentage by 
dose group. 
The deterioration (abnormalization of normalities or exacerbation of abnormalities) of laboratory 
parameters, electrocardiograms, physical examinations, and others from baseline will be 
analyzed using freqneyc and percentage, and listed. 
10.4 Bayesian Logistic Regression Model (BLRM) 
One goal of the BLRM is to make the risk of clinically significant toxicity with an incidence 
higher than 33% at the target dose not higher than 25% (EWOC criteria: Escalation with 
Overdose Control). The following is the statistical model: 
logit(𝜋𝑑) = log(𝛼) + 𝛽log ( 𝑑
𝑑∗) , where logit (𝜋) = log (
𝜋
1 −𝜋) 
πd represents the probability that a clinically significant toxic event will occur at dose d during 
the cycle of evaluating the maximum tolerable dose. d* = 250 mg is the reference dose. α is 
defined as the odds of clinically significant toxic event at the reference dose of 250 mg. The 
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The probability interval of clinically significant toxic events in patients at each dose level 
estimated using the statistical model is as follows: 
The probability interval when the dose is insufficient is [0.00, 0.16) 
The probability interval when the dose reaches the target toxicity is [0.16, 0.33) 
The probability interval when the dose exceeds the target toxicity is [0.33, 1.00] (these 
probability intervals may be adjusted according to relevant trials when necessary). 
The probability of clinically significant toxicity greater than 0.33 based on the dose 
recommended by the EWOC standard is small (posterior probability < 25%). 
The use of Bayesian statistical methods requires defining the prior probability distribution f(θ) of 
the unknown parameter vector θ. See Appendix 5 for details. 
11 INFORMED CONSENT AND ETHICS REGULATION 
11.1 Informed Consent 
The clinical investigator must fully inform the subjects that participation in the clinical trial is 
voluntary, and subjects have the right to withdraw from the trial at any stage without being 
discriminated against with their medical treatment and rights unaffected, and they can continue 
to receive other therapies. All subjects should be informed that the participation of the trial and 
their personal information will be kept confidential. The subjects should also be informed of the 
nature, objectives, expected potential benefits, and possible risks and inconvenience of the 
clinical trial, other alternative treatment options, and rights and obligations of the subjects in 
accordance with the "Declaration of Helsinki". Subjects are given sufficient time to consider 
whether to participate in the trial and sign the informed consent form. 
11.2 Ethics 
This study protocol must first be reviewed and approved in writing by the Ethics Committee of 
the Hospital before being implemented. The study protocol, protocol revisions, ICF, and other 
relevant documents such as recruitment advertisements should be submitted to the ethics 
committee. This clinical trial must be conducted in accordance with the Declaration of Helsinki, 
NMPA's GCP, and applicable laws and regulations. Before the trial is initiated, approval must be 
obtained from the ethics committee of the hospital. 
The study protocol must not be unilaterally modified without approvals from both the sponsor 
and investigator. The investigator can modify or deviate from the study protocol before obtaining 
an approval from the IRB/IEC only when in purpose of eliminating direct and immediate harm to 

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the subject. Also, the deviation or change and the corresponding reason, and the recommended 
protocol modification should be submitted to the IRB/IEC for review and discussed with the 
sponsor. The investigator must provide explanations and document any protocol deviations. 
During the study, any changes to this study protocol must be submitted to the ethics committee. 
If necessary, corresponding changes should be simultaneously made to other study documents 
and submitted and/or be approved according to the pertinent requirements of the ethics 
committee. The investigator is responsible for submitting the interim reports regularly according 
to the pertinent requirements of the ethics committee. After the end of the trial, the completion 
should be informed to the ethics committee. 
11.3 Regulatory Considerations 
Both SHR-1210 for injection and apatinib mesylate for injection are developed and submitted by 
Jiangsu Hengrui Pharmaceuticals Co., Ltd., and have been approved by the CFDA (now NMPA) 
and obtained Class I approval for new drug clinical trial. Oxaliplatin and levoleucovorin calcium 
in the FOLFOX4 chemotherapy regimen are chemotherapeutic drugs produced by Jiangsu 
Hengrui Pharmaceuticals Co., Ltd. and are in clinical use. At present, the National Clinical 
Research Center in the 81st Hospital of the Chinese People's Liberation Army (Nanjing) is 
leading the phase II clinical trial of SHR-1210 combined with apatinib mesylate or FOLFOX4 
regimen in patients with advanced primary liver cancer in accordance with the "Provisions for 
Drug Registration" and GCP . 
11.4 Confidentiality of Subject Information 
During the course of this study, every effort shall be made to protect the privacy of all subjects. 
Study-related documents, study reports, publications, as well as any published data will not 
include the name and other privacy information of the subject, except when required by law. To 
ensure the confidentiality of subjects' personal data, subject information shall be collected, 
transmitted, processed, and stored in accordance with applicable laws and regulations. 
12 QUALITY CONTROL AND ASSURANCE 
 
The clinical study site must be NMPA-approved drug clinical trial institutions with clinical 
study conditions; 
 
Study staff must be personnel trained for clinical trials with corresponding qualifications, 
and must work under the supervision of senior professionals; 
 
Before the trial is started, the clinical wards must be inspected to ensure that standard 
requirements are met and first-aid equipment are available; 

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 
Professional nursing staff are responsible for administering the drugs and they must be fully 
aware of the administration process to ensure subject compliance; 
 
Study sites must carry out the study in strict accordance with the protocol, and the eCRF 
must be completed truthfully; 
 
The Scientific Steering Committee must be established. The Scientific Steering Committee 
is responsible for providing general guidance on execution and implementation of the trial, 
including (but not limited to) safety and enrollment rate, as well as providing guidance on 
published data from perspective of science. 
 
The CRA should follow the standard operating procedure and monitor the clinical trial to 
ensure that all data are documented and reported accurately and completely, all eCRFs are 
entered correctly and consistent with source data, and the trial is implemented as per protocol; 
 
In the event of SAE, the sponsor must inform all study sites immediately, and suspend the 
study whenever necessary; 
 
Participating sites must allow audits by the sponsor and regulatory authorities. It is 
especially important for the investigator and study staff to provide time and convenience for 
monitoring and auditing. 
13 PUBLICATION OF STUDY RESULTS 
The study outcomes belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd. Hengrui does not limit 
the publication of any collected or research information by investigators, regardless of whether the 
results are beneficial to the study drug or not. However, investigators should let the sponsor have 
the opportunity to review any proposed publication or other forms of publication before document 
submission or publication to prevent unintentional leakage of confidential information or 
unprotected inventions. The investigator should provide Hengrui with the manuscript, abstract, or 
full text of all planned publications (poster, invited lectures, or guest lectures) at least 30 days prior 
to submission for publication or other forms of release. To protect the intellectual property, 
especially before the acquisition of patent, the investigator must agree to delay the publication, and 
the delay period will not exceed 60 days. Before open publication, Hengrui can require 
investigators to remove any previously unpublished confidential information (except for study 
results). If this study is part of a multicenter study, the investigator must agree that the first 
publication is an integrated result from all study sites. However, if a manuscript of the integrated 
analysis is not submitted after 12 months when the study is completed or terminated in all study 
sites, the investigator can independently publish results based on other requirements in this section. 

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14 TRIAL PROGRESS 
Scheduled duration: Feb. 2017 to Mar. 2019. 
15 TRIAL PROTOCOL COMPLIANCE 
The investigator shall try his/her best to avoid protocol violations. At any time, the investigator 
should not contact Jiangsu Hengrui Pharmaceuticals Co., Ltd. and ask for approval of protocol 
violations, because any authorized protocol violation should never be allowed. If the investigator 
believed that a certain protocol deviation could improve the implementation of the trial, the 
investigator must consider protocol revisions. However, the revised protocol can only be 
implemented after it is approved by Jiangsu Hengrui Pharmaceuticals Co., Ltd. and the medical 
ethics committee. All major protocol violations should be recorded and reported on the clinical 
trial report. 
16 STUDY SITES AND TRIAL STAFF 
16.1 Coordinating Center 
Name: The 81st Hospital of the Chinese People's Liberation Army 
Address: 34 Thirty-Four Biao, Yang Gong Jing, Qinhuai District, Nanjing City, Jiangsu Province, 
China 
Director of Clinical Trial Site: 
Principal Investigator: Shukui Qin, Professor 
Study Staff: Chief Physician 
Tel.: 
 
Associate Chief Physician 
Tel.: 
Secretary of Clinical Trial Site: 
Tel.: 
16.2 Sponsor  
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Medical Director of the Sponsor:  
Address: No. 7 Kunlunshan Road, Economic & Technological Development Zone, Lianyungang 
City, Jiangsu Province, China 
Tel.: 
E-mail: 
16.3 Other Participants 
To be added 

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37. Qin S, Cheng Y, Liang J et al. Efficacy and safety of the FOLFOX4 regimen versus 
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47. Malka D, Cervera P, Foulon S et al. Gemcitabine and oxaliplatin with or without cetuximab 
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Appendix 1. Response Evaluation Criteria in Solid Tumors Version 1.1 
(Excerpt) 
(New Response Evaluation Criteria in Solid Tumors: Revised RECIST Version 1.1) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
1 BACKGROUND 
Omitted 
2 PURPOSE 
Omitted 
3 MEASURABILITY OF TUMOR AT BASELINE 
3.1 Definition 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1 Measurable lesions 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter is to be 
recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Malignant lymph nodes: pathologically enlarged and measurable, single lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and during follow-up, only the short axis will be 
measured and followed. 
3.1.2 Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph node 
with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions. Non-measurable 
lesions include: meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 

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cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses unable to be 
diagnosed or followed by imaging techniques, and cystic lesions. 
3.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 
Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
 
Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by tomography techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above; 
 
Blastic lesions are non-measurable. 
Cystic lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
3.2 Methods of Measurement 
3.2.1 Measurements of lesions 

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All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
28 days (4 weeks) before the beginning of the treatment. 
3.2.2 Method of evaluation 
The same method and technique should be used to assess lesions at baseline and during 
follow-up. Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of cutaneous 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both imaging and clinical examination, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end 
of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT, MRI: CT is currently the best available and reproducible method for efficacy evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm CR when biopsies are obtained, or to 
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Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper normal limit at baseline, they must return to the 
normal levels for evaluation of complete response. Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line treatment in ovarian cancer. 
Cytology/histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual benign tumor tissue is commonly observed in 
lesions of germ cell neoplasm). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
can be considered if the measurable tumor has met the criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease. 
4 TUMOR RESPONSE ASSESSMENT 
4.1 Assessment of Overall Tumor Load and Measurable Lesions 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
load at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable lesions at baseline should be included in protocols where objective response is the 
primary endpoint. Measurable lesion is defined by the presence of at least one measurable lesion. 
In trials where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if enrollment is restricted 
to those with measurable lesions or whether patients with non-measurable lesions are also 
eligible. 
4.2 Baseline Documentation of "Target" and "Non-target" Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ), representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved, a maximum of two and 
four lesions respectively will be recorded). 

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Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal tissues which may be visible by 
imaging even if not involved by tumor metastasis. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes needs to be measured at baseline. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
tumor metastasis. Nodule size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smallest of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. Nodes with short axis ≥ 10 mm but < 15 mm should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions 
should be recorded as "present", "absent", or in rare cases "unequivocal progression". It is 
possible to record multiple target lesions involving the same organ as a single item on the case 
record form (e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
4.3 Response Criteria 
4.3.1 Evaluation of target lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
compared to baseline. 

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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 
5 mm (the appearance of one or more new lesions is also considered disease progression). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
4.3.2 Precautions for target lesion assessment 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the sum of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. CRFs or other 
data collection methods may therefore be designed to have target nodal lesions recorded in a 
separate section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. 
For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
"too small to measure". When this occurs it is important that a value be recorded on the CRF. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm could be assigned. (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by adipose tissues as in the retroperitoneum; however, if a lymph node is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm could be 
assigned in this circumstance as well). This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will prevent 
false evaluation based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. 

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Lesions that split or coalesce: When non-nodal lesions fragmented, the longest diameters of the 
fragmented portions should be added together to calculate the target lesion sum. Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that 
they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the coalesced lesion. 
4.3.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodules must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive disease (PD): Unequivocal progression of existing non-target lesions. Note: the 
appearance of one or more new lesions is also considered disease progression. 
4.3.4 Special notes on assessment of progression of non-target lesions 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease, to achieve unequivocal progression on the basis of 
the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that the overall tumor load has increased sufficiently to the point where treatment 
must be discontinued. A modest increase in the size of one or more non-target lesions is usually 
not sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable), a useful test that can be applied when assessing patients 
for unequivocal progression is to consider if the increase in overall disease load based on the 

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change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. For example, an increase in tumor burden 
representing an additional 73% increase in volume (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from "trace" 
to "large", an increase in lymphangitic disease from localized to widespread, or may be described 
in protocols as "sufficient to require a change in treatment". Examples include an increase in a 
pleural effusion from trace to large, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as "sufficient to require a change in therapy". If 
unequivocal progression is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must be substantial. 
4.3.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of radiographically detected lesions; however, the finding of a new lesion should 
be unequivocal. For example, it should not be attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor (for 
example, some new bone lesions that may be simply healing, or re-occurrence of pre-existing 
lesions). This is particularly important when the patient's baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT scan report 
as a new cystic lesion, which it is not. 
A lesion identified on a follow-up study that was not scanned at baseline is considered a new 
lesion and will indicate disease progression. An example of this is the patient who has visceral 
disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The patient's brain metastases are considered to be evidence of PD even if he/she did not have 
brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial identification. 
While FDG-PET response assessments generally need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible new disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following process: 

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Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, PD 
is confirmed. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the imaging examination, this is not PD. 
4.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement for confirmation. On occasion a response 
may not be documented until after the end of treatment so protocols should be clear if 
post-treatment assessments are to be considered in the evaluation of best overall response. 
Protocols must specify how any new treatment introduced before progression will affect best 
response evaluation. The patient's best overall response evaluation will depend on the findings of 
both target and non-target diseases and will also take the characteristics of new lesions into 
consideration. Furthermore, depending on the nature of the study and the protocol requirements, 
it may also require confirmatory measurement. Specifically, in non-randomized trials where 
response is the primary endpoint, confirmation of PR or CR is needed to determine either one is 
the best overall response. 
4.4.1 Time point response 
It is assumed that at each time point specified in protocol, an efficacy response occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 1. Time point response: patients with target (+/–non-target) disease. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 

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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
PR 
Non-PD or not all 
evaluable 
Non 
PR 
SD 
Non-PD or not all 
evaluable 
Non 
SD 
Not all evaluable 
Non-PD 
Non 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 
Table 2. Time point response: patients with non-target disease only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
Non 
CR 
Non-CR/Non-PD 
Non 
Non-CR/Non-PDa 
Not all evaluable 
Non 
Not evaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a: "Non-CR/non-PD" is preferred over SD for non-target disease. Since SD is increasingly used as an endpoint 
for efficacy evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 Missing assessments and unevaluable description 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements is made at an evaluation, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) has/have no effect on the 
assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and only two 
lesions were assessed at subsequent follow-up, but those gave a sum of 80 mm, the patient will 
be evaluated as PD status, regardless of the contribution of the missing lesion. 
4.4.3 Best overall response: all time points 
The best overall response is determined once all the data for the patient are known. 

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Best response determination in trials where confirmation of complete or partial response is not 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at the last cycle 
has a best overall response of PR). When SD is believed to be best response, it must also meet 
the protocol specified minimum time calculated from baseline. If the minimum time is not met 
when SD is otherwise the best overall response, the patient's best overall response depends on the 
subsequent assessments. For example, a patient who has SD at Cycle 1, PD at Cycle 2 and does 
not meet minimum duration for SD, will have a best overall response of PD. The same patient 
lost to follow-up after the first SD assessment would be considered not evaluable. 
Best overall response determination in trials where confirmation of complete or partial response 
is required: Complete or partial responses may be claimed only if the criteria for each are met at 
a subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
Table 3. Best overall response when confirmation of CR and PR required. 
Overall Response at 
First Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, 
otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, 
otherwise, NE) 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable. 
a: If a CR is truly met at first time point, then efficacy of any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, will still evaluated as PD at that point (since disease will 
reappear after CR). Best response would depend on whether minimum duration for SD is met. However, 
sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in fact 
the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed 
to PR and the best response is PR. 

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4.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodules decrease to a normal 
size of < 10 mm, they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodules are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have "zero" recorded on the case report form (CRF). 
In trials where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/evaluations will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as symptomatic 
deterioration. Efforts should be made to evaluate objective progression even after discontinuation 
of treatment. Symptomatic deterioration is not a description of an objective response: it is a 
reason for discontinuation of treatment. The objective response status of such patients is to be 
determined by evaluation of target and non-target disease as shown in Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study specific and 
should be clearly described in each protocol (depending on treatment duration and treatment cycle). 
In some circumstances it may be difficult to distinguish residual lesions from normal tissues. 
When the evaluation of complete response depends upon this definition, it is recommended to 
perform a biopsy before evaluating the efficacy of complete remission of local lesions. FDG-PET 
may be used to confirm a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled evaluation. If at 
the next scheduled evaluation, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 

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4.5 Frequency of Tumor Re-evaluation 
Frequency of tumor re-evaluation during treatment should be protocol specific and consistent 
with the type and schedule of treatment. However, in the Phase II trials where the beneficial 
effect of treatment is not known, follow-ups for every 6-8 weeks (timed to coincide with the end 
of a cycle) is reasonable. Interval adjustments could be justified in specific regimens or 
circumstances. The protocol should specify which organ sites are to be evaluated at baseline 
(usually those most likely to be involved with metastatic disease for the tumor type under study) 
and how often evaluations are repeated. Normally, all target and non-target sites are evaluated at 
each assessment. In selected circumstances, certain non-target organs may be evaluated less 
frequently. For example, bone scans may need to be repeated only when CR is identified in target 
disease or when progression in bone is suspected. 
After the treatment, the need for tumor re-evaluations depends on whether the trial has made the 
response rate or the time to an event (progression/death) an endpoint. If time to an event (e.g. 
TTP/DFS/PFS) is the main endpoint of the study, then routine scheduled re-evaluation of 
protocol specified sites of disease should be warranted. In randomized comparative trials in 
particular, the scheduled assessments should be performed as identified on a calendar schedule 
(for example: every 6-8 weeks on treatment or every 3-4 months after treatment) and should not 
be affected by delays in therapy, drug intervals or any other events that might lead to imbalance 
in a treatment arm in the timing of disease assessment. 
4.6 Confirmatory Measurement/Duration of Response 
4.6.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (phase II or III) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 

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4.6.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time criteria 
are first met for CR until the first date that recurrent or progressive disease is truly documented. 
4.6.3 Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint in a 
particular trial, the protocol should specify the minimal time interval required between two 
measurements for determination of SD. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account many 
parameters including disease types and stages, treatment cycle and standard practice. However, 
these limitations of the precision of the measured endpoint should be taken into account if 
comparisons between trials are to be made. 
4.7 PFS/TTP 
4.7.1 Phase II clinical trials 
This guideline is focused primarily on the use of objective response as study endpoints for phase 
II trials. In some circumstances, response rate may not be the optimal method to assess the 
potential anti-cancer activity of new agents/regimens. In such cases PFS/PPF at landmark time 
points, might be considered appropriate alternatives to provide an initial signal of biologic effect 
of new agents. It is clear, however, that in an uncontrolled trial, these measures are subject to 
criticism since an apparently promising observation may be related to biological factors such as 
patient selection and not the impact of the intervention. Thus, phase II screening trials utilizing 
these endpoints are best designed with a randomized control. Exceptions may exist where the 
behavior patterns of certain cancers are so consistent (and usually consistently poor), that a 
non-randomized trial is justifiable. However, in these cases it will be essential to document with 
care the basis for estimating the expected PFS or PPF in the absence of a treatment effect.  

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Appendix 2. Child-Pugh Score of Liver Function 
Parameter 
Score 
 
1 
2 
3 
Hepatic encephalopathy 
None 
Grade 1-2 
Grade 3-4 
Ascites 
None 
Mild 
Moderate and above 
Prothrombin time prolonged or INR 
1-3 s 
4-6 s 
> 6 s 
< 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: 
Class A is 5-6 points; Class B is 7-9 points; Class C is 10-15 points;  
Subjects with Class A or good Class B (i.e., a score of 7) can be enrolled. 
 
Appendix 3. ECOG Performance Status Scoring Criteria 
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 house work, office work; 
2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours; 
3 Capable of only limited selfcare, confined to bed or chair 50% or more of waking hours; 
4 Completely disabled; cannot carry on any selfcare, totally confined to bed or chair; 
5 Death 

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Appendix 4. Management Principles for Immune Related Adverse Events 
1. Management Principles for Gastrointestinal Adverse Events 
 
Non-inflammatory causes of disease should be excluded. Opioids/anesthetics may mask the symptoms of perforation. Do 
not use infliximab in the case of perforation/sepsis. 
Diarrhea/Colitis Grade 
(NCI CTCAE v4) 
Processing 
Visit 
Grade 1 
Diarrhea: Increase of < 4 stools per day 
over baseline 
Colitis: No symptom 
Grade 2 
Diarrhea: Increase of 4-6 stools per 
day over baseline; intravenous infusion 
of < 24 h is required; daily living is not 
affected 
Colitis: Abdominal pain; hematochezia 
Grade 3-4 
Diarrhea (Grade 3): Increase of  
≥ 7 stools per day over baseline; fecal 
incontinence; intravenous infusion of  
≥ 24 h is required; daily living is affected 
Colitis (Grade 3): Severe abdominal pain, 
indications for medical intervention, 
peritoneal sign 
Grade 4: Life threatening, perforation 
• Continue I-O treatment as per study 
protocol  
• Symptomatic treatment 
• Delay I-O treatment as per study 
protocol 
• Symptomatic treatment 
• Discontinue I-O treatment as per 
protocol 
• 1.0-2.0 mg/kg/day of 
methylprednisolone or equivalent IV 
dose 
• Add prophylactic antibiotics to 
prevent opportunistic infections 
• Consider lower GI endoscopy 
• Closely monitor aggravated symptoms. 
• Educate patients to report aggravated symptoms immediately 
If it is aggravated: 
• Provide treatment according to the method for Grade 3 or Grade 
3/4 situations 
If it is improved to Grade 1: 
• Resume I-O treatment as per study protocol 
If symptoms persist for > 5-7 days or recurred: 
• 0.5-1.0 mg/kg/day of methylprednisolone IV or equivalent PO dose 
• When the symptoms improve to Grade 1, reduce the dose of steroids for 
at least 1 month and consider prophylactic antibiotics to prevent 
opportunistic infections, then resume I-O treatment as per protocol 
If symptoms are aggravated or persisted after > 3-5 days of oral 
administration of steroids: 
• Provide treatment according to the method for Grade 3/4 situations 
If symptoms improve: 
• Continue steroid treatment until the symptoms return to Grade 1, 
then gradually reduce the dose of steroids for at least 1 month 
If continuing for > 3-5 days or recurring after improvement: 
• Add 5 mg/kg infliximab (if there are no contraindications).  
Note: In the case of perforation or septicemia, infliximab cannot be 
used 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose, it should be considered that the 
bioavailability of oral corticosteroids is relatively low. 

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2. Management Principles for Pulmonary Adverse Events 
 
 
 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a symptomatic treatment should 
be given while the I-O therapy should be continued. Imaging evaluation and consultations with the respiratory department 
should be performed. 
Pneumonia Grade 
(NCI CTCAE v4) 
Processing 
Visit 
Grade 1 
Only radiographic changes 
Grade 2 
Mild to moderate new 
symptoms 
Grade 3-4 
Severe new symptoms; new 
onset/aggravation of hypoxia; 
life-threatening 
• Consider delaying the I-O treatment 
• Monitor symptoms every 2-3 days 
• Consider consulting with respirologist and 
infectious diseases specialist 
•Delay I-O treatment as per study protocol 
•Consulting with respirologist and 
infectious diseases specialist 
•Monitor symptoms daily and consider 
hospitalization 
•1.0 mg/kg/day of methylprednisolone IV 
or equivalent PO dose 
•Consider bronchoscopy and lung biopsy 
•Discontinue I-O treatment as per study 
protocol 
•Hospitalization 
•Consulting with respirologist and 
infectious diseases specialist 
•2-4 mg/kg/day of methylprednisolone or 
equivalent IV dose 
•Add prophylactic antibiotics to prevent 
opportunistic infections 
•Consider bronchoscopy and lung biopsy 
• Repeat imaging examinations at least every 3 weeks 
If it is aggravated: 
• Provide treatment according to the method for Grade 2 or Grade 3-4 
situations 
• Repeat imaging examinations at least every 1-3 days 
If symptoms improve: 
• When symptoms return to near baseline levels, reduce the dose of 
steroids for at least 1 month and then resume the I-O treatment as per 
study protocol while considering prophylactic antibiotics 
If the symptoms are not improved or aggravated after 2 weeks: 
• Provide treatment according to the method for Grade 3 or Grade 4 
situations 
If symptoms improve to the baseline level: 
• Gradually reduce the dose of steroids for at least 6 weeks 
If the symptoms are not improved or aggravated after 48 hours: 
• Add other immunosuppressants (e.g., infliximab, cyclophosphamide, 
intravenous immunoglobulin or mycophenolate mofetil) 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose, it should be considered that the 
bioavailability of oral corticosteroids is relatively low. 

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3. Management Principles for Hepatic Adverse Events 
 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a symptomatic treatment should 
be given while the I-O therapy should be continued. Consider imaging examinations to rule out obstruction/tumor progression. 
Elevation Grade in the 
Hepatic Function Test 
(NCI CTCAE v4) 
• Continue I-O treatment as per study 
protocol 
Processing 
Visit 
Grade 1 
AST or ALT > 1.0-3.0 × ULN 
and/or T.bili > 1.0-1.5 × ULN 
Grade 2 
AST or ALT > 3.0 to ≤ 5 × 
ULN and/or T.bili > 1.5 to  
≤ 3 × ULN 
Grade 3-4 
ALT or AST > 5.0 × ULN 
and/or T. bili > 3.0 × ULN 
• Delay I-O treatment according to the 
study protocol 
• Increase monitoring frequency to once 
every 3 days 
•Discontinue I-O treatment* 
•Increase monitoring frequency to once 
every 1-2 days 
•1.0-2.0 mg/kg/day of methylprednisolone 
or equivalent IV dose** 
•Add prophylactic antibiotics to prevent 
opportunistic infections 
•Consultation with the gastroenterology 
department 
• Continue hepatic function monitoring as per study protocol 
If it is aggravated: 
• Provide treatment according to the method for Grade 2 or Grade 3/4 
situations 
If improving to baseline level: 
• Resume routine monitoring and resume I-O treatment according to the study 
protocol 
If elevation persists for > 5-7 days or aggravates: 
• Intravenous administration of 0.5-1mg/kg/day methylprednisolone or an 
equivalent orally administrated dose. If LFT returns to Grade 1 or baseline, 
reduce the dose of steroids for at least 1 month and consider prophylactic 
antibiotics to prevent opportunistic infections, and then resume I-O treatment 
as per study protocol 
If it returns to Grade 2: 
• Reduce the dose of steroids for at least 1 month 
If there is no improvement within >3-5 days, or if the symptoms are 
aggravated or deteriorated: 
• Add 1 g of mycophenolate mofetil, b.i.d 
• If the symptoms are not relieved within 3-5 days, consider other 
immunosuppressants based on local guidelines 
Once a patient given intravenous injections of steroids shows a sustained clinical improvement, the patient can switch to an equivalent dose of oral corticosteroids (e.g., 
prednisone) by the time or before the dose of steroid injections starts to be gradually reduced. When switching to oral corticosteroids with an equivalent dose, it should be 
considered that the bioavailability of oral corticosteroids is relatively low. 
*If AST/ALT ≤ 8×ULN and T.bili ≤ 5×ULN, the I-O treatment can be delayed rather than discontinued. 
**For grade 4 hepatitis, the recommended starting dose of methylprednisolone intravenous injection is 2 mg/kg/day. 

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4. Management Principles for Endocrine Adverse Events 
 
 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a symptomatic treatment should 
be given while the I-O therapy should be continued. Visual field tests, endocrinology consultation and imaging examinations are 
considered 
Asymptomatic TSH 
elevation 
• Assess endocrine functions 
• Consider pituitary scans 
Observation of symptoms and abnormalities in laboratory test 
results/pituitary scans: 
• Delay I-O treatment according to the study protocol 
• 1.0-2.0 mg/kg/day of methylprednisolone IV or equivalent PO dose 
• Start a corresponding hormone therapy 
No abnormalities in laboratory test results/pituitary MRI but the symptoms 
persist: 
• Repeat the laboratory test within 1-3 weeks and repeat the pituitary MRI 
scan 1 month later 
Symptomatic 
endocrinopathy 
Suspected adrenal crisis 
(Such as severe dehydration, 
hypotension, and shock 
incommensurate with the 
disease severity) 
• Delay or discontinue I-O treatment as per study protocol 
• Exclude sepsis 
• Intravenous injection of a stress dose of mineralocorticoid-containing 
steroids 
• Intravenous infusion 
• Consult an endocrinologist 
• If the adrenal crisis is ruled out, treat the symptomatic endocrinopathy using 
the methods described above 
• Continue I-O treatment as per study protocol 
• If TSH < 0.5 × LLN or TSH > 2 × ULN, or TSH results are out of range in 2 consecutive subsequent measurements: According 
to clinical indications, detect the level of free T4 in subsequent cycles; consider endocrinology consultation 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch 
to oral administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose in the lungs 
and liver, it should be considered that the bioavailability of oral corticosteroids is relatively low. 
If there is improvement (with or without 
hormone replacement): 
• Reduce the steroid dose for at least 1 
month, and consider use of prophylactic 
antibiotics to prevent opportunistic 
infections 
• Resume I-O treatment as per study protocol 
• Patients with adrenal insufficiency may 
need to continue the use of 
mineralocorticoid-containing steroids 

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5. Management Principles for Skin 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.)
Rash grade 
(NCI CTCAE v4) 
• Symptomatic treatment (e.g., antihistamines, topical 
steroids) 
• Continue I-O treatment as per study protocol 
Processing 
Visit 
Grade 1-2 
Coverage ≤ 30% of 
body surface area 
(BSA) 
Grade 3 
Coverage > 30% body 
surface area (BSA); or 
life-threatening results 
• Delay or discontinue I-O treatment as per study 
protocol 
• Consider skin biopsy 
• Consultation with the Department of Dermatology 
• 1.0-2.0 mg/kg/day of methylprednisolone or 
equivalent IV dose 
If symptoms persist for > 1-2 weeks or recur: 
• Consider skin biopsy 
• Delay I-O treatment as per study protocol 
• Consider 0.5-1.0 mg/kg/day of methylprednisolone IV or 
equivalent PO dose. Once improved, reduce the dose of steroids 
for at least 1 month and consider prophylactic antibiotics to 
prevent opportunistic infections, and resume I-O treatment 
according to the study protocol 
If it is aggravated: 
• Provide treatment according to the method for Grade 3-4 
situations 
If it is improved to Grade 1: 
• Reduce the dose of steroids for at least 1 month and add 
prophylactic antibiotics to prevent opportunistic infections 
• Resume I-O treatment as per study protocol 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose in the lungs and liver, it should 
be considered that the bioavailability of oral corticosteroids is relatively low. 

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Appendix 5. Definition of the prior probability distribution f(θ) of the 
unknown parameter vector θ in the BLRM 
This trial uses a prior probability distribution with less information: 
The prior distribution will be defined as a mixed-type distribution, а(θ) = a1f1(θ) + a2f2(θ) + 
a3f3(θ), where ai (i = 1, 2, 3) is the corresponding weight in the mixed normal distribution (a1+ 
a2+ a3 = 1) and fi(θ) follows a multivariate normal distribution with overall parameters μi and Σi 
(μi is the mean vector of the i-th element in the mixed normal distribution, and Σi is the 
covariance matrix of the i-th element in the mixed normal distribution). 
Σ𝑖= (
𝜎2 𝑖,11
𝜎 𝑖,11𝜎 𝑖,22𝜌𝑖
𝜎 𝑖,11𝜎 𝑖,22𝜌𝑖
𝜎2 𝑖,22
) 
The mixed-type distribution of prior probability has an advantage. They reflect different logical 
dose-toxic response curves, and are thus more reliable as the distribution of prior probability. 
Derivation of the prior distribution: 
Due to the lack of research in similar populations, relevant human experimental data cannot be 
obtained in the current research field. Therefore, the three components of the mixed distribution 
are established according to the following principles: 
1. Use a less informative prior distribution that assumes a median rate of 0.05 for clinically 
significant toxicities at the starting dose (125 mg), and a median rate of 0.30 for clinically 
significant toxicities at the expected maximum tolerable dose (500 mg). Thus obtained is the 
mean vector µ1 = (-2.99, 0.84). The setting of standard deviation reflects the great 
uncertainty of the mean values of the parameters. With the correlation coefficient set to 0, 
σ1,11 = 2, σ1,22 = 1, and ρ1 = 0 are obtained. The weight a1 of f1(θ) in the mixed prior 
distribution is set to 0.9. 
2. Use a prior distribution assuming that the drug is more toxic but less informative to reflect 
that the toxicity of the compound may be higher than expected. Based on this a priori 
hypothesis, the median rate of clinically significant toxicities at the starting dose (125 mg) is 
0.10, and the median rate of clinically significant toxicities at the expected maximum 
tolerable dose (500 mg) is 0.60. Based on the above assumptions, a μ2 = (-1.09, 0.46) is 
obtained. The standard deviation and correlation coefficient are the same as the first prior 
distribution with less information, i.e., σ2,11 = 2, σ2,22 = 1, and ρ2 = 0. The weight a2 of the 
second component in the mixed prior distribution is set to 0.05. 

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3. Use a prior distribution assuming that the drug is less toxic but less informative to reflect 
that the toxicity of the compound may be lower than expected. Based on this a priori 
hypothesis, the median rate of clinically significant toxicities at the starting dose (125 mg) is 
0.01, and the median rate of clinically significant toxicities at the expected maximum 
tolerable dose (500 mg) is 0.1. Based on the above assumptions, μ3 = (-4.24, -0.69) is 
obtained, which is a flat curve. The standard deviation and correlation coefficient are set to 
σ3,11 = 5, σ3,22 = 0.01, and ρ3 = 0. The weight a3 of the third component in the mixed prior 
distribution is set to 0.05. 
Table 1 summarizes the prior distribution. In addition, Table 2 shows the a priori probability of 
clinically significant toxicities at different doses and their corresponding probability of drug 
insufficiency, drug compliance, and drug overdose. The above table shows that the median 
probability of clinically significant toxicities derived from the prior probability distribution is 
consistent with the median prior probability derived from the prior distribution with less 
information. The uncertainty is high, confirming that the prior distribution can only provide 
limited amount of information. 
Table 1. Summary of prior distribution. 
Components of Prior Probability 
Weight in the Mixed Distribution 
Mean Vector 
Standard 
Deviation Vector 
1: Prior Probability Distribution with 
Less Information 
0.900 
-2.99 
0.84 
2.000, 1.000 
2: Prior probability distribution 
assuming a strong toxicity of the drug 
0.050 
-1.09  
0.46  
2.000, 1.000 
3: Prior probability distribution 
assuming a weak toxicity of the drug 
0.050 
-4.24  
-0.69 
5.000, 0.010 
Table 2. Prior probability of clinically significant toxic events at specific doses. 
Dose 
Probability of Clinically Significant Toxicity 
Rate Falling Within the Probability Interval 
 
 
Quantile 
 
[0-0.16) 
[0.16-0.33) 
[0.33-1) 
Mean 
Standard 
deviation 
2.5% 
50% 
97.5% 
125 mg 
0.894 
0.054 
0.052 
0.061 
0.143 
0 
0.007 
0.557 
250 mg 
0.728 
0.128 
0.143 
0.142 
0.206 
0 
0.049 
0.790 
375 mg 
0.499 
0.153 
0.346 
0.296 
0.314 
0.001 
0.16 
0.990 
500 mg 
0.397 
0.135 
0.467 
0.397 
0.358 
0.001 
0.282 
0.999 
 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 118 
Appendix 6. Packaging and Labeling of Study Drugs. 
Example of label (refer to the actual drug label) 
 
Small box label 
 
SHR-1210 for Injection    Clinical Trial Approval No.: 2016L01455/ 
2014L00877    Strength: 200 mg/vial 
FOR CLINICAL STUDY USE ONLY 
Study Title: A Phase II Clinical Study of PD-1 Antibody SHR-1210 Combined 
with Apatinib Mesylate or FOLFOX4 Regimen in the Treatment 
of Advanced Liver Cancer 
Study No.: SHR-1210-APTN-II-203-PLC 
Dosage Form: Lyophilized powder, 
Administration: 3 mg/kg, Q2W, intravenous drip   Note: Prepare according 
to the pharmacy manual 
Drug No.                         
Quantity: 1 vial per box 
Storage Method: Store at 2-8 °C away from light 
Batch No.:                      Expiry Date: MM/DD/20YY  
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Drug label of 
SHR-1210 
 
 
Vial Label 
 
SHR-1210 for Injection    Clinical Trial Approval No.: 
2016L01455/2014L00877    Strength: 200 mg/vial 
FOR CLINICAL STUDY USE ONLY 
Study Title:  A Phase II Clinical Study of PD-1 Antibody SHR-1210 
Combined with Apatinib Mesylate or FOLFOX4 Regimen in 
the Treatment of Advanced Liver Cancer 
Study No.: SHR-1210-APTN-II-203-PLC 
Dosage Form: Lyophilized powder, 
Administration: 3 mg/kg, Q2W, intravenous drip    Note: Prepare 
according to the pharmacy manual 
Subject No.:                          Drug No.                   
Cycle __, Dose __ 
Storage Method: Store at 2-8 °C away from light      
Batch No.:                       Expiry Date: MM/DD/20YY        
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd.       
 
 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 119 
 
Big Box Label 
 
SHR-1210 for Injection    Clinical Trial Approval No.: 
2016L01455/2014L00877    Strength: 200 mg/vial 
FOR CLINICAL STUDY USE ONLY 
Study Title: A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in 
the Treatment of Advanced Liver Cancer 
Study No.: SHR-1210-APTN-II-203-PLC           Dosage Form: 
lyophilized powder, 200 mg/vial 
Administration: 3 mg/kg, Q2W, intravenous drip    Note: Prepare 
according to the pharmacy manual 
Quantity: 20 vials per box (drug no. for this box of drug: xxxx-xxxx) 
Storage Method: Store at 2-8 °C away from light      
Batch No.:                       Expiry Date: MM/DD/20YY        
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
Manufacturer: Shanghai Hengrui Pharmaceutical Co., Ltd.     
 
Drug label of apatinib mesylate 
Pack label for the 250 mg/tablet strength (for the use in the 125 mg dose group) 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Strength: 250 mg/tablet 
Administration: Half a tablet per day, once a day after meals (the dosing 
time on each day should remain the same whenever possible) 
Batch No.: ×××××× 
Expiry Date: 2 years, till MM/DD/20YY 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 120 
Small box label for the 250 mg/tablet strength (for the use in the 125 mg dose group) 
 
 
Big box label for the 250 mg/tablet strength (for the use in the 125 mg dose group) 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 10 tablets per pack, 3 packs per box 
Strength: 250 mg/tablet 
Method of administration: Half tablet, once a day after meals (the dosing 
time on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ××××      Expiration Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: xx small boxes   Strength: 250 mg/tablet 
Method of administration: Half tablet, once a day after meals (the dosing 
time on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ×××× 
Expiry Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 121 
250 mg/tablet, pack label (for 250 mg dose group) 
 
 
 
 
 
 
 
  
 
 
250 mg/tablet, small box label (for 250 mg dose group) 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in 
the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 10 tablets per pack, 3 packs per box 
Strength: 250 mg/tablet 
Method of administration: 1 tablet, once a day after meals (the dosing time on each 
day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ××××      Expiration Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in 
the Treatment of Advanced Cancer 
For clinical use only 
Strength: 250 mg/tablet 
Method of Administration: 1 tablet per day, once a day after meals (the dosing 
time on each day should remain the same whenever possible) 
Batch No.: ×××××× 
Expiry Date: 2 years, till MM/DD/20YY 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 122 
Big box label for the 250 mg/tablet strength (for the use in the 250 mg dose group)  
 
 
Pack label for the 375 mg/tablet strength 
 
 
 
 
 
 
 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in 
the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: xx small boxes   Strength: 250 mg/tablet 
Method of administration: 1 tablet, once a day after meals (the dosing time on each 
day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ×××× 
Expiry Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
Strength: 375 mg/tablet 
Method of Administration: 1 tablet per day, once a day after meals (the 
dosing time on each day should remain the same whenever possible) 
Batch No.: ×××××× 
Expiry Date: 2 years, till MM/DD/20YY 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 123 
Small box label for the 375 mg/tablet strength 
 
 
Big box label for the 375 mg/tablet strength 
 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Medication for Cycle X 
Quantity: 10 tablets per pack, 3 packs per box 
Strength: 375 mg/tablet 
Method of administration: 1 tablet, once a day after meals (the dosing time 
on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ××××      Expiration Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen 
in the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: xx small boxes   Strength: 375 mg/tablet 
Method of administration: 1 tablet, once a day after meals (the dosing time 
on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ×××× 
Expiry Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 124 
250 mg/tablet, pack label (for 500 mg dose group) 
 
 
 
 
 
 
 
 
 
 
250 mg/tablet, small box label (for 500 mg dose group) 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 10 tablets per pack, 6 packs per box 
Strength: 250 mg/tablet 
Method of administration: 2 tablets, once a day after meals (the dosing time 
on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ××××      Expiration Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
Strength: 250 mg/tablet 
Method of administration: 2 tablets per day 
        Once a day after meals (the dosing time on each day should 
remain the same whenever possible) 
Batch No.: ×××××× 
Expiry Date: 2 years, till MM/DD/20YY 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 125 
250 mg/tablet, large box label (for 500 mg dose group) 
 
Label of oxaliplatin 
Box label for the 50 mg strength 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 
Regimen in the Treatment of Advanced Cancer 
For clinical use only 
 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: XX packs per box   Strength: 250 mg/tablet 
Method of administration: 2 tablets, once a day after meals (the dosing time 
on each day should remain the same whenever possible) 
Storage: ×××× 
Batch No.: ×××× 
Expiration Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in the 
Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 1 vial contained   Strength: 50 mg/vial 
Method of Administration: 85 mg/m2 (intravenous infusion), repeated once every two 
weeks 
Storage: Store in a sealed container away from light below 25 °C 
Batch No.: ×××× 
Expiry Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 126 
100 mg box label 
 
 
Label of levoleucovorin calcium 
25 mg box label 
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in the 
Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 1 vial   Strength: 100 mg/vial 
Method of Administration: 85 mg/m2 (intravenous infusion), repeated once every two 
weeks 
Storage: Store in a sealed container away from light below 25 °C 
Batch No.: ×××× 
Expiry Date: 2 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in the 
Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Drug No.: 
Quantity: 1 vial   Strength: 25 mg/vial 
Administration: 200 mg/m2 (2 h intravenous infusion), on D1, D2, and repeated once 
every 2 weeks 
Storage: Store in a sealed container away from light in a dry environment 
Batch No.: ×××× 
Expiry Date: 3 years, till MM/DD/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 

Investigational Drug No.: SHR-1210 
Study No.: SHR-1210-APTN-II-203-PLC 
Version No.: 2.0  Version Date: 12 May 2018 
 
Hengrui Confidential 
Page 127 
Label of 5-fluorouracil 
Box label for the 250 mg/vial, 5 vials/box strength  
 
Label of gemcitabine 
Box label for the 1.0 g/vial, 3 vials/box strength  
 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or FOLFOX4 Regimen in the 
Treatment of Advanced Cancer 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877 
Quantity: 5 vials   Strength: 250 mg/vial 
Administration: 400 mg/m2 (bolus injection), 600 mg/m2 (22 h intravenous infusion), 
on D1,  D2, and repeated once every 2 weeks 
Storage: Sealed and kept away from light 
Batch No.: ×××× 
Expiry: 18 months, until DD/MM/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist 
A Phase II Clinical Study of PD-1 Antibody SHR-1210 in 
Combination with Apatinib Mesylate or Chemotherapy in the 
Treatment of Advanced Primary Liver Cancer or Extrahepatic 
Cholangiocarcinoma 
For clinical use only 
Clinical Approval No.: 2016L01455/2014L00877/2014L00876 
Quantity: 3 vials contained   Strength: 1.0 g/vial 
Administration: 800 mg/m2 (intravenous drip), repeated once every 2 weeks 
Storage: Store in a sealed container in a dry environment 
Batch No.: ×××× 
Shelf life: 36 months  
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining drugs to the pharmacist