Conditions: Gastric Cancer GastroEsophageal Cancer
Keywords: PD-1 SHR-1210 Capecitabine Oxaliplatin Apatinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 67
Healthy volunteers: no

Brief summary:
The purpose of this trial is to estimate overall response rate (ORR) of SHR-1210 combined with capecitabine and oxaliplatin or with apatinib as first-line treatment in subjects with locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Detailed description:
Approximately 110 participants will be assigned to SHR-1210 + capecitabine + oxaliplatin combination therapy (Cohort 1), or SHR-1210 + apatinib combination therapy (Cohort 2).

Arms:
arm 1: Participants receive SHR-1210 200 mg, intravenously (IV) every 3 weeks(Q3W) plus capecitabine 1000 mg/m\^2 twice daily (BID) by continuous oral administration for 14 days, followed by a recovery period of 7 days, plus oxaliplatin 130 mg/m\^2, IV q3w; for 4-6 cycles followed by SHR-1210 plus apatinib 375 mg PO qd if there is no PD. arm 2: Participants receive SHR-1210 200 mg, intravenously (IV) every 3 weeks(Q3W) plus apatinib 375 mg daily (QD) continuous oral administration of each 3-week cycle.

Interventions: intervention 1: SHR-1210 intervention 2: Capecitabine intervention 3: Oxaliplatin intervention 4: Apatinib
Intervention descriptions: intervention 1: SHR-1210 is a humanized anti-PD1 IgG4 monoclonal antibody intervention 2: 1000 mg/m\^2 administered as continuous oral twice daily (BID) of each 3-week cycle. intervention 3: 130 mg/m\^2 administered IV Q3W on Day 1 of each 3-week cycle. intervention 4: 375 mg administered as continuous oral once daily (QD) of each 3-week cycle.

Protocol document:
Prot_000.pdf: 
Title: An Open-Label, Multi-Center, Phase II Study of Anti-PD-1 Antibody SHR-
1210 Plus Capecitabine and Oxaliplatin Sequenced by SHR-1210 with Apatinib 
Mesylate or Apatinib in Patients with Previously Untreated Advanced or Metastatic 
Gastric (GC) or Gastroesophageal Junction (GEJ) Cancer 
NCT number: NCT03472365 
Date: 8 Aug., 2018 


SHR-1210-II-207 
6.0 (8 Aug., 2018) 
 
 
Hengrui Confidential 
1 
Translated from Original Document 
                                  
 
AN OPEN-LABEL, MULTI-CENTER, PHASE II STUDY OF ANTI-PD-1 
ANTIBODY SHR-1210 PLUS CAPECITABINE AND OXALIPLATIN 
SEQUENCED BY SHR-1210 WITH APATINIB MESYLATE OR APATINIB 
IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OR 
METASTATIC GASTRIC (GC) OR GASTROESOPHAGEAL JUNCTION 
(GEJ) CANCER 
 
Protocol No.: 
SHR-1210-II-207 
Study Phase: 
II 
Version No.: 
6.0 
Version Date: 
8 Aug., 2018 
 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for 
use by clinical investigators only. Any disclosure is not permitted unless 
requested by current laws or regulations. The copyright is owned by Jiangsu 
Hengrui Pharmaceuticals Co., Ltd. or its subsidiaries. Any copy or 
distribution of information herein to any individuals not participating in this 
clinical study is not allowed, unless a confidentiality agreement has been 
signed with Jiangsu Hengrui Pharmaceuticals Co., Ltd. or its subsidiaries. 


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Hengrui Confidential 
2 
VERSION HISTORY/REVISION HISTORY 
 
Document 
Version Date 
Amendment Rationale and Summary of Changes 
Initial version 
(1.0) 
1 Nov., 2017 
Not applicable 
2.0 
15 Dec., 2017 
Added the information on the clinical study progress of SHR-1210 
combined with apatinib (section 1.1.4); 
Inaccurate text description: The legend "Table 17. Sample size 
calculation" in the list of tables in version 1.0 was actually Table 16 in 
the text. Checked the protocol text and modified the table to "Table 16. 
Sample size calculation" to keep the description correct and 
consistent. 
3.0 
9 Jan., 2018 
For more details, refer to independent document "List of Study 
Protocol Amendments Version 3.0". The main revisions are as 
follows: 
Deleted immunogenicity and PK tests; 
Deleted biomarker test; 
Deleted overall survival from the secondary endpoints; 
Modified "Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs) and laboratory abnormalities" to "incidence 
and severity of adverse events (AEs) and serious adverse events 
(SAEs), vital signs, ECG, and laboratory abnormalities" in the 
secondary endpoints. 
Deleted "Subjects shall be first included into cohort 1. The enrollment 
of cohort 2 is started only after the enrollment of cohort 1 is 
completed" from the study design. 
Deleted exclusion criterion 9 "The ascites is still uncontrollable after 
treatment". 
Modified the descriptions "treatment group 1" and "treatment group 2" 
in the study design of the protocol synopsis to "cohort 1" and "cohort 
2" to keep the text correct and consistent. 
4.0 
22 Jan., 2018 
The study design adopts a randomized method to assign the subjects to 
cohort 1 or cohort 2. 
Added Section 4.3 Randomization and Blinding. 
Recalculated the sample size according to the requirement for 
randomization. Nineteen subjects will be enrolled into cohort 1 and 
cohort 2 at the first stage, respectively. If at least 4 subjects achieve 
objective response, the second stage will be initiated. 
Besides, considering the 10% non-evaluable subjects, 48 and 62 
subjects should be enrolled into cohort 1 and 2, respectively. 


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5.0 
5 Jun., 2018 
Updated the treatment of cohort 1. 
Updated the original treatment for cohort 1 (at least four cycles of 
SHR-1210 combined with capecitabine and oxaliplatin sequenced by 
SHR-1210 monotherapy as maintenance treatment) to the following: 
SHR-1210 + capecitabine + oxaliplatin for 4-6 cycles, followed by 
SHR-1210 + apatinib in the treatment of the subjects without disease 
progression. 
Based on the above revisions, relevant contents including the title of 
the study, were updated: 
The title was updated to "An Open-Label, Multi-Center, Phase II 
Study of Anti-PD-1 Antibody SHR-1210 Plus Capecitabine and 
Oxaliplatin Sequenced by SHR-1210 with Apatinib Mesylate or 
Apatinib in Patients with Previously Untreated Advanced or 
Metastatic Gastric (GC) or Gastroesophageal Junction (GEJ) Cancer"; 
The study objectives were updated to "Primary objective: To evaluate 
the efficacy of the sequential therapy of SHR-1210 combined with 
capecitabine and oxaliplatin or SHR-1210 combined with apatinib 
mesylate as the first-line therapy for advanced or metastatic gastric 
(GC) or gastroesophageal junction (GEJ) cancer"; 
Secondary objective: "To evaluate the safety of the sequential therapy 
of SHR-1210 combined with capecitabine and oxaliplatin or 
SHR-1210 combined with apatinib mesylate for the treatment of 
advanced or metastatic gastric (GC) or gastroesophageal junction 
(GEJ) cancer". 
According to the latest CDE requirements on drug safety, relevant 
contents in the study were updated: 
a) AEs: AEs are recorded from the date of signing informed consent 
to the end of the safety follow-up (90 days after the last dose) or 
the start of a new anti-cancer therapy. 
b) Death caused by the symptoms and signs of PD will be reported 
as an SAE. 
c) "Definitely related", "possibly related" and "unlikely related" and 
"indeterminable" are all listed as adverse drug reactions. 
d) The collection and follow-up duration of AE/SAE are reinforced 
(see section 7.4.1). 
e) The CFDA and the National Health and Family Planning 
Commission have changed to other names but the GCP and 
Provisions for Drug Registration have not been updated yet. 
Therefore, the reporting of SAEs was updated: "The SAE must be 
reported to the relevant regulatory authorities, the sponsor, and 
the ethics committee within 24 hours of knowing of the event. 
The sponsor's email address for safety data is: 
hengrui_drug_safety@hrglobe.cn." 


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6.0 
8 Aug., 2018 
1. The safety data by 7 Aug., 2018 showed that the safety and 
tolerance of SHR-1210 combined with apatinib (500 mg/d) were 
poor: Among 11 patients receiving SHR-1210 + apatinib 
treatment, there were 4 SAEs related to apatinib (including grade 
3 transaminase increased, grade 3 erythema multiforme, grade 3 
upper gastrointestinal hemorrhage, and grade 4 skin toxicity). By 
referring to the latest data from other studies of SHR-1210 plus 
apatinib treatment and after discussion with PI, it is planned to 
reduce the dose of SHR-1210 plus apatinib to 375 mg/d. For more 
details, see section 5.1.5 Regimen of the drugs. 
Section 5.2.3 Dose Modification of Apatinib Mesylate has also 
been updated accordingly based on the above changes in the dose 
of apatinib: Depending on the initial dose of apatinib, the dose of 
apatinib mesylate can be reduced to 375 mg qd or 250 mg qd. 
2. Blood sampling for Pharmacokinetic study and for anti-drug 
antibodies were added to fully investigate the properties of 
SHR-1210 combined with apatinib and to more effectively 
analyze the safety and efficacy of the combined treatment (see 
section 3.1). 
3. Blood sampling burden is minimized as much as possible for the 
subjects based on the current medical practice while satisfying the 
medical requirements. For the HBV DNA test, the following 
requirement was proposed: If the Hepatitis B five items test 
indicates HBV infection [HBsAg positive] or a history of HBV 
infection, HBV DNA quantification shall be performed (see 
section 6.1). 
4. Capecitabine (0.15 g/tablet) and oxaliplatin (100 mg/bottle) were 
added to facilitate the subjects to receive the study drug based on 
the current medical practice (see section 5.1.2). 
5. In section 5.2.3 Dose Modification of Apatinib Mesylate, "dose 
delay" was revised to "dose interruption" to improve the 
correctness of description. 
6. In section 7.4.5 Pregnancy Report, reporting to the ethics 
committee was added with improvement of wording: "Female 
subjects who become pregnant during the study must withdraw 
from the study. If a female partner of a male subject becomes 
pregnant, the male subject will continue participation in the 
clinical study. The investigators must fill out the "Pregnancy 
Report/Follow-up Form for Hengrui's Clinical Studies" and 
report to the sponsor within 24 hours after becoming aware of the 
pregnancy, and report to the ethics committee promptly". 
 
 


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SPONSOR'S SIGNATURE PAGE 
 
I have read and confirmed this clinical study protocol (protocol no.: SHR-1210-II-207, version 
no.: 6.0, version date: 8 Aug., 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. 
 
 
 
 
 
 
_____________________ 
_____________________ 
_____________________ 
Medical Director  
(print) 
Medical Director  
(signature) 
Date of Signature 
 
 


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6 
PRINCIPAL INVESTIGATOR'S SIGNATURE PAGE (LEADING 
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 study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. 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 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 study. I will 
keep the personal information 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 Center: _______________________ 
 
 
_____________________ 
_____________________ 
_____________________ 
Principal Investigator  
(print) 
Principal Investigator 
(signature) 
Date of Signature 
 
 


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7 
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 study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. 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 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 study. 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 Center: ______________________ 
 
 
_____________________ 
_____________________ 
_____________________ 
Principal Investigator  
(print) 
Principal Investigator 
(signature) 
Date of Signature 
 


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Hengrui Confidential 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 8 
PROTOCOL SYNOPSIS ........................................................................................................... 13 
SCHEDULE OF ACTIVITIES ................................................................................................. 21 
ABBREVIATIONS ..................................................................................................................... 26 
1 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE .................... 28 
1.1. Background ................................................................................................................. 28 
1.1.1. Information on SHR-1210 .............................................................................. 29 
1.1.2. Information on apatinib mesylate ................................................................... 33 
1.1.3. Information on capecitabine and oxaliplatin ................................................... 35 
1.1.4. Progress in the Clinical Studies of SHR-1210 plus Apatinib ......................... 35 
1.2. Scientific Rationale ..................................................................................................... 36 
1.3. Potential Risks and Benefits ....................................................................................... 39 
1.3.1. Known potential risks ..................................................................................... 39 
1.3.2. Known potential benefits ................................................................................ 41 
2 
OBJECTIVES AND ENDPOINTS ................................................................................... 41 
2.1 
Study Objectives ......................................................................................................... 41 
2.2 
Study Endpoints .......................................................................................................... 41 
3 
STUDY DESIGN ................................................................................................................. 42 
3.1 
Pharmacokinetic and Immunogenicity Studies ........................................................... 43 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 44 
4.1 
Inclusion Criteria ........................................................................................................ 44 
4.2 
Exclusion Criteria ....................................................................................................... 46 
4.3 
Randomization and Blinding ...................................................................................... 48 
4.4 
Rescreening Criteria .................................................................................................... 48 
4.5 
Withdrawal or Discontinuation ................................................................................... 48 
4.5.1 Study withdrawal criteria ................................................................................ 49 
4.5.2 Criteria for treatment discontinuation ............................................................. 49 
4.5.3 Procedures for withdrawal or discontinuation ................................................ 50 
4.6 
Criteria for Continuing Treatment Beyond Disease Progression ............................... 50 
4.7 
Termination or Suspension of Study ........................................................................... 51 


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4.8 
Definition of End of Study .......................................................................................... 52 
5 
STUDY TREATMENT ...................................................................................................... 52 
5.1 
Overview of the Study Drugs ..................................................................................... 52 
5.1.1 Access to the drugs ......................................................................................... 52 
5.1.2 Drug information ............................................................................................ 52 
5.1.3 Drug storage and management ........................................................................ 54 
5.1.4 Preparation of study drugs .............................................................................. 54 
5.1.5 Administration of study drugs ........................................................................ 55 
5.2 
Dose Modification of Study Drugs ............................................................................. 56 
5.2.1 Dose modification of SHR-1210 .................................................................... 56 
5.2.2 Dose modification of capecitabine and oxaliplatin ......................................... 58 
5.2.3 Dose modification of apatinib mesylate ......................................................... 60 
5.3 
Duration of Treatment ................................................................................................. 61 
5.4 
Drug Management, Dispensation, Return and Disposal ............................................. 61 
5.5 
Recording of concomitant medications and concomitant treatments ......................... 62 
5.5.1 Other anti-tumor treatments or investigational drugs ..................................... 62 
5.5.2 Vaccines .......................................................................................................... 63 
5.5.3 Immunomodulators and corticosteroids .......................................................... 63 
5.5.4 Hematopoietic growth factor and blood transfusion ....................................... 63 
5.5.5 Anti-inflammatory treatment .......................................................................... 64 
5.5.6 Medications to be used with caution in subjects receiving  
apatinib during the study ................................................................................. 64 
5.5.7 Surgery ............................................................................................................ 65 
5.5.8 Supportive care ............................................................................................... 65 
5.6 
Recommended Symptomatic Treatment for Common Adverse  
Drug Reactions Related to SHR-1210 ........................................................................ 66 
5.6.1 Safety management rules for immuno-oncological medications .................... 66 
5.6.2 Infusion reactions ............................................................................................ 66 
6 
STUDY PROCEDURES .................................................................................................... 67 
6.1 
Screening Period ......................................................................................................... 67 
6.2 
Treatment Period/Follow-Up ...................................................................................... 70 
6.3 
End of Treatment/Withdrawal Visit ............................................................................ 71 


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6.4 
Follow-up period ......................................................................................................... 72 
6.4.1 Safety follow-up period .................................................................................. 72 
6.4.2 Survival follow-up .......................................................................................... 73 
6.5 
Unscheduled Visit ....................................................................................................... 73 
7 
STUDY EVALUATION ..................................................................................................... 74 
7.1 
Efficacy Evaluation ..................................................................................................... 74 
7.1.1 Efficacy endpoints .......................................................................................... 74 
7.1.2 Criteria for efficacy evaluation ....................................................................... 75 
7.2 
Safety Evaluation ........................................................................................................ 76 
7.2.1 Safety endpoints .............................................................................................. 76 
7.2.2 Definition of adverse event ............................................................................. 76 
7.2.3 Definition of serious adverse event................................................................. 77 
7.2.4 Progressive disease ......................................................................................... 78 
7.2.5 Immune-mediated adverse events ................................................................... 78 
7.2.6 Potential drug-induced liver injury ................................................................. 79 
7.2.7 Adverse Events of Special Interest ................................................................. 80 
7.3 
Classification of AEs and SAEs ................................................................................. 80 
7.3.1 Criteria for the severity of AEs ....................................................................... 80 
7.3.2 Criteria for causality between adverse events and study drugs ...................... 80 
7.4 
Follow-up and Reporting of Adverse Events .............................................................. 81 
7.4.1 Follow-up of AEs/SAEs ................................................................................. 81 
7.4.2 Reporting of adverse events ............................................................................ 81 
7.4.3 Reporting of serious adverse events ............................................................... 82 
7.4.4 Reporting of Special Interest Events............................................................... 82 
7.4.5 Pregnancy reporting ........................................................................................ 83 
8 
DATA ANALYSIS/STATISTICAL METHODS ............................................................ 83 
8.1 
Statistical Analysis Plan .............................................................................................. 83 
8.2 
Sample Size ................................................................................................................. 84 
8.3 
Analysis Population .................................................................................................... 85 
8.4 
Statistical Methods ...................................................................................................... 85 
8.4.1 General analysis .............................................................................................. 85 
8.4.2 Efficacy analysis ............................................................................................. 85 


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8.4.3 Safety analysis ................................................................................................ 86 
8.4.4 PK analysis...................................................................................................... 86 
8.4.5 Immunogenicity analysis ................................................................................ 87 
9 
SOURCE DOCUMENTS AND OBTAINING SOURCE DATA/DOCUMENTS ........ 87 
10 
QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 88 
11 
REGULATIONS, ETHICS, INFORMED CONSENT, AND SUBJECT  
PROTECTION .................................................................................................................... 88 
11.1 Regulatory Considerations .......................................................................................... 88 
11.2 Ethical Standards ........................................................................................................ 89 
11.3 IRB/IEC ...................................................................................................................... 89 
11.4 Informed Consent ........................................................................................................ 90 
11.4.1 ICFs and other written information for subjects ............................................. 90 
11.4.2 Informed consent process and records ............................................................ 90 
11.5 Confidentiality of Subject Information ....................................................................... 90 
12 
DATA MANAGEMENT .................................................................................................... 91 
12.1 Data Recording ........................................................................................................... 91 
12.1.1 Study medical records ..................................................................................... 91 
12.1.2 eCRF entry ...................................................................................................... 91 
12.1.3 eCRF review ................................................................................................... 92 
12.1.4 Data monitoring and auditing ......................................................................... 92 
12.2 Data Management ....................................................................................................... 93 
12.2.1 EDC database establishment ........................................................................... 93 
12.2.2 Data entry and verification.............................................................................. 93 
12.2.3 Database lock .................................................................................................. 93 
12.2.4 Data archiving ................................................................................................. 94 
12.3 Protocol Deviations ..................................................................................................... 94 
13 
PUBLICATION OF STUDY RESULTS .......................................................................... 94 
14 
EXPECTED STUDY SCHEDULE ................................................................................... 95 
15 
REFERENCES .................................................................................................................... 95 
Appendix 1 ECOG PS ................................................................................................................ 98 
Appendix 2 Cockroft-Gault Formula (for calculating the creatinine clearance) ................. 99 
Appendix 3 Response Evaluation Criteria in Solid Tumors ................................................. 100 


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Appendix 4 Management Principles for Immune Related Adverse Events ........................ 114 
Appendix 5 Percent Bone Marrow Content in Human Skeleton ......................................... 120 
Appendix 6 Prohibited Traditional Chinese Medicines During the Study Period ................ 121 
 
LIST OF TABLES 
Table 1. Binding affinity of SHR-1210 to human, monkey, and murine PD-1 antigens ............. 29 
Table 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 .......................................................... 29 
Table 3. PK parameters after a single intravenous infusion of SHR-1210 at  
different doses in cynomolgus monkeys ........................................................................ 32 
Table 4.  Efficacy results of the phase III clinical study of apatinib in GC (FAS) ....................... 34 
Table 5. Efficacy results of the phase II clinical study of apatinib in advanced GC (FAS)......... 35 
Table 6.  Administration plan of the study drugs .......................................................................... 55 
Table 7.  Dose modification criteria for SHR-1210 due to immune-related toxicity ................... 56 
Table 8. Dose modification criteria for capecitabine ................................................................... 59 
Table 9. Recommended dose modification of apatinib ................................................................ 60 
Table 10. Treatment recommendations for infusion reaction related to SHR-1210 ...................... 66 
Table 11. Preferred terms included in the IMAE analysis to support warnings  
and precautions .............................................................................................................. 79 
Table 12. Definition of potential drug-induced liver injury ........................................................... 79 
Table 13. Criteria for the severity of AEs ...................................................................................... 80 
Table 14. Requirements for collection and follow-up of AEs/SAEs ............................................. 81 
Table 15. Sample size calculation .................................................................................................. 84 
 
LIST OF FIGURES 
Figure 1. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab ......................... 30 
Figure 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab ................................. 30 
Figure 3. Survival analysis of the phase III clinical study of apatinib in GC (FAS) ..................... 34 
 
 


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PROTOCOL SYNOPSIS 
Study Title 
An Open-Label, Multi-Center, Phase II Study of Anti-PD-1 Antibody SHR-1210 Plus 
Capecitabine and Oxaliplatin Sequenced by SHR-1210 with Apatinib Mesylate or Apatinib in 
Patients with Previously Untreated Advanced or Metastatic Gastric (GC) or Gastroesophageal 
Junction (GEJ) Cancer 
Protocol No. 
SHR-1210-II-207 
Version No. 
6.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Objectives Primary objective: 
 
To evaluate the efficacy of the sequential therapy of SHR-1210 combined with 
capecitabine and oxaliplatin or SHR-1210 combined with apatinib mesylate as the 
first-line therapy for advanced or metastatic gastric (GC) or gastroesophageal junction 
(GEJ) cancer. 
Secondary objectives: 
 
To evaluate the safety of the sequential therapy of SHR-1210 combined with 
capecitabine and oxaliplatin or SHR-1210 combined with apatinib mesylate for the 
treatment of advanced or metastatic gastric (GC) or gastroesophageal junction (GEJ) 
cancer. 
Study Endpoints 
Primary endpoint: 
 
Objective response rate (ORR) 
Secondary endpoints: 
 
Progression free survival (PFS); 
 
Duration of response (DoR); 
 
Disease control rate (DCR); 
 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), vital 
signs, ECG, and laboratory abnormalities. 
Study Population Patients with unresectable, advanced or metastatic GC or GEJ cancer without previous systemic 
treatment. 
STUDY 
DESIGN 
This is a randomized, open-label, multi-center, phase II clinical study. 
A total of 98 patients with previously untreated advanced or metastatic gastric cancer or 
gastroesophageal junction cancer will be enrolled. The subjects are randomized in a 1:1 ratio into 
the sequential therapy of SHR-1210 combined with capecitabine and oxaliplatin treatment group 
(cohort 1, n = 43) or the SHR-1210 combined with apatinib treatment group (cohort 2, n = 55). 
 
Cohort 1 (sequential therapy of SHR-1210 combined with capecitabine and 
oxaliplatin): SHR-1210 + capecitabine + oxaliplatin for 4-6 cycles, followed by 
SHR-1210 + apatinib for subjects without progressive disease (PD); 
 
Cohort 2 (SHR-1210 combined with apatinib): SHR-1210 + apatinib. 


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A two-stage design is adopted to minimize the exposure of subject to ineffective treatment. 
Nineteen subjects will be enrolled into cohort 1 and cohort 2 at the first stage, respectively. If at 
least 4 subjects achieve objective response (complete response or partial response), the second 
stage will be initiated. And more subjects will be enrolled in cohort 1(to 43 subjects) and in cohort 
2 (to 55 subjects), respectively. 
In this study, the screening period should be no more than 28 days. After completing screening 
examinations and assessments, eligible subjects will enter the treatment period (21 days/cycle) and 
begin the study treatment and study visits according to the protocol. Tumor imaging assessment 
will be performed once in every 2 cycles (6 weeks ± 7 days) during the first 12 months (the first 
16 cycles) of the study treatment period and once every 3 cycles (9 weeks ± 7 days) thereafter. The 
subjects will complete safety examinations and imaging assessments upon discontinuation of the 
study treatment. 
Thereafter, the subjects will enter the follow-up period. Safety follow-up starts from the last dose 
of study treatment. The follow-up is performed once every 30 days (± 7 days) until 90 days after 
the last dose. The first safety follow-up is carried out at the study center; the second and the third 
follow-up visit are made via telephone calls. The survival follow-up period starts after the end of 
the safety follow-up period. The survival follow-up period ends upon the subject's death, lost to 
follow-up, withdrawal of informed consent, or study termination by sponsor. During this period, a 
follow-up shall be conducted every month via telephone or other effective methods to collect 
information on subject survival and subsequent treatments. For subjects who show no evidence of 
radiographic progression, an imaging evaluation should be continued at the frequency of response 
evaluations specified in the protocol, until progressive disease, death, lost to follow-up, withdrawal 
of informed consent, start of other anti-cancer treatments, or trial termination by the sponsor. 
Study Drugs and 
Method of 
Administration 
Cohort 1: SHR-1210 + capecitabine + oxaliplatin for 4-6 cycles, followed by SHR-1210 + 
apatinib for subjects without disease progression: 
 
SHR-1210, 200 mg, infuse over 30 min (the total infusion time should be no less than 
20 min and no more than 60 min, including rinsing period), q3w; 
 
Capecitabine, 1000 mg/m2, administered orally twice daily within 30 min after meals 
(once in the morning and once in the evening, with total daily dose of 2000 mg/m2). 
Two weeks of treatment is followed by 1 week of treatment interruption (i.e., drug 
administration from Day 1 to Day 14, and drug interruption from Day 15 to Day 21). 
One treatment cycle lasts for 3 weeks; 
 
Oxaliplatin, 130 mg/m2, mixed with 250-500 mL of 5% glucose solution, continuously 
administered by intravenous drip infusion for 2-6 h. Administered on Day 1 of each 
treatment cycle, once every 3 weeks; 
 
Apatinib mesylate, 375 mg, administered orally once daily. Administered with warm 
water approximately half an hour after meals (administration time should be the same 
in each day whenever possible). 
During the treatment of SHR-1210 combined with chemotherapy, SHR-1210 will be administered 
intravenously followed by oxaliplatin at least 30 min later on Day 1 of each cycle. 
Cohort 2: SHR-1210 + apatinib mesylate 
 
SHR-1210, 200 mg, infuse over 30 min (the total infusion time should be no less than 
20 min and no more than 60 min, including rinsing period), q3w; 
 
Apatinib mesylate, 375 mg, administered orally once daily. Administered with warm 
water approximately half an hour after meals (administration time should be the same 
in each day whenever possible). 
 


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All subjects should continue to receive the study treatment until progressive disease, intolerable 
toxicity, voluntary treatment discontinuation or study withdrawal by the subject, or discontinuation 
determined by the investigator. 
SHR-1210 is an immune checkpoint inhibitor and according to the experience of similar drugs, 
some subjects may experience delayed or early pseudo progression after receiving immunotherapy 
drugs. For subjects in the treatment group experiencing progressive disease (PD) for the first time, 
they may continue with the original treatment if they meet the criteria in section 4.6 Criteria for 
Continuing Treatment Beyond Disease Progression. Subjects who do not have progressive disease 
or intolerable toxicities may continue the SHR-1210 treatment for no more than 24 months. 
Subjects who do not have progressive disease after 24-month treatment may continue the apatinib 
monotherapy according to the prescribing information of apatinib. 
Inclusion Criteria Patients must meet all of the following criteria to be eligible. 
1. 
Pathologically or cytologically confirmed GC or GEJ cancer, with evidence of being 
unresectable, locally advanced, or metastatic; histologically confirmed 
adenocarcinoma mainly. 
2. 
Aged 18 or above, male and female. 
3. 
Patients who have not received systemic treatment (including HER-2 inhibitors) for 
advanced or metastatic GC/GEJ. Subjects who have received adjuvant or neoadjuvant 
therapy (including chemotherapy, radiotherapy, or radiochemotherapy) for GC/GEJ 
must have completed the last treatment at least 6 months prior to the first dose of study 
treatment. Palliative radiotherapy is permitted, but it must be completed 2 weeks prior 
to the start of study treatment. 
4. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
5. 
With measurable lesion as per RECIST 1.1 criteria. 
6. 
Life expectancy > 12 weeks. 
7. 
All acute toxicities due to previous anti-tumor treatments or surgeries must have 
resolved to Grade 0–1 (as per NCI CTCAE 4.03) or to the level specified in the 
inclusion/exclusion criteria. Other toxicities such as alopecia, which do not pose a 
safety risk to the subjects evaluated by investigators, are excluded. 
8. 
With adequate organs and bone marrow functions, as defined below: 
a) 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
b) 
Platelet count (PLT) ≥ 100,000/mm3 (100 × 109/L); 
c) 
Hemoglobin (Hb) ≥ 9 g/dL (90 g/L); 
d) 
Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance ≥ 
60 mL/min; 
e) 
Total bilirubin (BIL) ≤ 1.5 × ULN; 
f) 
Aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 
2.5 × ULN; for patients with liver metastasis, ALT and AST should be ≤ 5 × ULN; 
g) 
International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and activated 
partial thromboplastin time (APTT) ≤ 1.5 × ULN; 


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h) 
Urine protein < 2+; If urine protein is ≥ 2+, then the 24-hour urine protein must 
be ≤ 1 g; 
i) 
Thyroid stimulating hormone (TSH) ≤ ULN; in case of abnormalities, T3 and T4 
levels should be measured; if T3 and T4 levels are normal, the subject can be 
enrolled. 
9. 
Female patients of childbearing potential must have a negative serum pregnancy test 
within 3 days prior to the first dose, and be willing to use a recognized effective 
contraceptive measure (such as intra-uterine contraceptive devices, contraceptive pills, 
and condoms) during the study and within 3 months after the last dose of the study 
drugs; male patients with female partners of childbearing potential must either be 
surgically sterilized or agree to take effective contraceptive measures during the study 
and within 3 months after the last dose of the study drugs. 
10. Subjects must agree and have signed the informed consent form, be willing and able to 
follow the scheduled visits, study treatment, laboratory tests, and other study 
procedures. 
Exclusion 
Criteria 
Patients meeting any one of the followings are not eligible to participate in this study: 
1. 
Known HER2-positive. 
2. 
Prior treatment with anti-PD-1/PD-L1 antibodies, CTLA-4 antibodies, or other 
treatments targeting PD-1/PD-L1 and/or VEGFR inhibitors. 
3. 
Known allergies to the study drug or their excipients; severe allergic reactions to other 
monoclonal antibodies. 
4. 
Having received immunosuppressive drugs within 14 days prior to the first dose of 
SHR-1210, excluding intranasal and inhaled corticosteroids or systemic steroids of 
physiological doses (i.e., no more than 10 mg/d of prednisolone or equivalent). 
5. 
Having received live, attenuated vaccines within 4 weeks before the first dose or had 
such vaccination plan during the study. 
6. 
Presence of known uncontrolled or symptomatic active central nervous system (CNS) 
metastases, manifested as clinical symptoms, cerebral edema, spinal cord compression, 
carcinomatous meningitis, leptomeningeal disease, and/or progressive growth. Patients 
with a history of metastases to the central nervous system or spinal cord compression 
may be eligible if they are clearly treated and clinically stable 4 weeks after 
discontinuation of anticonvulsants and steroids before the first dose of study treatment. 
7. 
Presence of Grade > 1 peripheral neuropathy. 
8. 
Advanced diseases that are symptomatic, disseminated to viscera, and at risk of 
life-threatening complications in the short term (including uncontrollable massive 
[pleural, pericardial, and abdominal] exudate, pulmonary lymphangitis, and more than 
30% of hepatic involvement). 
9. 
Presence of any active autoimmune diseases or a history of autoimmune diseases 
(including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, 
enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, 
hypothyroidism; adult subjects with vitiligo or completely relieved childhood asthma 
can be enrolled if they do not require any intervention; patients with asthma requiring 
medical interventions with bronchodilators cannot be enrolled). 
10. Having been diagnosed with any other malignancies within 3 years before the 
enrollment, excluding adequately treated basal cell carcinoma or squamous cell skin 
cancer, or cervical carcinoma in situ. 


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11. Infection with human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS), active hepatitis B (HBV DNA ≥ 500 IU/mL), 
hepatitis C (hepatitis C antibody being positive and HCV-RNA being above the lower 
limit of detection of the assay), or co-infection of hepatitis B and C. 
12. Any of the following conditions observed within 6 months prior to the enrollment: 
myocardial infarction, severe/unstable angina, > NYHA Class II cardiac insufficiency, 
poorly controlled arrhythmia (including males with QTcF > 450 ms and females with 
QTcF > 470 ms, QTcF interval calculated with the Fridericia's formula), symptomatic 
congestive cardiac failure, or cerebrovascular accident (including transient ischemic 
attack or symptomatic pulmonary embolism). 
13. Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
14. Abnormal coagulation function (INR > 1.5 or activated partial thromboplastin time 
(APTT) > 1.5 × ULN), bleeding tendency, or receiving thrombolytics or anticoagulant 
therapy. 
15. Known hereditary or acquired hemorrhage and thrombophilia (hemophilia, 
coagulopathy, thrombocytopenia, hypersplenism, etc.). 
16. Obvious hemoptysis or a daily amount of hemoptysis of half a teaspoon (2.5 mL) or 
more within 2 months before the enrollment. 
17. Clinically significant hemorrhage symptoms or clear bleeding tendency within 3 months 
prior to participation in this study, such as GI bleeding, hemorrhagic gastric ulcer, 
baseline fecal occult blood++ and above, or vasculitis. 
18. Events of arterial/venous thrombosis within 6 months prior to participation in this 
study, such as cerebrovascular accidents (including transient ischemic attacks, cerebral 
hemorrhage, and cerebral infarction), deep vein thrombosis, and pulmonary embolism. 
19. Known hereditary or acquired hemorrhage and thrombophilia (hemophilia, 
coagulopathy, thrombocytopenia, hypersplenism, etc.). 
20. Requiring long-term anticoagulant therapy with warfarin or heparin; or requiring 
long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day). 
21. Complicated with severe infection (such as one requiring intravenous infusion of 
antibiotics, antifungals, or antivirals) within 4 weeks prior to the first dose, or any 
unexplained fever of > 38.5 °C observed during screening period/prior to the first dose. 
22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem 
cell transplantation. 
23. Having participated in clinical studies concerning any other drugs within 4 weeks prior 
to the first dose, or less than 5 half-lives from the last dose of study drugs. 
24. Known history of psychotropic substance abuse or drug abuse. 
25. Patients with other severe physical or psychiatric disorders or laboratory abnormalities, 
which may increase the risk of participating in this study or interfere with the study 
results, as well as those deemed unsuitable by the investigator. 


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Study withdrawal 
criteria 
Reasons for withdrawal may include: 
 
Withdrawal of informed consent and refusal of further follow-ups by subjects; 
 
Continuing participation in the study violating the patient's optimal benefit due to clinical 
AEs, laboratory abnormalities, or concurrent diseases, as assessed by the investigator; 
 
Other investigator-assessed reasons requiring withdrawal, such as the inability to provide 
voluntary consent due to imprisonment or quarantine; 
 
Lost to follow-up; 
 
Death; 
 
Study termination by the sponsor. 
Criteria for Study 
Termination 
The study treatment must be discontinued when any of the following occurs: 
 
Requests to discontinue the study treatment by subjects; 
 
Radiographic or clinical evidence of progressive disease, unless the subject meets the 
criteria for continuing treatment after progression; 
 
Occurrence of pregnancy during the study; 
 
Any clinical AEs, laboratory abnormalities, or other medical conditions indicating that 
the subject can no longer benefit from the treatment; 
 
Comprehensive deterioration of health status and inability to continue study 
participation; 
 
Significant protocol deviations such as ineligibility found after enrollment; 
 
Lost to follow-up; 
 
Study termination by the sponsor; 
 
Death; 
 
Other reasons as determined by the investigator. 
Determination of 
Sample Size 
The sample size will be calculated using Simon's two-stage design, with a power of 80% and a 
one-sided α of 0.05. The optimal method is used, that is, minimizing the subjects' exposure to 
ineffective treatment. Assuming that in the cohort 2 (SHR-1210 + apatinib), uninteresting level 
ORR (P0) = 15% and desirable target level ORR (P1) = 30%. The first stage requires 19 subjects, 
and the treatment should be effective in > 3 subject (i.e. a minimum of 4) before proceeding to the 
second stage. The first and the second stages require a total of 55 subjects, and the treatment should 
be effective in > 12 subjects (i.e., a minimum of 13) to be considered effective. 
Assuming that in the cohort 1 (sequential therapy of SHR-1210 + capecitabine + oxaliplatin), the 
uninteresting level ORR (P0) = 35% and desirable target level ORR (P1) = 55%. Under the 
condition that the power of test is 80% and α is 0.05 (one-sided), the first stage requires 19 subjects 
in both cohort 1 and cohort 2 for the purpose of consistency. The treatment should be effective 
in > 3 subjects (i.e. a minimum of 4) before proceeding to the second stage. The first and the 
second stages require a total of 43 subjects, and the treatment should be effective in > 20 subjects 
(i.e., a minimum of 21) to be considered effective. 


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The number of subjects and the required minimum number of subjects responding to the treatment 
at each stage for both cohorts are shown in the table below: 
 
P0 
P1 
N1 
R1 
N 
R 
Cohort 1 
35% 
55% 
19 
3 
43 
20 
Cohort 2 
15% 
30% 
19 
3 
55 
12 
N1: Number of subjects at the first stage; 
R1: Number of subjects responding to the treatment at the first stage shall be greater than this 
number; 
N: Final number of subjects; 
R: Final number of subjects responding to the treatment shall be greater than this number. 
At the first stage, 19 subjects are enrolled into each cohort. If ≥ 4 subjects in cohort 1 achieve 
response (CR or PR), the second stage will be initiated, and 24 more subjects are enrolled (more 
subjects are enrolled into cohort 1 until there are 43 subjects); if ≥ 4 subjects in cohort 2 achieve 
response, the second stage will be initiated, and 36 more subjects are enrolled (more subjects are 
enrolled into cohort 2 until there are 55 subjects). 
Considering the 10% non-evaluable subjects, 48 and 62 subjects should be enrolled into cohort 1 
and 2, respectively. 
Data Analysis/ 
Statistical 
Methods 
◼ 
General analysis 
For this study, efficacy data will be summarized in accordance with the following general 
principles using descriptive statistics, unless otherwise stated. 
Two-category and multi-category data will be summarized using frequency and percentage. 
Multi-category ordinal data will be summarized using cumulative frequency and percentage. 
Measurement data will be summarized using mean, standard deviation, median, maximum, and 
minimum. 
For time-event data, the survival rate and median survival time for the time of interest will be 
estimated using the Kaplan-Meier method. 
Serum drug concentrations will be summarized using mean or geometric mean, standard deviation, 
coefficient of variation or geometric coefficient of variation, median, maximum, and minimum. 
All statistical analyses will be performed using SAS version 9.2 or later. 
◼ 
Efficacy analysis 
In addition to the general principles of efficacy analysis described above, the analysis of primary 
and secondary efficacy indicators also includes: 
Objective response rate (ORR) and disease control rate (DCR): The 95% CI for ORR will be 
calculated using the Clopper-Pearson method. 
Progression-free survival (PFS): Survival curves will be plotted using the Kaplan-Meier method, 
and the 95% CI for median survival will be calculated using the Brookmeyer-Crowley method. 
Duration of response (DOR) will be analyzed using the same general principles, but the 95% 
confidence interval for the median and a survival curve may be added if appropriate. 


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◼ 
Safety analysis 
The AEs, SAEs, and adverse drug reactions will be analyzed mainly using descriptive statistics. 
Laboratory tests that are normal before the study but become abnormal after starting treatment will 
be described. 
◼ 
PK analysis  
PK analysis is performed based on the PK analysis set. PK concentrations and PK parameters 
(maximum and minimum concentration) are summarized by descriptive statistics. Apart from the 
statistics listed in the general analysis, PK concentration and PK parameter data (maximum and 
minimum concentration) will be also summarized descriptively using geometric mean (GM), 
coefficient of variation (CV%), and geometric CV% (GCV%). 
The correlation between drug exposure and toxicity is analyzed based on the maximum and 
minimum concentration of SHR-1210 and apatinib. 
◼ 
Immunogenicity analysis 
The immunogenicity will be analyzed based on the ADA analysis set. The concentration of 
anti-SHR-1210 antibodies (ADAs) will be analyzed using descriptive statistics. 
Treatment-emergent adverse events may be analyzed separately in the ADA-negative and 
ADA-positive groups. 
 


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SCHEDULE OF ACTIVITIES 
Study Procedures 
Screening Period 
Cycle 1 
Cycle 2 and 
beyond 
End of 
Treatment/ 
Withdrawal 
Follow-Up Period 
(at the end of treatment) 
D-28 ~ D-1 
D-7 ~ D-1 
D1 ± 3 [22] 
D1 ± 3 
Safety 
Follow-Up[23] 
Survival 
Follow-Up[24] 
Signing of Informed Consent Form[1] 
× 
 
 
 
 
 
 
Demographics 
× 
 
 
 
 
 
 
Medical History and Treatment 
History[2] 
× 
 
 
 
 
 
 
Verification of Eligibility 
 
× 
 
 
 
 
 
ECOG PS[3] 
 
× 
× 
× 
× 
× 
 
Vital Signs[4] 
 
× 
× 
× 
× 
× 
 
Physical Examination[5] 
 
× 
× 
× 
× 
× 
 
Virology[6] 
× 
 
 
 
 
 
 
Hematology[7] 
 
× 
× 
× 
× 
× 
 
Urinalysis[8] 
 
× 
× 
×[8] 
× 
× 
 
Fecal Occult Blood Test[9] 
 
× 
 
×[9] 
× 
× 
 
Clinical Chemistry[10] 
 
× 
× 
× 
× 
× 
 
Coagulation Function[11] 
 
× 
× 
× 
× 
× 
 
Thyroid Function[12] 
 
× 
× 
×[12] 
× 
× 
 
12-Lead ECG[13] 
 
× 
× 
× 
× 
× 
 
Echocardiography[14] 
 
× 
 
 
× 
 
 


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Study Procedures 
Screening Period 
Cycle 1 
Cycle 2 and 
beyond 
End of 
Treatment/ 
Withdrawal 
Follow-Up Period 
(at the end of treatment) 
D-28 ~ D-1 
D-7 ~ D-1 
D1 ± 3 [22] 
D1 ± 3 
Safety 
Follow-Up[23] 
Survival 
Follow-Up[24] 
Pregnancy Test[15] 
 
× 
 
 
× 
 
 
Oncology Imaging Examination[16] 
× 
 
 
×[16] 
×[16] 
×[16] 
×[16] 
Study Treatment[17] 
 
 
× 
× 
 
 
 
Blood Sampling for PK Study[18] 
 
 
×[19] 
×[19] 
× 
× 
 
Blood Sampling for ADA Detection[19] 
 
 
×[20] 
×[20] 
× 
× 
 
Adverse Events [20] 
× 
× 
× 
× 
× 
× 
× 
Concomitant 
Medications/Concomitant 
Treatments[21] 
× 
× 
× 
× 
× 
× 
 
Note: Other than the examinations and time points listed in the table, the investigator may add visits and other examinations if needed. Results should be 
documented in the corresponding sections of the electronic case report form (eCRF) (e.g., "Unscheduled Visit Examination"). 
[1] 
Except for tumor imaging evaluation and tumor tissue biopsies performed within the specified time limit prior to the first dose, written informed consent must 
be obtained from subjects before any study procedures. Subjects who have failed previous screening may be screened again in this study. The informed 
consent form must be re-signed and a new subject number should be given for re-screening. 
[2] 
Medical history and treatment history: including tumor history (diagnosis, surgery, radiotherapy, chemotherapy history) and history of other concurrent 
diseases. Among them, tumor diagnosis should include: the results of the histological diagnosis, pathological classification, histological grade, clinical stage, 
and time of first diagnosis prior to enrollment. 
[3] 
ECOG PS: The ECOG PS is evaluated within 7 days prior to the first dose, before drug administration on Day 1 of each cycle, at the end of treatment/upon 
withdrawal, and upon the first visit during the safety follow-up period. 
[4] 
Vital signs: Pulse rate, respiratory rate, body temperature and blood pressure; the vital signs are evaluated within 7 days prior to the first dose, before drug 
administration on Day 1 of each cycle, at the end of treatment/upon withdrawal, and upon the first visit during the safety follow-up period. 


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[5] 
Physical examination: Within 7 days prior to the first dose and at the end of treatment/upon withdrawal, a comprehensive physical examination (including 
general condition, head and face, skin, lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular system, abdomen, reproductive 
and urinary system, musculoskeletal system, nervous system and mental state) is performed; before drug administration on Day 1 of each cycle and upon the 
first visit of the safety follow-up period, symptom-directed physical examination can be performed if clinically indicated. 
[6] 
Virology: HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, HBV DNA (if the Hepatitis B five items test indicates HBV infection [HBsAg positive] or if the 
subjects have a history of HBV infection, HBV DNA quantification should be performed), HCV-Ab (if the result is positive, HCV RNA quantification should 
be performed), and HIV-Ab. 
[7] 
Hematology: Red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT), white blood cell count (WBC), absolute neutrophil count (ANC), and 
lymphocyte count; hematology test is performed within 7 days prior to the first dose, before drug administration on Day 1 of each cycle, at the end of 
treatment/upon withdrawal, and upon the first visit of the safety follow-up period. 
[8] 
Urinalysis: WBC, RBC, and urine protein. If the urine protein ≥ 2+, the 24-h urine protein quantification should be performed; the urinalysis is performed 
within 7 days prior to the first dose, before drug administration on Day 1 of every two cycles, at the end of treatment/upon withdrawal, and upon the first visit 
during the safety follow-up period. 
[9] 
Fecal occult blood test: Fecal occult blood test is performed within 7 days prior to the first dose (if the fecal occult blood is positive, the test should be 
performed again. If the result is still positive, gastrointestinal endoscopy should be performed), before drug administration on Day 1 of every two cycles, at 
the end of treatment/upon withdrawal, and upon the first visit during the safety follow-up period. 
[10] Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (γ-GT), total bilirubin (TBIL), direct 
bilirubin (DBIL), alkaline phosphatase (AKP), blood urea nitrogen (BUN, preferred) or urea, total protein (TP), albumin (ALB), creatinine (Cr), blood 
glucose (GLU), K+, Na+, Ca2+, Mg2+ and Cl-. The blood biochemistry test is performed within 7 days prior to the first dose, before the drug administration on 
Day 1 of each cycle, at the end of treatment/upon withdrawal, and upon the first visit of the safety follow-up period. 
[11] Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (FIB), and international 
normalized ratio (INR); coagulation function is evaluated within 7 days prior to the first dose, before drug administration on Day 1 of each cycle, at the end of 
treatment/upon withdrawal, and upon the first visit during the safety follow-up period. 
[12] Thyroid function: Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thyroxine (FT4). If FT3 and FT4 are unavailable, T3 and T4 can 
be used instead. The thyroid function is evaluated within 7 days prior to the first dose, before drug administration on Day 1 of every two cycles, at the end of 
treatment/upon withdrawal, and upon the first visit during the safety follow-up period. 


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[13] 12-Lead ECG: Attentions should be paid to QT, QTc, and PR-intervals. Performed within 7 days prior to the first dose, on Day 1 of each cycle before 
administration (retest is not required prior to the first dose if ECG is completed within 7 days prior to the first dose at screening), at the end of treatment/study 
withdrawal, and at the first visit during the safety follow-up period. 
[14] Echocardiography: Echocardiography is performed within 7 days prior to the first dose and at the end of treatment/upon withdrawal if clinically indicated. 
[15] Pregnancy test: Serum pregnancy test will be performed for women of childbearing potential. The serum pregnancy test is performed within 72 h prior to the 
first dose and at the end of treatment/upon withdrawal. 
[16] Tumor imaging evaluation: CT or MRI of the chest, abdomen, and pelvis. Brain MRI is required when brain metastasis is suspected and confirmed (if MRI is 
contraindicated, CT can be used instead). Bone scan is performed only when clinically indicated and must be performed within 42 days before the first dose. 
✓ 
At screening, tumor evaluations up to 4 weeks before the first dose and before signing the informed consent may be used as long as they meet the 
RECIST 1.1. 
✓ 
During the treatment period, imaging examination is performed once every two cycles (6 weeks) in the first 12 months (the first 16 cycles), then once 
every 3 cycles (9 weeks) thereafter. Imaging examination should be also performed if new lesions are suspected. Imaging examination should be 
performed when subjects withdraw from the study for any reason (± 4 weeks; the imaging examination does not need to be repeated if the time from the 
last examination is no more than 4 weeks). Imaging conditions should be the same as those at baseline (including slice thickness and contrast agent). 
The time window for tumor evaluation is ± 7 days. Additional tumor evaluations may be performed if PD is suspected (for example, worsening of 
symptoms). 
✓ 
During safety follow-ups and survival follow-ups, subjects in whom no radiographic progression is observed should continue to undergo imaging 
assessment at the original frequency until PD, death, lost to follow-up, or start of other anti-cancer treatments. 
✓ 
Subjects who discontinue treatment for reasons other than radiographically confirmed PD must also undergo imaging examination at the frequency 
specified in the protocol whenever possible until documented PD, start of a new anti-tumor treatment, or death. 
[17] Study treatment: Each cycle lasts for 21 days. Depending on the group of subjects, the following treatments are administered (for the administration method 
of the drugs, please refer to section 5.1.5): 
✓ 
Cohort 1 (sequential therapy of SHR-1210 combined with capecitabine and oxaliplatin): SHR-1210 200 mg, intravenous infusion, once every 3 weeks; 
capecitabine 1000 mg/m2, administered orally, twice daily, 2 weeks of treatment followed by 1 week of drug interruption; oxaliplatin 130 mg/m2, 
intravenous infusion, once every 3 weeks; subjects in whom no radiographic progression is observed, after 4-6 cycles of the above treatment, continue 
to receive the SHR-1210 + apatinib (375 mg, administered orally, once daily) treatment. 
✓ 
Cohort 2 (SHR-1210 combined with apatinib): SHR-1210 200 mg, intravenous infusion, once every 3 weeks; apatinib 375 mg, administered orally, 
once daily, continuous administration. 


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[18] Blood sampling for PK study: Blood samples are collected for PK study from subjects receiving SHR-1210 plus apatinib. Blood samples are collected once 
within 0.5 h before the administration of SHR-1210 + apatinib on Day 1, once at 3 h (± 5 min) after the drug administration, and once within 0.5 h before the 
administration of apatinib on Day 7 (a total of 3 blood sampling time points in the first cycle of SHR-1210 + apatinib). PK blood samples are collected at the 
same time points above for each cycle afterwards, for 6 cycles in total (including the first cycle of SHR-1210 plus apatinib). PK blood samples are collected 
once at 30 days (± 7 days), 60 days (± 7 days), and 90 days (± 7 days) after the last dose of study treatment, respectively (depending on the visit schedule if 
applicable). 
[19] Blood sampling for ADA detection: Blood samples are collected within 0.5 h before the drug administration on C1D1, C2D1, C4D1, C6D1, and C9D1, 
respectively. ADA blood samples are collected once every 4 cycles within 0.5 h before the drug administration since Cycle 9. ADA blood samples are 
collected once at 30 days (± 7 days), 60 days (± 7 days), and 90 days (± 7 days) after the last dose of study treatment, respectively (depending on the visit 
schedule if applicable). 
[20] AEs: AEs are recorded from the date of signing informed consent to the end of the safety follow-up (90 days after the last dose) or the start of a new 
anti-cancer therapy. The adverse events should be followed up until they are resolved, return to baseline levels or Grade ≤ 1, reach a stable state, or are 
reasonably explained (e.g., lost to follow-up, death). 
[21] Concomitant medications/concomitant treatments: Concomitant medications/concomitant treatments are recorded from within 30 days before the first dose 
until the end of the safety follow-up. After the end of treatment or withdrawal, only concomitant medications/concomitant treatments related to the 
treatment-related AEs are documented. 
[22] There is no need to repeat the laboratory tests (hematology, urinalysis, clinical chemistry, coagulation function, and thyroid function) and ECG before drug 
administration on D1 of Cycle 1, if such tests have already been performed at baseline within 7 days before the first dose. 
[23] Safety follow-up: Safety follow-up starts from the last dose of study treatment, once every 30 days (± 7 days) until 90 days after the last dose. The first safety 
follow-up visit (30 days ± 7 days) is carried out at the study center where the evaluations specified in the protocol will be completed. The second (60 days ± 
7 days) and the third (90 days ± 7 days) follow-up are made via telephone calls. The information on survival, concomitant medications/concomitant 
treatments and AEs are collected. 
[24] Survival follow-up: At the end of the safety follow-up period, the subjects will enter the survival follow-up period until death, lost to follow-up, withdrawal of 
informed consent or termination of the clinical study by the sponsor. During this period, visit will be conducted via telephone or other effective methods once 
every month to collect information on subject survival and subsequent treatments (if the subjects start a new anti-tumor treatment, the therapeutic regimen and 
the start and end time should be recorded). 
 


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ABBREVIATIONS 
Abbreviations 
Full Name 
12-Lead ECG 
12-Lead electrocardiogram 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CDK 
Cyclin-dependent kinase 
Cl- 
Blood chlorine 
Cr 
Creatinine 
CR 
Complete Response 
CRF 
Case report form 
CRO 
Contract research organization 
CTLA-4 
Cytotoxic T Lymphocyte Antigen 4 
D 
Day 
DC 
Dendritic Cell 
DCR 
Disease Control Rate 
DoR 
Duration of Response 
EC 
Ethics committee 
ER 
Estrogen Receptor 
FAS 
Full Analysis Set 
GC 
Gastric Cancer 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction cancer 
h 
Hour 
Hb 
Hemoglobin 
HER-2 
Human epidermal growth factor receptor 2 
HR 
Hazard Ratio 
HUVEC 
Human umbilical vein endothelial cells 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
irAE 
Immune-related Adverse Event 
IU 
International unit 
K+ 
Serum potassium 
kg 
Kilogram 


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Abbreviations 
Full Name 
LDH 
Lactate dehydrogenase 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
MTD 
Maximum tolerated dose 
Na+ 
Plasma sodium 
NEUT 
Neutrophil 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed death-ligand 1 
PDGFR 
Platelet-derived growth factor receptors 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetics set 
PPS 
Per-Protocol Set 
PR 
Partial Response 
PLT 
Blood platelet 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria In Solid Tumors 
sec 
Second 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SS 
Safety Set 
sUA 
Serum uric acid 
T-BIL 
Total bilirubin 
TEAE 
Treatment Emergent Adverse Event 
UA 
Uric acid 
URBC 
Urine red blood cell 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell count 
 


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1 INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
1.1. Background 
Gastric cancer (GC) is one of the common malignancies with poor prognosis, seriously threatening 
human health. In 2012, there were approximately 951 thousand new cases of GC and 
approximately 723 thousand GC-related deaths worldwide, ranking the 5th in incidence and the 3rd 
in mortality of all malignant tumors. China is a country with a high prevalence of GC. The number 
of cases developing GC and deaths related to GC in China accounted for 42.6% and 45.0%, 
respectively, the data worldwide. In the past decade, the incidence and mortality of GC have 
remained stable in urban areas of China, but numbers of male were on the rise in rural areas and 
there was little change in rural females. According to the latest statistics from the National Center 
for Cancer Registry, in 2015, there were approximately 679 thousand newly diagnosed cases of 
GC and approximately 498 thousand GC-related deaths in China. 
Surgery is the primary treatment for early GC, and the 5-year survival rate of GC patients receiving 
surgical treatment is about 40-50%. However, early GC is usually asymptomatic, which makes the 
diagnosis difficult. For this reason, early GC may remain undetected. At present, the five-year 
survival rate of GC is about 27% in China. For patients with advanced or metastatic gastric cancer, 
chemotherapy can relieve symptoms and achieve survival benefit compared with best supportive 
care. Combination chemotherapy based on fluorouracil and platinum is the mainstream first-line 
treatment at present. The median survival of GC patients receiving this combination chemotherapy 
is 9.5 to 13 months. Therefore, there is an urgent clinical need to develop more effective treatment 
regimen to improve the current treatment of advanced GC. 
This study involves recombinant humanized anti-PD-1 monoclonal antibody injection 
(SHR-1210), a new class 1 therapeutic biological product that has not been marketed either in 
China or abroad. Preclinical studies have shown that SHR-1210 has comparable in vivo 
pharmacological and safety profiles to those of drugs of the same class abroad, and may have a 
better clinical potential for anti-tumor treatment. Phase I clinical studies have been conducted on 
SHR-1210 in Australia and China since 2015. Several clinical studies are currently underway. 
This study also involves apatinib mesylate (trade name: Aitan), which was launched in 2014 by 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. Apatinib is a small molecule targeted medicine and 
acts as a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR). 
Apatinib exerts its anti-angiogenic effect to treatment cancer mainly by inhibiting VEGFR. China 
Food and Drug Administration (CFDA, now National Medical Products Administration, NMPA) 
approved apatinib for the treatment of advanced GC and gastroesophageal junction (GEJ) 
adenocarcinoma on 17 Nov., 2014. 


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This study is a clinical study on the inhibitor targeting the VEGF-VEGFR pathway combined 
PD-1 monoclonal antibody for the treatment of advanced GC. The goal is to lay a solid foundation 
for new combination therapies urgently needed in clinical practice. The present study has 
important clinical and academic significance. 
1.1.1. Information on SHR-1210 
1.1.1.1. Pharmacology and mechanism of action 
Programmed death-1 (PD-1) is a protein receptor expressed on the surface of T cells 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-4. It is primarily expressed on 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 DCs. Humanized anti-PD-1 monoclonal antibody can specifically bind to PD-1, 
block the interaction between PD-1 and its ligands, and restore T cell immune response to tumor 
cells. 
1.1.1.2. Pharmacodynamics 
Experiments on the binding affinity of SHR-1210 antibody to human, monkey and rat antigens 
(Table 1) showed that the affinities of SHR-1210 to human and monkey PD1 antigens were quite 
close at 6.9 nM and 4.1 nM, respectively, but no binding was detected with rat PD-1 antigens. 
SHR-1210 shows an affinity of 3.0 nM for the antigen (human PD-1) and its activity is comparable 
to that of the control antibodies Nivolumab and Pembrolizumab (Table 2). 
Stationary Phase 
Mobile Phase 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
6.9 
SHR-1210 
Murine PD-1 antigen 
Extremely weak signals, no binding 
detected 
Monkey PD-1 antigen (-hFc) 
SHR-1210 
4.1 
Table 1. Binding affinity of SHR-1210 to human, monkey, and murine 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 
Table 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 


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Experimental results from inhibition of PD-1/PD-L1 binding by SHR-1210 showed that (Figure 1 
and Figure 2) in vitro binding inhibition activity of SHR-1210 was similar to those of nivolumab 
and pembrolizumab. The IC50 of inhibition activities of SHR-1210, nivolumab, and 
pembrolizumab was 0.70 nM/0.79 nM and 0.79 nM/0.77 nM, respectively. 
 
Figure 1. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab 
 
Figure 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab 


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1.1.1.3. Toxicology studies 
In a pre-clinical acute toxicity experiment in cynomolgus monkeys, 8 cynomolgus monkeys (half 
male and half female) were randomly divided into 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, body weight, food 
intake, and coagulation related to SHR-1210 were observed. Lymphocytes decreased for both 
sexes at doses ≥ 200 mg/kg. Serum globulin increased and albumin decreased at doses ≥ 
400 mg/kg. Since the magnitude of these changes was small, they were not considered harmful 
effects. The maximum tolerated dose (MTD) of SHR-1210 was ≥ 800 mg/kg. 
In a completed preclinical repeated dose toxicity study in cynomolgus monkeys, continuous 
intravenous administration of SHR-1210 at 20, 50, and 100 mg/kg for 4 weeks (5 total doses) was 
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. 
Apatinib primarily caused slight changes in body weight, food intake, liver function, and bone in 
rats. After 4 weeks of drug discontinuation, all other changes were recovered except that the bone 
changes were partially recovered. 15 mg/(kg•d): The safe dose in male and female rats. 50 
mg/(kg·d): The toxicity dose of male and female rats, and female rats are more sensitive. The 
3-month oral application of 30 mg/(kg•d) of apatinib capsules in Beagle dogs showed no 
significant toxicity. 
1.1.1.4. Pharmacokinetic study 
For SHR-1210 PK parameters after a single intravenous drip infusion in cynomolgus monkeys, see 
Table 3. 
Dosage 
(mg/kg) 
Gender T1/2 (hr) 
Tmax 
(hr) 
Cmax 
(μg/ml) 
AUClast 
(hr×μg/ml) 
Vz (ml/kg) Cl 
(ml/hr/kg) 
MRTlast 
(hr) 
 
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 
1 
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 


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Dosage 
(mg/kg) 
Gender T1/2 (hr) 
Tmax 
(hr) 
Cmax 
(μg/ml) 
AUClast 
(hr×μg/ml) 
Vz (ml/kg) Cl 
(ml/hr/kg) 
MRTlast 
(hr) 
 
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 
2 
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 
 
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 
3 
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 
Table 3. PK parameters after a single intravenous infusion of SHR-1210 at different doses 
in cynomolgus monkeys 
1.1.1.5. Progress in the clinical studies of SHR-1210 
Since 2015, Jiangsu Hengrui Pharmaceuticals Co., Ltd. has conducted 4 phase I clinical studies of 
SHR-1210 at multiple sites in Australia and China, which preliminarily validated the safety, 
tolerability and efficacy of SHR-1210 in patients with advanced solid tumors who have failed 
existing standard treatments. 
By the end of 2016, 140 subjects with solid tumor had been enrolled in China and abroad, 
including 116 subjects enrolled in China and 24 subjects enrolled in Australia. Tolerability 
observation showed that different doses of SHR-1210 (1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg and 
fixed doses of 60 mg, 200 mg, and 600 mg) were well tolerated. No DLTs were observed in any of 
the dose groups during the tolerability observation period, i.e., the maximum tolerated dose 
(MTD) is greater than 10 mg/kg or 600 mg. 
The investigator-assessed adverse drug reactions possibly related to the investigational drug 
(SHR-1210) mainly included the following: reversible capillary proliferation, rash, pruritus, 
fatigue, asthenia, fever, anemia, nausea, vomiting, headache, dizziness, diarrhea, serum 
transaminase increased, serum bilirubin increased, prolonged QT interval, hypothyroidism, 
hyperthyroidism and hypophysitis. The majority of the adverse drug reactions were Grade 1-2 and 
could be controlled with or without medical intervention. 


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1.1.2. Information on apatinib mesylate 
Apatinib is a potent and selective inhibitor of vascular endothelial growth factor receptor-2 
(VEGFR-2). The activity assay showed that its inhibitory effect against VEGFR-2 is stronger than 
that of drugs of same class (sorafenib, sunitinib, pazopanib, etc.); its selectivity for VEGFR-2 is 
≥ 30 times stronger than that of other targets (VEGFR-1/PDGFR, SRC, etc.). Apatinib can 
effectively inhibit the in vitro lumen formation of Human Umbilical Vein Endothelial Cells 
(HUVEC) and the formation of arterial ring capillaries in rats, and has a strong inhibitory effect 
against neovascularization. 
The efficacy and safety of apatinib monotherapy in advanced GC were evaluated in two 
randomized controlled studies. The efficacy and safety of apatinib in the treatment of advanced 
GC were evaluated in a multicenter, randomized, double-blind, placebo-controlled phase III 
clinical study. A total of 267 patients with advanced gastric cancer, including gastroesophageal 
junction adenocarcinoma, who had failed second-line treatment (definition of treatment failure: 
intolerable toxic and side effects, progressive disease during treatment, or recurrence after the end 
of treatment) were enrolled in the study. The median age of patients treated with apatinib was 58 
years old, and 75% were male; 27% had an ECOG PS of 0 and 73% had an ECOG PS of 1; about 
60% of the patients had once received radical surgery, including about 22% with total gastrectomy 
and 35% with gastrectomy; 68% of the primary lesions were GC, and 22% were GEJ 
adenocarcinoma; 21% of the patients had more than 2 organs affected by metastases cumulatively, 
and 56% of the patients had liver metastases; 92% of the patients were clinically classified as stage 
IV; 66% of the patients had once received at least 2 types of systemic chemotherapy; the basic 
drugs used in first-line chemotherapy included fluorouracil, platinum, paclitaxel, and doxorubicin; 
the second-line chemotherapy is primarily based on irinotecan. The investigational treatment 
group and the placebo group were comparable in baseline features and demographics of subjects. 
The subjects were randomized in a 2:1 ratio to receive either apatinib tablet 850 mg treatment once 
daily (n = 176) or placebo once daily (n = 91) in 28-day cycle. The mean chemotherapy cycles 
were 2.9 in the treatment group, with 72% of the subjects receiving 2 or more cycles of treatment. 
The primary efficacy endpoint was overall survival (OS). The secondary efficacy endpoints 
included progression-free survival (PFS), disease control rate (DCR), and objective response rate 
(ORR). The median overall survival in the investigational treatment group was prolonged 
compared with the placebo group, while the death risk was reduced by about 30%. The secondary 
endpoints PFS and DCR were also higher in the treatment group than those in the placebo group. 
Generally, no symptoms specific to advanced GC or deterioration of health-related life quality 
were caused. Table 4. lists the primary efficacy results, and Figure 3. shows the survival curves. 


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Endpoint 
Treatment Group (n = 176) 
Placebo Group (n = 91) 
Overall survival (OS) 
 
 
Median (mOS, month) 
6.5 
4.7 
HR (95% CI) 
0.709 (0.537, 0.937) 
 
Progression-free survival (PFS) 
 
 
Median (mPFS, month) 
2.6 
1.8 
HR (95% CI) 
0.444 (0.331, 0.595) 
 
Objective Response Rate (CR + PR) 
2.84% 
0 
Clinical Benefit Rate (CR + PR + SD) 42.05% 
8.79% 
Table 4.  Efficacy results of the phase III clinical study of apatinib in GC (FAS) 
 
 
Figure 3. Survival analysis of the phase III clinical study of apatinib in GC (FAS) 
In the treatment group and the placebo group, the incidences of adverse drug reactions were 
92.05% and 71.43%, respectively; the incidences of Grade 3/4 adverse drug reactions were 
51.70% and 24.18%, respectively. Among the common adverse drug reactions (incidence ≥ 5%), 
the ones that were statistically different between the two groups in incidence included hematologic 
toxicities (WBC decreased, granulocytopenia, and thrombocytopenia) and non-hematologic 
toxicities (proteinuria, hypertension, hand-and-foot syndrome, asthenia, and hoarse voice). The 
incidences of serious adverse drug reactions in the investigational treatment group and the control 
group were 6.25% and 6.59%, respectively. The common serious adverse drug reaction was upper 
gastrointestinal hemorrhage in both groups. 
Treatment group 
Survival Rate 
Placebo group 
Time Point from Randomization 
(Months) 


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Another multi-center, randomized, double-blind, placebo-controlled, parallel-group phase II 
clinical study also targeted advanced GC patients who failed second-line chemotherapy. A total of 
141 subjects were enrolled, including 48 subjects in the placebo group, 47 subjects in the 850 mg 
qd group, and 46 subjects in the 425 mg bid group. Each cycle lasted for 28 days, and the primary 
endpoint was PFS. Results: The mPFS was 3.7 months in the 850 mg QD group and 3.2 months in 
the 425 mg bid group, with statistically significant differences compared with the placebo group 
(P < 0.0001). The median survival and the ORR in the two treatment groups were higher than those 
in the placebo group. Table 5 lists the data on primary efficacy results. 
Endpoint 
850 mg QD Group (n = 47) 
Placebo Group (n = 48) 
Overall survival (OS) 
 
 
Median (mOS, month) 
3.7 
1.4 
HR (95% CI) 
0.232 (0.133, 0.406) 
 
Progression-free survival (PFS) 
 
 
Median (mPFS, month) 
4.8 
2.5 
HR (95% CI) 
0.513 (0.319, 0.826) 
 
Objective Response Rate (CR + PR) 
6.38% 
0 
Clinical Benefit Rate (CR + PR + SD) 51.06% 
10.42% 
Table 5. Efficacy results of the phase II clinical study of apatinib in advanced GC (FAS) 
In this study, the incidences of adverse drug reactions in the apatinib 850 mg QD group and 
placebo group were 78.72% and 56.25%, respectively; the incidences of Grade 3/4 adverse drug 
reactions were 30.04% and 16.67%, respectively. 
The National Medical Products Administration (NMPA) approved apatinib for the treatment of 
advanced GC and GEJ cancer in 2014. 
1.1.3. Information on capecitabine and oxaliplatin 
Capecitabine and oxaliplatin have already been marketed as routine first-line cytotoxic drugs for 
advanced GC. Refer to their respective prescribing information for details. 
1.1.4. Progress in the Clinical Studies of SHR-1210 plus Apatinib 
As of 25 Aug., 2017, Hengrui had conducted two clinical studies of SHR-1210 plus apatinib. 
SHR-1210-APTN-II-202-NSCLC is an ongoing phase II study. The objective is to evaluate the 
safety and efficacy of SHR-1210 plus apatinib in non-squamous NSCLC subjects who had 
metastases or disease progression after multimodal therapy. SHR-1210 is infused intravenously at 
a fixed dose of 200 mg Q2W for a 28-day cycle with a maximum treatment period of 2 years. In the 
meantime, apatinib tablet 250 mg, 375 mg or 500 mg is given orally once daily for 28 consecutive 
days as a cycle. 


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SHR-1210-APTN-II-203-PLC is an ongoing open-label phase II clinical study. The objective is to 
evaluate the safety and tolerability of SHR-1210 plus apatinib mesylate or FOLFOX4 (OXA + 
calcium levofolinate + 5-Fu) in untreated advanced primary liver cancer (PLC) subjects and 
advanced PLC subjects who failed or were intolerant of systemic treatment, molecular targeted 
therapy, or systemic chemotherapy. Subjects are enrolled into treatment group A or B based on 
whether they have received systemic treatment, targeted therapy or systemic chemotherapy before. 
Subjects in Group A (having received systemic treatment) receive SHR-1210 plus apatinib 
mesylate (APTN) treatment, in which SHR-1210 is intravenously infused at 3 mg/kg Q2W. The 
optimal dose of apatinib is explored by elevating from low to high dose. Apatinib tablets 125 mg, 
250 mg, 375 mg or 500 mg are given orally once daily for 28 consecutive days as a cycle. Subjects 
in Group B (having received no systemic treatment) receive SHR-1210 plus FOLFOX4 regimen, 
in which SHR-1210 is infused intravenously at 3 mg/kg Q2W, and FOLFOX4 regimen Q2W. 
A total of 18 subjects in the above two studies have received SHR-1210 plus apatinib treatment. 
None of the subjects experienced DLT, serious adverse events, or unexpected adverse drug 
reactions, and no subject discontinued treatment due to adverse drug reactions. The SHR-1210 
combined with apatinib at a dose level of 375 mg/day is currently being investigated. 
1.2. Scientific Rationale 
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 patients to kill tumors, which may be the most effective and safest way 
to treat tumors. 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 
immune response. Specific killer T cells have certain biological activities in the early stage of the 
cancer development, 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. 
With better understanding of the mechanism of controlling host response to tumor at the molecular 
level, the identification of signaling pathways that restrict anti-cancer immune response has been 
further promoted. The programmed death-1 (PD-1) pathway, one of the most critical checkpoint 
pathways responsible for regulating tumor-induced immunosuppression, has been substantiated. 
PD-1 is a protein receptor expressed on the surface of T cells and mainly responsible for regulating 
cell apoptosis. PD-1 is a member of the CD28 family and has a 23% consistency amino acid 
sequence with cytotoxic T lymphocyte antigen 4 (CTLA-4). However, its expression is different 


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from that of CTLA-4. PD-1 is mainly expressed on activated T cells, B cells and myeloid cells. 
PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is mainly expressed on T cells, B cells, 
macrophages, and dendritic cells (DCs), and is up-regulated on activated cells. PD-L1 is 
up-regulated in many cancers. PD-L1 expression is closely related to shortened survival and poor 
prognosis in various cancers, including lung cancer, kidney cancer, pancreatic cancer and ovarian 
cancer. Tumor-infiltrating lymphocytes in patients with cancers usually express PD-1 and their 
anti-tumor function is impaired. Pre-clinical studies have shown that blocking PD-1 or PD-L1 can 
enhance T-cell function and promote tumor cell lysis. 
A number of pharmaceutical companies are currently developing monoclonal antibodies targeting 
PD-1/PD-L1. By blocking the binding of PD-1/PD-L1, these monoclonal antibodies maximize a 
patient's own immune response against tumors, thereby achieving the purpose of killing tumor 
cells. Bristol-Myers Squibb (BMS) and Merck have jointly developed PD-1 monoclonal 
antibodies (nivolumab and pembrolizumab), which have been approved by FDA for anti-tumor 
treatment of various cancers. In Jul. 2014, nivolumab was approved by the Japanese Ministry of 
Health, Labour and Welfare for the treatment of advanced melanoma. It was approved by the FDA 
for the treatment of melanoma in Dec. 2014, approved by the FDA for the treatment of non-small 
cell lung cancer in Mar. 2015, and approved by the FDA for the treatment of renal cell carcinoma 
in Nov. 2015. In 2016, nivolumab was approved for use in the treatment of classical Hodgkin's 
lymphoma. In Sep. 2014, Pembrolizumab was approved by the FDA for the treatment of advanced 
melanoma. In Oct. 2015, Pembrolizumab was approved by the FDA for the treatment of non-small 
cell lung cancer. 
PD-1/PD-L1 inhibitors will play a very important role in the combination anti-cancer treatment 
regimens. These drugs will revolutionize the current treatment regimens and become the backbone 
of the combination therapy. This view has already been verified for the treatment of melanoma. 
CheckMate-069 study showed that nivolumab combined with CTLA-4 inhibitor ipilimumab 
reduced the mortality by 60% (HR=0.40; 95% CI, 0.22-0.71; P < 0.002) compared with 
ipilimumab monotherapy. For melanoma patients harboring wild-type BRAF, the ORR of the 
combination therapy was 60%, while the ORR of ipilimumab monotherapy was 11%. Therefore, 
the FDA accelerated the approval of nivolumab in combination with ipilimumab as a treatment for 
patients with unresectable or metastatic melanoma who harbor wild-type BRAF V600. According 
to the reports in the 2016 Annual Meeting of the American Gastroenterological Association and 
the annual meeting of the American Society of Clinical Oncology, in the CheckMate-032 study, 
nivolumab was administered to 59 patients with intermediate to advanced esophageal cancer and 
gastric cancer. The overall response rate was 14%. The response rate of PD-L1 positive (> 1%) 
patients was 27%, including one case of complete response. The 1-year survival rate was 36%. 


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Several studies on the anti-tumor mechanism have laid the basis for immunotherapy combined 
with targeted therapy. Some evidence suggests that targeted molecular therapies can enhance 
certain aspects of the "cancer-immunity cycle" (such as tumor antigenicity, T cell 
activation/transport/infiltration, etc.) to synergistically enhance the efficacy of the 
immunotherapy. In particular, targeted molecular therapies targeting the MAPK and the VEGF 
pathways can have a direct impact on cancer cell growth and tumor angiogenesis, as well as on 
tumor antigenicity and intratumoral T cell infiltration. Studies have shown that molecular 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. This 
provides a strong basis for tumor immunotherapy combined with targeted therapy. 
Chemotherapy can adjust the interactions between the tumor and immunity, thereby assisting the 
immune system to exert antitumor effects. Chemotherapy can cause death of tumor cells and as a 
result, more tumor antigens are produced and presented to the antigen-presenting cells. Tumor cell 
death can reduce soluble and membrane-bound factors that inhibit tumor-infiltrating T cells. In 
addition, chemotherapy affects the regulatory network of the immune system by reducing the 
amount of regulatory T cells. The immunogenic chemotherapy, such as oxaliplatin combined with 
immune checkpoint inhibitors, can trigger T-cell infiltration and have a synergistic anti-tumor 
effect. This treatment regimen is expected to exert a persistent anti-tumor effect. A phase I/II study 
of nivolumab showed that patients with advanced NSCLC who received nivolumab combined 
with chemotherapy (gemcitabine + cisplatin or pemetrexed + cisplatin) achieved an objective 
response rate of 33-47% (while historical data showed that the ORR of chemotherapy was 
15-32%) and had a longer duration of response. 
At present, many clinical studies have been conducted on PD-1-targeting treatment in advanced 
GC and achieved encouraging results. Several clinical studies of pembrolizumab have been carried 
out in advanced GC patients. KEYNOTE -012 study is a phase Ib clinical study of pembrolizumab 
monotherapy in advanced GC. A total of 39 (19 Asian patients from Japan, Korea, and Taiwan) 
PD-L1 positive patients with recurrent or metastatic GC or GEJ cancer were enrolled in the study. 
These patients were treated with pembrolizumab (10 mg/kg, q2w). Among 36 evaluable patients, 8 
patients achieved partial response (PR), with an ORR of 22%. Compared with conventional 
chemotherapy, pembrolizumab was better tolerated. The common AEs were fatigue (18%), 
hypothyroidism (13%), itch (13%), and arthralgia (10%). Grade 3-4 AEs occurred in 5 subjects, 
including grade 3 fatigue in 2 subjects, grade 3 rash vesicular in 1 subject, grade 3 peripheral 
sensory neuropathy in 1 subject, and grade 4 pneumonia in 1 subject. 


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In a subsequent phase II study (KEYNOTE-059), the patients were divided into two cohorts. In 
cohort 1, 259 subjects with recurrent or metastatic GC or GEJ cancer who had received 
chemotherapy at least twice were enrolled and given pembrolizumab 200 mg q3w. The results 
showed that the ORR was 11.2% and the median duration of response was 8.1 months. Grade ≥ 3 
treatment-related adverse events (TRAEs) were observed in 43 subjects (16.6%). The treatment 
was interrupted in 2 subjects due to TRAEs (abnormal liver function in 1 subject and bile duct 
stricture in 1 subject). Fatal AEs occurred in 2 subjects (acute renal failure in 1 subject and pleural 
effusion in 1 subject). In cohort 2, 25 subjects (including 17 Asian subjects) with untreated 
recurrent or metastatic HER2- GC/GEJ cancer were enrolled and given the following combination 
treatment regimen: Pembrolizumab (200 mg) + 5-FU (800 mg/m2)/capecitabine (1000 mg/m2, for 
Japanese subjects) + cisplatin (80 mg/m2), once every 3 weeks. The ORR was 60%. The ORR of 
PD-L1 positive and PD-L1 negative patients was 68.8% and 37.5%, respectively. The median 
DoR was 4.6 months. The DoR of PD-L1 positive and PD-L1 negative patients was 4.6 months 
and 5.4 months, respectively. The median PFS was 6.6 months, and the median OS was 
13.8 months. Grades 3-4 TRAEs occurred in 76% of the subjects. The treatment was interrupted in 
3 subjects due to TRAEs (Grade 3 stomatitis in 1 subject, Grade 2 hypacusia in 1 subject, and 
creatinine increased in 1 subject). None of the TRAEs were fatal. 
The CHECKMATE032 study evaluated the efficacy of nivolumab monotherapy or nivolumab in 
combination with ipilimumab in patients with advanced GC/GEJ cancer who had progression after 
previous chemotherapy. Among them, 59 patients were treated with nivolumab 3 mg/kg q2w. The 
ORR was 12%. The ORR of PD-L1 positive and PD-L1 negative patients was 18% and 12%, 
respectively. The median DoR was 7.1 months. The ORR of the N1I3 group (nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg) and the N3I1 group (nivolumab 3 mg/kg + ipilimumab 1 mg/kg) was 24% 
and 8%, respectively. TRAEs were observed in 66% of the subjects. The common Grade 3 AEs 
were AST increased (5%) and ALT increased (3%). Other AEs included pneumonia, fatigue, 
diarrhea, vomiting and hypothyroidism. 
In summary, preliminary results of immune checkpoint inhibitor in the treatment of advanced GC 
suggest that it may be a new effective treatment regimen for advanced GC. 
1.3. Potential Risks and Benefits 
1.3.1. Known potential risks 
Any investigational drug or treatment may have unpredictable or even serious side effects. 
As of 25 Aug., 2017, a total of 539 patients with advanced cancer had been treated with SHR-1210 
(either monotherapy or in combination with other drugs). Among them, 414 subjects (76.8%) 
reported ≥ 1 AE. The most common (incidence > 5%) treatment-related AEs were hemangioma 
(64.7%), hemangioma of skin (25.0%), asthenia (9.3%), capillary disorder (8.3%), aspartate 


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aminotransferase increased (8.2%), pruritus (7.8%), rash (7.6%), alanine aminotransferase 
increased (6.7%), fever (6.5%), white blood cell count decreased (6.1%), anemia (5.9%), blood 
bilirubin increased (5.9%), hypothyroidism (5.6%), and conjugated bilirubin increased (5.0%). 
There were a total of 38 SAEs related to SHR-1210, mainly including hemangioma of skin 
(6 events), abnormal liver function (4 events), interstitial pneumonia (3 events), and infectious 
pneumonia (2 events). 
Investigator-assessed immune-mediated AEs were predominantly skin toxicities (such as rash and 
capillary proliferation). Most immune-mediated AEs were grade 1-2 in severity. The above data 
was compared with adverse drug reactions reported for other approved anti-PD-1 antibodies - 
nivolumab from BMS and pembrolizumab from Merck. The incidence and severity were both low. 
Overall, the adverse drug reactions of this product are expected to be similar to those of nivolumab 
and pembrolizumab. Recommended management of common side effects and protocol-specified 
dose modifications have been established for this study, so that, in the presence of clinical benefit, 
subjects may continue the SHR-1210 treatment. 
All monotherapies using anti-PD-1 antibodies outperformed conventional chemotherapy and 
targeted therapy in terms of adverse drug reactions on the whole. However, immune-related 
adverse reactions still require special attention, mainly including immune-related interstitial 
pneumonia, rash, thyroiditis, as well as those with lower incidence (≤ 1%), such as vitiligo, colitis, 
nephritis, hepatitis, uveitis, adrenal insufficiency, and nerve paralysis. These immune-related 
adverse reactions are mostly mild and manageable. Very few are SAEs or potentially 
life-threatening. Thanks to established procedures for toxicity management, the majority of 
immune-mediated AEs can be adequately controlled. 
Subjects receiving macromolecular protein monoclonal antibody drugs may also encounter other 
risks including infusion reactions, which prominently manifest as chills, shivers, facial and 
peripheral cyanosis, followed by fever and probably accompanied by nausea, vomiting, headache, 
dizziness, dysphoria, delirium, etc. In severe cases, there may be coma, fall in blood pressure, and 
symptoms such as shock and respiratory failure, etc. These risks may arise due to various factors 
during intravenous infusion, such as pyrogens, drugs, impurities, low temperature of drug formulation, 
high concentration of drug, and high rate of infusion, etc. SHR-1210 is a fully humanized monoclonal 
antibody. Its reported infusion reactions were low in incidence and mild in severity. 
Capecitabine and oxaliplatin are common cytotoxic chemotherapeutic drugs with clear list of AEs. 
Clinical studies and medical practice have demonstrated that the common (≥ 5%) AEs associated 
with capecitabine plus oxaliplatin (XELOX regimen) include the following: neurotoxicity (19%), 
nausea (16%), diarrhea (15%), vomiting (11%), fatigue (8%), hand-and-foot syndrome (7%), 
neutrophils reduced (7%), anorexia (6%), and stomatitis (5%). 


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Medical examinations during the study may also pose risks to the subjects. Frequent tumor 
imaging examinations may expose subjects to low-dose radiation more frequently. However, since 
advanced or metastatic gastric cancer usually progresses rapidly, frequent imaging tumor 
examinations are necessary to determine the presence of progressive disease. 
1.3.2. Known potential benefits 
As mentioned before, gastric cancer (GC) is one of the common malignancies, seriously 
threatening human health and lives. Many GC patients have already miss the optimal surgical 
timing at the time of diagnosis. They usually have poor life quality and heavy disease burden. 
Despite an active combination chemotherapy, the median survival of patients with advanced or 
metastatic GC is only about 1 year. PD-1 inhibitors (used alone or in combination with other 
drugs) have achieved encouraging results in the treatment of GC. It is expected that more GC 
patients can benefit from PD-1 inhibitors. 
2 OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary objective: 
 
To evaluate the efficacy of the sequential therapy of SHR-1210 combined with 
capecitabine and oxaliplatin or SHR-1210 combined with apatinib mesylate as the 
first-line therapy for advanced or metastatic gastric (GC) or gastroesophageal junction 
(GEJ) cancer. 
Secondary objectives: 
 
To evaluate the safety of the sequential therapy of SHR-1210 combined with capecitabine 
and oxaliplatin or SHR-1210 combined with apatinib mesylate for the treatment of advanced 
or metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer. 
2.2 
Study Endpoints 
Primary endpoint: 
• 
Objective response rate (ORR). 
Secondary endpoints: 
• 
Progression free survival (PFS); 
• 
Duration of response (DoR); 
• 
Disease control rate (DCR); 
• 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), vital 
signs, ECG, and laboratory abnormalities. 


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3 STUDY DESIGN 
This is a randomized, open-label, multi-center, phase II clinical study. 
A total of 98 subjects with previously untreated advanced or metastatic gastric cancer (GC) or 
gastroesophageal junction cancer (GEJ) will be enrolled. The subjects are randomized in a 1:1 
ratio into the sequential therapy of SHR-1210 combined with capecitabine and oxaliplatin 
treatment group (cohort 1, n = 43) or the SHR-1210 combined with apatinib treatment group 
(cohort 2, n = 55). 
 
Cohort 1 (sequential therapy of SHR-1210 combined with capecitabine and oxaliplatin): 
SHR-1210 + capecitabine + oxaliplatin for 4-6 cycles, followed by SHR-1210 + apatinib 
in the treatment of the subjects without disease progression; 
 
Cohort 2 (SHR-1210 combined with apatinib): SHR-1210 + apatinib; 
A two-stage design is adopted to minimize the exposure of subject to ineffective treatment. 
Nineteen subjects will be enrolled into cohort 1 and cohort 2 at the first stage, respectively. If at 
least 4 subjects achieve objective response (complete response or partial response), the second 
stage will be initiated. 
All subjects should continue to receive the study treatment until progressive disease, intolerable 
toxicity, voluntary treatment discontinuation or study withdrawal by the subject, or 
discontinuation determined by the investigator. 
SHR-1210 is an immune checkpoint inhibitor and according to the experience of similar drugs, 
some subjects may experience delayed or early pseudo progression after receiving immunotherapy 
drugs. Therefore, for subjects in the treatment group experiencing progressive disease (PD) for the 
first time, they may continue with the original treatment if they meet the criteria in section 4.6 
Criteria for Continuing Treatment Beyond Disease Progression. Subjects who do not have 
progressive disease or intolerable toxicities may continue the SHR-1210 treatment for no more 
than 24 months. 
Subjects who do not have progressive disease after 24-month treatment may continue the apatinib 
monotherapy according to the prescribing information of apatinib. 
In this study, the screening period is no more than 28 days, and eligible subjects will enter the 
study treatment period (every 21 days being a treatment cycle) after completing the screening and 
assessment and receive study treatment and visits as specified in the protocol. Tumor imaging 
assessment is performed once every 2 treatment cycles (6 weeks ± 7 days) during the first 
12 months (first 16 treatment cycles) of the study treatment period and once every 3 cycles 
(9 weeks ± 7 days) thereafter. Subjects should complete corresponding safety examinations and 


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imaging assessments prior to exiting. Then, the subjects enter the safety follow-up period. They 
are followed up until 90 days after the last dose. After the safety follow-up is completed, subjects 
will then enter the survival follow-up period. Survival information will be collected once per 
month. During the follow-up period (including safety follow-ups and survival follow-ups), 
subjects who have no disease progression and withdraw should continue to undergo tumor 
assessment according to the original schedule until PD, death, lost to follow-up, withdrawal of 
informed consent, start of other anti-tumor treatments, or study termination by the sponsor. 
Specific study procedures is presented in section 6. 
3.1 
Pharmacokinetic and Immunogenicity Studies 
The PK and ADA properties of SHR-1210 monotherapy and the PK properties of apatinib 
monotherapy in GC patients have already been evaluated in previous studies. However, there are 
only limited data regarding the PK and ADA available on the combined use of SHR-1210 and 
apatinib in GC patients. Although the probability of interactions between large and small 
molecules is very small, there is not enough evidence that SHR-1210 does not interact with 
apatinib in humans at all. Neither are there data to support the judgment of whether apatinib affects 
the immunogenicity of SHR-1210. 
The existing clinical studies on the combined use of SHR-1210 and apatinib have indicated the 
toxic and side effects of the combination therapy. Therefore, it is of high importance to collect data 
on the blood drug concentration of apatinib to determine its toxic and side effects. The correlation 
between the toxic and side effects and the combined use of the two drugs can be further assessed 
based on the blood drug concentration of SHR-1210 and apatinib. 
The PK and ADA data of SHR-1210 and apatinib are also crucial for interpreting the 
pharmacodynamic data. In addition, the improvement in pharmacodynamic effect with the 
combination therapy relative to the monotherapy of either drug can be compared at the same 
exposure dose. Such investigations are of high significance for subsequent clinical study design and 
dose selection. These data can also be comprehensively analyzed with the data from other studies to 
compare the exposure of combination therapy in patients with different tumors and provide further 
basis for how to use SHR-1210 and apatinib combination therapy in a more rational manner. 
◆ PK blood samples are collected from subjects receiving SHR-1210 plus apatinib at the 
following time points: 
a) In the first treatment cycle of SHR-1210 + apatinib administration, blood samples 
are collected once within 0.5 h pre-administration, once at 3 h (± 5 min) 
post-administration on Day 1, and once within 0.5 h pre-administration of apatinib 
on Day 7. There are 3 time points for blood sampling during Cycle 1 of SHR-1210 
plus apatinib; 


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b) After that, PK blood samples are collected at the above time points during each 
cycle, for 6 cycles in total (including the first cycle of SHR-1210 plus apatinib); 
c) ADA blood samples are collected once at 30 days (± 7 days), 60 days (± 7 days), and 
90 days (± 7 days) after the last dose of study treatment, respectively (depending on 
the visit schedule if applicable). 
d) At each time point, 5 mL of venous blood is collected (2 mL for apatinib assay, and 3 
mL for SHR-1210 assay). 
◆ Time points for ADA blood sample collection: 
a) Blood samples are collected within 0.5 h before the drug administration on C1D1, 
C2D1, C4D1, C6D1, and C9D1, respectively. ADA blood samples are collected once 
every 4 cycles within 0.5 h before the drug administration since the Cycle 9.  
b) ADA blood samples are collected once at 30 days (± 7 days), 60 days (± 7 days), and 
90 days (± 7 days) after the last dose of study treatment, respectively (depending on 
the visit schedule if applicable). 
c) At each blood sampling time point, 4 mL of venous blood is collected. 
4 SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible. 
1. Pathologically or cytologically confirmed GC or GEJ cancer, with evidence of being 
unresectable, locally advanced, or metastatic; histologically confirmed adenocarcinoma 
mainly. 
2. Aged 18 or above, male and female. 
3. Patients who have not received systemic treatment (including HER-2 inhibitors) for 
advanced or metastatic GC/GEJ. Subjects who have received adjuvant or neoadjuvant 
therapy (including chemotherapy, radiotherapy, or radiochemotherapy) for GC/GEJ must 
have completed the last treatment at least 6 months prior to the first dose of study 
treatment. Palliative radiotherapy is permitted, but it must be completed 2 weeks prior to 
the start of study treatment. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
5. With measurable lesion as per RECIST 1.1 criteria. 


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6. Life expectancy > 12 weeks. 
7. All acute toxicities due to previous anti-tumor treatments or surgeries must have resolved 
to Grade 0–1 (as per NCI CTCAE 4.03) or to the level specified in the 
inclusion/exclusion criteria. Other toxicities such as alopecia, which do not pose a safety 
risk to the subjects evaluated by investigators, are excluded. 
8. With adequate organs and bone marrow functions, as defined below: 
a) 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
b) 
Platelet count (PLT) ≥ 100,000/mm3 (100 × 109/L); 
c) 
Hemoglobin (Hb) ≥ 9 g/dL (90 g/L); 
d) 
Serum creatinine ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance ≥ 60 
mL/min; 
e) 
Total bilirubin (BIL) ≤ 1.5 × ULN; 
f) 
Aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 2.5 × 
ULN; for patients with liver metastasis, ALT and AST should be ≤ 5 × ULN; 
g) 
International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and activated 
partial thromboplastin time (APTT) ≤ 1.5 × ULN; 
h) 
Urine protein < 2+; If urine protein is ≥ 2+, then the 24-hour urine protein must be 
≤ 1 g; 
i) 
Thyroid stimulating hormone (TSH) ≤ ULN; in case of abnormalities, T3 and T4 
levels should be measured; if T3 and T4 levels are normal, the subject can be 
enrolled. 
9. Female patients of childbearing potential must have a negative serum pregnancy test 
within 3 days prior to the first dose, and be willing to use a recognized effective 
contraceptive measure (such as intra-uterine contraceptive devices, contraceptive pills, 
and condoms) during the study and within 3 months after the last dose of the study drugs; 
male patients with female partners of childbearing potential must either be surgically 
sterilized or agree to take effective contraceptive measures during the study and within 3 
months after the last dose of the study drugs. 
10. Subjects must agree and have signed the informed consent form, be willing and able to 
follow the scheduled visits, study treatment, laboratory tests, and other study procedures. 


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4.2 
Exclusion Criteria 
Patients meeting any one of the followings are not eligible to participate in this study: 
1. Known HER2-positive. 
2. Prior treatment with anti-PD-1/PD-L1 antibodies, CTLA-4 antibodies, or other 
treatments targeting PD-1/PD-L1 and/or VEGFR inhibitors. 
3. Known allergies to the study drug or their excipients; severe allergic reactions to other 
monoclonal antibodies. 
4. Having received immunosuppressive drugs within 14 days prior to the first dose of 
SHR-1210, excluding intranasal and inhaled corticosteroids or systemic steroids of 
physiological doses (i.e., no more than 10 mg/d of prednisolone or equivalent). 
5. Having received live, attenuated vaccines within 4 weeks before the first dose or had 
such vaccination plan during the study. 
6. Presence of known uncontrolled or symptomatic active central nervous system (CNS) 
metastases, manifested as clinical symptoms, cerebral edema, spinal cord compression, 
carcinomatous meningitis, leptomeningeal disease, and/or progressive growth. Patients 
with a history of metastases to the central nervous system or spinal cord compression 
may be eligible if they are clearly treated and clinically stable 4 weeks after 
discontinuation of anticonvulsants and steroids before the first dose of study treatment. 
7. Presence of Grade > 1 peripheral neuropathy. 
8. Advanced diseases that are symptomatic, disseminated to viscera, and at risk of 
life-threatening complications in the short term (including uncontrollable massive 
[pleural, pericardial, and abdominal] exudate, pulmonary lymphangitis, and more than 
30% of hepatic involvement). 
9. Presence of any active autoimmune diseases or a history of autoimmune diseases 
(including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, 
enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; 
adult subjects with vitiligo or completely relieved childhood asthma can be enrolled if 
they do not require any intervention; patients with asthma requiring medical 
interventions with bronchodilators cannot be enrolled). 
10. Having been diagnosed with any other malignancies within 3 years before the 
enrollment, excluding adequately treated basal cell carcinoma or squamous cell skin 
cancer, or cervical carcinoma in situ. 


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11. Infection with human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS), active hepatitis B (HBV DNA ≥ 500 IU/mL), 
hepatitis C (hepatitis C antibody being positive and HCV-RNA being above the lower 
limit of detection of the assay), or co-infection of hepatitis B and C. 
12. Any of the following conditions observed within 6 months prior to the enrollment: 
myocardial infarction, severe/unstable angina, > NYHA Class II cardiac insufficiency, 
poorly controlled arrhythmia (including males with QTcF > 450 ms and females with 
QTcF > 470 ms, QTcF interval calculated with the Fridericia's formula), symptomatic 
congestive cardiac failure, or cerebrovascular accident (including transient ischemic 
attack or symptomatic pulmonary embolism). 
13. Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
14. Abnormal coagulation function (INR > 1.5 or activated partial thromboplastin time 
(APTT) > 1.5 × ULN), bleeding tendency, or receiving thrombolytics or anticoagulant 
therapy. 
15. Known hereditary or acquired hemorrhage and thrombophilia (hemophilia, 
coagulopathy, thrombocytopenia, hypersplenism, etc.). 
16. Obvious hemoptysis or a daily amount of hemoptysis of half a teaspoon (2.5 mL) or more 
within 2 months before the enrollment. 
17. Clinically significant hemorrhage symptoms or clear bleeding tendency within 3 months 
prior to participation in this study, such as GI bleeding, hemorrhagic gastric ulcer, 
baseline fecal occult blood++ and above, or vasculitis. 
18. Events of arterial/venous thrombosis within 6 months prior to participation in this study, 
such as cerebrovascular accidents (including transient ischemic attacks, cerebral 
hemorrhage, and cerebral infarction), deep vein thrombosis, and pulmonary embolism. 
19. Known hereditary or acquired hemorrhage and thrombophilia (hemophilia, 
coagulopathy, thrombocytopenia, hypersplenism, etc.). 
20. Requiring long-term anticoagulant therapy with warfarin or heparin; or requiring 
long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day). 
21. Complicated with severe infection (such as one requiring intravenous infusion of 
antibiotics, antifungals, or antivirals) within 4 weeks prior to the first dose, or any 
unexplained fever of > 38.5 °C observed during screening period/prior to the first dose. 


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22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell 
transplantation. 
23. Having participated in clinical studies concerning any other drugs within 4 weeks prior to 
the first dose, or less than 5 half-lives from the last dose of study drugs. 
24. Known history of psychotropic substance abuse or drug abuse. 
25. Patients with other severe physical or psychiatric disorders or laboratory abnormalities, 
which may increase the risk of participating in this study or interfere with the study 
results, as well as those deemed unsuitable by the investigator. 
4.3 
Randomization and Blinding 
Only Patients who meet all the inclusion criteria shall be randomly enrolled in this study. In the 
event that an ineligible patient is randomized, or erroneously start the treatment, or an enrolled 
subject no longer meets the eligibility criteria before starting the study treatment, the sponsor's 
representative and the investigator must jointly discuss whether the subject should continue or 
withdraw from the study. The sponsor should ensure that appropriate documentation is retained 
with regards to such decisions. 
This study is an open-label study and does not involve blinding. 
4.4 
Rescreening Criteria 
In this study, rescreening is allowed. That is, subjects who sign the informed consent form and 
enter the screening process but do not meet the inclusion criteria and have not yet started the 
treatment may be rescreened. Test/examination results from the first screening that meet the 
inclusion/exclusion criteria may be reused in the rescreening, provided that they are within the 
window period. During rescreening, a new subject No. is assigned. 
4.5 
Withdrawal or Discontinuation 
Subjects may withdraw the informed consent and withdraw from the study at any time. The 
investigator can determine whether the subject needs to withdraw from the study based on the 
occurrence of AEs. In addition, if the subject is not eligible for enrollment or violates the protocol, 
or due to management and/or other safety reasons, the investigator or the sponsor may withdraw 
the subject from the study. 


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4.5.1 
Study withdrawal criteria 
Reasons for withdrawal may include: 
 Withdrawal of informed consent and refusal of further follow-ups by subjects; 
 Continuing participation in the study violating the patient's optimal benefit due to clinical 
AEs, laboratory abnormalities, or concurrent diseases, as assessed by the investigator; 
 Other investigator-assessed reasons, such as the inability to provide voluntary consent due 
to imprisonment or quarantine, or significant protocol violations; 
 Lost to follow-up; 
 Death; 
 Study termination by the sponsor. 
The reasons for the subject's withdrawal from the study must be recorded in CRF and the subject's 
medical record. 
It is noteworthy that withdrawal of informed consent refers to the subject withdrawing the consent 
to be further contacted, or no longer agreeing to provide information via a previously authorized 
person. Whenever possible, subjects should notify the investigator in writing that they no longer 
agree to be followed. The investigator should specify and record the withdrawal of the informed 
consent. That is, whether the subject no longer consents to continue study treatment, or whether 
the subject no longer consents to receive the follow-up visits specified in the protocol either. 
4.5.2 
Criteria for treatment discontinuation 
The study treatment must be discontinued when any of the following occurs: 
 Requests to discontinue the study treatment by subjects; 
 Radiographic or clinical evidence of progressive disease, unless the subject meets the 
criteria for continuing treatment beyond progression (see Section 4.6); 
 Occurrence of pregnancy during the study; 
 Any clinical AEs, laboratory test abnormalities, or other medical conditions indicating that 
the subject can no longer benefit from the treatment; 
 Comprehensive deterioration of health status and inability to continue study participation; 
 Significant protocol deviations such as ineligibility found after enrollment or 
incompliance; 


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 Lost to follow-up; 
 Study termination by the sponsor; 
 Death; 
 Other reasons as determined by the investigator. 
4.5.3 
Procedures for withdrawal or discontinuation 
The efficacy and safety examinations to be completed upon study withdrawal as specified in the 
protocol must be completed as much as possible. In addition, the safety follow-up should be 
completed along with fully documented AEs and their outcomes. The investigator can recommend 
or provide new or alternative treatments to a subject based on the condition of the subject. Subjects 
showing no progressive disease should continue to be followed up for imaging evaluation as much 
as possible, until the start of a new anti-tumor treatment or progressive disease. 
Unlike subjects withdrawing their informed consent to withdraw from the study, subjects who 
request discontinuation of study treatment will remain in the studies and should be followed up 
according to the study procedures specified in the protocol. 
Survival status should still be followed even if the subject refuses further visits, unless the subject 
withdraws the consent to provide further information or the consent to be further contacted. In 
such case, no study assessment is performed, nor any data are collected. 
4.6 
Criteria for Continuing Treatment Beyond Disease Progression 
Some subjects receiving immunotherapy can still benefit from continuing treatment 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. The study 
treatment may be continued beyond progressive disease (PD) 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 obvious deterioration in subject's performance status, and no marked worsening of 
cancer-related symptoms; 
• 
Subjects must sign the informed consent form prior to continuing study treatment, in 
which potential risks, discomforts, and other treatment options shall be included; 
• 
Continued study treatment must be reviewed and approved by the principal investigator 
of the study center. 


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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 beyond progression, the subject 
should continue to be treated, evaluated, and followed up according to the protocol requirements. 
Subjects should withdraw from the study if further disease progression is observed at the next 
assessment. The initial date of investigator-assessed progression should be used for all statistical 
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 progressive disease, the progression will be reported as "general deterioration". More 
objective evidences (eg., imaging confirmation) of progressive disease of these subjects should be 
obtained whenever possible after treatment discontinuation. 
For subjects who withdraw from the study due to unacceptable toxicity without radiographic 
disease progression observed, the imaging examination should be performed at the same 
frequency, until PD or initiation of other anti-tumor treatments. The radiographic evidence of PD 
of these subjects must be obtained whenever possible. 
4.7 
Termination or Suspension of Study 
This study can be terminated early or suspended if there are sufficient reasons. This may result 
from the decision of the regulatory authorities, changes in comments by the ethics committee, 
efficacy or safety issues of the study medications, or the judgment of the sponsor. In addition, the 
sponsor reserves the right to terminate the research and development of SHR-1210 at any time. 
The party who decides to suspend/terminate the study should notify the investigator, sponsor, and 
regulatory authorities in writing, documenting the reasons for suspension/termination. The 
investigator must immediately notify the ethics committee and sponsor, and provide relevant 
reasons. 
The reasons for termination or suspension of the study may include: 
 Confirmed unexpected, major, or unacceptable risks to the subjects; 
 Existing efficacy data supporting study termination; 
 Confirmed ineffectiveness of the study treatment; 
 A major error in the protocol found during the implementation of the study; 


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 Extreme difficulties in completing the study due to poor compliance with protocol, such as 
severe delays in subject recruitment or frequent protocol deviations; 
 Incomplete or undetectable data; 
 Changes in the sponsor's development strategy for the investigational drug; 
 Valueless study results. 
The study may continue once that issues related to drug safety, protocol compliance, and data 
quality have been resolved and approved by the sponsor, ethics committee, or CFDA (now 
NMPA). 
4.8 
Definition of End of Study 
End of the study is defined as the last subject last visit (LSLV) or the last subject completing 24 months 
of study treatment after enrollment (whichever occurs first). 
5 
STUDY TREATMENT 
5.1 
Overview of the Study Drugs 
5.1.1 
Access to the drugs 
The study drugs are uniformly packaged, tested, and provided by the sponsor (see corresponding 
Certificate of Analysis). 
5.1.2 
Drug information 
Investigational drug: SHR-1210 for injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: lyophilized powder. 
Strength: 200 mg (proposed) in 20-mL vials. 
Batch No.: see Certificate of Analysis 
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 refrigerator. Do not freeze. 


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Apatinib Mesylate Tablets 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: tablet. 
Strength: 250 mg/tablet; 375 mg/tablet 
Batch No.: see Certificate of Analysis 
Route of administration: oral administration after meals (best to take the two drugs at the same 
time each day). 
Shelf life: 2 years. 
Storage conditions: away from light, sealed, stored below 25 °C. 
Capecitabine Tablet 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: tablet. 
Strength: 0.5 g/tablet; 0.15 g/tablet. 
Batch No.: see Certificate of Analysis 
Route of administration: oral administration after meals. 
Shelf life: 24 months. 
Storage conditions: kept in a cool and dry place. 
Oxaliplatin for Injection 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: injection. 
Strength: 50 mg/bottle or 100 mg/bottle. 
Batch No.: see Certificate of Analysis 
Route of administration: intravenous infusion. 
Shelf life: 24 months. 
Storage conditions: sealed and stored below 25 °C. 


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5.1.3 
Drug storage and management 
The investigator or authorized personnel (such as a pharmacist) is responsible for ensuring that all 
study drugs are stored in a safe zone with appropriate storage conditions and controlled access, and 
that the storage is in compliance with regulatory requirements. 
The study drugs should be stored in their original containers according to the storage conditions in 
section 5.1.2, and the storage conditions are consistent with the label. For inconsistencies between 
the storage conditions on the label with those in other materials (e.g., Investigator's Brochure), the 
storage conditions on the label should be followed. 
The study center shall record the daily maximum and minimum temperature of all storage zones 
(such as freezer, refrigerator, or room temperature). Documentation should begin with the receipt 
of the study drug until the last subject completes the last visit. Even if a continuous monitoring 
system is employed, a written log must be kept to ensure a correct record of storage temperature. 
The temperature monitoring and storage devices (such as refrigerator) should be regularly 
inspected to ensure proper operation. 
Any deviations related to the labeled conditions on the product should be immediately reported 
upon discovery. The study center shall take active measures to restore the study drugs under the 
storage conditions described on the label, and the temperature deviation and the measures taken 
shall be reported to the sponsor. 
Study drugs that are affected by temperature deviations must be temporarily quarantined until 
approved by the sponsor for further use, and such case is not considered a protocol deviation. The use 
of affected study drugs without the approval of the sponsor is considered a protocol deviation. The 
sponsor will provide a detailed procedure on reporting temperature deviations to the study center. 
For subjects who take the medications at home, the staff at the study center will provide guidance 
for the subjects on the proper method of drug storage as the storage conditions. 
The study drugs are not allowed to be used in treatments outside of this study. 
5.1.4 
Preparation of study drugs 
The study drugs should be prepared by qualified or experienced study staff (such as study nurse) 
according to the drug brochures or package insert of marketed drugs. 
SHR-1210 does not contain preservatives, and must be prepared using aseptic technique. Refer to 
the brochure for drug preparation. 
Other study drugs (apatinib mesylate, capecitabine and oxaliplatin) have already been marketed 
and should be prepared according to the package inserts. 


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5.1.5 
Administration of study drugs 
SHR-1210 
SHR-1210, intravenous infusion at a fixed dose of 200 mg over 30 min (the total infusion time 
should be no less than 20 min and no more than 60 minutes, including rinsing period), once every 
3 weeks. 
Apatinib Mesylate Tablets 
375 mg, administered orally once daily. Administered with warm water approximately half an 
hour after meals (administration time should be the same in each day whenever possible). 
Capecitabine 
1000 mg/m2, administered orally twice daily 30 min after meals (once in the morning and once in 
the evening; with a total daily dose of 2000 mg/m2). Two weeks of treatment is followed by 1 week 
of rest period (i.e., drug administration from Day 1 to Day 14, and drug interruption from Day 15 
to Day 21) in 3 week cycle. 
Oxaliplatin 
130 mg/m2, intravenous infusion with 250-500 mL of 5% glucose solution, given over 2-6 h; 
administered on Day 1 of each treatment cycle, once every 3 weeks. 
SHR-1210 will be administered intravenously followed by oxaliplatin at least 30 min interval on 
Day 1 of each cycle. 
Study Treatment Drug 
Treatment Cycle (21 days)  
Cohort 1 
SHR-1210 200 mg 
Day 1 
 
Capecitabine 1000 mg/m2 Day 1-Day 14 
4-6 cycles 
Oxaliplatin 130 mg/m2 
Day 1 
 
 
SHR-1210 200 mg 
Day 1 
 
 
Apatinib 375 mg 
Day 1-Day 21 
 
Cohort 2 
SHR-1210 200 mg 
Day 1 
 
Apatinib 375 mg 
Day 1-Day 21 
 
Table 6.  Administration plan of the study drugs 


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5.2 
Dose Modification of Study Drugs 
5.2.1 
Dose modification of SHR-1210 
Dose increases and reductions of SHR-1210 are not permitted. If SHR-1210 treatment is 
interrupted due to a toxicity, the subject may resume the treatment at the original dose after the 
toxicity is resolved. AEs related to SHR-1210 may be immune toxicities, and may occur shortly 
after the first dose or several months after the last dose. If the conditions listed in Table 7 occur, the 
use of SHR-1210 should be interrupted. During the study, the investigator must consult with the 
sponsor if the investigator considers that an adjustment listed in Table 7 is inappropriate based on 
the benefit-to-risk ratio of subjects or that SHR-1210 treatment should be interrupted or resumed 
due to a condition not listed in the table. 
Table 7.  Dose modification criteria for SHR-1210 due to immune-related toxicity 
SHR-1210-Related 
Toxicity 
Grade for 
Interruption 
Resumption 
Discontinuation 
Diarrhea/Colitis 
Grade 2-3 
Recovered to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 4 
Discontinuation 
Discontinuation 
AST/ALT or Bilirubin 
Increased 
Grade 2 
Recovered to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 3-4 
Discontinuationa 
Discontinuation 
Type 1 Diabetes Mellitus 
(new onset) or 
Hyperglycemia with Signs 
of β-cell Failure 
Grade 3-4 or 
new-onset type 
1 diabetes 
SHR-1210 treatment may only be resumed after the clinical and 
metabolic conditions of the subject are stabilized. 
Hyperthyroidism 
Grade 3 
Toxicity reduced to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 4 
Discontinuation 
Discontinuation 
Hypothyroidism 
Grade 2-4 
Study treatment can be continued after starting thyroxine replacement 
therapy 


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SHR-1210-Related 
Toxicity 
Grade for 
Interruption 
Resumption 
Discontinuation 
Pneumonia 
Grade 2 
Toxicity reduced to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 3-4 
Discontinuation 
Discontinuation 
Immune-Related 
Hypophysitis 
Grade 2-3 
The SHR-1210 treatment may 
continue after the toxicity 
reduces to Grade 0-1 and the 
hormone replacement therapy 
starts. 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 4 
Discontinuation 
Discontinuation 
Renal Failure or Nephritis 
Grade 2 
Toxicity reduced to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 3-4 
Discontinuation 
Discontinuation 
Infusion reactions 
Grade 2b 
Symptoms disappeared 
Discontinue the drugs if the symptoms 
recur after adequate premedication. 
Grade 3-4 
Discontinuation 
Discontinuation 
Other T-related toxicitiesc 
Grade 3 
Toxicity reduced to Grade 0-1 
Toxicity has not resolved by 12 weeks 
after the last dose, or the 
corticosteroid dose cannot be reduced 
to prednisone 10 mg/day (or 
equivalent) or lower within 12 weeks 
after the last dose. 
Grade 4 
Discontinuation 
Discontinuation 
Treatment should be discontinued if any grade ≥ 3 treatment-related AE recurs (grade ≥ 2 pneumonia) 
or any life-threatening event recurs. 
a) For subjects with liver metastasis and grade 2 AST or ALT increased at baseline, if the AST or 
ALT increased ≥ 50% from baseline persists for at least 1 week, the treatment shall be 
discontinued. 
b) If the symptoms resolve within 1 hour after dechallenge, and the infusion can be resumed at 
50% of the initial infusion rate. Otherwise, the treatment can only be resumed until symptoms 
are fully resolved. Premedication is required prior to the next dose. Refer to section 5.6.2 
"Recommendations on infusion reaction management" for further management. 


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c) For subjects with intolerable or persistent grade 2 treatment-related AEs, the investigator may 
consider interrupting SHR-1210 treatment if appropriate, and the treatment should be 
discontinued if toxicity fails to decrease to Grade 0-1 within 12 weeks after the last dose. 
5.2.2 
Dose modification of capecitabine and oxaliplatin 
For subjects receiving SHR-1210 combined with capecitabine and oxaliplatin (XELOX regimen), 
dose modification can be made based on toxicities. 
For non-severe or non-fatal toxicities (eg., alopecia, appetite change and nail discoloration), dose 
modification may not be necessary as judged by the investigator. 
Dose modification caused by toxicities of a single drug in the combination therapy will not affect 
the usage of other drugs according to the plan. 
This is because the capecitabine- and/or oxaliplatin-related toxicities cannot resolve within one 
same treatment cycle. The administration of capecitabine and/or oxaliplatin can be delayed for no 
more than 6 weeks. If the toxicities still do not resolve by 6 weeks, the capecitabine and/or 
oxaliplatin treatment will be discontinued, unless the investigator considers that the subjects will 
benefit from the continuing treatment of the capecitabine and/or oxaliplatin. 
⚫ Dose modification of capecitabine 
Toxicities caused by capecitabine can be managed by symptomatic treatment and/or interruption 
or dose reduction. The recommended dose modification criteria for capecitabine are shown in 
Table 8. The dose cannot be increased again after the reduction. 
Grading of Adverse 
Drug Reactions 
Modification During Treatment 
Dose Modification in the 
Next Cycle (% initial 
dose) 
Grade 1 
Maintain original dose 
Maintain original dose 
Grade 2 
First occurrence 
Interrupt until recovery to Grade 0-1 
100% (1000 mg/m2) 
Second occurrence 
75% (750 mg/m2) 
Third occurrence 
50% (500 mg/m2) 
Fourth occurrence 
Permanently discontinue the treatment 
 
Grade 3 
First occurrence 
Interrupt until recovery to Grade 0-1 
75% (750 mg/m2) 
Second occurrence 
50% (500 mg/m2) 
Third occurrence 
Permanently discontinue the treatment 
 


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Grading of Adverse 
Drug Reactions 
Modification During Treatment 
Dose Modification in the 
Next Cycle (% initial 
dose) 
Grade 4 
First occurrence 
Permanently discontinue the treatment 
Or 
if the investigator believes that continuing treatment is 
beneficial to the subjects, then interrupt the treatment until the 
AE recovers to Grade 0-1 before resuming treatment. 
50% (500 mg/m2) 
Table 8. Dose modification criteria for capecitabine 
⚫ Dose modification of oxaliplatin 
Dose modification due to neurotoxicity 
 
For Grade 2 peripheral sensory neurotoxicity (moderate paresthesia or dysesthesia) or 
limited instrumental activities of daily living, oxaliplatin may be interrupted. After the 
toxicity recovers to grade ≤ 1, oxaliplatin can be resumed at 75% of the initial dose. If 
oxaliplatin treatment has been interrupted for more than 4 weeks due to neurotoxicity 
(2 consecutive doses), oxaliplatin treatment should be discontinued permanently. 
 
For grade ≥ 3 peripheral sensory neurotoxicity (severe paresthesia or dysesthesia) or 
limited activities of daily living, oxaliplatin should be discontinued permanently. 
Dose modification due to renal injury 
 
There is no need to adjust the dose of oxaliplatin for mild or moderate renal function 
impairment (CrCl > 50 mL/min). 
 
For severe renal function impairment, the dose of oxaliplatin should be adjusted to 75% 
of the initial dose. 
Dose modification due to hematologic toxicities 
 
For Grade 2 or 3 thrombocytopenia, the dose of oxaliplatin should be adjusted to 75% of 
the initial dose. For Grade 4 thrombocytopenia, the dose of oxaliplatin should be adjusted 
to 50% of the initial dose. 
 
For Grade 3 or 4 neutropenia or febrile neutropenia, the dose of oxaliplatin should be 
adjusted to 75% of the initial dose. 


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5.2.3 
Dose modification of apatinib mesylate 
Dose modifications caused by apatinib-related toxicities include the following: treatment 
interruption (no more than 28 days), dose reduction (to 375 mg qd or 250 mg qd, depending on the 
initial dose of apatinib), and permanent discontinuation. 
The treatment may be delayed and the dose be reduced for Grade ≥ 3 hematologic toxicity or ≥ 2 
non-hematologic toxicity; for non-hematologic toxicity, manageable nausea and vomiting, and 
fever (below 38 °C) of dete rmined cause, active symptomatic treatment can be administered first. 
There is no need to immediately delay the treatment or reduce the dose. 
In case of apatinib-related toxicity, administration should be delayed until recovery, and then the 
original dose should be resumed or the dose should be reduced by one dose level. The minimum 
dose allowable is 250 mg/d. If the dose is still intolerable at the reduced dose of 250 mg/d, apatinib 
should be permanently discontinued (refer to Table 9 for the recommended dose modification 
method). Dose increase of apatinib is not allowed during the study period. 
Table 9. Recommended dose modification of apatinib 
Apatinib-Related 
Toxicities 
Grade 
Dose Delay 
or Not 
Criteria for 
Resuming 
Dose 
Modification 
Method 
Criteria for 
Discontinuation 
Hematologic 
Toxicity 
Grade 1-2 
No 
— 
— 
— 
Grade 3 
Yes 
Until the toxicity 
recovers to Grade 
≤ 2 
Resume at 
original dose 
Apatinib 
interruption for 
more than 28 days 
Grade 4 
 
Until the toxicity 
recovers to Grade 
≤ 2 
Reduce the dose 
by one level 
Non-Hematologic 
Toxicity 
Grade 1 
No 
— 
— 
— 
Grade 2 (last for 
 ≥ 7 days) 
Yes 
Until the toxicity 
recovers to Grade 
≤ 1 
Resume at 
original dose 
Apatinib 
interruption for 
more than 28 days 
Grade 3 
Yes 
Until the toxicity 
recovers to Grade 
≤ 1 
Reduce the dose 
by one level 
Hypertension 
Grade 3 (after 
corrective treatment) 
Yes 
Until the toxicity 
recovers to Grade 
≤ 1 
Reduce the dose 
by one level 
Apatinib 
interruption for 
more than 28 days 
Proteinuria 
(without 
significant 
increase in blood 
creatinine) 
Grade 3 (24-h urine 
protein quantification) 
Yes 
Until the toxicity 
recovers to Grade 
≤ 2 
Reduce the dose 
by one level 
Apatinib 
interruption for 
more than 28 days 


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Apatinib-Related 
Toxicities 
Grade 
Dose Delay 
or Not 
Criteria for 
Resuming 
Dose 
Modification 
Method 
Criteria for 
Discontinuation 
Hand-and-Foot 
Syndrome 
Grade 3 
Yes 
Until the toxicity 
recovers to Grade 
≤ 1 
Reduce the dose 
by one level 
Apatinib 
interruption for 
more than 28 days 
Headache 
Grade 2 (last for  
≥ 7 days) or Grade 3 
Yes 
Until the toxicity 
recovers to Grade 
≤ 1 
Reduce the dose 
by one level 
Apatinib 
interruption for 
more than 28 days 
In this study, the minimum dose of apatinib allowable is 250 mg/d. If the subjects still cannot tolerate the dose of 250 
mg/d, apatinib should be permanently discontinued. 
For subjects with gastrointestinal perforation, wound dehiscence needing clinical management, 
fistula, severe hemorrhage, nephrotic syndrome or hypertensive crisis, apatinib should be 
permanently discontinued. 
5.3 
Duration of Treatment 
All subjects should continue to receive the study treatment until progressive disease, intolerable 
toxicity, voluntary treatment discontinuation or study withdrawal by the subject, or 
discontinuation determined by the investigator. 
SHR-1210 is an immune checkpoint inhibitor and according to the experience of similar drugs, 
some subjects may experience delayed or early pseudo progression after receiving immunotherapy 
drugs. For subjects in the treatment group experiencing progressive disease (PD) for the first time, 
they may continue with the SHR-1210 treatment if they meet the criteria in section 4.6 Criteria for 
Continuing Treatment Beyond Disease Progression. Subjects who do not have progressive disease 
or intolerable toxicities may continue the SHR-1210 treatment for no more than 24 months. 
Subjects who do not have progressive disease after 24-month treatment may continue the apatinib 
monotherapy according to the prescribing information of apatinib. 
5.4 
Drug Management, Dispensation, Return and Disposal 
Designated personnel are responsible for management, dispensation, and return of study drugs. 
The investigator must ensure that all study drugs are used by enrolled subjects only and the dose 
and route of administration comply with Section 5.1.4. Remaining or expired drugs should be 
returned to the sponsor or destroyed at the study center according to the specified procedures, and 
may not be used for non-participants. 
During distribution of the drugs, a drug receipt form should be signed by both parties in duplicate, 
one copy for the study center and one copy for the sponsor. When returning remaining drugs and 
empty packaging, both parties must sign the drug retrieval form. The dispensation and return of 
every drug should be immediately documented on designated forms. 


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The CRA is responsible for monitoring the supply, use, and storage of study drugs, and disposal of 
remaining medications. 
⚫ Disposal of study drugs 
The sponsor or authorized personnel is responsible for disposing the study drugs. Drug disposal 
should be well documented. 
5.5 
Recording of concomitant medications and concomitant treatments 
Concomitant medications/treatments refer to any drugs/treatments that are given for the interest of 
subjects as determined by the investigator. 
All concomitant medications, blood products, and non-drug interventions (eg., paracentesis) that 
are given to the subjects from 30 days prior to the first dose to the end of the safety visit must be 
strictly documented in the CRF according to GCP requirements. 
Prohibited medications and vaccines specified in the study protocol are strictly prohibited during 
the entire course of study. If the subject develops a comorbidity requiring treatment with a prohibited 
drug, the investigator should consult with the sponsor before discontinuing the study treatment or 
using the prohibited drug. Whether the subject will continue the study treatment or receive a 
prohibited drug should be jointly decided by the investigator, the sponsor, and the subject. 
In addition to the following contents, for subjects who receive apatinib mesylate, capecitabine and 
oxaliplatin treatment, the latest package insert of marketed drugs or medical practices regarding 
contraindications and precautions shall be also taken for reference. 
5.5.1 
Other anti-tumor treatments or investigational drugs 
Other anti-tumor treatments not specified in the protocol are not permitted while subjects are 
receiving study treatment, including CDFA (NMPA)-approved Chinese herbal preparations for 
anti-tumor treatments (see Appendix 6 Prohibited Traditional Chinese Medicines During the 
Study Period) and immunomodulators (including but not limited to interferon, interleukin-2, and 
thymosin). 
Participation in other drug/medical device clinical studies is not permitted. 
Other systemic anti-tumor treatments such as chemotherapy, molecular targeted therapy, hormone 
therapy, immunotherapy, biological therapy, and radiotherapy are not permitted. 
Subjects can receive bisphosphonate for the treatment of bone metastases. If systemic treatment or 
local analgesia is not effective in controlling painful lesions of bone metastases, a small area of 
palliative radiotherapy (the area of the radiotherapy must be < 5% of the bone marrow region, and 
the percent bone marrow in human is shown in Appendix 5 Percent Bone Marrow Content in 
Human Skeleton) is allowed. 


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Palliative treatment of local lesions that may cause obvious symptoms is permitted. For example, 
local radiotherapy or surgery may be considered for bone lesions that cause pain. However, the 
following criteria must all be met. It is also recommended to consult with the sponsor prior to 
starting palliative treatment. 
1) The investigator must assess whether there is progressive disease in subjects who require 
local treatment due to symptom exacerbations during the study; 
2) Subjects with progressive disease have to meet the criteria for continuation of treatment 
beyond progression; 
3) The locally treated lesions should not be the target lesions. 
5.5.2 
Vaccines 
Live attenuated vaccines should not be given within 4 weeks before the first dose or during the 
study period. Subjects who are expected to require live attenuated vaccines during the study period 
are not recommended for enrollment. 
Inactivated vaccines for preventing infectious diseases, such as pneumonia, influenza, are 
permitted. Any other vaccines should be discussed with the sponsor before administration. 
5.5.3 
Immunomodulators and corticosteroids 
Concomitant immunosuppressive therapy is not permitted (except when treating treatment-related 
adverse events). 
Concomitant immunostimulants are not permitted (except when treating treatment-related AEs). 
Long-term, systemic use of corticosteroids is prohibited. The use of corticosteroids for ≤ 1 week as 
premedication for chemotherapy or contrast media allergies as specified in the package insert is 
permitted. Systemic treatment with corticosteroids is permitted for individual subjects after 
discussing with the sponsor. Short term (≤ 3 weeks) use of corticosteroids for non-autoimmune 
diseases is permitted (such as delayed allergic reactions caused by contact allergens). 
Emergency use, topical application, inhalation, eye drops, or local injections of corticosteroids are 
permitted. Physiological replacement doses (such as adrenal replacement doses) of systemic 
corticosteroids (≤ 10 mg/d of prednisone or equivalent) are permitted. 
5.5.4 
Hematopoietic growth factor and blood transfusion 
Any granulocyte colony-stimulating factor, erythropoietin, thrombopoietin, and other 
hematopoietic stimulation factors, as well as blood transfusion and blood products (eg., albumin) 
are prohibited as primary prophylaxis before treatment. However, these treatments are allowed for 
treating AEs. 


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5.5.5 
Anti-inflammatory treatment 
Anti-inflammatory medications or narcotic analgesics can be given if there are no known or 
foreseeable drug interactions and if these drugs are not prohibited in the protocol. 
5.5.6 
Medications to be used with caution in subjects receiving apatinib during the study 
Drugs that may affect the metabolism of apatinib or prolong QT interval should be used with 
caution in subjects in cohort 2 (SHR-1210 + apatinib). 
⚫ Drugs that may have drug-drug interactions with apatinib mesylate 
In vitro metabolic enzymes studies have shown that apatinib is mainly metabolized by CYP3A4. 
When apatinib is used concomitantly with strong inhibitors of CYP3A4 (itraconazole, 
clarithromycin, voriconazole, telithromycin, saquinavir, and ritonavir), the plasma concentration 
of apatinib may rise up. When apatinib is used concomitantly with CYP3A4 inducers 
(dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, and rifapentine), the 
plasma concentration of apatinib may decrease. When other combined medications are needed, it 
is recommended to choose alternative drugs that do not inhibit or induce CYP3A4. If a strong 
inducer or inhibitor of CYP3A4 enzyme must be used concomitantly, it is necessary to consider 
whether to modify the dose based on clinical observation. 
⚫ Drugs that prolong the QT interval of the heart 
As tinib drugs may cause toxicities of prolonged QT interval in clinical applications, drugs that 
may prolong the QT interval should be used with caution during the study. These mainly include, 
but are not limited to, the following categories of drugs: 
 
Antibiotics: fluoroquinolones: sparfloxacin, gatifloxacin, levofloxacin, moxifloxacin, 
ofloxacin, ciprofloxacin; macrolides: erythromycin, clarithromycin, telithromycin, 
azithromycin, roxithromycin, and metronidazole. 
 
Antiarrhythmics: quinidine, procainamide, disopyramide, flecainide, propafenone, 
amiodarone, dronedarone, sotalol, dofetilide, and ibutilide. 
 
Drugs used to relieve angina: ranolazine and ivabradine. 
 
Antipsychotics: risperidone, fluphenazine, droperidol, haloperidol, thioridazine, 
pimozide, olanzapine, and clozapine. 
 
Antifungal drugs: voriconazole and posaconazole. 
 
Antimalarial drugs: mefloquine and chloroquine. 
 
Antihistamines: terfenadine, astemizole, and hydroxyzine. 


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 
Gastrointestinal drugs: antiemetics: ondansetron, granisetron, dolasetron, droperidol 
(0.625-1.25 mg may be a safe dose), hydroxyzine; prokinetics: cisapride, domperidone, 
metoclopramide. 
 
Antidepressants: amitriptyline, imipramine, clomipramine, dosulepin, and doxepin. 
5.5.7 
Surgery 
Any surgery conducted during the study period must be justified and necessary. The interval 
between the surgery and study treatment must not affect the recovery of the wound as much as 
possible and the investigation on hemorrhage of unknown cause. An interruption of study treatment 
1 week before the surgery is recommended. Re-administration of the drugs after surgery will be 
determined on the basis of clinical assessment of wound healing and postoperative recovery. 
5.5.8 
Supportive care 
Palliative and supportive care for disease-related symptoms should be based on the investigator's 
judgment and relevant guidelines (e.g., "American Society of Clinical Oncology Clinical Practice 
Guideline"). 
Subjects should be given optimal supportive care during the treatment. 
It is not recommended to enroll subjects with uncontrolled cancer pain. Subjects requiring 
analgesics must have a stable analgesic regimen before enrollment. Palliative radiotherapy for 
symptomatic lesions (such as bone metastasis or perineural invasion) should be completed at least 
2 weeks before enrollment. Local treatment should be considered before the start of study 
treatment, if appropriate, for asymptomatic metastatic lesions where further growth may result in 
dysfunction or intractable pain (e.g., epidural metastasis without spinal cord compression). 
RANKL inhibitors (receptor activator of nuclear factor κB ligand inhibitor such as denosumab) are 
prohibited. Subjects with uncontrolled hypercalcemia (calcium ion > 1.5 mmol/L or calcium > 
12 mg/dL or corrected serum calcium > ULN), or subjects who need to continue treatment with 
bisphosphonates or denosumab for symptomatic hypercalcemia are not recommended to be enrolled. 
Patients who receive bisphosphonate therapy only to prevent skeletal-related events and have no 
history of clinically significant hypercalcemia may be enrolled. Patients receiving denosumab prior to 
enrollment must agree to replace denosumab with a bisphosphate after entering the study. 
Existing hormone replacement therapies are permitted. For example, subjects receiving treatment 
with a GnRH agonist can be enrolled in this study provided that the GnRH agonist has been 
well-tolerated for at least 3 months prior to enrollment. Likewise, patients with a history of 
autoimmune-mediated hypothyroidism who are receiving stable doses of thyroid hormone 
replacement therapy may be enrolled in this study. Patients with type 1 diabetes who are receiving 
on stable insulin therapy and have properly controlled blood glucose can be enrolled. 


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5.6 
Recommended Symptomatic Treatment for Common Adverse Drug Reactions Related 
to SHR-1210 
5.6.1 
Safety management rules for immuno-oncological medications 
AEs caused by immuno-oncology (I-O) medications 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 management procedures of similar approved drugs provide references 
to assist the investigator in assessing and dealing with adverse events involving the following 
systems: GI tract, kidneys, lungs, liver, endocrine, skin, and nervous system. Safety management 
rules for immuno-oncology drugs are presented in Appendix 4 Management Principles for 
Immune Related Adverse Events. 
5.6.2 
Infusion reactions 
During the course of this study, the investigator should pay close attention to potential infusion and/or 
allergic reactions, especially acute immune-mediated adverse reactions (including cytokine storms). 
SHR-1210 is a fully humanized monoclonal antibody with little potential for infusion or allergic 
reactions, and thus, in general, no prophylactic medications are required prior to SHR-1210 
infusion. Based on published relevant information, an allergic reaction/event is most likely to 
occur within 24 h after infusion. If an allergic reaction/event occurs, the infusion should be slowed 
or interrupted based on the subject's condition, and supportive treatment should be given. In 
addition, prophylactics should be given before further administration. Possible allergic reactions 
include fever, chills, shiver, headache, rash, arthralgia, hypotension/hypertension, and 
bronchospasm. 
Management of allergic reactions should be based on the medical practice and guidelines of the 
study center. The treatment recommendations for infusion reaction are shown below (Table 10) for 
reference. 
Table 10. Treatment recommendations for infusion reaction related to SHR-1210 
CTCAE 
Grade 
Clinical Symptoms 
Recommended 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 
can be given at least 30 min before the administration of 
SHR-1210. 
Continued use 


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CTCAE 
Grade 
Clinical Symptoms 
Recommended Management 
SHR-1210 
Treatment 
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 should be given 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 min before the administration of 
SHR-1210. Corticosteroids (equivalent to 25 mg of 
hydrocortisone) can be used when necessary. 
Interrupt. 
Re-administer at 50% 
of the initial rate after 
symptoms resolve. 
Restore the original 
infusion rate if no 
complications occur 
within 30 minutes. 
Closely monitor. If the 
symptoms recur, no 
more infusion shall be 
given. 
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; 
Administer normal saline by intravenous infusion. 
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 1:10,000 
adrenaline solution is recommended. Intravenous 
infusion of diphenhydramine 50 mg and 
methylprednisolone 100 mg (or equivalent dose) can be 
given if necessary. 
Medical practices and guidelines for treating allergic 
reactions at the study center are followed. Bedside 
observation and close monitoring until recovery. 
Discontinuation 
6 STUDY PROCEDURES 
6.1 
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. 
Subjects must sign the informed consent form before undergoing screening procedures for this 
study. Data from laboratory tests and imaging evaluation performed prior to informed consent for 
routine clinical practice may be used if they are within the specified window period. 
Unless otherwise stated, the following screening procedures should be completed within 28 days 
prior to the start of the study treatment. 
• 
Obtain informed consent form signed by the subject. 
• 
Collection of demographics: gender, date of birth, ethnicity, height, and weight. 


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• 
Collection of adverse events: Collect adverse events starting from the signing of ICF. 
• 
Tumor diagnosis: date of pathological diagnosis, pathologic grade, pathologic stage 
(TNM), clinical stage, site of metastatic lesion, time to disease progression or recurrence 
from the last treatment. 
• 
History of cancer treatment 
✓ History of tumor surgery: surgery, date; 
✓ History of radiotherapy: site, dose, and start and end dates. 
✓ History of neoadjuvant chemotherapy: chemotherapy regimen, cycles, and start and 
end dates; 
✓ History of adjuvant chemotherapy: chemotherapy regimen, cycles, and start and end 
dates; 
✓ History of concurrent disease, past medications, and medication allergies; 
• 
Virology: HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, HBV DNA (if the Hepatitis B five 
items test indicates HBV infection [HBsAg positive] or if the subjects have a history of 
HBV infection, HBV DNA quantification should be performed), HCV-Ab (if the result is 
positive, HCV RNA quantification should be performed), and HIV-Ab. 
• 
Imaging examinations: CT or MRI of the chest, abdomen, and pelvic cavity. Brain MRI 
(if MRI is contraindicated, CT scan can be used instead) is required for suspected or 
confirmed brain metastases. Bone scan is performed only when clinically indicated and 
must be performed within 42 days prior to the first dose. At screening, tumor evaluations 
up to 4 weeks before the first dose of study treatment and before the signing of the 
informed consent may be used as long as they meet relevant requirements. 
• 
Concomitant medications/concomitant treatments: Concomitant medications/ 
concomitant treatments within 30 days prior to the first dose of the study drug are 
documented. 
The following screening procedures should be completed within 7 days prior to the start of the 
study treatment. A pregnancy test should be completed within 72 hours prior to the start of the 
study treatment. 
• 
ECOG PS. 
• 
Vital signs: pulse, respiratory rate, body temperature, and blood pressure. 


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• 
Comprehensive physical examination: general condition, head and face, skin, lymph 
nodes, eyes, ears, nose and throat, oral cavity, respiratory system, cardiovascular system, 
abdomen, reproductive-urinary system, musculoskeletal system, nervous system, mental 
state, etc.; 
• 
Hematology: Red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT), white 
blood cell count (WBC), absolute neutrophil count (ANC), and lymphocyte count. 
• 
Urinalysis: WBC, RBC, and urine protein. If urine protein is ≥ 2+, then a quantitative 
24-h urine protein test should be added. 
• 
Fecal occult blood (OB) test: Fecal occult blood test is performed within 7 days prior to 
the first dose (if the fecal occult blood is positive, the test should be performed again. If 
the result is still positive, gastrointestinal endoscopy should be performed), on Day 1 of 
every two cycles, at the end of treatment/upon withdrawal, and upon the first visit during 
the safety follow-up period. 
• 
Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), 
alkaline phosphatase (AKP), blood urea nitrogen (BUN, preferred) or urea, total protein 
(TP), albumin (ALB), creatinine (Cr), blood glucose (GLU), K+, Na+, Ca2+, Mg2+ and Cl-. 
• 
Thyroid function: Including serum thyroid stimulating hormone (TSH), free 
triiodothyronine (FT3), and free thyroxine (FT4). If FT3 and FT4 cannot be obtained, T3 
and T4 are allowed for substitution; 
• 
Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time 
(PT), thrombin time (TT), fibrinogen (FIB), and international normalized ratio (INR). 
• 
12-Lead ECG: Attentions should be paid to QT, QTc, and PR-intervals. The investigator 
may decide to add other investigations if the results are abnormal. 
• 
Echocardiography: Including left ventricular ejection fraction (LVEF) assessment. 
Echocardiography is performed once within 7 days before the enrollment. After that, 
echocardiography is performed if clinically indicated and at the end of treatment/upon 
withdrawal. 
• 
Pregnancy test (serum pregnancy test will be performed for women of childbearing 
potential). 


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6.2 
Treatment Period/Follow-Up 
The treatment period starts from the subject's first dose. The first dose of the study drugs should be 
given as close as possible to the time of completing the screening examinations and confirming the 
subjects' eligibility for the study. Each treatment cycle lasts for 21 days. 
All examinations and evaluations (except for imaging evaluations) should be completed within 
3 days pre-administration. There is no need to repeat the laboratory tests (hematology, urinalysis, 
blood biochemistry, coagulation function test, and thyroid function test) and electrocardiography 
on Day 1 of Cycle 1, if such tests have already been performed at the baseline within 7 days before 
the first dose. 
◆ For subjects receiving the SHR-1210 + apatinib treatment for the first time, blood 
samples should be collected for PK and immunogenicity testing. The specific procedures 
can be found in the schedule of activities or section 3.1 "Pharmacokinetic and 
Immunogenicity Studies" in the protocol. 
◆ The following evaluations should be completed before the drug administration in 
each cycle: 
 
ECOG PS 
 
Vital signs 
 
Physical examination: Specific physical examination is performed if clinically 
indicated. 
 
Hematology 
 
Clinical chemistry 
 
Coagulation function 
 
12-Lead ECG 
 
Collection of AEs 
 
Documentation of concomitant medications/concomitant treatments 
◆ The following evaluations should be completed every 2 cycles prior to administration: 
 
Urinalysis 
 
Thyroid function 
 
Fecal occult blood 


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◆ Imaging examination: Imaging examination is performed once every 2 cycles (6 weeks ± 
7 days) in the first 12 months (the first 16 cycles), then once every 3 cycles (9 weeks ± 
7 days). Imaging examination should be also performed if new lesions are suspected. 
Imaging examination should be performed when subjects withdraw from the study for 
any reason (the imaging examination does not need to be repeated if the time from the 
last examination is no more than 4 weeks). Imaging conditions should be the same as 
those at baseline (including slice thickness and contrast agent). The time window for 
imaging examination is ± 7 days. Unscheduled imaging examination may be performed 
if PD is suspected (for example, worsening of symptoms). The date of imaging 
examination is calculated by the calendar day and will not be adjusted due to dose delays. 
Subjects with CR and PR should receive repeated imaging examination once to confirm the 
efficacy. Repeated tumor imaging should be performed at least 4 weeks after the initial response 
(4 weeks after the initial response or the next scheduled imaging evaluation). If the subject's 
imaging evaluation time is less than 4 weeks to the next scheduled imaging time, the next 
scheduled imaging evaluation is not required, and the imaging evaluation can be resumed at 
subsequent scheduled time point. 
6.3 
End of Treatment/Withdrawal Visit 
If relevant assessments and examinations have not been performed within 7 days before the last 
dose, the following procedures should be followed: 
• 
ECOG PS 
• 
Vital signs 
• 
Comprehensive physical examination: general condition, head and face, skin, lymph 
nodes, eyes, ears, nose and throat, oral cavity, respiratory system, cardiovascular system, 
abdomen, reproductive-urinary system, musculoskeletal system, nervous system, mental 
state, etc.; 
• 
Hematology 
• 
Urinalysis 
• 
Fecal occult blood 
• 
Clinical chemistry 
• 
Coagulation function 
• 
Thyroid function 


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• 
ECG 
• 
Imaging examination: Imaging examination should be performed in time (± 4 weeks; 
there is no need to repeat the imaging examination upon withdrawal if the time from the 
previous examination to the discontinuation is less than 4 weeks). Subjects who 
discontinue treatment for reasons other than radiographically confirmed PD must also 
undergo imaging examination at the frequency specified in the protocol until 
documented of confirmed PD, start of a new anti-tumor treatment, or death. 
• 
Collection of AEs 
• 
Documentation of concomitant medications/concomitant treatments 
6.4 
Follow-up period 
6.4.1 
Safety follow-up period 
Safety follow-up starts from the last dose of study treatment. The follow-up is performed once 
every 30 days (± 7 day s) until 90 days after the last dose. 
The first safety follow-up (30 days ± 7 days) is carried out at the study center where the evaluations 
specified in the protocol are completed. The second (60 days ± 7 days) and the third (90 days ± 
7 days) follow-up are made via telephone calls. The information on survival, concomitant 
medications/concomitant treatments and AEs are collected. 
◆ During the first safety follow-up (30 ± 7 days), the subjects should receive the following 
evaluations at the study center (if the subject has started a new anti-tumor treatment 
before the first safety follow-up, then the follow-up should be completed before starting 
the new anti-tumor treatment): 
 
ECOG PS 
 
Vital signs 
 
Physical examination: Specific physical examination is performed if clinically 
indicated. 
 
Hematology 
 
Urinalysis 
 
Fecal occult blood 
 
Clinical chemistry 
 
Thyroid function 


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 
Coagulation function 
 
ECG 
 
Collection of AEs 
 
Documentation of concomitant medications/concomitant treatments 
◆ For the second (60 days after the last dose) and the third safety follow-ups (90 days after 
the last dose), the subjects' survival information and AEs can be collected via 
telephone calls. 
◆ Imaging examination: Subjects without radiographically confirmed disease progression 
should receive imaging examination at the same frequency as that during the treatment 
period. 
6.4.2 
Survival follow-up 
The survival follow-up period starts after the end of the safety follow-up period. The survival 
follow-up period ends upon the subject's death, lost to follow-up, withdrawal of informed consent, 
or study termination by sponsor. During this period, an effective follow-up such as telephone 
follow-up is conducted once every month to collect information on subject survival and 
subsequent treatments (if the subject has started a new anti-cancer treatment, the therapeutic 
regimen and the start and end time should be recorded). 
For subjects who show no evidence of radiographic progression, imaging evaluation will be 
continued at the same frequency of efficacy evaluations specified in the protocol, until progressive 
disease, death, lost to follow-up, withdrawal of informed consent, start of other anti-cancer 
treatment, or study termination by the sponsor. Evidence of radiographic progression should be 
collected as much as possible for these subjects. 
6.5 
Unscheduled Visit 
The following shall be documented during unscheduled visits when subjects develop AEs during 
the study: 
• 
Concomitant medications/treatments; 
• 
Adverse events; 
• 
All relevant examinations (including imaging evaluations, if any). 


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7 STUDY EVALUATION 
7.1 
Efficacy Evaluation 
7.1.1 
Efficacy endpoints 
The primary efficacy endpoint of this study is objective response rate (ORR). 
Objective response rate (ORR): the proportion of treated subjects with a best overall response 
(BOR) of complete response (CR) or partial response (PR) as per RECIST 1.1 criteria. If the 
subject achieves CR or PR, conformation should be done at least 4 weeks (28 days) after the first 
evaluation. Best overall response refers to the best response assessed by the investigator, or the 
best response from the date of enrollment to the first documentation of progression as per RECIST 
1.1 or to the start of a new anti-tumor treatment (whichever comes first). For subjects without 
documented progression or new anti-cancer treatment, BOR will be determined based on all 
response evaluations. For subjects who continue SHR-1210 treatment beyond progression, the 
best overall response should be based on the efficacy assessment at the time of first documented 
progression as per RECIST 1.1. Efficacy evaluation should be performed once every 2 cycles 
(6 weeks ± 7 days) in the first 12 months (first 16 cycles) from the study treatment. Then it is 
performed once every 3 cycles (9 weeks ± 7 days) after 12 months until PD (or discontinuation of 
the study treatment for subjects continuing the SHR-1210 after PD), lost to follow-up, withdrawal 
of informed consent or death. 
Secondary efficacy endpoints include progression free survival (PFS), duration of response (DoR) 
and disease control rate (DCR). 
Progression-free survival (PFS): The time between the date of enrollment and the first documented 
tumor progression (as per RECIST 1.1 criteria, regardless of whether treatment is continued), or 
death due to any cause, whichever occurs first. When determining PFS, clinical exacerbations 
without definite evidence of progressive disease (as per RECIST 1.1) is not considered progressive 
disease. For subjects who die without any prior reports of progression, the date of death is 
considered the date of progression. Subjects without progressive disease or death will be censored 
on the date of their last evaluable tumor assessment. Subjects without tumor assessments during 
the study or death will be censored on their date of enrollment. Subjects who discontinue the 
treatment for reasons other than progressive disease (no subsequent tumor assessments) will be 
censored on their date of study discontinuation. For subjects who have not previously reported 
progressive disease but have initiated subsequent anti-tumor therapy, they will be censored on the 
date of their last evaluable tumor evaluation before starting the subsequent anti-tumor therapy, or 
they will be censored when starting the subsequent anti-tumor therapy. When subjects are not 
censored on the date of study discontinuation or the date of starting new anti-tumor treatment, the 


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scheduled sensitivity analysis will confirm PFS based only on the time of radiologically confirmed 
progression events. The occurrence of a new tumor will not be considered a progressive disease 
and is not censored. 
Disease control rate (DCR): the proportion of subjects with a best overall response of complete 
response (CR), partial response (PR), or stable disease (SD) as per RECIST 1.1 criteria. If the 
subject achieves CR or PR, conformation should be done at least 4 weeks (28 days) after the first 
evaluation. Best overall response refers to the best response assessed by the investigator, or the 
best response from the date of enrollment to the first documentation of progression as per RECIST 
1.1 or to the start of a new anti-tumor treatment (whichever comes first). For subjects without 
documented progression or new anti-cancer treatment, BOR will be determined based on all 
response evaluations. For subjects who continue SHR-1210 treatment beyond progression, the 
best overall response should be based on the efficacy assessment at the time of first documented 
progression as per RECIST 1.1. 
Duration of response (DoR) is defined as the period of time from the first documented tumor 
response (as per RECIST 1.1) to the first documented objective progression (as per RECIST 1.1) 
or death of any cause. Subjects without progressive disease or death will be censored on the date of 
their last tumor assessment. Subjects who start any subsequent anti-tumor therapy (excluding 
palliative radiotherapy of non-target bone lesions or central nervous system lesions during the 
study treatment) without previously reported progressive disease will be censored on the date of 
last tumor assessment prior to the start of new anti-tumor treatment, or on the date of starting the 
new anti-tumor treatment. 
7.1.2 
Criteria for efficacy evaluation 
Objective response rate (ORR) as well as PFS, DCR and DoR based on tumor response will be 
evaluated by imaging examinations according to RECIST 1.1 (see Appendix 3 Response 
Evaluation Criteria in Solid Tumors). 
For the record and assessment of survival, the subjects will be followed up by effective visits such 
as telephone calls on survival once every month after withdrawing from the study until death, lost 
to follow-up, withdrawal of informed consent, or study termination by the sponsor. 
Assessments of tumor response include all known or suspected lesions. 
Assessments of tumor response include all known or suspected lesions. Imaging includes CT or 
MRI scans of the chest, abdomen, or pelvis. Brain CT or MRI is performed for subjects with 
known or suspected brain metastasis, while bone scan and/or bone X-ray scan is performed for 
subjects with known or suspected bone metastasis. 


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Imaging assessment at screening must be performed within 28 days prior to the first study dose, 
and first tumor assessment during the treatment period should be performed 6 weeks (± 7 days) 
after starting study treatment. Imaging evaluation should be performed once every 2 cycles (6 weeks ± 
7 days) in the first 12 months (first 16 cycles) during the treatment. Then it is performed once 
every 3 cycles (9 weeks ± 7 days) after 12 months until PD, lost to follow-up, death, withdrawal of 
informed consent, start of other anti-tumor treatment or study termination by the sponsor. 
If the subject achieves CR or PR, conformation should be done at least 4 weeks (28 days) after the 
first evaluation. In case of SD, tumor assessment should be performed at least once after at least 
6 weeks (± 7 days) after  enrollment, and the measurements must meet the criteria for SD at least once. 
The same imaging technique should be used in subsequent tumor evaluations for the same type of 
lesions as at screening. Anti-tumor activity assessment shall be carried out during the screening 
period and treatment process through radiography according to the study procedure; tumor 
evaluation should also be performed when progressive disease is suspected (such as exacerbation 
of symptoms) and upon withdrawal (if evaluation is not performed within the past 4 weeks). 
All subjects should continue to undergo tumor assessments according to the study protocol, 
regardless of dose interruptions or dose delays. If discontinuation is indicated due to deterioration 
of overall health in absence of objective evidence of progressive disease, such event shall be 
reported as symptomatic deterioration. Objective progressive disease (i.e. confirmed 
radiographically) should be documented even after treatment discontinuation. 
Evaluation is done according to RECIST 1.1. 
Documentation and imaging data of all subjects must be accessible for source validation and peer 
review. 
7.2 
Safety Evaluation 
7.2.1 
Safety endpoints 
Safety parameters for this study include clinical symptoms, vital signs, physical examination, 
laboratory tests (hematology, urinalysis, blood biochemistry, thyroid function, and coagulation 
function). AEs are evaluated according to NCI CTCAE Version 4.03, including type, incidence, 
severity, start and end date, whether it is an SAE, causality with the study drugs, and outcome. 
7.2.2 
Definition of adverse event 
An adverse event (AE) refers to any untoward medical occurrence in a study subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. 
In this study, AEs should be documented from signing informed consent until the end of the safety 
follow-up period (90 days after the last dose of the study drugs) or the start of new anti-tumor 
treatment. AEs include any adverse symptoms or signs, abnormal laboratory tests or diseases. AEs 
include the following: 


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1) Worsening of pre-existing (prior to enrollment) medical conditions/diseases (including 
symptoms, signs, and laboratory test abnormalities); 
2) Any new adverse medical conditions (including symptoms, signs, and newly diagnosed 
diseases); 
3) Clinically significant abnormal laboratory findings. 
The investigator should record any AEs that have occurred in detail, including the description of 
the AEs and all relevant symptoms, time of occurrence, severity, relationship to the investigational 
drugs, duration, measures taken, and final results and outcomes. 
7.2.3 
Definition of serious adverse event 
A serious adverse event (SAE) refers to a medical occurrence during the clinical study that results 
in hospitalization, prolonged hospitalization, disability, incapacity, life-threatening or death, or 
congenital malformation. The following medical events are included: 
• 
Events resulting in death; 
• 
Life-threatening events (defined as when the subject is at immediate risk of death at the 
time of the event); 
• 
Events resulting in hospitalization or prolonged hospitalization; 
• 
Events resulting in 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). 
During the study, AEs resulting in hospitalization or prolonged hospitalization should be 
considered SAEs. Hospitalization does not include the following: 
✓ Hospitalization at a rehabilitation institution 
✓ Hospitalization at a sanatorium 
✓ General emergency admission 
✓ Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
✓ Social reasons (medical insurance reimbursement, etc.) 


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Hospitalization or prolonged hospitalization not related to the worsening of AEs is not considered 
an SAE. For example: 
✓ Hospitalization due to the pre-existing disease without new AEs and aggravation of the 
pre-existing disease (e.g., hospitalization to examine laboratory abnormalities that have 
persisted from before the study until now); 
✓ Hospitalization for management reasons (e.g., annual physical examination); 
✓ Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
✓ Elective hospitalization unrelated to worsening of AEs (e.g., elective surgery); 
✓ Scheduled treatment or surgery that should be documented throughout the entire study 
protocol and/or in the subjects' individual baseline information; 
✓ Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) and non-invasive procedures should not be 
reported as AEs. However, when a condition resulting in such procedures meets the definition of 
an AE, it should be reported as so. For example, acute appendicitis during the AE reporting period 
should be reported as an AE, and the resulting appendicectomy shall be recorded as the treatment 
of the AE. 
7.2.4 
Progressive disease 
Progressive disease is defined as the worsening of the subject's conditions caused by the 
indications of the study, including radiological progressions and progressions in clinical symptoms 
and signs. New metastases relative to the primary tumor or progressions of the previous metastases 
are recognized as PD. Life-threatening events, hospitalization or prolonged hospitalization, or 
events resulting in permanent or severe disability/incapacity/impairment of work ability, congenital 
anomalies or birth defects arising from the symptoms and signs of the progressive disease are not 
reported as SAEs. Death caused by the symptoms and signs of PD will be reported as an SAE. 
7.2.5 
Immune-mediated adverse events 
Immune-mediated AE (IMAE) refers to specific events (including pneumonia, diarrhea/colitis, 
hepatitis, nephritis/renal dysfunction, rash, and endocrinopathy) related to immunosuppressive 
treatment. Endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes, 
and adrenal insufficiency) are often excluded, as they are usually unrelated to treatment and are 
usually managed in the absence of interventions with immunosuppressants. Preferred terms 
included in the IMAE analysis to support warnings and precautions are shown in Table 11. 


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IMAE Type 
PT included in IMAE (MedDRA) 
Pneumonia 
Pneumonia, interstitial pneumonia 
Diarrhea/Colitis 
Diarrhea, colitis, enterocolitis 
Hepatitis 
Hepatotoxicity, hepatitis, hepatitis acute, autoimmune hepatitis, AST increased, ALT 
increased, bilirubin increased, ALP increased 
Adrenal Insufficiency 
Adrenal Insufficiency 
Hypothyroidism/thyroiditis 
Acute thyroiditis (collapse due to frequent thyroiditis), autoimmune thyroiditis 
(collapse due to frequent thyroiditis) 
Hyperthyroidism 
Hyperthyroidism 
Hypophysitis 
Hypophysitis 
Diabetes Mellitus 
Diabetes mellitus, diabetic ketoacidosis 
Nephritis and kidney 
dysfunction 
Nephritis, hepatitis acute, tubulointerstitial nephritis, renal failure acute, renal failure, 
creatinine increased 
Rash 
Rash, maculo-papular rash 
Table 11. Preferred terms included in the IMAE analysis to support warnings and 
precautions 
7.2.6 
Potential drug-induced liver injury 
Drug-induced liver injury will be considered if AST and/or ALT levels are abnormal accompanied 
with abnormal elevation of total bilirubin, the following criteria are met, and when there are no 
other causes of liver injury. These cases should always be considered as important medical events 
and reported as SAEs. 
Potential drug-induced liver injury is defined as follows (Table 12): 
Baseline 
Period 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment 
period 
 
ALT or AST ≥ 3 × ULN 
 
with TBIL ≥ 2 × ULN 
 
and ALP ≤ 2 × ULN 
 
and no hemolysis 
 
AST or ALT ≥ 2 × baseline level, and ≥ 3 × 
ULN; or AST or ALT ≥ 8 × ULN 
 
with TBIL increase ≥ 1 × ULN or ≥ 3 × ULN 
Table 12. Definition of potential drug-induced liver injury 
After being notified of the abnormal results, the subjects should return to the study center for an 
assessment as soon as possible (preferably within 48 h). Assessments include the laboratory tests, 
detailed medical history, and physical assessment, and the possibility of hepatic tumor (primary or 
secondary) should be considered. 
Except for the reexaminations of AST and ALT, albumin, creatine kinase, TBIL, direct and 
indirect bilirubin, γ-GT, prothrombin time (PT)/international normalized ratio (INR), and ALP 
should also be examined. Detailed medical history should include history of alcohol use, 


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acetaminophen, soft drugs, various supplements, family diseases, occupational exposure, sexual 
behavior, travel, contact with jaundice patients, surgery, blood transfusion, hepatic diseases, and 
allergies. Further tests may include the testing for acute hepatitis A, B, C and E, and hepatic 
imaging (such as biliary tract). If the above laboratory criteria are confirmed upon re-examination, 
the possibility of potential drug-induced liver injury should be considered in the absence of any 
other causes of abnormal liver function, without waiting for all liver function test results. Potential 
drug-induced liver injury should be reported as an SAE. 
7.2.7 
Adverse Events of Special Interest 
Special interest events include the following: 
 
Grade ≥ 3 infusion reactions; 
 
Grade ≥ 2 diarrhea/colitis, uveitis, and interstitial pneumonia; 
 
Grade ≥ 3 other immune-related AEs; 
 
Grade 4 amylase or lipase increased. 
7.3 
Classification of AEs and SAEs 
7.3.1 
Criteria for the severity of AEs 
The severity of AEs is determined using NCI-CTCAE v4.03. Refer to the following criteria for 
AEs not listed in NCI-CTCAE v4.03 (Table 13): 
Grade Clinical Description of Severity 
1 
Mild; asymptomatic or mild clinical symptoms; clinical or laboratory test abnormality only; 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 
Resulting in death 
Table 13. Criteria for the severity of AEs 
7.3.2 
Criteria for causality between adverse events and study drugs 
AEs include all unexpected clinical manifestations. All the AEs occurring after the signing of the 
ICF must be reported as an AE, regardless of whether the AEs are related to the study drugs, 
whether the subject is allocated to the investigational drug group, and whether the subject has been 
administered with the drug. Any discomforts complained by the subject or changes in objective 
laboratory measurements during the treatment period should be truthfully recorded. The severity, 


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duration, measures taken, and the outcome of AEs should also be documented. The study 
physician shall assess the relationship between the AE and the study drugs by considering the time 
sequence between the administration of study drug and the occurrence of AE, characteristics and 
toxicology of the study drug, concomitant medications, underlying diseases, medical history, 
family history, as well as dechallenge and rechallenge. The causality assessment will be provided 
using the following five categories "definitely related, possibly related, unlikely related, definitely 
unrelated, and indeterminable". Events that are assessed to be "definitely related", "possibly 
related", "unlikely related", and "indeterminable" will be listed as adverse drug reactions. When 
calculating the incidence of adverse events, the total of these four categories will be used as the 
numerator and the total number of subjects for safety evaluation will be used as the denominator. 
7.4 
Follow-up and Reporting of Adverse Events 
7.4.1 
Follow-up of AEs/SAEs 
All AEs/SAEs should be followed up until they are resolved, return to baseline levels or Grade ≤ 1, 
reach a stable state, or are reasonably explained (e.g., lost to follow-up, death). 
During each visit, the investigator should ask about the situation of AEs/SAEs that occur after the 
last visit and provide follow-up information in a timely manner based on the sponsor's query 
request. Principles of collection and follow-up of AEs/SAEs after the last dose at the end of 
treatment are shown in the table below. 
Table 14. Requirements for collection and follow-up of AEs/SAEs 
Classification 
Collection/Documentation 
Requirements 
Follow-Up Requirements 
Unrelated AEs 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related AEs 
Until the end of safety follow-up 
period 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 
Unrelated SAEs 
(including SIEs) 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related SAEs 
(including SIEs) 
No time limit 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 
7.4.2 
Reporting of adverse events 
AEs are recorded from the date of signing informed consent to the end of the safety follow-up 
(at 90 days after the last dose) or the start of a new anti-cancer therapy. 


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During each visit, the investigator should inquire about AEs that occur since the last visit. AEs 
should be followed-up until the end of the event, a stable state, returning to baseline levels or 
Grade ≤ 1, obtaining a reasonable explanation, lost to follow-up, or death. Follow-up information 
should be readily available when requested by the sponsor. 
7.4.3 
Reporting of serious adverse events 
Serious adverse events (SAEs) that occur from the signing of the informed consent form until 90 
calendar days (inclusive) after the last dose will be collected. In the event of an SAE, whether it is 
an initial report or a follow-up report, the investigator must complete the "NMPA Serious Adverse 
Event Report Form" immediately, with a signature and date. It must have been reported to the 
relevant regulatory authorities, the sponsor, and the ethics committee within 24 hours of knowing 
of the event. 
The sponsor's email address for safety data is: hengrui_drug_safety@hrglobe.cn. 
SAEs that occurred 90 days after the last study dose were generally not reported unless they were 
suspected to be related to the study drugs. The symptoms, severity, causality with the study drug, 
time of onset, time of treatment, measures taken, time and method of follow-up, and outcome 
should be documented in detail 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 discontinuation 
of past treatment, or comorbidities during the study), the causality should be explained in the 
description section of the SAE report form. If the severity of an ongoing 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. 
7.4.4 
Reporting of Special Interest Events 
For SIEs specified in the study protocol, the investigator must complete the "Report of Special 
Interest Event for Hengrui Clinical Studies" and report to the sponsor within 24 hours of knowing 
of the event. 
If the SIE is also an SAE, the "NMPA Serious Adverse Event Report Form" should also be 
completed and reported to the relevant authorities according to the SAE reporting procedure. 
SIEs are shown in section 7.2.7. 


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7.4.5 
Pregnancy reporting 
Female subjects who become pregnant during the study must withdraw from the study. If a female 
partner of a male subject becomes pregnant, the male subject will continue participation in the 
clinical study. The investigators must fill out the "Pregnancy Report/Follow-up Form for 
Hengrui's Clinical Studies" and report to the sponsor within 24 h after becoming aware of the 
pregnancy, and report to the ethics committee promptly. 
The investigator should follow up the pregnancy outcome until 1 month after delivery, and report 
the outcome to the sponsor and the ethics committee. 
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 the subject also experiences an SAE during the pregnancy, the "NMPA Serious Adverse Event 
Report Form" should also be filled out and reported according to the SAE reporting procedure. 
8 DATA ANALYSIS/STATISTICAL METHODS 
Data analysis will be completed by Hengrui and/or a designated CRO. Data analysis will be carried 
out without distinction of study centers. (Data from all participating study centers will be combined). 
Subjects who have failed the screening (those who have signed the informed consent form but 
have not receive any treatment) will not be included in any analysis. These subjects will be 
presented in a separate list. 
Reasons for withdrawal will be summarized and listed. The listing should include: date of first and 
last dose, duration of study drug exposure, and date of withdrawal. 
8.1 
Statistical Analysis Plan 
The primary objective of this study is to evaluate the efficacy of the sequential therapy of 
SHR-1210 combined with capecitabine and oxaliplatin (cohort 1) or SHR-1210 combined with 
apatinib mesylate (cohort 2) as a first-line treatment for advanced or metastatic Gastric (GC) or 
gastroesophageal junction (GEJ) cancer. The primary efficacy endpoint is ORR. 
Detailed summaries and methods of statistical analyses for the data collected from the study shall 
be included in the statistical analysis plan (SAP), which shall 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 major impact on the SAP, as determined by the sponsor or principal investigator. Relevant 
content in statistical analysis plan that is relevant to this protocol may be revised. However, if 
revised content involves the main and/or key factors of the protocol (such as the definition of 
endpoints or their analysis), such content in the protocol will be revised. 


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8.2 
Sample Size 
The sample size will be calculated using Simon's two-stage design, with a power of 80% and a 
one-sided α of 0.05. The optimal method is used, that is, minimizing the subjects' exposure to 
ineffective treatment. Assuming that in the cohort 2 (SHR-1210 + apatinib), uninteresting level 
ORR (P0) = 15% and desirable target level ORR (P1) = 30%. The first stage requires 19 subjects, 
and the treatment should be effective in > 3 subject (i.e. a minimum of 4) before proceeding to the 
second stage. The first and second stage require a total of 55 subjects, and the treatment should be 
effective in > 12 subjects (i.e., a minimum of 13) to be considered effective. 
Assuming that in the cohort 1 (sequential therapy of SHR-1210 + capecitabine + oxaliplatin), the 
uninteresting level ORR (P0) = 35% and desirable target level ORR (P1) = 55%. Under the 
condition that the power of test is 80% and α is 0.05 (one-sided), the first stage requires 19 subjects 
in both cohort 1 and cohort 2 for the purpose of consistency. The treatment should be effective in > 
3 subjects (i.e. a minimum of 4) before proceeding to the second stage. The first and second stage 
require a total of 43 subjects, and the treatment should be effective in > 20 subjects (i.e., a 
minimum of 21) to be considered effective. 
The number of subjects and the required minimum number of subjects responding to the treatment 
at each stage for both cohorts are shown in Table 15: 
Cohort 
P0 
01 
N1 
R1 
N 
R 
Cohort 1 (sequential therapy of SHR-1210 + capecitabine + oxaliplatin) 35% 
55% 
19 
3 
43 
20 
Cohort 2 (SHR-1210 + apatinib) 
15% 
30% 
19 
3 
55 
12 
Table 15. Sample size calculation 
N1: Number of subjects at the first stage 
R1: Number of subjects responding to the treatment at the first stage shall be greater than this number 
N: Final number of subjects 
R: Final number of subjects responding to the treatment shall be greater than this number 
At the first stage, 19 subjects are enrolled into each cohort. If ≥ 4 subjects in cohort 1 achieve 
response (CR or PR), the second stage will be initiated, and 24 more subjects are enrolled (more 
subjects are enrolled into cohort 1 until there are 43 subjects); if ≥ 4 subjects in cohort 2 achieve 
response, the second stage will be initiated, and 36 more subjects are enrolled (more subjects are 
enrolled into cohort 2 until there are 55 subjects). 
Considering the 10% non-evaluable subjects, 48 and 62 subjects should be enrolled into cohort 1 
and 2, respectively. 


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8.3 
Analysis Population 
This study will involve the following analysis sets: 
▪ 
Full analysis set (FAS): All enrolled subjects who are randomized and received at least 
one dose of the study drugs. This analysis set will be used for the efficacy analysis. 
▪ 
Per-protocol set (PPS): A subset of the FAS. Subjects with important protocol deviations 
judged to have a significant impact on treatment efficacy are excluded from this analysis 
set. The list of subjects included into or excluded from the PPS should be reviewed and 
determined by the sponsor and the investigator before the database is locked. 
▪ 
Safety set (SS): All enrolled subjects who have received at least one dose of the study 
drugs and have post-administration safety data. 
▪ 
Evaluable set (ES): A subset of the FAS, defined as the all enroll subjects receive at least 
one dose of the study drugs and receive post-baseline tumor assessment at least once. 
▪ 
PK analysis set (PKS): Defined as all enrolled subjects who receive the study drugs and 
have evaluable post-dose PK data (concentration and/or parameters). 
▪ 
Immunogenicity analysis set (ADA): All enrolled subjects who receive at least one dose 
of the study drugs and have baseline as well as at least one post-baseline evaluable ADA 
data. 
8.4 
Statistical Methods 
8.4.1 
General analysis 
In this study, unless otherwise stated, all data will be summarized using descriptive statistics in 
accordance with the following general principles. 
Continuous variables will be summarized using mean, standard deviation, median, maximum, and 
minimum; the categorical variables will be summarized using frequency and percentage; for time 
to event data, the survival rate will be estimated using the Kaplan-Meier method and the survival 
curves will be plotted; blood concentration data will be summarized using geometric mean, 
geometric standard deviation, geometric coefficient of variation, mean, standard deviation, 
coefficient of variation, median, maximum, and minimum. 
8.4.2 
Efficacy analysis 
Efficacy analysis will be based on FAS and PPS. ORR is summarized using descriptive statistics 
by stage and dose group. PFS, DoR, and DCR are only summarized by treatment group. 


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ORR analysis provides the number and proportion of subjects with response (CR + PR) and 
estimates the two-sided 95% exact CI of overall ORR. In cohort 1 and cohort 2, 19 subjects will be 
analyzed in the first stage after completing the efficacy evaluation, respectively. Then, based on 
the judgment criteria in Table 15 and the safety data, it is determined whether to discontinue or 
continue the treatment in this cohort. 
Both PFS and DoR are time-event data. Kaplan-Meier method will be used to draw survival curve 
and estimate median survival time. The 95% CI (two-sided) of overall median survival is also 
estimated if necessary. DCR will provide the number and proportion of subjects determined to 
achieve CR + PR + SD. The 95% CI (two-sided) of DCR is estimated if necessary. 
8.4.3 
Safety analysis 
The safety analysis is based on the safety set (by actual treatment received). According to 
Hengrui's Standard Reporting Procedures, safety will be only summarized using descriptive 
statistics, including but not limited to the following. The specific analysis is described in the 
statistical analysis plan: 
 
Subject disposition and populations; 
 
Subjects' basic characteristics (including demographics, life history, medical history, and 
medication history); 
 
Discontinuations; 
 
Summary of adverse events (of all causes and treatment-related); 
 
Incidence and severity of adverse events (of all causes and treatment-related); 
 
Summary of serious adverse events; 
 
Causality analysis of adverse events; 
 
Occurrence of abnormal laboratory measurements, vital signs, and ECG data. 
8.4.4 
PK analysis 
PK analysis is performed based on PKS. PK concentrations and PK parameters (maximum and 
minimum concentration) are summarized by descriptive statistics. Apart from the statistics listed 
in the general analysis, PK concentration and PK parameter data (maximum and minimum 
concentration) will be also summarized descriptively using geometric mean (GM), coefficient of 
variation (CV%), and geometric CV% (GCV%). 
The correlation between drug exposure and toxicity is analyzed based on the maximum and 
minimum concentration of SHR-1210 and apatinib. 


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8.4.5 
Immunogenicity analysis 
The immunogenicity will be analyzed based on the ADA analysis set. The concentration of 
anti-SHR-1210 antibodies (ADAs) will be analyzed using descriptive statistics. 
Treatment-emergent adverse events may be analyzed separately in the ADA-negative and 
ADA-positive groups. 
9 SOURCE DOCUMENTS AND OBTAINING SOURCE 
DATA/DOCUMENTS 
According to ICH E6, relevant regulations, and requirements for subject's personal information 
protection of the study centers, each study center must properly keep all the treatment and 
scientific records related to this study. As a part of the study that Jiangsu Hengrui Pharmaceuticals 
Co., Ltd. sponsors or participates in, each study center must allow sponsor or its authorized 
representatives as well as regulatory authorities to inspect (and copy, if permitted by law) clinical 
records for quality review, audit, and evaluations of safety, study progress, and data validity. 
Source data are information required to reconstruct and evaluate the clinical study, and are the 
original documentation of clinical findings, observations, and other activities. These source 
documents and data records include but are not limited to: hospital record, laboratory records, 
memos, subject diary cards, pharmacy dispensing records, recordings of advisory meetings, 
recorded data from automated devices, copies or transcripts that are verified to be accurate and 
intact, microfiche, photographic negatives, microfilms or magnetic disks, X-ray films, and 
subject's documents and records that are kept in the pharmacies, laboratories, and medical 
technology departments that are involved in this study. 
The investigator is responsible for ensuring that the source data is accurate, clear, 
contemporaneous, original and attributable, regardless of whether the data is handwritten or 
entered electronically. In routine clinical study activities, if the source data is created (first 
entered), modified, maintained, archived, retrieved, or transmitted through a computer system 
(and/or any other type of electronic device), such systems must comply with all applicable laws 
and regulations governing the use of electronic records and/or electronic signatures. Such systems 
may include, but are not limited to, electronic medical record/health record, adverse event 
follow-ups/reporting, evaluation required by the protocol and/or drug inventory records. 
When written records obtained through such a system are used in place of the electronic version 
for specified activities, these written records must be certified copies. A certified copy consists of a 
copy of the verified original information, dated and signed, and is an exact copy with all attributes 
and information that are identical to the original document. 


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10 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure study quality, the sponsor and the investigator will jointly discuss and formulate a 
clinical study plan before the formal study initiation. All study personnel participating in the study 
will receive GCP training. 
All the study centers must comply with the SOPs for the management of the study drug, including 
receipt, storage, dispensing, return, and destruction (if applicable). 
According to the GCP guidelines, necessary measures must be taken at the design and 
implementation phases of the study to ensure that all collected data are accurate, consistent, intact, 
and reliable. All observed results and abnormal findings in the clinical study must be verified and 
recorded in a timely manner to ensure data reliability. All devices, equipment, reagents, and 
standards used in various tests in the study must have stringent specifications and be operated 
under normal conditions. 
The investigator will input data required by the protocol into the eCRF. The CRA will check 
whether the eCRF is completely and accurately filled and guide the study center personnel for 
necessary revision and addition. 
The drug regulatory authorities, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), sponsor's monitor and/or auditor may carry out systemic inspection of study-related 
activities or documents to assess whether the study is implemented based on the study protocol, 
SOPs, and relevant regulations (such as Good Laboratory Practices [GLP] and Good 
Manufacturing Practices [GMP]) and whether the study data is recorded in a prompt, truthful, 
accurate, and complete manner. The audit should be performed by personnel not directly involved 
in this clinical study. 
11 REGULATIONS, ETHICS, INFORMED CONSENT, AND SUBJECT 
PROTECTION 
11.1 Regulatory Considerations 
According to the corresponding regulatory requirements in China, an application should be 
submitted to the CFDA (now NMPA) before starting a new drug study and the clinical study can 
only be carried out after approval is obtained. The clinical approval number for SHR-1210 is 
2016L01455. 
The legal basis for the design of this protocol is as follows: 
1) Provisions for Drug Registration 
2) Good Clinical Practice 


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3) Consensus on ethical principles based on international ethics guidelines, including the 
Declaration of Helsinki and the Council for International Organizations of Medical 
Sciences (CIOMS) International Ethics Guidelines 
4) ICH Guidelines 
5) Other applicable laws and regulations 
11.2 Ethical Standards 
This study protocol must first be reviewed and approved in writing by the IEC/IRB 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 study must comply with the "Declaration of Helsinki", NMPA's (former CFDA) "Good 
Clinical Practice" (GCP), and other relevant regulations. Before the study is initiated, approval 
must be obtained from the IEC/IRB 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 IEC/IRB only when in purpose of eliminating direct and immediate harm to the 
subject. Besides, the deviation or change and the corresponding reason, and the recommended 
protocol modification should be submitted to the IEC/IRB for review. The investigator must 
provide explanations and document any protocol deviation. 
During the study, any changes to this study protocol must be submitted to the IEC/IRB. 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 IEC/IRB. The 
investigator is responsible for submitting the interim reports regularly according to the pertinent 
requirements of the IEC/IRB. After the end of the study, the completion should be informed to the 
IEC/IRB. 
11.3 IRB/IEC 
Prior to the initiation of the study, the study protocol, informed consent form, subject recruitment 
materials and other materials provided to the subjects must first be approved by the IRB/IEC. Subjects 
may be enrolled only after the protocol and ICF have been approved. The revision of the study 
protocol should be approved by IRB/IEC. The investigator and the sponsor must provide a copy of the 
Investigator's Brochure or product information for subjects and any relevant updates to the IRB/IEC. 
The investigator and the sponsor must submit reports, updates, or other data (e.g., expedited safety 
reports, modifications, and management letters) according to the requirements of the competent 
authority or institution's procedures to the IRB/IEC. 


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11.4 Informed Consent 
11.4.1 ICFs and other written information for subjects 
The ICF includes all the elements required by the ICH, GCP, and regulatory authorities, and is 
consistent with the ethical principles mentioned in the Declaration of Helsinki. 
The ICF describes the study drugs and study process in detail and fully explains the risks of the 
study to the subjects. Written documentation of informed consent must be obtained before starting 
any study-related procedures. 
All revisions to the ICF must be approved by the ethics committee, who will decide whether the 
subjects who have signed the previous version of the ICF are required to sign the new one. 
The ICF should state that the identity of the subjects must be remained confidential, but the 
authorized representative of the sponsor and regulatory authorities are allowed to access the 
information. 
11.4.2 Informed consent process and records 
Informed consent will begin before an individual decides to participate in the clinical study and 
continues during the entire clinical study. The risks and potential benefits of participating in the 
study should be discussed fully and in detail with the subjects or their legal representatives. 
Subjects will be asked to read and review the ICF that has been approved by the IEC/IRB. The 
investigator will explain the clinical study to the subjects and answer any questions posed by the 
subjects. Subjects can only participate in the study after they have signed the ICFs. During the 
clinical study, subjects can withdraw the informed consents at any time. One copy of the signed 
ICF will be kept by the subjects. Even if a patient refuses to participate in this study, his or her 
rights will be fully protected, and the nursing quality will not be affected. 
11.5 Confidentiality of Subject Information 
The confidentiality of subject information will be strictly enforced by the investigator, participated 
study personnel, and sponsor and its representative. In addition to the clinical information, 
confidentiality also simultaneously covers biological samples and genetic tests of the subjects. 
Therefore, the study protocol, documents, data, and other information generated from these 
materials will be kept strictly confidential. All relevant study or data information should not to be 
disclosed to any unauthorized third-party without prior written approval from the sponsor. 
Other authorized representatives of the sponsor, IRB or regulatory authorities, and the representatives 
of the pharmaceutical company that provides the study drugs can examine all the documents and 
records that are maintained by the investigator, including but are not limited to the medical records and 
subject's administration records. The study center should allow access to these records. 


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The contact information of the subjects will be safely kept in each study center and only used 
internally during the study. When the study is ended, all the records will be kept in a secure place 
based on the time limit specified by local IRB and regulations. 
Subject's study data that are collected for statistical analysis and scientific reports should not 
include the subject's contact information and identification information. Instead, individual 
subjects and their study data will be given a unique study identification number. The study data 
entry and study management system used by the study personnel at the study centers shall be 
confidential and password-protected. At the end of the study, all identification information in the 
study database will be erased and archived. 
12 DATA MANAGEMENT 
12.1 Data Recording 
Data will be collected and managed using the electronic case report form (eCRF). 
The investigator must retain all study records and source documents preferably as long as possible, 
up to the maximum time required by applicable regulations and guidelines, or SOP of the study 
center, or as specified by sponsor, whichever is longest. The investigator must first contact the 
sponsor prior to the destruction of any study-related records. 
If the investigator withdraws from the study (e.g., change of positions, retirement), the records 
should be transferred to a designated personnel approved by both parties (e.g., another 
investigator). The sponsor must be notified in writing for such transfers. 
12.1.1 Study medical records 
As source documents, the medical records should be completely retained. The investigator should 
be responsible for filling and keeping the study medical record. The subject information on the 
cover of the medical record should be checked each time before filling the record. The medical 
record should be written in a neat and legible way so that the sponsor's CRA could verify the data 
with eCRF during each monitoring visit. 
12.1.2 eCRF entry 
Clinical study data are collected using the HRTAU EDC system. 
Each staff that is authorized to sign the eCRF must meet the sponsor's training requirements and 
must only log in the electronic data capture system with the individual user account provided by 
the sponsor. The user account shall not be shared with others and shall not be assigned to another 
staff. 


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Entry: The data in the eCRF are from and should be consistent with the source documents, such as 
the original medical records and laboratory test reports. Any observations or test results in the trial 
should be entered in the eCRF in a timely, accurate, complete, clear, normative and verifiable 
manner. Data should not be changed arbitrarily. All items in the CRF should be filled out, with no 
blank or omissions. 
Modifications: The system instructions must be followed when correcting the eCRF data as 
needed, and the reason for data correction must be recorded. The logic verification program in the 
system will verify the integrity and logic of the clinical study data entered into the EDC system and 
generate an error message prompt for questionable data. The investigator or CRC is permitted to 
modify or explain the problematic data. If necessary, multiple inquiries can be raised until the 
event of problematic data is resolved. 
Laboratory tests: The investigator should conduct all tests as well as collect, input and report 
subject information and data according to the follow-up time window. As a source document, the 
laboratory test report must be complete and the results should be documented in the eCRF in a 
timely manner. 
In addition, source data also include original copies of data recorded or generated by automated 
instruments, photographic negative, X-ray, CT or MRI, ECG records, and subject daily logs. 
These documents must at least indicate the subject number and date of the procedure performed. If 
possible, the medical review of these records should be documented, and signed and dated by the 
investigator. The information from these source documents must be entered into the eCRF in a 
timely manner. 
12.1.3 eCRF review 
The investigator or designated personnel should fill out, review, and submit the eCRF in a timely 
manner. The investigator or the data input staff (CRC) should promptly respond to queries raised 
by the monitor, data manager, and medical reviewer. After data cleaning is completed, the 
investigator will sign the completed eCRF for verification. 
12.1.4 Data monitoring and auditing 
The authorized representatives (such as CRA, auditors, etc.) of sponsor must be allowed to 
regularly visit all the study centers to evaluate the quality of data and whether the study is complete 
and reliable. These representatives will perform an on-site review of the study records by directly 
comparing these records with the source documents, discuss the implementation of the study with 
the investigator, and confirm whether the study facilities still meet the requirements. 


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Monitoring content: To confirm that the study protocol is adhered to; the records on CRF is correct 
and complete, and consistent with the original medical records and laboratory test results, and 
whether there are errors or omissions in the data. According to the monitoring plan, the CRA will 
verify the completeness, consistency, and accuracy of study data in the database. The CRA will 
discuss any queries with study personnel and direct them to add or correct the data whenever 
necessary. Ensure that the data in the eCRF are consistent with source data. This process is also 
known as source data verification (SDV). 
In addition, inspectors from regulatory departments may also evaluate the study. These personnel 
must also be allowed to review the eCRF, source documents, and other study documents, and to 
inspect the study facilities. Audit reports must be kept confidential. If the regulatory department 
plans to conduct an inspection, the investigator must immediately notify the sponsor and promptly 
provide the inspection report. 
12.2 Data Management 
12.2.1 EDC database establishment 
The data manager will establish a study data collection system and database according to the study 
protocol, which will be available for online usage before the first subject is enrolled. Before use, all 
EDC users should receive adequate training and get the corresponding account to log into the 
system. (Access to EDC system will only be granted to the study center staff who have completed 
the training.) 
12.2.2 Data entry and verification 
The investigator or CRC should input data into the EDC system in accordance with the 
requirements of the visit procedures and the eCRF completion guide. After submitting the eCRF, 
the CRA, data manager, and medical personnel should review the data. Questions during the 
review will be submitted to the investigator or CRC in the form of queries. After data cleaning is 
completed, the investigator should sign the completed eCRF for verification. 
12.2.3 Database lock 
After the clinical study is completed, the study director, sponsor, statistician, and data manager 
will conduct a joint review before statistical analysis mainly to determine the analysis data set for 
each case, the judgment of missing values, and the handling of outliers. 
After the established database is considered correct by review, the database will locked. After the 
database is locked, the data must be properly stored for future reviews, and the database should be 
statistically analyzed by the statistician. 


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After SDV is completed by the CRA, the data manager and medical reviewer will conduct a final 
quality control of all data in the database, summarize all protocol deviations and violations during 
the study, and hold the data review meeting. The database will be locked after quality requirements 
are met. The data manager will export the data to the statistics department for data analysis. 
12.2.4 Data archiving 
After the study is completed, the eCRFs of the subjects must be generated from the EDC system in 
the PDF format and kept on non-rewritable CD-ROM/DVD, which will be archived by the sponsor 
and various institutions for auditing and/or inspection. 
All materials shall be preserved and managed in accordance with GCP requirements, and 
necessary documents of clinical studies shall be preserved until 2 years after the investigational 
drug is approved for marketing or 5 years after the termination of the clinical study. 
12.3 Protocol Deviations 
Protocol deviation refers to any practice that does not comply with study protocol, GCP or SOP. 
This non-compliance may occur in the subject and may also occur in the investigator or other study 
personnel. Study centers must prepare corresponding corrective measures and implement them 
immediately if a protocol deviation occurs. 
Study centers have the responsibility to maintain constant vigilance, complete the identification of 
protocol deviations in a timely manner, and complete the actions required by the protocol, to 
identify and report protocol deviations in a timely manner. All deviations must be documented in 
the source documents and reported to the sponsor. Protocol deviations must be submitted to local 
IRB in accordance with local ethical regulations. The principal investigator or study personnel of 
the study center is responsible for understanding and complying with local ethical standards. 
13 PUBLICATION OF STUDY RESULTS 
The study results belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd. Hengrui does not restrict 
the publication of any collected or research information by investigators, regardless of whether the 
results are beneficial to the investigational drug or not. However, the investigator 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, synopsis, 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 should agree 
to delay the publication, and the delay period should not exceed 60 days. Before open publication, 
Hengrui can require the investigator to delete any previously unpublished confidential information 


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(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 centers. However, if a manuscript of 
the integrated analysis is not submitted 12 months after the study is completed or terminated in all 
study centers, the investigator can independently publish results based on other requirements in 
this section. 
14 EXPECTED STUDY SCHEDULE 
Anticipated enrollment of the first subject: Dec. 2017 
Anticipated enrollment of the last subject: Dec. 2018 
Anticipated study completion: Dec. 2020 
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15) Liu L, Mayes PA, Eastman S et al. The BRAF and MEK Inhibitors Dabrafenib and 
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Programmed Death-1(MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, 
Pharmacodynamics, and Immunologic Correlates. J Clin Oncol 2010 Jul. 28:3167-3175. 
17) David F. McDermott, Michael B Atkins. PD-1 as a potential target in cancer therapy. Cancer 
Medicine 2013; 2(5): 662–673. 
18) Omid Hamid, Caroline Robert, Adil Daud, et al. Safety and Tumor Responses with 
Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med 2013.DOI: 
10.1056/NEJMoa1305133. 
19) Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination 
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20) Suzanne L. Topalian, F Stephen Hodi, Julie R, Brahmer, et al. Safety, Activity, and Immune 
Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med 2012;366: 2443-54. 
21) Gatti L, Cassinelli G, Zaffaroni N et al. New mechanisms for old drugs: Insights into 
DNA-unrelated effects of platinum compounds and drug resistance determinants. Drug 
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22) Jedd D. Wolchok, Axel Hoos, Steven O'Day.Guidelines for the Evaluation of Immune 
Therapy Activity in Solid Tumors: Immune-Related Response Criteria.Clin Cancer Res 
2009;15(23):7412–20 
23) Omid Hamid, Richard D Carvajal.Anti-programmed death-1 andanti-programmed 
death-ligand 1 antibodies in cancer therapy. Expert Opin. Biol. Ther. (2013)13(6):847-861 
24) Caroline Robert, Antoni Ribas, Jedd D Wolchok. Anti-programmed-death-receptor-1 
treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a phase 1 trial. 
http://dx.doi.org/10.1016/S0140-6736(14)60958-2 
25) Chuan-Yong Mu, Jian-An Huang, Ying Chen.High expression of PD-L1 in lung cancer may 
contribute to poorprognosis and tumor cells immune escape through suppressingtumor 
infiltrating dendritic cells maturation. Med Oncol (2011) 28:682–688 
26) Changping Wu, Yibei Zhu, Jingting Jiang.Immunohistochemical localization of 
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Acta histochemica108(2006) 19 - 24. 
 


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Appendix 1 ECOG PS 
Grade 
Performance Status 
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 self-care; totally confined to bed or chair. 
 
 


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Appendix 2 Cockroft-Gault Formula (for calculating the creatinine clearance) 
Serum creatinine: mg/dL 
Creatinine clearance rate in males ( ml
min) = (140 −Age) × Weight
72 × Serum creatinine 
Creatinine clearance rate in females ( ml
min) = 0.85 × (140 −Age) × Weight
72 × Serum creatinine
 
 
Serum creatinine: μmol/L 
Creatinine clearance rate in males ( ml
min) =
(140 −Age) × Weight
0.818 × Serum creatinine 
Creatinine clearance rate in females ( ml
min) = 0.85 × (140 −Age) × Weight
0.818 × Serum creatinine  
Age in years, weight in kilogram (kg). 
 
 


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Appendix 3 Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) 
(New Response Evaluation Criteria in Solid Tumors: Revised RECIST Version 1.1) 
1  BACKGROUND 
Omitted 
2  PURPOSE 
Omitted 
3  MEASURABILITY OF TUMOR AT BASELINE 
3.1  Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1  
Measurable 
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 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodule 
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 
cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses unable to be diagnosed 
or followed by imaging techniques, and cystic lesions. 


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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  Specifications by Methods of Measurements 
3.2.1  
Measurement of lesions 
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. 


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3.2.2  
Method of assessment 
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 and MRI: CT is currently the best available and reproducible method for response 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 
determine relapse in trials where recurrence following CR or surgical excision is an endpoint. 
Tumor biomarkers: Tumor biomarkers 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 biomarkers 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 studies in ovarian cancer. 


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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 PD. 
4  TUMOR RESPONSE EVALUATION 
4.1  Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden 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 subjects have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). 
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 ≥ 15mm 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, 


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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 with a short axis of 20 mm qualifies as a 
malignant and 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 nodules 
(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 
with baseline. 
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 PD). 
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  
Special notes on the assessment of target lesions 
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 


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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 can be assigned. (Note: It is less likely that this rule will be used for lymph nodules 
since they usually have a definable size when normal and are frequently surrounded by adipose 
tissues as in the retroperitoneum; however, if a lymph nodule is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm can 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. 
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 
biomarker level. All lymph nodules must be non-pathological in size (< 10 mm short axis). 


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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
biomarker 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 PD. 
4.3.4  
Special notes on assessment of progression of non-target disease 
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 qualify 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 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 PD; 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 


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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 is not scanned at baseline will be considered a new 
lesion and will indicate PD. 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 evaluations 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: 
▪ 
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 


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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 into consideration the characteristics of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomized studies where response is the primary 
endpoint, confirmation of PR or CR is needed to determine either one is the BOR. 
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: subjects with target (+/– non-target) disease 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 
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; NE, not evaluable. 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 
Table 2. Time point response: subjects with non-target disease only 
Non-Target Lesion 
New Lesion 
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 
response evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 


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4.4.2 
Missing assessments and unevaluable designation 
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 three 
measured lesions with a baseline sum of 50 mm and only two lesions with a sum of 80 mm were 
assessed at a subsequent follow-up, the patient has achieved PD status, regardless of the 
contribution of the missing lesion. 
4.4.3 
Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
BOR determination in studies where confirmation of complete or partial response is not required: 
BOR in these studies 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 BOR 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 BOR, the 
patient's BOR 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 BOR of PD. The same 
patient lost to follow-up after the first SD assessment would be considered not evaluable. 
BOR determination in studies 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 BOR 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 


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Overall Response at First 
Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
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; 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 be evaluated as PD at that point (since disease will reappear after CR). 
Best response will depend on whether minimum duration for SD is met. However, sometimes CR may be claimed 
when subsequent scans suggest small lesions are likely still present and in fact the subject has 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. 
4.4.4 
Special notes on response evaluation 
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 nodules. As noted earlier, this means that subjects with CR may not 
have a total sum of zero on the CRF. 
In trials where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response evaluation. 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 studies it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
Subjects with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD 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 subjects is to be determined by 
evaluation of target and non-target lesion as shown in Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study specific and 
shall 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 


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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. 
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 studies 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 can 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 study 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 is warranted. In randomized comparative studies 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 holidays or any other events that might lead to imbalance in a treatment 
group in the timing of disease assessment. 
4.6 Confirmatory Evaluation /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 


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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. 
4.6.2 
Duration of overall response 
The duration of overall response will be 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 will be 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 SD for a minimum period of time is an endpoint in a particular study, 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 periodicity 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 studies 
This guideline is focused primarily on the use of objective response endpoints for phase II clinical 
studies. 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 


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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 studies 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 4 Management Principles for Immune Related Adverse Events 
The principles specified in this section can be used as reference for the investigator when 
managing immune-related AEs. The principles can be added after discussion with the 
representatives of the sponsor. The principles are applicable to all immuno-oncology drugs and 
regimens. 
The general principle is that AEs should be carefully evaluated and the differential diagnosis be 
made in accordance with the standard medical practice. Non-inflammatory causes should be 
considered and properly handled. 
Corticosteroids are preferable drug for immuno-oncology treatment-related AEs. An oral dose 
equivalent to the recommended IV dose can be considered for ambulatory patients with low grade 
toxicity. The low bioavailability of oral administration should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Consultation with an internist or surgeon is recommended, especially before an invasive 
diagnostic or therapeutic procedure. 
The frequency and severity of related adverse events included in these protocols will depend on the 
cancer immunotherapy or regimen being used. 
 
 


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1. Management Principles for Gastrointestinal Adverse Events 
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/Colorectitis Grade 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1 
Diarrhea: Increase of < 4 stools per 
day over baseline; 
Colitis: No symptom. 
 
Continue the 
immunotherapy according 
to the study protocol; 
 
Symptomatic treatment. 
 
Closely monitor aggravated symptoms. 
 
Educate subjects to report aggravated 
symptoms immediately. 
If it is aggravated: 
 
Provide treatment according to the 
method for grade 2 or grade 3/4 situations. 
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. 
 
Delay the immunotherapy 
according to the study 
protocol; 
 
Symptomatic treatment. 
If it is improved to Grade 1: 
 
Resume the immunotherapy according to 
the study protocol. 
If it lasts for > 5-7 days or relapses: 
 
Intravenous administration of 
0.5-1.0 mg/kg/d methylprednisolone or an 
equivalent orally administrated 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 the 
immunotherapy as per study protocol. 
If the symptoms aggravated or persisted after  
> 3-5 days of oral administration of steroids: 
 
Provide treatment according to the 
method for grade 3/4 situations. 
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 interventions, peritoneal 
signs; 
Grade 4: Life-threatening, 
perforation 
 
Terminate the 
immunotherapy according 
to the study protocol; 
 
Intravenous administration 
of 1.0-2.0 mg/kg/d 
methylprednisolone or an 
equivalent dose via 
intravenous injection; 
 
Add prophylactic 
antibiotics to prevent 
opportunistic infections; 
 
Consider lower GI 
endoscopy. 
If symptoms improve: 
 
Continue steroid treatment until the 
symptoms recover to grade 1, then 
gradually reduce the dose of steroids for at 
least 1 month. 
If it lasts for > 3-5 days or relapses after 
improvement: 
 
Add 5 mg/kg infliximab (if there are no 
contraindications). Note: Do not use 
infliximab in the case of 
perforation/sepsis. 
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. 
 


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2. Management Principles for Pulmonary AEs 
Inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a 
symptomatic treatment should be given while the immunotherapy should be continued. Imaging 
evaluation and consultations with the respiratory department should be performed. 
Grade of Pneumonitis 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1 
Only radiographic changes 
 
Consider delaying the 
immunotherapy; 
 
Monitor symptoms every  
2-3 days; 
 
Consider consulting with 
respirologist and infectious 
diseases specialist. 
 
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. 
Grade 2 
Mild to moderate new 
symptoms 
 
Delay the immunotherapy 
according to the study protocol; 
 
Consult with respirologist and 
infectious diseases specialist; 
 
Intravenous administration of 
1.0 mg/kg/d 
methylprednisolone or an 
equivalent orally administrated 
dose; 
 
Consider bronchoscopy and 
lung biopsy. 
 
Repeat imaging examinations 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 
immunotherapy 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 3/4 situations. 
Grade 3-4 
Severe new symptoms; new 
onset/aggravation of hypoxia; 
life-threatening. 
 
Terminate the immunotherapy 
according to the study protocol; 
 
Consult with respirologist and 
infectious diseases specialist; 
 
Intravenous administration of 
2-4 mg/kg/d 
methylprednisolone or an 
equivalent dose via intravenous 
injection; 
 
Add prophylactic antibiotics to 
prevent opportunistic 
infections; 
 
Consider bronchoscopy and 
lung biopsy. 
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 h: 
 
Add other immunosuppressants  
(e.g., infliximab, cyclophosphamide, 
intravenous immunoglobulin or 
mycophenolate mofetil). 
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. 
 
 


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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 immunotherapy should be continued. Consider 
imaging examinations to rule out obstruction/tumor progression. 
Elevation Grade in the 
Hepatic Function Test 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1 
AST/ALT > 3 × ULN 
and/or TBIL>1 × ULN 
but ≤ 1.5 × ULN 
 
Continue the immunotherapy 
according to the study protocol. 
 
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. 
Grade 2 
AST/ALT > 3 × ULN, but 
≤ 5 × ULN 
and/or TBIL> 1.5 × ULN 
but ≤ 3 × ULNN 
 
Delay the immunotherapy 
according to the study protocol; 
 
Increase the monitoring 
frequency to once every 3 days. 
If symptoms recover to the baseline level: 
 
Resume routine monitoring and resume the 
immunotherapy according to the study 
protocol. 
If elevation persists for > 5-7 days or aggravates: 
 
Intravenous administration of 0.5-1 mg/kg/d 
methylprednisolone or an equivalent orally 
administrated dose. If LFT recovers to grade 
1 or to the baseline level, reduce the dose of 
steroids for at least 1 month, and consider 
prophylactic antibiotics to prevent 
opportunistic infection and then resume the 
immunotherapy according to study protocol. 
Grade 3-4 
AST/ALT > 5 × ULN 
and/or TBIL> 3 × ULN 
 
Terminate the immunotherapy 
according to the study protocol*; 
 
Increase the monitoring 
frequency to once every 
1-2 days; 
 
Intravenous administration of 
1.0-2.0 mg/kg/d 
methylprednisolone or an 
equivalent dose via intravenous 
injection**; 
 
Add prophylactic antibiotics to 
prevent opportunistic infections; 
 
Consultation with the 
gastroenterology department. 
If it recovers to Grade 2: 
 
Reduce the dose of steroids for at least 1 
month. 
If not improving, or even aggravating or recurring 
after > 3-5 days: 
 
Add mycophenolate mofetil 1 g bid; 
 
If the symptoms are not relieved within 
3-5 days, other immunosuppressants are 
considered 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 TBIL ≤ 5 × ULN, the immunotherapy can be delayed rather than discontinued. 
**For Grade 4 hepatitis, the recommended starting dose of methylprednisolone intravenous injection is 2 mg/kg/d. 


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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 immunotherapy should be continued. Visual 
field tests, endocrinology consultation and imaging examinations are considered. 
Asymptomatic TSH elevation 
 
Continue the immunotherapy according to the study protocol; 
 
If TSH < 0.5 × LLN or TSH > 2 × ULN, or the 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. 
Symptomatic endocrinopathy 
 
Assess endocrine functions; 
 
Consider pituitary scans; 
 
Observation of symptoms and 
abnormalities in laboratory test 
results/pituitary scans: 
 
Delay the immunotherapy 
according to the study protocol; 
 
Intravenous administration of 
1-2 mg/kg/d 
methylprednisolone or an 
equivalent orally administrated 
dose; 
 
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. 
If there is improvement (with or without 
hormone replacement): 
 
Reduce the dose of steroids for at 
least 1 month and consider 
prophylactic antibiotics to prevent 
opportunistic infections; 
 
Resume immunotherapy according 
to the study protocol; 
 
Patients with adrenal insufficiency 
may need to continue the use of 
mineralocorticoid-containing 
steroids. 
Suspected Adrenal Crisis (e.g., 
severe dehydration, hypotension, 
and shock that does not match 
the severity of the disease) 
 
Terminate the immunotherapy according to the study protocol; 
 
Exclude sepsis; 
 
Intravenous administration of a stress dose of steroids containing 
mineralocorticoids; 
 
Intravenous infusion; 
 
Consult an endocrinologist; 
 
If adrenal crisis is ruled out, treat the symptomatic endocrinopathy using the 
methods described above. 
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 in the lungs and liver, it 
should be considered that the bioavailability of oral corticosteroids is relatively low. 


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5.  Management Principles for Skin Adverse Events 
Rash Grade 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1-2 
Coverage ≤ 30% body 
surface area (BSA) 
 
 
Symptomatic 
treatment (e.g., 
antihistamines, 
topical steroids); 
 
Continue the 
immunotherapy 
according to the 
study protocol. 
If symptoms persist for > 1-2 weeks or recur: 
 
Consider skin biopsy; 
 
Delay the immunotherapy according to the study protocol; 
 
Consider intravenous administration of 0.5-1.0 mg/kg/d 
methylprednisolone or an equivalent orally administrated 
dose. Once improved, reduce the dose of steroids for at least 
1 month and consider prophylactic antibiotics to prevent 
opportunistic infections, and resume immunotherapy 
according to the study protocol. 
If it is aggravated: 
 
Provide treatment according to the method for grade 3/4 
situations. 
Grade 3-4 
Coverage ≥ 30% body 
surface area (BSA); or 
life-threatening results 
 
Delay or 
discontinue the 
immunotherapy as 
per the study 
protocol; 
 
Consider 
consultation with 
the Department of 
Dermatology; 
 
Intravenous 
administration of 
1.0-2.0 mg/kg/d 
methylprednisolone 
or an equivalent 
dose via intravenous 
injection. 
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 the immunotherapy according to the study 
protocol. 
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 in the lungs and liver, it 
should be considered that the bioavailability of oral corticosteroids is relatively low. 
 
(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.) 
 
 


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Appendix 5 Percent Bone Marrow Content in Human Skeleton 
 
 
 


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Appendix 6 Prohibited Traditional Chinese Medicines During the Study Period 
Traditional Chinese medicines prohibited during the study include but are not limited to the 
following: 
✓ Huatan Huisheng tablet 
✓ Brucea Javanica oil soft capsule 
✓ Mandarin melon berry syrup 
✓ Cantharidin 
✓ Cinobufotalin 
✓ Bufotoxin 
✓ Kang'ai injection 
✓ Kanglaite injection 
✓ Zhongjiefeng injection 
✓ Aidi injection 
✓ Awei Huapi ointment 
✓ Kangaiping pill 
✓ Fukang capsule 
✓ Xiaoaiping 
✓ Pingxiao capsule 
✓ Pingxiao tablet 
✓ Shendan Sanjie capsule 
✓ Ankangxin capsule 
✓ Boshengaining 
✓ Zedoary turmeric oil and glucose injection 
✓ Kanglixin capsule 
✓ Cidan capsule 

SAP_001.pdf: 
Title: An Open-Label, Multi-Center, Phase II Study of Anti-PD-1 Antibody SHR-
1210 Plus Capecitabine and Oxaliplatin Sequenced by SHR-1210 with Apatinib 
Mesylate or Apatinib in Patients with Previously Untreated Advanced or Metastatic 
Gastric (GC) or Gastroesophageal Junction (GEJ) Cancer 
NCT number: NCT03472365 
Date: 22 Dec., 2020 


Protocol No.: SHR-1210-II-207 
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Statistical Analysis Plan 
 
1 
Translated from Original Document 
                                   
 
 
 
AN OPEN-LABEL, MULTI-CENTER, PHASE II STUDY OF ANTI-PD-1 
ANTIBODY SHR-1210 PLUS CAPECITABINE AND OXALIPLATIN 
SEQUENCED BY SHR-1210 WITH APATINIB MESYLATE OR 
APATINIB IN PATIENTS WITH PREVIOUSLY UNTREATED 
ADVANCED OR METASTATIC GASTRIC (GC) OR 
GASTROESOPHAGEAL JUNCTION (GEJ) CANCER 
 
Statistical Analysis Plan 
(SAP) 
 
Author: Yanfei Tai 
 
Company: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
Version: 1.0 
 
Date: 22 Dec., 2020 
 
 


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2 
This SAP has been reviewed by the following personnel before being approved and effective. 
Functional Role 
Reviewer 
Medical Science 
 
Statistics 
 
Clinical Pharmacology  
 
 
 


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TABLE OF CONTENTS 
1 
REVISION ............................................................................................................................. 7 
2 
PROTOCOL AMENDMENT .............................................................................................. 7 
3 
INTRODUCTION ................................................................................................................. 7 
3.1 
Study Design .................................................................................................................. 7 
3.2 
Study Objectives ............................................................................................................. 8 
3.2.1 
Primary objective ............................................................................................. 8 
3.2.2 
Secondary objective ......................................................................................... 8 
4 
INTERIM ANALYSIS, FINAL ANALYSIS, AND UNBLINDING ................................ 9 
4.1 
Interim Analysis ............................................................................................................. 9 
4.2 
Final Analysis ................................................................................................................. 9 
4.3 
Unblinding ...................................................................................................................... 9 
5 
STATISTICAL HYPOTHESES AND DECISION RULES ............................................. 9 
6 
ANALYSIS SETS .................................................................................................................. 9 
6.1 
Full Analysis Set (FAS) .................................................................................................. 9 
6.2 
Per-Protocol Set (PPS) ................................................................................................... 9 
6.3 
Safety Analysis Set ....................................................................................................... 10 
6.4 
Evaluable Set ................................................................................................................ 10 
6.5 
PK Analysis Set (PKS) ................................................................................................. 10 
6.6 
Immunogenicity Analysis Set (ADA) .......................................................................... 10 
7 
MISALLOCATION OF TREATMENT GROUPS ......................................................... 10 
8 
PROTOCOL DEVIATION ................................................................................................ 10 
9 
EVALUATION ENDPOINTS ............................................................................................ 11 
9.1 
Efficacy Endpoints ....................................................................................................... 11 
9.2 
Safety Endpoints ........................................................................................................... 11 
9.3 
Other Endpoints ............................................................................................................ 11 
9.4 
Covariates ..................................................................................................................... 11 
9.5 
Analysis Window ......................................................................................................... 12 
10 HANDLING OF MISSING VALUES ............................................................................... 12 
10.1 Handling of Missing Data of Tumor Assessment ........................................................ 12 
10.2 Handling of Missing Data of Safety Evaluation ........................................................... 12 
10.3 Handling of Missing Data of Tumor Biomarkers ......................................................... 12 


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11 STATISTICAL ANALYSIS ............................................................................................... 12 
11.1 Subject Distribution ...................................................................................................... 13 
11.2 Demographics and Other Disease Characteristics ........................................................ 13 
11.2.1 
Demographics ................................................................................................ 13 
11.2.2 
Tumor diagnosis ............................................................................................ 13 
11.2.3 
History of drug allergy .................................................................................. 13 
11.2.4 
Medical history .............................................................................................. 14 
11.2.5 
History of concomitant diseases .................................................................... 14 
11.2.6 
Tumor treatment history ................................................................................ 14 
11.2.7 
Medication history and concomitant medication ........................................... 14 
11.3 Drug Compliance .......................................................................................................... 14 
11.4 Safety Analysis ............................................................................................................. 15 
11.4.1 
Adverse event ................................................................................................ 15 
11.4.2 
Laboratory test ............................................................................................... 17 
11.4.3 
Vital signs ...................................................................................................... 18 
11.4.4 
Physical examination ..................................................................................... 18 
11.4.5 
12-Lead ECG ................................................................................................. 18 
11.4.6 
ECOG PS ....................................................................................................... 18 
11.4.7 
Other safety data ............................................................................................ 18 
11.5 Efficacy Analysis .......................................................................................................... 19 
11.5.1 
Primary efficacy endpoint analysis ................................................................ 19 
11.5.1.1 
Best overall response (BOR) ....................................................... 19 
11.5.1.2 
Objective response rate (ORR) .................................................... 20 
11.5.2 
Secondary efficacy endpoint analysis ............................................................ 20 
11.5.2.1 
Disease control rate (DCR) ......................................................... 20 
11.5.2.2 
Duration of response (DoR) ........................................................ 20 
11.5.2.3 
Progression free survival (PFS) ................................................... 21 
11.5.3 
Exploratory efficacy analysis ........................................................................ 22 
11.5.3.1 
Overall survival (OS) .................................................................. 22 
11.5.3.2 
Time to objective response (TTOR) ............................................ 23 
11.5.3.3 
Subgroup analysis of ORR, PFS, and OS ................................... 23 
11.6 Statistical Analysis of PK ............................................................................................. 24 


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11.7 Statistical Analysis of PD ............................................................................................. 24 
11.8 Statistical analysis of immunogenicity (ADA) ............................................................. 24 
12 APPENDICES...................................................................................................................... 25 
 
LIST OF TABLES 
Table 2. Progressive disease and censoring of the duration of response ...................................... 21 
Table 3. Date of progressive disease, death, or censoring ............................................................ 22 
 
 


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ABBREVIATIONS 
AE 
Adverse event 
BOR 
Best overall response 
CR 
Complete response 
DCR 
Disease control rate 
DoR 
Duration of response 
FAS 
Full analysis set 
ORR 
Objective response rate 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
PR 
Partial response 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SS 
Safety set 
TTOR 
Time to objective response 
 
 


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1 REVISION 
None. 
2 PROTOCOL AMENDMENT 
Added overall survival (OS), time to objective response (TTOR), and subgroup analysis as 
exploratory efficacy analysis to provide guidance for subsequent phase III clinical studies 
3 INTRODUCTION 
This statistical analysis plan is formulated to provide specific statistical analysis and reporting 
methods or strategies for a phase II study on the efficacy and safety of SHR-1210 plus 
capecitabine and oxaliplatin sequential treatment (cohort 1) or SHR-1210 plus apatinib (cohort 2) 
in previously untreated advanced or metastatic gastric or gastroesophageal junction cancer. The 
final draft of this plan will be completed before database locking and will be signed by various 
functional departments for confirmation. 
3.1 
Study Design 
This is a randomized, open-label, multi-center, phase II clinical study. 
A total of 98 patients with previously untreated advanced or metastatic gastric cancer or 
gastroesophageal junction cancer will be enrolled. Subjects will be randomized to receive 
sequential therapy of SHR-1210 plus capecitabine and oxaliplatin (cohort 1, n = 43) or SHR-
1210 plus apatinib treatment (cohort 2, n = 55). 
Cohort 1 (sequential therapy of SHR-1210 combined with capecitabine and oxaliplatin): SHR-
1210 + capecitabine + oxaliplatin for 4-6 cycles, followed by SHR-1210 + apatinib for subjects 
without progressive disease (PD); 
Cohort 2 (SHR-1210 combined with apatinib): SHR-1210 + apatinib. 
A two-stage design is adopted to minimize the exposure of subject to ineffective treatment. 
Nineteen subjects will be enrolled into cohort 1 and cohort 2 at the first stage, respectively. If at 
least 4 subjects achieve objective response (complete response or partial response), the second 
stage will be initiated. And more subjects will be enrolled in cohort 1(to 43 subjects) and in 
cohort 2 (to 55 subjects), respectively. 
In this study, the screening period should be no more than 28 days. After completing screening 
examinations and assessments, eligible subjects will enter the treatment period (21 days/cycle) 
and begin the study treatment and study visits according to the protocol. Tumor imaging 
assessment will be performed once in every 2 cycles (6 weeks ± 7 days) during the first 
12 months (the first 16 cycles) of the study treatment period and once every 3 cycles (9 weeks ± 
7 days) thereafter. The subjects will complete safety examinations and imaging assessments 
upon discontinuation of the study treatment. 


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Thereafter, the subjects will enter the follow-up period. The safety follow-up period will start 
after the last administration, and the subjects are followed up every 30 days (±7 days) until 90 days 
after the last administration. The first safety follow-up will be carried out at the study site; the 
second and the third follow-up visits will be made via telephone calls. The survival follow-up 
period starts after the end of the safety follow-up period. The survival follow-up period ends 
upon the subject's death, lost to follow-up, withdrawal of informed consent, or study termination 
by sponsor. During this period, a follow-up will be conducted every month via telephone or other 
effective methods to collect information on subject survival and subsequent treatments. For 
subjects who show no evidence of radiographic progression, an imaging evaluation should 
continue at the frequency of response evaluations specified in the protocol, until progressive 
disease, death, lost to follow-up, withdrawal of informed consent, start of other anti-cancer 
treatments, or trial termination by the sponsor. 
All subjects should continue to receive the study treatment until progressive disease, intolerable 
toxicity, voluntary treatment discontinuation or study withdrawal by the subject, or 
discontinuation determined by the investigator. 
SHR-1210 is an immune checkpoint inhibitor and according to the experience of drugs of same 
class, some subjects may experience delayed or early pseudoprogression after receiving 
immunotherapy drugs. Therefore, if subjects in the treatment group who have experienced 
progressive disease (PD) for the first time meet the criteria for continuing treatment after 
progressive disease, they can continue to be treated according to the original treatment regimen. 
Subjects who do not have progressive disease or intolerable toxicities may continue the SHR-
1210 treatment for no more than 24 cumulative months. 
Subjects who do not have progressive disease after 24-month treatment may continue the 
apatinib monotherapy according to the prescribing information of apatinib. 
3.2 
Study Objectives 
3.2.1 Primary objective 
To evaluate the efficacy of the sequential therapy of SHR-1210 combined with capecitabine and 
oxaliplatin or SHR-1210 combined with apatinib mesylate as the first-line therapy for advanced 
or metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer. 
3.2.2 Secondary objective 
To evaluate the safety of the sequential therapy of SHR-1210 combined with capecitabine and 
oxaliplatin or SHR-1210 combined with apatinib mesylate for the treatment of advanced or 
metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer. 


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4 
INTERIM ANALYSIS, FINAL ANALYSIS, AND UNBLINDING 
4.1 
Interim Analysis 
At the end of Stage I of this study, it will be judged whether to continue the trial in a certain 
cohort according to the rules in Section 5. 
4.2 
Final Analysis 
The final analysis will be performed after the database is locked and released. 
4.3 
Unblinding 
This is an open-label clinical study and does not involve unblinding. 
5 STATISTICAL HYPOTHESES AND DECISION RULES 
Cohort 
H0 
H1 
N1 
R1 
N 
R 
Power 
Alpha 
Cohort 1 35% ORR 
55% ORR 
19 
4 
43 
21 
80% 
0.05 
Cohort 2 15% ORR 
30% ORR 
19 
4 
55 
13 
80% 
0.05 
N1: Number of subjects at the first stage; 
R1: The minimum effective number of subjects required in Stage I; if the effective number of subjects in Stage I is 
less than R1, the trial will be discontinued because of invalidity. If ≥ 4 subjects in cohort 1 show disease response 
(CR or PR), the study will enter Stage II and 24 subjects will be added. If ≥ 4 subjects in cohort 2 show disease 
response, the study will enter Stage II and 36 subjects will be added (55 subjects in cohort 2). 
N: Final number of subjects; 
R: The minimum effective number of subjects eventually required. If the total effective number of subjects is less 
than R after the end of Stage II (cohort 1 fails to show at least 21 subjects of disease responses, and cohort 2 fails to 
show at least 13 subjects of disease responses), subsequent drug study will be not considered necessary. 
6 ANALYSIS SETS 
6.1 
Full Analysis Set (FAS) 
It includes all subjects who are randomized and have received study drugs at least once. This 
analysis set will be used for the efficacy analysis. 
6.2 
Per-Protocol Set (PPS) 
It is a subset of the full analysis set, and subjects with important protocol deviations judged to 
have a significant impact on treatment efficacy will be excluded from this set. The list of subjects 
included into or excluded from the PPS should be reviewed and determined by the sponsor and 
the investigator before the database is locked. 


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6.3 Safety Analysis Set 
It includes all enrolled subjects who have received the study drugs at least once and have post-
administration safety evaluation data. 
6.4 
Evaluable Set 
It is a subset of FAS and includes all enrolled subjects who have received the study drugs at least 
once and have at least one post-baseline tumor assessment. 
6.5 
PK Analysis Set (PKS) 
It includes all enrolled subjects who have received the study drugs and have post-administration 
PK evaluation data (concentration and/or parameter). 
6.6 
Immunogenicity Analysis Set (ADA) 
It includes all enrolled subjects who have received the study drugs at least once and have 
baseline and at least one set of post-baseline ADA evaluation data. 
7 MISALLOCATION OF TREATMENT GROUPS 
Not applicable. 
8 PROTOCOL DEVIATION 
The protocol deviation analysis is based on FAS. Protocol deviations may include but are not 
limited to the following types: 
• 
Not meeting the inclusion/exclusion criteria; 
• 
Meeting the withdrawal criteria but the subject has not withdrawn from the study; 
• 
Not taking study drugs according to the protocol, such as taking wrong doses and missed 
doses; 
• 
Using combined medications prohibited by the protocol, such as other anti-tumor drugs and 
adjuvant drugs related to tumor treatment (including anti-cancer Chinese medicine); 
• 
Non-compliance to the procedures stipulated in the protocol, such as omission of blood 
sample collection, and blood sample collection time exceeding the time window. 
In addition, the list of subjects experiencing protocol deviations should be reviewed and 
confirmed before the database is locked. 
The corresponding listing of subjects excluded from PPS due to important protocol deviations 
will be reported. 


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9 
EVALUATION ENDPOINTS 
9.1 
Efficacy Endpoints 
Primary endpoint: 
• 
Objective response rate (ORR): the percentage of participants in the analysis 
population who have a complete response (CR) or a partial response (PR). 
Secondary endpoints: 
• 
Progression free survival (PFS): the time from the start of study treatment (the time 
of the first administration provided by the investigator) to the time of objective 
progressive disease or death due to any cause, whichever occurs first. 
• 
Duration of response (DoR): the time from first evidence of CR or PR until first 
evidence of disease progression or death due to any cause. The date of response is the 
date of first documented response rather than the date of confirmation. 
• 
Disease control rate (DCR): the percentage of participants in the analysis population 
who have CR, PR, or stable disease (SD). 
9.2 
Safety Endpoints 
The following safety data will be collected according to the study protocol. 
• 
Adverse event 
• 
Laboratory test data 
• 
Vital signs data 
• 
12-Lead ECG 
• 
ECOG PS 
• 
Physical examination 
9.3 
Other Endpoints 
Not applicable. 
9.4 
Covariates 
Not applicable. 


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9.5 Analysis Window 
Data obtained from post-baseline visits will be summarized by protocol visits shown in eCRF, 
with no need to consider whether the visit window specified by the protocol has been exceeded. 
When a planned visit is missing, or one of the test items in the planned visit is missing or its 
results are invalid, the unplanned visit closest to the planned visit will be considered as the 
protocol visit. If the time of two unplanned visits is equally close to the time of planned visit, the 
later unplanned visit will be selected as the protocol visit. All visits in the protocol will be sorted 
in chronological order. In addition, once defined as a protocol visit, an unplanned visit will no 
longer be defined as other protocol visits. In the analysis carried out by visits, the statistical 
analysis will be performed according to the planned time points in the protocol, i.e., the time 
points of unplanned visits do not need to be shown. 
10 HANDLING OF MISSING VALUES 
10.1 
Handling of Missing Data of Tumor Assessment 
When missing, the tumor assessment data will be treated according to RECIST (v1.1, refer to the 
table in appendix for details). 
10.2 
Handling of Missing Data of Safety Evaluation 
Unless otherwise specified, missing safety endpoint values will not be imputed. Please refer to 
Appendix 1.4 for the imputing of date/time of adverse events and concomitant medications. 
10.3 
Handling of Missing Data of Tumor Biomarkers 
Missing tumor biomarker data will not be imputed. 
11 STATISTICAL ANALYSIS 
The statistical analysis involved in this study will be carried out in accordance with cohorts. The 
statistical analysis plan must be finalized before database locking. Statistical tables, listings, and 
figures will be generated using SAS (v9.4). 
In this study, unless otherwise stated, all data will be summarized using descriptive statistics in 
accordance with the following general principles. 
Measurement data will be summarized by mean, standard deviation, median, maximum, and 
minimum. The decimal places of minimum and maximum should be consistent with those 
recorded on the CRF, mean and median have one more decimal place than those of the raw data, 
and the standard deviation has 2 more decimal places than that of the raw data. Count data will 
be summarized by frequency and percentage; categorical variables will be statistically described 
using the frequency and percentage of each category, with one decimal place rounded for 
percentages. 


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Time-to-event data will adopt the Kaplan-Meier method to estimate survival rates and plot 
survival curves; serum concentration data will be summarized using geometric mean, geometric 
standard deviation, geometric coefficient of variation, mean, standard deviation, coefficient of 
variation, median, maximum, and minimum. 
11.1 
Subject Distribution 
The reasons for screening failure will be summarized by frequency and percentage, and the 
percentage will be calculated using the number of subjects subjected to screening as the 
denominator. 
All enrolled subjects will be divided into cohorts and summarized by frequency and percentage. 
In addition, as for subject distribution, the following information will be summarized by 
frequency and percentage for cohorts: 
• 
Number of subjects enrolled; 
• 
Number of subjects withdrawn from the study; 
• 
Number of subjects whose study is underway; 
• 
Reason for treatment discontinuation; 
• 
Reason for subject withdrawal after the end of study; 
The percentages will be calculated using the number of all enrolled subjects as the denominator. 
In addition, the corresponding listing of subjects will be provided. 
11.2 
Demographics and Other Disease Characteristics 
This analysis will be carried out based on FAS. 
11.2.1 Demographics 
Demographics (age, gender, ethnicity, height, body weight, BMI [kg/m2]) and ECOG PS will be 
summarized and listed by cohort. The calculation of age (years) is based on the date of signing of 
the informed consent form and the date of birth. 
The BMI calculation formula is: Baseline body weight (kg)/baseline height (m2). 
11.2.2 Tumor diagnosis 
The descriptive statistics of baseline disease characteristics will be provided by cohort. 
11.2.3 History of drug allergy 
The descriptive statistics of allergy history data will be provided and listed by cohort. 


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11.2.4 Medical history 
The descriptive statistics of medical history data will be provided and listed by cohort. 
11.2.5 History of concomitant diseases 
The descriptive statistics of medical history data will be provided and listed by cohort. 
11.2.6 Tumor treatment history 
The frequency and percentage of subjects with history of tumor surgery, history of radiotherapy, 
history of neoadjuvant chemotherapy, history of adjuvant chemotherapy, and other tumor 
treatment history will be summarized. 
11.2.7 Medication history and concomitant medication 
Prior medications are defined as drugs whose use has been completed before the first dose of the 
investigational drug during the treatment period. Concomitant medications are defined as drugs 
that are used after the first dose of the investigational drug, or drugs that are used before the first 
dose of the investigational drug but are continued to be used during the treatment period. 
Medication history and concomitant medications will be descriptively summarized and listed by 
cohort. 
11.3 
Drug Compliance 
The descriptive statistics of the exposure time, amount of exposure, number of treatment cycle, 
frequency of dose interruption, frequency and reason of dose discontinuation, frequency and 
reason of dose delay, final dosage, and reason for dose modification of study drugs (SHR-1210, 
oxaliplatin, apatinib, and capecitabine) will be summarized by cohort. In this study, SHR-1210 
and oxaliplatin will be administered via intravenous drip infusion. The amount of apatinib and 
capecitabine dispensed and returned at each visit will be counted by tablet. The strength of apatinib 
is 375 mg/tablet and 250 mg/tablet, and that of capecitabine is 500 mg/tablet and 150 mg/tablet. 
1) 
Actual cumulative drug exposure (mg) 
SHR-1210: 
Dose per cycle in study = 200 mg × Actual dosing percentage (%)  
Oxaliplatin: 
Dose per cycle in study = Total dose of this dosing (mg) × Actual dosing percentage (%)  
Apatinib: 
Dose per cycle in study = Total daily actual dose × Number of days the corresponding dose is 
used (days) 


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Capecitabine: 
Actual dose per cycle in study = Total daily actual dose × Number of days the corresponding 
dose is used (days) = Total daily dose × (Start date - End date + 1) 
2) 
Scheduled dose (mg) 
SHR-1210: 
200 mg per cycle. 
Oxaliplatin: 
Scheduled dose per cycle = Total dose of this dosing (mg)  
Apatinib: 
Scheduled dose per cycle = Total dose of this dosing (mg)  
Capecitabine: 
Scheduled dose per cycle = Total daily scheduled dose × Number of da ys the corresponding dose 
is used (days) 
3) 
Subject compliance (%) = (Actual dose/Scheduled dose) × 100%.  
All study drugs will be listed and analyzed by cohort, subject code, treatment stage, dosing date, 
and actual dose. 
4) 
Duration of exposure to study drugs (weeks) = (Date of last dosing - Date of first dose + 
1)/7. 
Actual dose, scheduled dose, and compliance will be summarized by drug and cohort. 
11.4 
Safety Analysis 
The safety analysis will be carried out based on the safety set by cohort. 
11.4.1 Adverse event 
An adverse event (AE) refers to any untoward medical occurrence in a study subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. In this study, AE should be collected from the signing of informed consent form 
(ICF) to 90 days after the last dosing of study drugs. AE includes any adverse symptom or sign, 
laboratory test abnormality, or disease. AE will be summarized separately in different stages of 
cohort 1 (SHR-1210 + capecitabine + oxaliplatin, sequence by SHR-1210 + apatinib mesylate, 
and total) and cohort 2. 


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AE will be analyzed based on treatment-emergent adverse event (TEAE). TEAE is defined as an 
AE that occurs or becomes aggravated on the same day or after the first dosing of study drugs 
but not later than 90 days after the last dosing of study drugs. Only TEAE will be summarized 
and analyzed. A separate data listing will be provided only for AE that occurs before treatment. 
Each AE will be coded by MedDRA (v23.0) and graded by NCI-CTCAE v4.03. For the same 
SOC and/or PT, multiple cases of the same events that occur 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. 
A summary description report will be provided for the number and percentage of subjects 
experiencing at least one TEAE, treatment-related TEAE (SHR-1210, oxaliplatin, capecitabine, 
and apatinib), severe TEAE (CTCAE Grade ≥ 3), TEAE leading to study drug 
discontinuation/interruption, treatment-related TEAE leading to drug 
discontinuation/interruption, TEAE leading to dose modification of study drugs, treatment-
related TEAE leading to dose modification of the study drugs, TEAE leading to subject 
withdrawal from treatment, serious adverse event (SAE), and death. 
In the TEAE summary table, AE occurring after the study drug treatment will be analyzed by 
MedDRA system organ class (SOC) and preferred term (PT), and descriptive statistics will be 
provided by frequency and percentage. The summary table contains the number of subjects 
experiencing at least one TEAE, TEAEs leading to treatment withdrawal, SAEs, TEAEs related 
to each study drug, and CTCAE Grade ≥ 3 treatment-related TEAE, along with CTCAE grades. 
After study drug treatment, each TEAE, SAE, TEAE of special interest, immune-related TEAE, 
and possible liver injury event, along with CTCAE grade, in each cohort will be summarized by 
SOC and PT, and each treatment-related TEAE and SAE related to study drugs will be 
summarized by SOC and PT. Immune-related AE will also be summarized by immune-related 
category and PT. The incidence of AE is calculated based on the number of subjects having an 
AE, instead of the number of AE episodes. For TEAE occurring after the start of study treatment, 
causality with study drugs consists of definitely related, possibly related, and indeterminable; if 
causality is missing, the TEAE will be considered drug-related for analysis. TEAE with CTCAE 
grade missing will be counted as missing. 
TEAE of special interest includes the following: 
• 
Grade ≥ 3 infusion reaction; 
• 
Grade ≥ 2 diarrhea/colitis, uveitis, and interstitial pneumonia; 
• 
Other Grade ≥ 3 immune-related AE; 
• 
Grade 4 amylase or lipase increased. 


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Each AE, TEAE leading to dose interruption or modification, TEAE leading to treatment 
withdrawal, severe TEAE, and death will be listed. 
For immune-related TEAE (classified by immune-related TEAE), the descriptive summary of the 
number and percentage of subjects have received corticosteroids or immunomodulators, received 
immunomodulators, received corticosteroids (further divided into systemic and topical 
administration), and received high-dose corticosteroids (defined as at least one dose or daily dose 
of ≥ 40 mg prednisone or equivalent; further divided into systemic and topical administration), 
and the starting dose and duration of high-dose corticosteroids will also be provided. The dosage 
of different hormonal drugs will be converted into the equivalent dose of prednisone according to 
the following formula: 0.75mg of dexamethasone = 5 mg of prednisone = 4mg of 
methylprednisolone = 20mg of hydrocortisone = 0.8mg of betamethasone. 
If one subject experiences one AE and receives two or more hormones during the presence of the 
AE, the starting dose of the hormone used first will be involved in the statistics of starting doses 
(i.e., the starting dose(s) of subsequent hormone therapy/therapies will not be involved in the 
statistics of starting doses). Then, the cumulative duration of the use of multiple hormones (time 
overlapping of hormone therapies should be avoided in the calculation) will be summarized as 
the duration of dosing. If one AE category (such as the category of immune-related AE) contains 
more than one AE (by PT), this AE category will be treated as one AE when being summarized. 
When the initial dose is summarized, if the dosing frequency of hormones is more than once a 
day, it will be converted into a single daily dose before being summarized. When the duration of 
dosing is summarized, if the end date of hormone drug treatment is unknown, it will be imputed 
with the start date of the last dose of the hormone drug treatment. 
Corrective treatment, site, maximum diameter, incidence of hemorrhage, and incidence of 
infection will also be summarized for reactive capillary endothelial proliferation. 
11.4.2 Laboratory test 
The baseline laboratory test is defined as the most recent test before the first administration. 
The quantitative parameter of hematology, blood biochemistry, and urinalysis in each cohort at 
baseline, the laboratory test result after treatment, the change from the baseline, and the 
normal/abnormal change from the baseline will be summarized by visit. The hematology, blood 
biochemistry, and urinalysis of each cohort will be summarized by the normal/abnormal changes 
before and after treatment. 
All laboratory test results will be listed by subject ID, among which, abnormal values will be 
marked and indicated for clinical significance (if any). 


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11.4.3 Vital signs 
The vital sign baseline is defined as the last sign result tested before the first administration. 
The vital signs of each cohort will be summarized by visit using descriptive statistics. At the same 
time, the changes from baseline will also be summarized and analyzed by descriptive statistics. 
All vital signs will be listed. 
11.4.4 Physical examination 
The physical examination baseline is defined as the last examination result before the first 
administration. 
The physical examination will be summarized by the normal/abnormal changes before and after 
treatment. 
The abnormal results of physical examination will be listed. 
11.4.5 12-Lead ECG 
Baseline is defined as the most recent test data before the first dose. 
Items concerning ECG include: HR (times/min), PR interval (ms), QT interval (ms), and QTc 
(ms). The measured value and change from baseline of each ECG variable at each time point will 
be summarized using descriptive statistics. At the same time, ECG will be summarized by the 
normal/abnormal changes before and after treatment. 
If QTcF is not directly provided on the ECG report, it will be obtained using the following 
formula (Fridericia formula): 
QTcF = QT/(RR1/3) 
RR = 60/heart rate (s) 
Related data will also be reported in the form of listing. 
11.4.6 ECOG PS 
Baseline is defined as the most recent test data before the first dose. 
The ECOG PS of each cohort will be analyzed by descriptive statistics. 
All ECOG PS will be reported in the form of listing. 
11.4.7 Other safety data 
Examinations such as echocardiography, virology, fecal occult blood, pregnancy, and 
coagulation function will be listed. 


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11.5 
Efficacy Analysis 
The tumor assessment at each time point will be conducted by the investigator as per RECIST 
(v1.1). The descriptive statistics of ORR will be summarized by stages (Stage I: 19 subjects 
respectively in cohort 1 and cohort 2 who have completed the response evaluation; Stage II: the 
remaining subjects who have completed the response evaluation) and cohorts, while PFS, DoR, 
and DCR will be only summarized by cohort. The efficacy analysis will be carried out based on 
FAS. If a subject's baseline or post-baseline tumor assessment is missing, the subject's is non-
evaluable (NE) in response. For the maximum post-baseline change in the sum of the longest 
diameter of the target lesion, a waterfall plot will be drawn by cohort; for the post-baseline 
change in each visit regarding the sum of longest diameter of the target lesion relative to the 
baseline, a spider chart will be drawn by cohort. 
11.5.1 Primary efficacy endpoint analysis 
11.5.1.1 Best overall response (BOR) 
BOR is defined as the best response recorded from the start of the treatment until objective 
recording of progressive disease (PD) by RECIST (v1.1) or start of subsequent anti-cancer 
therapy (whichever occurs first). For subjects without documented progression or new anti-
cancer treatment, BOR will be determined based on all response evaluations. BOR recorded 
during this period will be based on the confirmed response. For the criteria for response 
confirmation, see Appendix 1.3. 
• 
Confirmed CR: Response evaluated as CR and reconfirmed as CR at a later time point 
(at least 4 weeks later and before PD). 
• 
Confirmed PR:  
− 
Response evaluated as CR but reconfirmed as PR (CR not reached) at a later time 
point (at least 4 weeks later and before PD). 
− 
Response evaluated as PR but reconfirmed as CR/PR at a later time point (at least 
4 weeks later and before PD). 
• 
Confirmed SD: 
− 
Response evaluated as CR/PR but reconfirmed as SD (CR/PR not reached). 
− 
Response evaluated as SD at least once within 5 weeks after the start of the study 
(visit window: 6 weeks - 7 days). 
• 
PD: Progressive disease not meeting the requirements for confirmed CR, PR, and SD 
• 
NE: Other conditions 


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A response will be judged as PR, if a patient has two non-consecutive results of PR, the interval 
between the two is more than four weeks, and no PD occurs during the interval. Similarly, a 
response will be judged as CR, if a patient has two non-consecutive results of CR, the interval 
between the two is more than four weeks, and no PD occurs during the interval. 
CR or PR occurring after the start of subsequent anti-cancer treatment will not be included in the 
calculation of BOR. 
BOR (CR, PR, SD, PD, and NE) will be analyzed by frequency and percentage. 
11.5.1.2 Objective response rate (ORR) 
ORR is defined as the proportion of subjects whose BORs have been confirmed as CR or PR by 
RECIST (v1.1). 
When the first response evaluation data of a subject after treatment are missing or unknown, the 
subject is not evaluable (NE) and will only be included in the denominator for percentage 
calculation. 
ORR of a single cohort and its two-sided 95% exact (Clopper-Pearson) confidence interval will 
be calculated. 
The confirmed CR, PR, SD, and PD will be listed and summarized. 
The analysis for ORR will be repeated based on FAS, PPS, and ES. 
11.5.2 Secondary efficacy endpoint analysis 
11.5.2.1 Disease control rate (DCR) 
DCR is defined as the percentage of subjects in the analysis population who have BOR 
evaluation of CR, PR, or SD. 
When the response evaluation data of a subject after treatment are missing or unknown, the 
subject is not evaluable (NE) and will be included in the denominator for percentage calculation. 
DCR and its two-sided 95% exact (Clopper-Pearson) confidence interval will be calculated. 
11.5.2.2 Duration of response (DoR) 
DoR is defined as the time from first documented evidence of CR or PR until the date of first 
documented evidence of progressive disease or death due to any cause. The end date of response 
must be consistent with the date of progressive disease or death of PFS. Tumor response is based 
on the confirmation, and the response that has not been confirmed will not be included. The date 
of response is the date of first observation (the last date of imaging assessment of visit, not the 
date of visit), not the date of confirmation. Table 2 describes information on progressive disease, 
death, or censoring. 


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For DoR, survival curves will be plotted using the Kaplan-Meier method and the 95% CI for 
median time will be calculated using the Brookmeyer-Crowley method. In addition, a swimmer 
plot will be drawn for each cohort. 
Way to interpret Table 2: From the first question until the occurrence of progressive disease, 
death or censoring, and the corresponding date. 
Table 2. Progressive disease and censoring of the duration of response 
 
 
No 
Yes 
1. 
Has the subject's response evaluation been 
confirmed as CR 
PR? 
Not included in the analysis 
Skip to 2 
2. 
Are new anti-cancer drugs used before 
progressive disease or death? 
Skip to 3 
Censoring 
The date of censoring is the 
date of the last objective 
tumor assessment before the 
use of the new anti-cancer 
drug 
3. 
Has the subject experienced progressive 
disease? 
Skip to 5 
Skip to 4 
4. 
Is the progressive disease of the subject 
recorded after an unacceptably long time 
interval (the response evaluation is missing 
by > 2 times, i.e., 98 days)? 
The end date of response is the 
date of progressive disease 
Censoring 
The date of censoring is the 
date of the last objective 
tumor assessment before the 
long-term lost to follow-up 
5. 
Is the subject dead? 
Censoring 
The date of censoring is the date 
of the last objective tumor 
assessment 
Skip to 6 
6. 
Is the death of the subject recorded after an 
unacceptably long time interval (the 
response evaluation is missing by > 2 times, 
i.e., 98 days)? 
The end date of response is the 
date of death 
Censoring 
The date of censoring is the 
date of the last objective 
tumor assessment before the 
long-term lost to follow-up 
11.5.2.3 Progression free survival (PFS) 
PFS refers to the time from the start of randomization to the date of objective progressive disease 
or death (caused by any reason), whichever occurs first. Table 3 describes progressive disease, 
death, or censoring. 


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Table 3. Date of progressive disease, death, or censoring 
 
 
No 
Yes 
1. 
Does the subject have a baseline objective 
tumor assessment? 
Censoring 
The date of censoring is the 
date of randomization 
Skip to 2 
2. 
Are new anti-cancer drugs used before 
progressive disease or death? 
Skip to 3 
Censoring 
The date of censoring is the date 
of the last objective tumor 
assessment before the use of the 
new anti-cancer drug 
3. 
Has the subject experienced progressive 
disease? 
Skip to 5 
Skip to 4 
4. 
Is the progressive disease of the subject 
recorded after an unacceptably long time 
interval (the response evaluation is missing 
by > 2 times, i.e., 98 days)? 
Progressive disease 
The date of progression is 
the date of earliest recorded 
progressive disease 
Censoring 
The date of censoring is the date 
of the last objective tumor 
assessment before the long-term 
lost to follow-up 
5. 
Is the subject dead? 
Censoring 
The date of censoring is the 
date of the last objective 
tumor assessment 
Skip to 6 
6. 
Is the death of the subject recorded after an 
unacceptably long time interval (the 
response evaluation is missing by > 2 times, 
i.e., 98 days)? 
Progressive disease 
The date of progression is 
the date of death 
Censoring 
The date of censoring is the date 
of the last objective tumor 
assessment before the long-term 
lost to follow-up 
The time of PFS is based on the time of the imaging examination rather than the time of the visit. 
The RECIST imaging examination time (targeted lesion, non-targeted lesion, and new lesion) for 
a special visit may be different, and the following rules apply: 
• 
The date of progression will be based on the earliest date leading to progression. 
• 
The date of censoring will be based on the last date of objective tumor assessment. 
Survival curves will be plotted using the Kaplan-Meier method and the 95% CI for median time 
will be calculated using the Brookmeyer-Crowley method. 
11.5.3 Exploratory efficacy analysis 
11.5.3.1 Overall survival (OS) 
OS is defined as the time from the start of randomization to the death of the subject caused by 
any reasons. Survival curves will be plotted using the Kaplan-Meier method and the 95% CI for 
median time will be calculated using the Brookmeyer-Crowley method. The 6-month, 9-month, 
and 12-month OS rates and their 95% CIs in the two cohorts will be estimated. 


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Censoring rules: For subjects who are still alive at the last follow-up, their OS will be censored at 
the date of last follow-up. For subjects who are lost to follow-up, their OS will be censored at the 
last confirmed survival time before lost to follow-up. The censored OS is defined as the time 
from randomization to censoring. OS will be calculated in months using the following formula: 
(Date of OS event or censored date - date of randomization + 1)/30.4375. 
11.5.3.2 Time to objective response (TTOR) 
TTOR is defined as the period of time from the start of randomization to the first documented 
BOR of objective response (as per RECIST 1.1). 
TTOR will only be measured in subjects with a BOR after treatment. The date of response is the 
date of first documented response but not the date of confirmation. TTOR will be statistically 
described by the number of subjects, mean, standard deviation, median, minimum, and 
maximum. 
11.5.3.3 
Subgroup analysis of ORR, PFS, and OS 
The subgroup analysis is exploratory and will only be performed based on FAS. This study 
includes the following subgroups: 
• 
Length of chemotherapy cycles (≤ 4 cycles vs. > 4 cycles) (only in cohort 1) 
• 
Age (< 60 vs. ≥ 60) 
• 
Gender (male vs. female) 
• 
Baseline ECOG PS score (0 vs. 1) 
• 
Peritoneal metastasis (yes vs. no) 
• 
Liver metastasis (yes vs. no) 
• 
Metastasis sites (≤ 2 vs. > 2) 
• 
History of radical gastrectomy (yes vs. no) 
• 
Lesion site (stomach vs. gastroesophageal junction) 
In order to explore the impact of subgroup factors on the ORR, the ORR and its two-sided 95% 
exact CI (Clopper-Pearson) in each subgroup of a single cohort will be calculated. The PFS and 
OS for each subgroup of a single cohort will be plotted using the Kaplan-Meier method and the 
95% CI for median time will be calculated using the Brookmeyer-Crowley method. 


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11.6 
Statistical Analysis of PK 
Descriptive statistical analysis will performed for the PK drug concentrations of SHR-1210 and 
apatinib. 
11.7 
Statistical Analysis of PD 
Not applicable 
11.8 
Statistical analysis of immunogenicity (ADA) 
The number and percentage of subjects with positive ADA and negative ADA will be 
summarized using descriptive statistics. 
For the population with positive ADA, the following items will be analyzed: the onset of ADA 
positive, the number and percentage of subjects with transient positive post-baseline results 
(transient ADA positive is defined as the subjects who are negative at baseline and have only one 
ADA-positive sample post baseline before the last sample and are not persistent ADA positive), 
the number and percentage of subjects with persistent positive post-baseline results (persistent 
ADA positive can be divided to two categories: 1) negative at baseline, there are at least two 
positive samples post baseline, where the first and last ADA-positive samples are separated by a 
period >16 weeks, or 2) negative at baseline, the last post-baseline sample is positive, or the last 
post-baseline sample is negative and the second last post-baseline sample is positive), and the 
number and percentage of subjects with other positive post-baseline results (other ADA positive 
is defined as the subjects who are negative at baseline, have at least two ADA positive samples 
post baseline, but not persistent ADA positive, and the last sample is negative). 
In the meantime, the safety of ADA-positive and negative subjects will be summarized so as to 
investigate the effects of ADA on safety. ADA-positive subjects refer to subjects with post-
baseline ADA-positive samples, mainly including: a: the subjects who have the baseline negative 
and post-baseline positive samples, or b. the subjects who have both baseline and post-baseline 
positive samples, and the titer of the post-baseline samples is ≥ 4-fold of the baseline titer. ADA-
negative subjects are those who are not ADA positive. 
The number and percentage of subjects with neutralizing antibodies (Nabs) positive will be 
summarized using descriptive statistics. 
Immunogenicity raw data will be reported in the form of listing. 


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12 APPENDICES 
Appendix 1.1 Time Point Response: Subjects with Target Lesions (Including or Excluding 
Non-Target Lesions) 
Target Lesion 
Non-Target Lesion 
New lesion 
Overall Response at the Time Point 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 
PR 
Non-PD or not all 
Non 
PR 
 
evaluable 
 
 
SD 
Non-PD or not all 
Non 
SD 
 
evaluable 
 
 
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 
Appendix 1.2 Time Point Response - Subjects with Non-target Lesions Only 
Non-Target Lesion 
New lesion 
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 
response evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
Appendix 1.3 Best Overall Response with CR and PR to Be Confirmed 
Evaluation at the 
Previous Time Point 
Evaluation at the 
Subsequent Time Point 
BOR 
CR 
CR 
CR 
CR 
PD, missing 
SD (> 6 weeks from the start of treatment (5 weeks after 
subtracting 1 week of visit window)) 
CR 
PR or SDa 
Note: This situation generally will not occur. 
 
 
⚫ 
If the last evaluation is CR, then a little bit of the lesion in 
the next evaluation will lead to the response evaluation of 
PD. The BOR depends on whether the minimum time of 
6 weeks for SD is met. If met, it is SD. 


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Evaluation at the 
Previous Time Point 
Evaluation at the 
Subsequent Time Point 
BOR 
PR 
PR, unconfirmed CR 
PR 
PR 
SD, missing 
SD 
PR 
PD 
SD (> 6 weeks from the start of treatment (5 weeks after 
subtracting 1 week of visit window)) 
SD 
SD, unconfirmed 
SD 
 
PR, unconfirmed CR 
 
SD 
NE –> SD 
SD 
PR 
NE –> PR 
PR 
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 any disease seen at a subsequent time point, even the disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best overall response will depend on whether minimum duration for SD is met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions are likely still present and in fact the subject have PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
overall response is PR. 
Appendix 1.4 Rules for Imputing Incomplete Dates of AE and CM: 
Date 
Start Date 
End Date 
Missing "Day" 
Impute with the start day of study 
treatment when the year and month of 
the occurrence are identical to those 
of study treatment; otherwise, impute 
with the first day of the 
corresponding month 
Impute with the last day of the month 
Missing "Month" and "Day" 
Impute with the start month and day 
of study treatment when the year of 
the occurrence is identical to that of 
study treatment; otherwise, impute 
with "1 Jan." 
31 Dec. 
Missing "Year", "Month", and "Day" No imputation 
No imputation 
Note: All imputed dates must be before the date of end/termination of study and date of death.