Clinical trial NCT03558191
Conditions: Nasopharyngeal Carcinoma
Keywords: Recurrent/Metastatic Nasopharyngeal Carcinoma PD-1
Sponsor: Jiangsu HengRui Medicine Co., Ltd.
Start date: 2018-08-14; Completion date: 2021-12-30
Enrollment: 156 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, single-arm, multi-center, phase 2 Study of SHR-1210 in recurrent/metastatic nasopharyngeal carcinoma(R/M NPC) patients who have received previous at least two lines of chemotherapy.

Detailed description:
The primary objective of this phase 2 study is to assess objective response rate of SHR-1210 in patients with R/M NPC. The secondary objective is to observe the duration of response, progression free survival, time to response, overall survival and safety of SHR-1210 in R/M NPC. ADA is also investigated.

Arms: arm 1: SHR-1210 injection, 200 mg/dose, intravenous infusion over 30 minutes, once every 2 weeks .
Interventions: intervention 1: SHR-1210
Intervention descriptions: intervention 1: A humanized monoclonal immunoglobulin PD-1 antibody

Protocol documents:
Prot_000.pdf: 
Title: A single-arm, open-label, multi-center, phase II clinical study of anti-PD-1 
antibody SHR-1210 in recurrent/metastatic nasopharyngeal carcinoma subjects who 
have received previous at least two lines of chemotherapy   
Clinical trial registration number: NCT03558191 
Date: 10 Aug., 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 


<Camrelizumab for Injection> 
<SHR-1210-II-209> 
<Final Version 3.0>, < (Version Date): 10 Aug., 2020> 
 
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Translated from Original Document 
 
 
 
A SINGLE-ARM, OPEN-LABEL, MULTI-CENTER, 
PHASE II CLINICAL STUDY OF ANTI-PD-1 ANTIBODY 
SHR-1210 IN RECURRENT/METASTATIC 
NASOPHARYNGEAL CARCINOMA PATIENTS WHO 
HAVE RECEIVED PREVIOUS AT LEAST TWO LINES 
OF CHEMOTHERAPY 
Protocol No.: SHR-1210-II-209 
Study Phase: II 
Compound Code: SHR-1210  
Compound Name: Camrelizumab 
Medical Director: Qing Yang 
Leading Center of Clinical Study: Sun Yat-sen University Cancer Center 
Principal Investigator: Prof. Li Zhang 
 
Version No.:  3.0 
Version Date:  10 Aug., 2020 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
No. 7 Kunlunshan Road, Lianyungang Economic and Technological Development 
Zone, Jiangsu 222047, China 
 
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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Sponsor's Signature Page 
 
I have read and confirmed this clinical study protocol (protocol no.: SHR-1210-II-209, version 
no.: 3.0, version date: 10 Aug., 2020). 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. 
 
 
 
 
 
 
 
Qing Yang 
  
  
Study Director (print) 
 Study Director (signature) 
 Signature Date 
(DD/MM/YYYY) 
 
 


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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 investigational drug; I have read the materials of preclinical studies of the 
investigational drug and the protocol for this clinical study (protocol no.: SHR-1210-II-209, 
version no.: 3.0, version date: 10 Aug., 2020). 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) 
 Signature Date 
(DD/MM/YYYY) 
 
 


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Principal Investigator's Signature Page (Participating Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. I have received the Investigator's 
Brochure for the investigational drug; I have read the materials of preclinical studies of the 
investigational drug and the protocol for this clinical study (protocol no.: SHR-1210-II-209, 
version no.: 3.0, version date: 10 Aug., 2020). 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) 
 Signature Date 
(DD/MM/YYYY) 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 5 
LIST OF TABLES ........................................................................................................................ 9 
LIST OF FIGURES .................................................................................................................... 10 
PROTOCOL SYNOPSIS ........................................................................................................... 11 
SCHEDULE OF ACTIVITIES ................................................................................................. 17 
ABBREVIATIONS ..................................................................................................................... 21 
1 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE .................... 24 
1.1 
Background ................................................................................................................ 24 
1.2 
Scientific Rationale .................................................................................................... 24 
1.2.1 
Study rationale ............................................................................................. 24 
1.2.2 
Rationale for drug development .................................................................. 25 
1.2.3 
Basis of administration regimen .................................................................. 30 
1.3 
Potential Risks and Benefits ...................................................................................... 31 
1.3.1 
Known potential risks .................................................................................. 31 
1.3.2 
Known potential benefits ............................................................................. 32 
2 
OBJECTIVES AND ENDPOINTS ................................................................................... 32 
2.1 
Study Objectives ........................................................................................................ 32 
2.1.1 
Primary objective ......................................................................................... 32 
2.1.2 
Secondary objective ..................................................................................... 32 
2.1.3 
Exploratory objectives ................................................................................. 33 
2.2 
Study Endpoints ......................................................................................................... 33 
2.2.1 
Primary endpoint .......................................................................................... 33 
2.2.2 
Secondary endpoints .................................................................................... 33 
2.2.3 
Exploratory endpoints .................................................................................. 33 
3 
STUDY DESIGN ................................................................................................................. 34 
3.1 
Overview of Study Design ......................................................................................... 34 
3.2 
Methods to Reduce Bias ............................................................................................ 34 
3.2.1 
Enrollment/randomization/blinding ............................................................. 34 


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3.2.2 
Blinded assessment ...................................................................................... 34 
3.2.3 
Unblinding ................................................................................................... 34 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 34 
4.1 
Inclusion Criteria ....................................................................................................... 35 
4.2 
Exclusion Criteria ...................................................................................................... 36 
4.3 
Withdrawal from Study or Treatment Discontinuation ............................................. 37 
4.3.1 
Study withdrawal criteria ............................................................................. 37 
4.3.2 
Criteria for treatment discontinuation .......................................................... 38 
4.3.3 
Procedures for withdrawal or discontinuation ............................................. 38 
4.4 
Termination or Suspension of Study ......................................................................... 39 
4.5 
Definition of End of Study......................................................................................... 39 
5 
INVESTIGATIONAL DRUG ........................................................................................... 39 
5.1 
Overview of Investigational Drug ............................................................................. 39 
5.1.1 
Access to investigational drug ..................................................................... 39 
5.1.2 
Dosage form, appearance, packaging, and label .......................................... 40 
5.1.3 
Storage and stability of investigational drug ............................................... 40 
5.1.4 
Drug preparation .......................................................................................... 41 
5.1.5 
Administration of investigational drugs ...................................................... 42 
5.1.6 
Dose modification and delay ....................................................................... 43 
5.1.7 
Dose tracking ............................................................................................... 45 
5.1.8 
Precautions for special drug delivery devices .............................................. 45 
5.2 
Dosing Regimen ........................................................................................................ 46 
5.3 
Drug Management, Dispensation and Retrieval ........................................................ 46 
5.3.1 
Disposal of investigational drugs ................................................................. 46 
5.4 
Concomitant Treatment ............................................................................................. 46 
5.4.1 
Other anti-tumor/cancer or study drugs ....................................................... 47 
5.4.2 
Supportive care ............................................................................................ 48 
6 
STUDY PROCEDURES .................................................................................................... 51 
6.1 
Screening ................................................................................................................... 52 
6.2 
Enrollment ................................................................................................................. 54 


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6.3 
Treatment Period........................................................................................................ 54 
6.4 
Follow-Up .................................................................................................................. 55 
6.5 
Visit for Early Discontinuation of Treatment ............................................................ 56 
6.6 
Unscheduled Visits .................................................................................................... 57 
7 
IMMUNOGENICITY STUDIES ...................................................................................... 57 
7.1 
Immunogenicity and Drug Trough Concentration Blood Sampling and  
Processing .................................................................................................................. 57 
7.1.1 
Blood sampling time .................................................................................... 57 
7.1.2 
Processing and storage of blood samples .................................................... 57 
7.1.3 
Shipping of clinical samples ........................................................................ 58 
8 
BIOMARKER TESTING .................................................................................................. 58 
9 
EVALUATION ................................................................................................................... 58 
9.1 
Efficacy Evaluation.................................................................................................... 58 
9.2 
Safety Evaluation ....................................................................................................... 59 
9.2.1 
Pregnancy test .............................................................................................. 59 
9.2.2 
Adverse events ............................................................................................. 59 
9.2.3 
Laboratory safety evaluation ....................................................................... 59 
9.2.4 
Vital signs and physical examinations ......................................................... 59 
9.2.5 
12-Lead ECG ............................................................................................... 59 
10 
ADVERSE EVENT REPORTING ................................................................................... 60 
10.1 Adverse Event (AE) ................................................................................................... 60 
10.1.1 Definition of adverse event .......................................................................... 60 
10.1.2 AE severity grading criteria ......................................................................... 60 
10.1.3 Causality assessment .................................................................................... 61 
10.2 Serious Adverse Event (SAE).................................................................................... 61 
10.2.1 Definition of serious adverse event ............................................................. 61 
10.2.2 Hospitalization ............................................................................................. 62 
10.2.3 Progressive disease ...................................................................................... 63 
10.2.4 Potential drug-induced liver injury .............................................................. 63 
10.2.5 Other anti-tumor treatments ......................................................................... 64 


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10.2.6 SAE reporting .............................................................................................. 64 
10.2.7 Follow-up of AEs/SAEs .............................................................................. 64 
10.3 Pregnancy................................................................................................................... 65 
10.4 Adverse Events of Special Interest ............................................................................ 65 
11 
CLINICAL MONITORING .............................................................................................. 65 
12 
DATA ANALYSIS/STATISTICAL METHOD ............................................................... 67 
12.1 Sample Size................................................................................................................ 67 
12.2 Statistical Analysis Plan............................................................................................. 67 
12.3 Statistical Hypothesis and Decision Rule .................................................................. 67 
12.4 Analysis Population ................................................................................................... 68 
12.5 Statistical Methods ..................................................................................................... 68 
12.5.1 Basic methods .............................................................................................. 68 
12.5.2 Primary efficacy endpoint analysis .............................................................. 68 
12.5.3 Secondary efficacy endpoints analysis ........................................................ 69 
12.5.4 Handling of missing data ............................................................................. 69 
12.5.5 Safety analysis ............................................................................................. 69 
12.5.6 Exploratory analysis .................................................................................... 70 
13 
DATA MANAGEMENT .................................................................................................... 70 
13.1 Data Recording .......................................................................................................... 70 
13.1.1 eCRF entry ................................................................................................... 70 
13.1.2 eCRF review ................................................................................................ 70 
13.2 Data Monitoring ......................................................................................................... 71 
13.3 Data Management ...................................................................................................... 71 
13.3.1 EDC database establishment ........................................................................ 71 
13.3.2 Data entry and verification .......................................................................... 71 
13.3.3 Data review and database locking ............................................................... 71 
13.3.4 Data archiving .............................................................................................. 72 
14 
SOURCE DATA AND DOCUMENTS ............................................................................. 72 
15 
QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 72 
16 
REGULATIONS, ETHICS, INFORMED CONSENT, AND SUBJECT 


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PROTECTION .................................................................................................................... 73 
16.1 Regulatory Considerations ......................................................................................... 73 
16.2 Ethical Standards ....................................................................................................... 73 
16.3 Independent Ethics Committee .................................................................................. 74 
16.4 Informed Consent ...................................................................................................... 74 
16.4.1 ICFs and other written information for subjects .......................................... 74 
16.4.2 Informed consent process and records ......................................................... 74 
16.5 Confidentiality of Subject Information ...................................................................... 75 
17 
PUBLISHING OF STUDY RESULTS ............................................................................. 75 
18 
CLINICAL STUDY PROGRESS ..................................................................................... 76 
19 
REFERENCES .................................................................................................................... 76 
Appendix I. ECOG PS ................................................................................................................ 77 
Appendix II. Creatinine Clearance Calculation ...................................................................... 78 
Appendix III. Prohibited Traditional Chinese Medicine ........................................................ 79 
Appendix IV. Response Evaluation Criteria in Solid Tumors ............................................... 80 
Appendix V. The 2017 Chinese Staging of Nasopharyngeal Carcinoma  
(the 2008 Revised Expert Consensus on Staging of Nasopharyngeal Carcinoma) ............... 93 
 
LIST OF TABLES 
Table 1. 
Binding affinity of SHR-1210 to human, monkey, and murine PD-1 antigens ...... 26 
Table 2. 
Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigen ............ 26 
Table 3. 
PK parameters of SHR-1210 after a single intravenous infusion at  
different doses in cynomolgus monkeys ................................................................. 28 
Table 4. 
SHR-1210 dose modifications ................................................................................ 44 
Table 5. 
Classification and clinical treatment recommendations for infusion reactions ...... 50 
 


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LIST OF FIGURES 
Figure 1. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab .................. 27 
Figure 2. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab .......................... 27 
 
 


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PROTOCOL SYNOPSIS 
Study Title 
A single-arm, open-label, multi-center, phase II clinical study of anti-PD-1 antibody SHR-
1210 in recurrent/metastatic nasopharyngeal carcinoma subjects who have received previous 
at least two lines of chemotherapy 
Protocol No. 
SHR-1210-II-209 
Version No. 
3.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Principal 
Investigator 
Prof. Li Zhang 
Participating Study 
Centers 
Sun Yat-Sen University Cancer Center and 7 other domestic centers 
Study Objectives 
Primary objective: To evaluate the objective response rate (ORR) of SHR-1210 in subjects 
with recurrent/metastatic nasopharyngeal carcinoma (NPC) who have failed at least two lines 
of chemotherapy by independent review committee (IRC). 
Secondary objective: To evaluate the efficacy and safety of SHR-1210 in subjects with 
recurrent/metastatic nasopharyngeal carcinoma who have failed at least two lines of 
chemotherapy. 
Exploratory objectives: 
(1) 
To evaluate the relationship between PD-L1 expression in tumor tissues and efficacy 
of SHR-1210. 
(2) 
To evaluate the relationship between immune-related cells (T lymphocytes, B 
lymphocytes, macrophages, dendritic cells, and bone marrow-derived suppressor 
cells) in tumor microenvironment and efficacy of SHR-1210. 
(3) 
To evaluate the immunogenicity of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma, and to investigate the correlation between immunogenicity 
and efficacy/safety. 
Study Endpoints 
Primary endpoint 
IRC-assessed ORR of SHR-1210 in subjects with recurrent/metastatic nasopharyngeal 
carcinoma who have failed at least two lines of chemotherapy 
Secondary endpoints 
Efficacy 
 
Investigator-assessed ORR 
 
Duration of response (DoR); 
 
Disease control rate (DCR); 
 
Time to response (TTR); 
 
Progression-free survival (PFS) as per RECIST 1.1; 
 
Overall survival (OS) 


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Safety 
 
Incidences and severity of adverse events (AEs) and serious adverse events (SAEs), 
laboratory abnormalities, as per NCI-CTCAE V4.03 
 
Incidence of treatment interruption and discontinuation due to AEs 
Exploratory endpoints 
 
To evaluate the relationship between PD-L1 expression and efficacy of SHR-1210 
 
To evaluate the relationship between immune-related cells (T lymphocytes, B 
lymphocytes, macrophages, dendritic cells, and bone marrow-derived suppressor cells) in 
tumor microenvironment and efficacy of SHR-1210 
 
To investigate the anti-SHR-1210 antibodies (ADAs) in subjects after injection of  
SHR-1210 
Study Population 
Patients with recurrent/metastatic nasopharyngeal carcinoma who have failed at least two 
lines of chemotherapy 
Study Design 
This is a single-arm, open-label, multi-center phase II clinical study to investigate and 
evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 in subjects with 
recurrent/metastatic nasopharyngeal carcinoma who have failed at least two lines of 
chemotherapy. 
Investigational Drug Recombinant humanized anti-PD-1 monoclonal antibody for injection (SHR-1210) 
(Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd.) 
Method of 
Administration 
SHR-1210: intravenous infusion (premedication not required) at a fixed dose of 200 mg over 
30 min (no less than 20 min and no more than 60 min, including flushing), on D1 and D15 of 
each 4-week cycle. The treatment will continue until the occurrence of confirmed PD, 
intolerable toxicity, voluntary withdrawal by the subject, or treatment discontinuation 
determined by the investigator. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Aged 18-75 years (inclusive), male or female; 
2. 
Moderately differentiated or undifferentiated locally recurrent/metastatic nasopharyngeal 
carcinoma (WHO type II-III) in histopathology; 
3. 
Patients in clinical stage IVb who have previously failed first-line platinum-based 
monotherapy or combined chemotherapy and second-line monotherapy or combined 
chemotherapy [the 2017 Chinese Staging of Nasopharyngeal Carcinoma (the 2008 
Revised Expert Consensus on Staging of Nasopharyngeal Carcinoma)]. Definition of 
treatment failure: ongoing chemotherapy after recurrence/metastasis or progressive 
disease after treatment; concurrent chemoradiotherapy, with progression within 6 months, 
may be counted as first-line treatment; all modifications of dosing regimen due to drug 
intolerance are not considered treatment failure; 
4. 
ECOG PS: 0-1; 
5. 
Life expectancy ≥ 12 weeks; 


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6. 
At least one measurable lesion per the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1), and the measurable lesions should not have been treated locally such as 
with radiotherapy; 
7. 
Fresh tissues or tissue samples for biomarker (such as PD-L1) analysis must be provided. 
Fresh tissues are preferred. Archival samples of 5-8 paraffin embedded sections with a 
thickness of 3-5 μm are also acceptable when a fresh biopsy is not accessible; 
8. 
Major organ functions must meet the following requirements (no blood components or 
cell growth factors are allowed to be used within 2 weeks before the start of study 
treatment): 
a. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. 
Platelets ≥ 90 × 109/L; 
c. 
Hemoglobin ≥ 9 g/dL; 
d. 
Serum albumin ≥ 2.8 g/dL; 
e. 
Bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 1.5 × ULN; for liver metastasis, ALT and 
AST ≤ 5 × ULN; 
f. 
Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault); 
9. 
Female patients of childbearing potential must have a negative pregnancy test result 
within 72 h prior to the start of study treatment, and be willing to take at least 2 highly 
effective contraceptive measures during the study and within 60 days after the last dose 
of the investigational drug (around 5 half-lives of the drug + menstrual cycle). Male 
patients with partners of childbearing potential must take at least two contraceptive 
measures during the study and within 120 days after the last dose of the investigational 
drug (around 5 half-lives of the drug + sperm production cycle); 
10. Patients must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 
Exclusion Criteria 
Patients meeting any of the following are ineligible to participate in this study 
1. 
Patients with any active autoimmune disease or history of autoimmune disease (e.g., 
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, 
nephritis, hyperthyroidism, and hypothyroidism (may be enrolled after effective 
hormone replacement therapy); patients with vitiligo or asthma in childhood that has 
completely relieved and requires no intervention in adulthood and patients requiring 
medical interventions with bronchodilators may be enrolled); 
2. 
Patients with clinically symptomatic metastases to central nervous system (e.g., cerebral 
edema) requiring hormone interventions, or progression of brain metastasis. Patients who 
have received treatment for metastasis to brain or meninges may be enrolled if MRI and 
clinically stable (without the need of > 10 mg/day prednisone or equivalent); 
3. 
Patients with other malignant tumors previously or currently (except for malignant 
tumors that have been cured with a cancer-free survival of more than 5 years, e.g., basal 
cell carcinoma, cervical carcinoma in situ, and papillary thyroid carcinoma); 
4. 
Uncontrolled cardiac symptoms or disease, such as (1) > NYHA Class II cardiac failure, 
(2) unstable angina, (3) myocardial infarction within one year, and (4) clinically 
significant supraventricular or ventricular arrhythmias requiring clinical interventions; 


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5. 
Patients requiring systemic treatment with corticosteroids (> 10 mg/day of prednisone or 
equivalent) or other immunosuppressive medications within 14 days prior to 
administration of the investigational drug. In the absence of active autoimmune disease, 
inhaled or topical use of corticosteroids and an equivalent dose to > 10 mg/day of 
prednisone for adrenal hormone replacement are permitted; 
6. 
Patients who have received chemotherapy or targeted therapy less than 4 weeks prior to 
the start of  study treatment; palliative radiotherapy for symptomatic control is permitted 
but must be completed at least 2 weeks prior to the start of study treatment, and no 
additional radiotherapy should be scheduled for the same lesion; patients with an AE 
induced by past treatment that has not recovered to CTCAE Grade ≤ 1 (except for 
alopecia and sequelae of relevant neurotoxicity of previous platinum therapy); 
7. 
Patients with active infection or unexplained pyrexia > 38.5 °C at screening or prior to 
the first dose (those with tumor-induced pyrexia may be enrolled as per the judgment of 
the investigator); 
8. 
Patients with congenital or acquired immune deficiency (such as HIV infection), active 
hepatitis B (HBV-DNA ≥ 104 copies/mL or 2000 IU/mL) or hepatitis C (positive anti-
HCV antibodies, and HCV RNA titer higher than the lower limit of detection of the 
analytical method); 
9. 
Patients who have participated in other clinical studies within 1 month before the start of 
study treatment or are participating in other clinical studies; 
10. Patients who have received live vaccines within 4 weeks before the start of study 
treatment; 
11. Patients who have used systemic antibiotics within 1 month before the start of study 
treatment; 
12. Patients who have received previous treatment with other anti-PD-1 antibodies or other 
checkpoint monoclonal antibodies, including immunotherapy targeting CTLA-4 and PD-
L1; 
13. Patients with known history of psychotropic substance abuse, alcoholism, or drug abuse; 
14. Pregnant or lactating women; 
15. Other factors, as determined by the investigator, which may result in premature 
discontinuation of treatment. For example, other serious medical conditions (including 
mental illnesses) requiring concomitant treatment, serious laboratory abnormalities, 
family or social factors, and other conditions that may affect patients' safety or the 
collection of study data. 
Immunogenicity 
Study 
Collection time for immunogenicity blood samples: 
Once before the administration on C1D1, C2D1, C3D1, and C4D1, once every 3 cycles after 
Cycle 4, and once before withdrawal from study. 


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Study Withdrawal 
Criteria 
A subject must withdraw from/discontinue the treatment when any one of the following 
conditions occurs: 
1. 
The subjects withdraw informed consent and request to withdraw from the study; 
2. 
Imaging examinations show progressive disease; 
As per RECIST v1.1, a confirmation is required 4-6 weeks after the first occurrence of 
progressive disease (except those with rapid progression or significant clinical progression); 
Subjects with re-confirmed progressive disease may continue the treatment if clinically stable 
(as assessed by the investigator) until further radiographic progression; 
Definition of stable clinical symptoms: a. no clinically significant symptoms or changes in 
laboratory tests; b. no changes in the performance status score (deterioration); and c. non-
tumor rapid progression and tumor progression not involving major organs/sites (e.g., spinal 
cord compression); 
3. 
Cumulative use of SHR-1210 for 2 years; 
4. 
Subjects with intolerable toxicity; 
5. 
Subjects with poor compliance; 
6. 
Subjects lost to follow-up or becoming pregnant; 
7. 
Other reasons for which the investigator considers a withdrawal necessary. 
Study Treatment 
Discontinuation 
Criteria 
The discontinuation criteria of this study include but are not limited to the following: 
1. 
Discovery of unexpected, important, or unacceptable risks to the subjects; 
2. 
Major errors in the protocol found during the implementation of the study; 
3. 
Ineffective investigational drug/treatment, or meaninglessness to continue the study; 
4. 
Discontinuation as determined by the sponsor due to reasons such as severe delay in 
enrollment or frequent protocol deviations. 
Sample Size 
Determination 
Efficacy hypothesis 
According to study SHR-1210-101, the ORR of all dose groups (n = 93) of NPC subjects was 
29.0%, and the ORR of the 200 mg dose group (n = 68) was 36.8%. In the subgroup analysis, 
the ORR of all dose groups (n = 58) of subjects who had failed at least two lines of 
chemotherapy was 27.6%, and the ORR of the 200 mg dose group (n = 43) was 37.2%. Also, 
referring to the efficacy results of similar drugs, the intended study for registration will use a 
dose of 200 mg, and a conservative estimate of the upper limit of ORR is set at 26%. 
Pembrolizumab for the treatment of head and neck squamous cell carcinoma was approved by 
the FDA with an ORR of 16% in a single-arm study. Therefore, it is stipulated that the lower 
limit of the 95% confidence interval for the ORR for this study should not be less than 15%. 
Sample size calculation 
According to the above efficacy hypothesis (ORR = 26%), with a one-sided alpha = 0.025, 
enrolling 139 subjects can achieve a power of 90% that the lower limit of 95% confidence 
interval for ORR is not less than 15%. In order to ensure that the 139 subjects are included in 
the evaluation, assuming a dropout rate of 10%, 155 subjects should be enrolled. 


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Statistical Methods 
Categorical data will be descriptively summarized using statistics including the frequency (n) 
and percentage (%), as well as the 95% confidence interval of the overall percentage when 
necessary. Continuous data will be descriptively summarized using statistics including the 
mean, standard deviation (SD), median, minimum, and maximum. For time to event data, the 
Kaplan-Meier method will be used to estimate the survival function, plot the survival curve, 
and estimate the median survival time, and its 95% confidence interval will be calculated. 
Safety analysis: 
For safety analysis, the following data (but not limited to) will be descriptively summarized 
based on the safety set. 
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; 
Laboratory measurements, vital signs, ECG, and their changes from baseline; 
Number and rate of laboratory measurements, vital signs, and ECG data "changed from 
normal to abnormal" or "exacerbated abnormally" after the trial. 
Efficacy analysis: 
The objective response rate (ORR) and disease control rate (DCR) and their 95% confidence 
intervals (Clopper-Pearson method) will be estimated. 
The Kaplan-Meier method will be used to estimate the PFS, DoR, and OS and the 
corresponding 95% confidence intervals will be calculated (Brookmeyer-Crowley method 
based on log-log transformation, with the standard error calculated using the Greenwood 
formula). 
TTR will be described using mean, standard deviation, median, maximum, and minimum. 
Other analyses: 
Subject disposition and populations; 
Subjects' basic characteristics (including demographics, life history, medical history, and 
medication history); 
Discontinuations; 
Exploratory analysis, etc. 
Study Time 
Estimated enrollment of the first subject: Jun. 2018 
Estimated enrollment of the last subject: Mar. 2019 
Estimated study completion: one year after the last subject's first dose, the subjects 
undergoing treatment will enter the expansion study of SHR-1210 for continued treatment and 
observation. 


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SCHEDULE OF ACTIVITIES 
 
Screening Period 
(-28 days) 
Treatment Period 
End of 
Treatment/
Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window 
D-28 to D-1 
D-7 to D-1 
D1 
D15 ± 3  
D1 ± 3  
D15 ± 3  
30 days  
(± 7 days) after 
the last dose[23] 
60 and 90 days 
(± 7 days) after 
the last dose[23] 
Signing of Informed Consent 
Form[1] 
√ 
 
 
 
 
 
 
 
 
Verification of Eligibility 
 
√ 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
Medical History[2] 
√ 
 
 
 
 
 
 
 
 
ECOG PS[3] 
 
√ 
 
 
√ 
 
√ 
 
 
Vital Signs[4] 
 
√ 
 
√ 
√ 
√ 
√ 
 
 
Physical Examination[5] 
 
√ 
 
√ 
√ 
√ 
√ 
 
 
Blood Routine[6] 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
 
Urinalysis[7] 
 
√ 
 
 
√ 
 
√ 
 
 
Fecal Occult Blood[8] 
 
√ 
 
 
√ 
 
 
 
 
Blood Biochemistry[9] 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
 
Thyroid Function[10] 
 
√ 
 
 
√ 
 
√ 
√ 
 
Coagulation Function[11] 
 
√ 
 
 
 
 
 
 
 


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Screening Period 
(-28 days) 
Treatment Period 
End of 
Treatment/
Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window 
D-28 to D-1 
D-7 to D-1 
D1 
D15 ± 3  
D1 ± 3  
D15 ± 3  
30 days  
(± 7 days) after 
the last dose[23] 
60 and 90 days 
(± 7 days) after 
the last dose[23] 
EBV-DNA Test[12] 
√ 
 
 
 
√ 
 
√ 
 
 
Liver-Related Serology[13] 
√ 
 
 
 
 
 
 
 
 
ECG[14] 
 
√ 
 
√ 
√ 
√ 
√ 
 
 
Echocardiography[15] 
 
√ 
 
 
 
 
 
 
 
Pregnancy Test[16] 
 
√ 
 
 
 
 
√ 
 
 
Tumor Imaging Evaluation[17] 
√ 
 
√ 
 
 
Administration of SHR-1210[18] 
 
 
√ 
√ 
√ 
√ 
 
 
 
Adverse Events[19] 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Concomitant Medication[20] 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Immunogenicity[21] 
 
 
√ 
 
√ 
 
√ 
 
 
Tumor Tissue[22] 
√ 
 
 
 
 
 
 
 
 
Survival Follow-Up[24] 
 
 
 
 
 
 
 
√ 
√ 
Note: Other than the examinations and time points listed in the table, the investigator may add visits and other investigations at any time when needed. Results 
should be documented in the "Unscheduled Examinations" section of eCRF.  
[1] An informed consent form signed by the subject or legal representative must be first obtained before starting screening. 
[2] Medical history: including tumor history (diagnosis, surgery, radiotherapy, chemotherapy history, as well as use of antibiotics within 3 months before 
enrollment) and history of other concurrent diseases. 
[3] ECOG PS: within 7 days before the first dose, before each administration of each cycle (do not need to be tested for the first dose if completed within 7 days 
before the first dose at screening), and at the end of treatment/upon withdrawal. 


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[4] Vital signs: blood pressure, pulse, body temperature, and respiratory rate; within 7 days before the first dose, before each administration of each cycle (do 
not need to be tested for the first dose if completed within 7 days before the first dose at screening), and at the end of treatment/upon withdrawal. 
[5] Physical examination: within 7 days before the first dose and at the end of treatment/upon withdrawal, a comprehensive physical examination (including 
head and face, skin, lymph nodes, neck, 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 each administration of each cycle (do not need to be tested for the 
first dose if completed within 7 days before the first dose at screening); symptom-directed physical examination can be performed if clinically indicated. 
[6] Blood routine: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, lymphocyte count; within 7 days before the first dose, before each 
administration of each cycle (do not need to be tested for the first dose if completed within 7 days before the first dose at screening), at the end of 
treatment/upon withdrawal, and 30 days after the last dose. 
[7] Urinalysis: WBC, RBC, and urine protein. Within 7 days before the first dose, before administration on D1 of each cycle, and at the end of treatment/upon 
withdrawal. In case of a urine protein ≥ 2+, a 24-h urine protein test (quantitative) should be added. 
[8] Fecal occult blood: within 7 days before the first dose, on D1 of each cycle. 
[9] Blood biochemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea nitrogen (preferred) or urea, total protein, albumin, creatinine, blood 
glucose, lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-. Within 7 days before the first dose, before each administration of each cycle (do not need to 
be tested for the first dose if completed within 7 days before the first dose at screening), at the end of treatment/upon withdrawal, and 30 days after the last 
dose. 
[10] Thyroid function: TSH, FT3, FT4. Within 7 days before the first dose, before administration on D1 of each cycle, at the end of treatment/upon withdrawal, 
and 30 days after the last dose. 
[11] Coagulation function: APTT, PT, FIB, INR. Within 7 days before the first dose. 
[12] EBV-DNA test: at screening, before administration on D1 of every 2 cycles, and at the end of treatment/upon withdrawal. 
[13] Serology: HBsAg (if positive, HBV-DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, HCV-RNA test required), and HIV-Ab. 
Within 14 days before the first dose. 
[14] ECG: within 7 days before the first dose, before each administration of each cycle (do not need to be tested for the first dose if completed within 7 days 
before the first dose at screening), and at the end of treatment/upon withdrawal. 
[15] Echocardiography: within 7 days before the first dose; performed when clinically indicated. 
[16] Pregnancy test: for women of childbearing potential only. Within 72 h before the first dose, and at the end of treatment/upon withdrawal. 


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[17] Tumor imaging evaluation: CT or MRI of the nasopharynx, neck, chest and abdomen (including pelvic cavity); scanning with contrast is preferred if not 
contraindicated. 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 administration and before informed consent may be used as long as they meet the RECIST 1.1. 
 
During the treatment period, imaging examinations should be performed every 8 weeks on the same sites as those of the baseline examinations. 
Examinations should also be performed as appropriate when new lesions are suspected. Tumor examinations should be performed in time when 
subjects withdraw from the study due to any reasons (± 4 weeks, but not required to be repeated if the time from the previous 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). Subjects who discontinue treatment for reasons other than imaging-confirmed PD must also undergo a tumor evaluation 
every 8 weeks until documentation of confirmed PD, start of a new anti-tumor treatment, lost to follow-up, or death. Subjects showing CR or PR for 
the first time (whichever comes first) should undergo imaging evaluation for confirmation at least 4 weeks (28 days) later, with a time window of + 7 days. 
[18] Administration of SHR-1210: once every 2 weeks. Administrations are given on D1 and D15 of each 4-week cycle. 
[19] Adverse events: As per NCI CTCAE V4.03, any adverse event that occurs during the safety information collection period should be observed and 
documented. The safety information collection period is from the signing of the informed consent form to the start of a new anti-tumor treatment beyond or 
within 90 days after the last dose. After the safety information collection period, only treatment-related adverse events are collected. All investigational 
drug-related adverse events should be followed up until resolved, returning to baseline or ≤ Grade  1, reaching a steady state, obtaining a reasonable 
explanation, lost to follow-up, or death. 
[20] Concomitant medications: Concomitant medications from 30 days before the first dose to 90 days after the last dose will be documented; only concomitant 
medications for treatment-related AEs will be documented from 30 days after the end of treatment. (The use of all antibiotics within 3 months before 
administration and during study treatment period will be documented) 
[21] Immunogenicity blood sampling: once before the administration on C1D1, C2D1, C3D1, and C4D1; once every 3 cycles after Cycle 4; and once before 
withdrawal from study. 
[22] Tumor tissue: collected before enrollment; fresh biopsy is preferred, otherwise collect archived tumor tissue specimens. 
[23] 90 days after the last dose: Subjects must return to the study center for a follow-up 30 days after the last dose, and the safety information can be obtained 
via telephone calls on D60 and D90 after the last dose (including AE outcome, new SAEs and AEs of special interest); the time window is ± 7 days.  
[24] Survival follow-up: starting from the last dose, once per month, with a time window of ± 7 days.  


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ABBREVIATIONS 
Abbreviation 
Full Name 
12-Lead ECG 
12-Lead electrocardiogram 
Ab 
Antibody 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
ASR 
Age-standardized rate 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
Ca2+ 
Calcium 
CFDA 
China Food and Drug Administration (now NMPA) 
CI 
Confidence interval 
CIOMS 
The Council for International Organizations of Medical Sciences 
Cl- 
Blood chlorine 
Cr 
Creatinine 
CR 
Complete response 
CRA 
Clinical research associate 
CRC 
Clinical research coordinator 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte antigen 4 
D 
Day 
DC 
Dendritic cell 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


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Abbreviation 
Full Name 
EDC 
Electronic data capture system 
FAS 
Full analysis set 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
γ-Glutamyl transpeptidase 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
hr 
Hour 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator's brochure 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
IRC 
Independent review committee 
iRECIST 
Modified RECIST 1.1 for immune based therapeutics 
IV 
Intravenously 
IU 
International unit 
K+ 
Serum potassium 
kg 
Kilogram 
LSLV 
Last subject last visit 
Mg2+ 
Magnesium 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic resonance imaging 
Na+ 
Plasma sodium 
NCI 
National Cancer Institute 
NPC 
Nasopharyngeal carcinoma 


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Abbreviation 
Full Name 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PI 
Principal investigator 
PLT 
Blood platelet 
PR 
Partial response 
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
sec 
Second 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation/stable disease 
SDV 
Source data verification 
SOP 
Standard operating procedure 
T1DM 
Type 1 diabetes mellitus 
TSH 
Thyroid-stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
W 
Week 
WBC 
White blood cell count 
WHO 
World Health Organization 
μg 
Microgram 
μm 
Micrometer 
 
 


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1 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
1.1 
Background 
Nasopharyngeal carcinoma is a relatively rare tumor worldwide, but has a higher incidence in 
Asian populations, with an age-standardized rate (ASR) of 2.3 in men and 0.9 in women. 
Especially in Southeast Asian populations, the ASR is 6.4 in men and 2.4 in women (1). 
Nasopharyngeal carcinoma in China also shows a significant geographical pattern. It ranks first 
in the incidence of head and neck tumors and has a significant geographical pattern, mainly 
concentrated in southern China, with an annual incidence of up to 80/100,000 (2). 
Radiotherapy is the primary treatment of early-stage nasopharyngeal carcinoma. The 5-year 
overall survival rates of stage I and IIA subjects are 90% and 84%, respectively. However, 
approximately 20-37% of subjects will have local recurrence or distant metastasis. Cisplatin-
based combination chemotherapy is the first-line treatment regimen for such subjects. The 
response rate can reach 50-80%, the median time to progression is 5-11 months, and the median 
overall survival is around 12-20 months. For subjects who have failed first-line chemotherapy, 
there is no particularly effective treatment option. Although second-line chemotherapy drugs 
such as gemcitabine and capecitabine show some efficacy, the median survival of subjects has 
not been significantly improved, at only 7-11 months (3). For distant metastases of 
nasopharyngeal carcinoma, on the one hand, it is difficult to achieve a durable response. Most 
subjects will have progressive disease within a short period of time after the initial response, and 
the recurrence site will generally be resistant to the second chemotherapy. On the other hand, it 
may result in mucositis, vomiting, myelosuppression, and other toxic side effects, which are 
intolerable for most subjects. Therefore, there is an urgent need to develop new drugs for the 
treatment of recurrent/metastatic nasopharyngeal carcinoma. 
1.2 
Scientific Rationale 
1.2.1 
Study rationale 
Approximately 90% of nasopharyngeal carcinoma is histopathologically classified as 
undifferentiated or poorly differentiated squamous cell carcinoma, characterized by EBV virus 
infection and a large number of immune infiltration (mainly by T cells) in the primary tumor. 
Activated immune cells are very important in the removal of residual tumor foci. According to 
reports, local infiltration of T lymphocytes is a prognostic factor for nasopharyngeal carcinoma. 
However, there are many immunosuppressive mechanisms in the tumor microenvironment that 
can inactivate T cells, leading to an increased risk of recurrence (4). 


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The programmed cell death protein-1 (PD-1) pathway is one of the most critical checkpoint 
pathways responsible for regulating tumor-induced immunosuppression. PD-1 is a protein 
receptor expressed on the surface of T cells discovered in 1992 and is involved in the process of 
cell apoptosis. PD-1 is a member of the CD28 family and has a 23% consistency in amino acid 
sequence with cytotoxic T lymphocyte antigen 4 (CTLA-4). However, its expression is different 
from CTLA. It is primarily expressed by 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. PD-L1 is expressed in 
approximately 89% of EBV-related nasopharyngeal carcinoma. The binding of PD-1 and PD-L1 
can activate the PD-1 pathway and lead to T cell failure, ultimately resulting in a poor prognosis 
of this type of nasopharyngeal carcinoma [1]. Therefore, immune checkpoint inhibitors against 
PD-1/PD-L1 may be a new method of treating nasopharyngeal carcinoma. 
KEYNOTE-028 is a phase Ib clinical trial of Merck's pembrolizumab (MK-3475) conducted in 
subjects with advanced solid tumors with positive PD-L1 expression. Among the 27 evaluable 
subjects with nasopharyngeal carcinoma, 7 showed PR and 14 showed SD, with a best ORR of 
25.9% (95% CI: 11.1-46.3) (5). Bristol Myers Squibb announced the results of the cohort of 24 
subjects with advanced nasopharyngeal carcinoma in the study of nivolumab in the treatment of 
virus-related tumors (CheckMate-358) (6) at the 2017 ASCO. The ORR was 20.8% and the DCR 
was 45.8%. Currently, Bristol Myers Squibb's nivolumab (PD-1 inhibitor), Novartis' PDR001 
(PD-1 inhibitor), Merck's pembrolizumab (MK-3475) (PD-1 inhibitor), and Merck/Pfizer's 
avelumab (anti-PD-L1 antibody) are currently under phase II clinical trials for the treatment of 
recurrent/metastatic nasopharyngeal carcinoma subjects who failed platinum-based treatments. 
The preliminary efficacy of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of 
nasopharyngeal carcinoma further suggests that it may become a new generation of drugs for the 
treatment of nasopharyngeal carcinoma. 
1.2.2 
Rationale for drug development 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. used PD-1 as a target and recombinant PD-1 protein 
as an immunogen to obtain a series of PD-1 antibodies in mice. Through a large number of in 
vitro binding assays, in vitro ligand blocking assays, T cell proliferation assays, animal 
experiments, and antibody druggability assessments, an antibody prototype was selected. Then, a 
humanized design of the murine antibody prototype was carried out through computer 
simulations, resulting in several humanized anti-PD-1 monoclonal antibodies. Finally, SHR-
1210, the one with the highest activity among those antibodies, was selected for further 
development. Phase I clinical trials have been conducted by Hengrui in Australia and China 
since 2015. Several clinical studies are currently underway. 


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1.2.2.1 
Preclinical study results of SHR-1210 
1.2.2.1.1 
Drug name and physicochemical properties 
[Generic Name]: SHR-1210 Injection 
[English Name]: SHR-1210 Injection 
[Molecular Weight]: approx. 146.3 kDa 
1.2.2.1.2 
Pharmacology and mechanism of action 
Humanized anti-PD-1 monoclonal antibody can specifically bind to PD-1, blocking the 
interaction between PD-1 and its ligands, and restore T cell immune response to tumor cells. 
1.2.2.1.3 
Pharmacodynamic studies 
(1) 
Antibody affinity 
Results from affinity assays involving SHR-1210 and human, monkey, and murine PD-1 
antigens showed that the affinity of SHR-1210 for human and monkey PD-1 antigens were 6.9 nM 
and 4.1 nM, respectively. No binding was detected with murine PD-1 antigens. See Table 1 for 
details. 
Table 1. 
Binding affinity of SHR-1210 to human, monkey, and murine PD-1 antigens 
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 
Results from the binding affinity assay showed that the binding affinity of SHR-1210 to human 
PD-1 antigen was 3.0 nM, similar to nivolumab and MK3475. See Table 2 for details. 
Table 2. 
Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigen 
Antibody 
Antigen 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
MK3475 
Human PD-1 antigen 
3.2 
(2) 
Inhibition of PD-1/PD-L1 binding by SHR-1210 
Results from inhibition of PD-1/PD-L1 binding by SHR-1210 showed that the in vitro binding 
inhibition activity of SHR-1210 was similar to those of nivolumab and pembrolizumab (see 
Figure 1 and Figure 2). IC50 values were 0.70 nM/0.79 nM and 0.79 nM/0.77 nM, respectively. 
 
 


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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 
1.2.2.1.4 
Toxicology studies 
In a pre-clinical single dose toxicity study in cynomolgus monkeys, 8 monkeys (half male and 
half female) were randomized to 2 groups. The animals in Group 2 were given an intravenous 
injection of SHR-1210 once every other day at doses of 200, 400, and 800 mg/kg, respectively, 
in a dose-escalation manner. No changes in clinical symptoms, 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, consecutively 
intravenous administration of SHR-1210 at 20, 50, and 100 mg/kg/dose once a week for 4 weeks 
(5 doses in total) was well-tolerated in animals of 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 
seen. No changes in organ weight, gross lesions, or histopathological changes associated with 
SHR-1210 were found. 


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1.2.2.1.5 
Pharmacokinetic study 
The PK parameters obtained after a single intravenous infusion of SHR-1210 in cynomolgus 
monkeys are shown in Table 3. 
Table 3. 
PK parameters of SHR-1210 after a single intravenous infusion at different 
doses in cynomolgus monkeys 
Dose 
(mg/kg) Gender 
T1/2 
(hr) 
Tmax 
(hr) 
Cmax 
(µg/mL)  
AUClast 
(hr·µg/mL)  
Vz 
(mL/kg) 
Cl 
(mL/hr/kg) 
MRTlast 
(hr) 
1 
Female 76.06 ± 32.93  0.83 ± 0.29  31.16 ± 11.25  
1716.12 ± 453  
54.09 ± 14.85  0.57 ± 0.17  80.95 ± 18.58  
 
Male 
91.72 ± 25.26  0.83 ± 0.29  35.96 ± 13.09  
2359.7 ± 684.07  
55.15 ± 20.51  0.37 ± 0.06  102.23 ± 38.56  
 
Overall 83.89 ± 27.62  0.83 ± 0.26  33.56 ± 11.23  
2037.91 ± 627.32  54.62 ± 16.02  0.47 ± 0.15  91.59 ± 29.47  
3 
Female 92.95 ± 22.60  0.83 ± 0.29  81.09 ± 12.66  6896.79 ± 1673.36  40.75 ± 12.66  0.44 ± 0.11  120.92 ± 49.96  
 
Male 
113.54 ± 8.26  1.67 ± 0.58  71.65 ± 10.85  6380.25 ± 2062.85  47.05 ± 27.05  0.47 ± 0.12  127.10 ± 59.25  
 
Overall 103.25 ± 18.94  1.25 ± 0.61  76.37 ± 11.74  6638.51 ± 1703.60  43.91 ± 19.21  0.46 ± 0.11  125.01 ± 49.13  
10 
Female 169.70 ± 38.96  2.17 ± 1.76  217.46 ± 20.22 31357.28 ± 9338.28  41.25 ± 25.76  0.33 ± 0.1  
179.68 ± 73.6  
 
Male 
128.94 ± 35.93  0.67 ± 0.29  251.88 ± 6.49  26779.98 ± 7205.43  30.9 ± 30.2  
0.31 ± 0.05  113.25 ± 44.39  
 
Overall 149.32 ± 40.28  1.42 ± 1.39  234.67 ± 23.15  29068.63 ± 7869.83  36.07 ± 25.34  0.32 ± 0.07  146.46 ± 65.42  
1.2.2.2 
Clinical study results 
Camrelizumab for injection (Hengrui R&D code: SHR-1210) is a humanized PD-1 antibody 
independently developed and manufactured by Jiangsu Hengrui Pharmaceuticals Co., Ltd. On 
26 Jan., 2016, it was approved for clinical studies (2016L01455). As of 15 Oct., 2017, a total of 
14 clinical studies in the population with advanced malignant tumors have been carried out: 
including 4 on advanced solid tumors, 3 on non-small cell lung cancer (NSCLC), 1 on 
hepatocellular carcinoma (HCC), 1 on esophageal cancer (ESC), 1 on melanoma, 1 on 
nasopharyngeal carcinoma (NPC), 1 on primary liver cancer (PLC), 1 on classic Hodgkin's 
lymphoma (cHL), and 1 on extranodal NK/T cell lymphoma. In 2016, three phase I clinical 
trials, i.e., SHR-1210-101, SHR-1210-102, and SHR-1210-103, were carried out in China. As of 
28 Feb., 2018, the three phase I clinical trials in China had enrolled 123, 36, and 98 subjects, 
respectively. All studies have not been completed and are still in progress. 
Study SHR-1210-101 mainly included subjects with advanced solid tumors who have failed 
standard treatment or lack effective treatment methods. The study consisted of three stages, 
including bridge escalation, PK expansion, and clinical expansion. In Stage I, a "3 + 3" dose 
escalation mode was adopted, as well as three groups of calculated doses of SHR-1210 (1 mg/kg, 
3 mg/kg, and 10 mg/kg) and one group of fixed-dose bridge escalation (200 mg/time, equivalent 
to the calculated dose of 3 mg/kg). In Stage II, dose expansion was carried out based on the 
preliminary safety data from Stage I, with 8-12 subjects with solid tumor enrolled in each dose 
group. Stage III was clinical expansion and set a fixed-dose group (200 mg/time). Subjects with 
nasopharyngeal carcinoma and lung cancer with brain metastases were included. 


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 
Pharmacokinetic results from SHR-1210-101: 
The pharmacokinetic results of the 49 subjects in the first two stages of study SHR-1210-101 
showed that, after a single intravenous infusion of SHR-1210 in subjects with advanced solid 
tumors, most PK parameters of the dose groups (1 mg/kg, 3 mg/kg, 200 mg/time, and 10 mg/kg) 
showed a proportional dose-response relationship. Among them, Cmax was linearly associated to 
dose administered, and the in vivo exposure (AUC0-last and AUC0-inf) increased with the increase 
of dose administered. Meanwhile, the half-life (t1/2) of SHR-1210 also increased with the 
increase of dose, while the clearance rates (CLs) decreased slowly with the increase of dose. This 
may be due to the characteristic that endocytosis of macromolecular drugs after binding to the 
receptor results in receptor-mediated drug metabolism (TMDD). After repeated administrations, 
the serum SHR-1210 of each dose group generally reached a steady state after 3-5 treatment 
cycles. The maximum and minimum concentrations of SHR-1210 increased with the increase of 
dose. There was generally no accumulation at steady state. During repeated administrations, the 
overall receptor occupancy rate of each dose group of SHR-1210 maintained at approximately 
75%. PD-1 receptor occupancy is the theoretical prerequisite for the anti-tumor effect of SHR-
1210. This result suggested that SHR-1210 can fully occupy the PD-1 receptor and block the  
PD-1/PD-L1 signaling pathway at an administration frequency of Q2W. 
 
Efficacy results from study SHR-1210-101 in patients with advanced nasopharyngeal 
carcinoma 
In study SHR-1210-101, a total of 31 subjects with nasopharyngeal carcinoma were enrolled in 
the first two stages. Stage III was clinical expansion and set a fixed-dose group (200 mg/time), 
with 62 subjects with nasopharyngeal carcinoma enrolled. A total of 93 subjects with advanced 
nasopharyngeal carcinoma were enrolled in the study. All subjects were in advanced stage, more 
than 90% of whom were in clinical stage IV; 55% of subjects had ≥ 3 organs with metastasis; 
more than 65% of subjects had received at least two lines of chemotherapy, of which 28% had 
received second-line chemotherapy and 34% had received third-line and above chemotherapy. 
The overall objective response rate was 29.0% (1 CR + 26 PR), and the disease control rate was 
58.1% (1 CR + 26 PR + 27 SD). Especially in the 68 subjects of the 200 mg dose group, the 
objective response rate was 36.8% (1 CR + 24 PR), and the disease control rate was 64.7% (1 CR 
+ 24 PR + 19 SD). In the subgroup analysis, 58 subjects had previously received at least two 
lines of chemotherapy, the objective response rate was 27.6% (1 CR + 15 PR), and the disease 
control rate was 51.7% (1 CR + 15 PR + 14 SD). A total of 43 subjects in the 200 mg dose group 
who had previously received at least two lines of chemotherapy had an objective response rate of 
37.2% (1 CR + 15 PR) and a disease control rate of 58.1% (1 CR + 15 PR + 9 SD). 
 
Safety summary of the 3 phase I studies of SHR-1210 


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After camrelizumab was approved for clinical trials in 2016, 3 phase I clinical studies have been 
carried out in China, all of which are studies on the safety and tolerability in subjects with 
advanced solid tumors. As of 28 Feb., 2018, a total of 258 subjects with advanced solid tumors 
who failed standard treatment were included in the 3 phase I studies. The subjects included 
190 males and 68 females, with an age of 51.2 ± 11.22 year s old; height of 166.68 ± 7.568 cm; 
weight of 61.00 ± 11.130 kg; BMI of 21.92 ± 3.461 kg/m 2; 130 subjects (50.4%) had a baseline 
ECOG PS of 0 and 127 subjects (49.2%) had a baseline ECOG PS of 1; 257 subjects (99.6%) 
had a history of systemic chemotherapy; 155 subjects (60.1%) had a history of radiotherapy. 
Among the 258 subjects, the adverse events related to camrelizumab for injection were mostly of 
CTCAE Grade 1-2, and the incidence of ≥ Grade 3 treatment-related adverse events was 31.8%; 
common treatment-related adverse events mainly included skin and subcutaneous tissue 
disorders: cutaneous capillary endothelial proliferation (81.8%), pruritis (22.1%), rash (16.3%); 
general disorders: asthenia (37.6%), fever (20.9%); blood and lymphatic system disorder: anemia 
(27.5%); investigations: aspartate aminotransferase increased (21.7%), alanine aminotransferase 
increased (18.6%), conjugated bilirubin increased (16.7%), white blood cell count decreased 
(14.7%), blood sodium decreased (14.3%), blood bilirubin increased (12.0%); renal and urinary 
disorder: proteinuria (22.1%); endocrine disorder: hypothyroidism (19.8%); metabolism and 
nutrition disorder: hypoproteinemia (19.4%); respiratory, thoracic, and mediastinal disorders: 
cough (19.0%); gastrointestinal disorders: diarrhea (11.2%), nausea (10.5%); infections and 
infestations: upper respiratory tract infection (10.1%). Common hematological adverse events 
included anemia. Common non-hematological adverse events included cutaneous capillary 
endothelial proliferation, ALT and AST increased, fever, rash, and blood bilirubin increased. 
Cutaneous capillary endothelial proliferation was a unique skin reaction of SHR-1210 with a 
high incidence. However, it was mild, clinically tolerable, and disappeared after dose 
discontinuation. 
1.2.3 
Basis of administration regimen 
Preliminary data analysis of the safety and efficacy of SHR-1210 at the calculated doses (1-10 mg/kg) 
and fixed dose (200 mg) showed no DLT in all dose groups in this study, but similar type and 
frequency of adverse events between groups. The proportions (the number of subjects with 
adverse events / the total number of subjects) of subjects who had at least one ≥ Grade 3 
treatment-related adverse events in the 1 mg/kg, 3 mg/kg, 200 mg/time, and 10 mg/kg dose 
groups were 0/13, 2/12, 3/12, and 1/12, (0%, 16.7%, 25%, and 8.3% in percentage), respectively. 
There was no significant correlation between different doses and safety. The proportions (the 
number of subjects with response/the total number of subjects) of subjects who achieved disease 
response in the 1 mg/kg, 3 mg/kg, 200 mg/time, and 10 mg/kg dose groups were 0/13, 2/12, 
4/12, and 4/12, respectively; the ORRs were 0%, 16.7%, 33.3%, and 33.3%, respectively. In this 


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study, the pharmacokinetic behavior of SHR-1210 in subjects with advanced solid tumors at 
the fixed dose of 200 mg/time and the calculated dose of 3 mg/kg after single and multiple 
administrations was generally the same. The serum concentration-time curves were similar, with 
the exposure distribution mostly overlapping and all within the exposure range of the study dose 
(1-10 mg/kg). The steady-state concentrations and accumulation ratios of SHR-1210 in serum 
after multiple administrations at the fixed dose of 200 mg/time and the calculated dose of 3 mg/kg 
were similar, and the levels of receptor occupancy at steady-state minimum concentration were 
close and maintained at a high level (with arithmetic averages of 77% and 75%, respectively). 
Combined with preliminary data on pharmacokinetics, pharmacodynamics, safety, and efficacy, 
doses of 200 mg or 3 mg/kg are recommended for later clinical studies. In addition, preliminary 
data analysis of the safety and efficacy of SHR-1210 showed that the range of acceptable 
therapeutic doses of SHR-1210 was large; the safety and efficacy of the fixed dose of 200 mg 
were both within the range of the calculated doses (1-10 mg/kg). It was inferred that the 
difference in subjects' weight did not have a significant impact on the coefficient of variation of 
the final in vivo drug exposure (PK). In summary, considering the convenience of clinical 
operations, a fixed dose of 200 mg can be used instead of the calculated dose of 3 mg/kg. 
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 28 Feb., 2018, the summary results of the safety data of the 3 phase I clinical studies 
suggested that: the adverse events related to camrelizumab for injection were mostly of CTCAE 
Grade 1-2, and the incidence of ≥ Grade 3 treatment-related adverse events was 31.8%; common 
treatment-related adverse events mainly included skin and subcutaneous tissue disorders: 
cutaneous capillary endothelial proliferation (81.8%), pruritis (22.1%), rash (16.3%); general 
disorders: asthenia (37.6%), fever (20.9%); blood and lymphatic system disorder: anemia 
(27.5%); investigations: aspartate aminotransferase increased (21.7%), alanine aminotransferase 
increased (18.6%), conjugated bilirubin increased (16.7%), white blood cell count decreased 
(14.7%), blood sodium decreased (14.3%), blood bilirubin increased (12.0%); renal and urinary 
disorder: proteinuria (22.1%); endocrine disorder: hypothyroidism (19.8%); metabolism and 
nutrition disorder: hypoproteinemia (19.4%); respiratory, thoracic, and mediastinal disorders: 
cough (19.0%); gastrointestinal disorders: diarrhea (11.2%), nausea (10.5%); infections and 
infestations: upper respiratory tract infection (10.1%). 
The above data showed that camrelizumab treatment may cause immune-related adverse events 
such as abnormal liver function and abnormal thyroid function. With the use of monotherapy of 
nivolumab, the incidence of hypothyroidism was 9%. The incidence of aspartate 


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aminotransferase increased or alanine aminotransferase increased varied across studies, with 
higher incidences in studies related to malignant melanoma, lung cancer, and Hodgkin's 
lymphoma, at 16-33%. With the use of pembrolizumab monotherapy, the incidence of 
hypothyroidism was 8.5% and the incidence in head and neck cancer was 15%. The incidence of 
aspartate aminotransferase increased or alanine aminotransferase increased varied as reported in 
different studies. In the studies in malignant melanoma and lung cancer, the incidence was 
approximately 21-26%. In KETNOTE 021, the incidence of alanine aminotransferase increased 
was as high as 40%. Thus, in addition to cutaneous capillary endothelial proliferation, common 
immune-related adverse events of SHR-1210 were similar to those reported of similar products. 
Cutaneous capillary endothelial proliferation has been confirmed to be a benign skin reaction. 
The onset may be related to the inflammatory response of type 2 helper T cells (Th2) and type 
M2 macrophages in the epidermis and dermis of skin induced by camrelizumab, resulting in 
massive up-regulation of VEGF-A and excessive proliferation of capillaries. Cutaneous capillary 
endothelial proliferation in areas prone to rubbing may cause damage and bleeding. Cutaneous 
capillary endothelial proliferation in exposed areas such as the face also had some impact on the 
appearance of the subjects. Based on the mechanism of PD-1 monoclonal antibody, adverse 
reactions in various body systems may occur. Therefore, safety risks exist during the medication. 
Close follow-up is necessary during the course of the clinical study. Interventions and actions 
should be adopted in a timely manner. 
1.3.2 
Known potential benefits 
There is currently no standard recommended second-line treatment for advanced 
recurrent/metastatic nasopharyngeal carcinoma. In study SHR-1210-101, the 93 subjects with 
advanced nasopharyngeal carcinoma showed gratifying preliminary results. Participating in this 
study and receiving investigational treatment may benefit subjects with advanced 
nasopharyngeal carcinoma. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary objective 
 
To evaluate the ORR of SHR-1210 in subjects with recurrent/metastatic nasopharyngeal 
carcinoma who have failed at least two lines of chemotherapy by IRC. 
2.1.2 
Secondary objective 
 
To evaluate the efficacy and safety of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma who have failed at least two lines of chemotherapy. 


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2.1.3 
Exploratory objectives 
 
To evaluate the relationship between PD-L1 expression in tumor tissues and efficacy of 
SHR-1210. 
 
To evaluate the relationship between immune-related cells (T lymphocytes, B 
lymphocytes, macrophages, dendritic cells, and bone marrow-derived suppressor cells) 
in tumor microenvironment and efficacy of SHR-1210. 
 
To evaluate the immunogenicity of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma, and to investigate the correlation between immunogenicity 
and efficacy/safety. 
2.2 
Study Endpoints 
2.2.1 
Primary endpoint 
 
IRC-assessed ORR of SHR-1210 in subjects with recurrent/metastatic nasopharyngeal 
carcinoma who have failed at least two lines of chemotherapy 
2.2.2 
Secondary endpoints 
Efficacy 
 
Investigator-assessed ORR 
 
Duration of response (DoR); 
 
Disease control rate (DCR); 
 
Time to response (TTR); 
 
Progression-free survival (PFS) as per RECIST 1.1; 
 
Overall survival (OS) 
Safety 
 
Incidences and severity of adverse events (AEs) and serious adverse events (SAEs), 
laboratory abnormalities, as per NCI-CTCAE V4.03 
 
Incidence of treatment interruption and discontinuation due to AEs 
2.2.3 
Exploratory endpoints 
 
To evaluate the relationship between PD-L1 expression and efficacy of SHR-1210 
 
To evaluate the relationship between immune-related cells (T lymphocytes, B 
lymphocytes, macrophages, dendritic cells, and bone marrow-derived suppressor cells) 
in tumor microenvironment and efficacy of SHR-1210. 
 
To investigate the anti-SHR-1210 antibodies (ADAs) in subjects after injection of SHR-
1210 


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3 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a single-arm, open-label, multi-center phase II clinical study to investigate and evaluate 
the efficacy and safety of anti-PD-1 antibody SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma who have failed at least two lines of chemotherapy. A total of 155 
subjects will be enrolled. 
After being fully informed and providing a written informed consent form, eligible subjects will 
receive SHR-1210 200 mg, IV, q2W, in treatment cycles of 4 weeks. Treatment will continue 
until the criteria for treatment discontinuation as specified in the protocol are met. After the end 
of treatment, subjects will continue safety visits and survival follow-ups. Subjects who 
discontinue the treatment due to reasons other than progressive disease will also be followed for 
tumor progression after the end of treatment. 
After subjects are enrolled in the study, safety follow-up will be conducted before administration 
of SHR-1210 on D1 and D15 of each treatment cycle. After treatment begins, response will be 
assessed once every 2 cycles until the end of treatment, withdrawal of informed consent, or 
death. 
3.2 
Methods to Reduce Bias 
3.2.1 
Enrollment/randomization/blinding 
This is a single-arm study. Subjects will be allocated sequentially. There are no randomization 
and blinding processes. 
3.2.2 
Blinded assessment 
Not applicable. 
3.2.3 
Unblinding 
Not applicable. 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The enrollment of eligible subjects is critical to ensure the outcome of the study. Subjects must 
meet the following criteria to be allowed to participate in this study. Any medical or non-medical 
conditions of a subject are considered for his/her eligibility. 


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4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1. 
Aged 18-75 years (inclusive), male or female; 
2. 
Moderately differentiated or undifferentiated locally recurrent/metastatic nasopharyngeal 
carcinoma (WHO type II-III) in histopathology; 
3. 
Patients in clinical stage IVb who have previously failed first-line platinum-based 
monotherapy or combined chemotherapy and second-line monotherapy or combined 
chemotherapy [the 2017 Chinese Staging of Nasopharyngeal Carcinoma (the 2008 Revised 
Expert Consensus on Staging of Nasopharyngeal Carcinoma), Appendix V]. Definition of 
treatment failure: ongoing chemotherapy after recurrence/metastasis or progressive disease 
after treatment; concurrent chemoradiotherapy, with progression within 6 months, may be 
counted as first-line treatment; all modifications of dosing regimen due to drug intolerance 
are not considered treatment failure; 
4. 
ECOG PS: 0-1 (refer to Appendix I for ECOG scoring criteria); 
5. 
Life expectancy ≥ 12 weeks; 
6. 
At least one measurable lesion per the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1), and the measurable lesions should not have been treated locally such as with 
radiotherapy; 
7. 
Fresh tissues or tissue samples for biomarker (such as PD-L1) analysis must be provided. 
Fresh tissues are preferred. Archival samples of 5-8 paraffin embedded sections with a 
thickness of 3-5 μm are also acceptable when a fresh biopsy is not accessible; 
8. 
Major organ functions must meet the following rules (no blood components or cell growth 
factors are allowed to be used within 2 weeks before the start of study treatment): 
g. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L  
h. 
Platelets (PLT) ≥ 90 × 109/L; 
i. 
Hemoglobin (Hb) ≥ 9 g/dL; 
j. 
Serum albumin ≥ 2.8 g/dL; 
k. 
Bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 1.5 × ULN; for liver metastasis, ALT and AST 
≤ 5 × ULN; 
l. 
Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault, see Appendix II); 


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9. 
Female patients of childbearing potential must have a negative pregnancy test result within 
72 h prior to the start of study treatment, and be willing to take at least 2 highly effective 
contraceptive measures during the study and within 60 days after the last dose of the 
investigational drug (around 5 half-lives of the drug + menstrual cycle). Male patients with 
partners of childbearing potential must take at least two contraceptive measures during the 
study and within 120 days after the last dose of the investigational drug (around 5 half-lives 
of the drug + sperm production cycle); 
10. Patients must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 
4.2 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded: 
1. 
Patients with any active autoimmune disease or history of autoimmune disease (e.g., 
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, 
nephritis, hyperthyroidism, and hypothyroidism (may be enrolled after effective hormone 
replacement therapy); patients with vitiligo or asthma in childhood that has completely 
relieved and requires no intervention in adulthood and patients requiring medical 
interventions with bronchodilators may be enrolled); 
2. 
Patients with clinically symptomatic metastases to central nervous system (e.g., cerebral 
edema) requiring hormone interventions, or progression of brain metastasis. Patients who 
have received treatment for metastasis to brain or meninges may be enrolled if MRI shows 
clinical stability (without the need of > 10 mg/day prednisone or equivalent); 
3. 
Patients with other malignant tumors previously or currently (except for malignant tumors 
that have been cured with a cancer-free survival of more than 5 years, e.g., basal cell 
carcinoma, cervical carcinoma in situ, and papillary thyroid carcinoma); 
4. 
Uncontrolled cardiac symptoms or disease, such as (1) > NYHA Class II cardiac failure, (2) 
unstable angina, (3) myocardial infarction within the past year, and (4) clinically significant 
supraventricular or ventricular arrhythmias requiring clinical interventions; 
5. 
Patients requiring systemic treatment with corticosteroids (> 10 mg/day of prednisone or 
equivalent) or other immunosuppressive medications within 14 days prior to administration 
of the investigational drug. In the absence of active autoimmune disease, inhaled or topical 
use of corticosteroids and an equivalent dose to > 10 mg/day of prednisone for adrenal 
hormone replacement are permitted; 


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6. 
Patients who have received chemotherapy or targeted therapy less than 4 weeks prior to the 
start of study treatment; palliative radiotherapy for symptomatic control is permitted but 
must be completed at least 2 weeks prior to the start of study treatment, and no additional 
radiotherapy should be scheduled for the same lesion; patients with an AE induced by past 
treatment that has not recovered to CTCAE Grade ≤ 1 (except for alopecia and sequelae of 
relevant neurotoxicity of previous platinum therapy); 
7. 
Patients with active infection or unexplained pyrexia > 38.5 °C at screening or prior to the 
first dose (those with tumor-induced pyrexia may be enrolled as per the judgment of the 
investigator); 
8. 
Patients with congenital or acquired immune deficiency (such as HIV infection), active 
hepatitis B (HBV-DNA ≥ 104 copies/mL or 2000 IU/mL) or hepatitis C (positive anti-HCV 
antibodies, and HCV RNA titer higher than the lower limit of detection of the analytical method); 
9. 
Patients who have participated in other clinical studies within 1 month before the start of 
study treatment or are participating in other clinical studies; 
10. Patients who have received live vaccines within 4 weeks before the start of study treatment; 
11. Patients who have used systemic antibiotics within 1 month before the start of study 
treatment; 
12. Patients who have received previous treatment with other anti-PD-1 antibodies or other 
checkpoint monoclonal antibodies, including immunotherapy targeting CTLA-4 and PD-L1; 
13. Patients with known history of psychotropic substance abuse, alcoholism, or drug abuse; 
14. Pregnant or lactating women; 
15. Other factors, as determined by the investigator, which may result in premature 
discontinuation of treatment. For example, other serious medical conditions (including 
mental illnesses) requiring concomitant treatment, serious laboratory abnormalities, family 
or social factors, and other conditions that may affect patients' safety or the collection of 
study data. 
4.3 
Withdrawal from Study or Treatment Discontinuation 
4.3.1 
Study withdrawal criteria 
A subject must withdraw from/discontinue the treatment when any one of the following 
conditions occurs:  
1. 
The subjects withdraw informed consent and request to withdraw from the study; 
2. 
Imaging examinations show progressive disease; 


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As per RECIST v1.1, the confirmation is required 4-6 weeks after the first documentation of 
progressive disease (except those with rapid progression or significant clinical progression); 
Subjects with re-confirmed progressive disease may continue the treatment if clinically stable (as 
assessed by the investigator) until further radiographic progression; 
Definition of clinically stable: a. no clinically significant symptoms or changes in laboratory 
tests; b. no changes in the performance status score (deterioration); and c. non-tumor rapid 
progression and tumor progression not involving major organs/sites (e.g., spinal cord 
compression); 
3. 
Cumulative use of SHR-1210 for 2 years; 
4. 
Subjects with intolerable toxicity; 
5. 
Subjects with poor compliance; 
6. 
Subjects lost to follow-up or becoming pregnant; 
7. 
Other reasons for which the investigator considers a withdrawal necessary. 
4.3.2 
Criteria for treatment discontinuation 
The termination criteria of this study include but are not limited to the following: 
1. 
Discovery of unexpected, important, or unacceptable risks to the subjects; 
2. 
Major errors in the protocol found during the implementation of the study; 
3. 
Ineffective investigational drug/treatment, or meaninglessness to continue the study; 
4. 
Termination as determined by the sponsor due to reasons such as severe delay in enrollment 
or frequent protocol deviations. 
4.3.3 
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 need to be continuously followed-up for 
imaging evaluation until the subjects begin a new anti-tumor treatment or show progressive 
disease. 


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Subject's survival status should still be followed up even when the subject refuses to visit the 
study center, unless the subject withdraws consent to provide further information or consent to 
be further contacted. In such case, no study assessment is performed, nor any data are collected. 
The sponsor can retain and continue to use all data collected before withdrawal of informed 
consent, unless the subject requests a retraction of collected data. 
4.4 
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, 
Hengrui 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 risk to the subjects. 
 
Existing efficacy data supporting study termination. 
 
Poor protocol compliance. 
 
Incomplete or undetectable measures. 
 
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). 
4.5 
Definition of End of Study 
Two years after the last subject's first dose. 
5 
INVESTIGATIONAL DRUG 
5.1 
Overview of Investigational Drug 
5.1.1 
Access to investigational drug 
The investigational drug is supplied by the sponsor, packaged uniformly and certified (see 
corresponding Certificate of Analysis). 


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Concomitant medications and preventive medications for adverse events are not investigational 
drug and are not provided by the sponsor. Such drugs are all marketed products and are purchased 
and stored by the study center based on the package insert or outlined product properties. 
5.1.2 
Dosage form, appearance, packaging, and label 
SHR-1210 for injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: lyophilized powder 
Strength: 200 mg in 20 mL vials. 
Batch No.: see label 
Route of administration: intravenous infusion 
Shelf life: 2 years (tentative) from the date of manufacture. 
Storage conditions: sealed, protected from light, stored at 2-8 °C in a medical refrigerator. Do not 
freeze. 
Label: For illustrative purposes only; refer to the actual product label 
 
5.1.3 
Storage and stability of investigational drug 
The investigator or the authorized representative thereof (e.g., pharmacist) will ensure that all 
investigational drugs are stored in a secure and access-controlled area conforming to storage 
conditions and regulatory requirements. 
For Clinical Study Use Only 
SHR-1210 for Injection Strength: 200 mg/vial 
Dosage Form: Lyophilized 
Powder Drug No.: **** 
Subject ID: __________  Administration Date:   
DD/MM/YYYY 
Study Title: A single-arm, open-label, multi-center, phase II clinical study of anti-PD-1 
antibody SHR-1210 in recurrent/metastatic nasopharyngeal carcinoma subjects who have 
received previous at least two lines of chemotherapy 
Study No.: SHR-1210-II-209 
Clinical Study Approval No.: 2016L01455 
Method of Administration: intravenous infusion 
Note: Prepare according the 
requirements of the protocol 
Storage: sealed, protected from light, store at 2-8 °C  
Batch No.:   
 
 
Expiry Date: DD/MM/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 


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The investigational drugs should be stored in their original container and match with the labels. 
For inconsistence of the storage conditions on the label with those in other materials (such as 
IB), the label should be followed. 
Daily maximum and minimum temperatures of all storage areas (such as freezer, refrigerator, 
and room temperature) must be recorded by the study center. Documentation should begin with 
the receipt of the investigational drugs 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 drug should be immediately reported 
upon discovery. The study center shall take active measures to restore the investigational drugs 
under the storage conditions described on the label, and the temperature deviation and the 
measures taken shall be reported to the sponsor. 
Investigational drugs affected by the temperature deviation should be isolated temporarily and 
may only be used after approval by the sponsor and if it is not a protocol deviation. The use of 
affected investigational 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. 
5.1.4 
Drug preparation 
SHR-1210 should be prepared by qualified or experienced study staff, such as physicians, 
pharmacists, and medical assistants (approved by national authorities or study center operating 
guidelines) according to the drug preparation manual (drug manual). 
Refer to the drug manual of SHR-1210 for blending, concentration (preparation), and 
administration of the injection. Since this drug does not contain any antimicrobial preservatives 
or bacteriostatic agents, care must be taken to ensure that the preparations are sterile. 
The total storage period (overall duration in the refrigerator and room temperature storage) from 
the preparation of SHR-1210 to administration should not exceed 24 h. Please refer to the 
pharmacy manual for details on storage of prepared medication at room temperature/under light 
and in the refrigerator. 
Expired or remaining drug solutions must be disposed. 


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5.1.5 
Administration of investigational drugs 
SHR-1210 is an intravenous injection drug that must be administered by qualified or experienced 
study staff in the outpatient department or ward of the study center. Administration outside the 
study center is not permitted. 
Subjects must complete all clinically required examinations except for tumor evaluations within 
72 h before each dose to determine whether continuing the medication is appropriate. 
SHR-1210 is administered through intravenous infusion at 200 mg/time over 30 min (no less 
than 20 min and no more than 60 min, including flushing). Do not administer through 
intravenous bolus or rapid bolus injection. The intravenous infusion should be performed 
through a medical infusion bag using an infusion set with an in-line filter (0.2 μM). Do not 
administer other medications with this infusion line before or after the infusion. Administration 
will be given on D1 and D15 of each 4-week cycle. The treatment will continue until the 
occurrence of confirmed PD, intolerable toxicity, voluntary withdrawal by the subject, or 
treatment discontinuation determined by the investigator. 
The drug may be administered within 3 days before or after the scheduled administration day. 
Administration beyond 3 days after the scheduled administration day will be considered a dose 
delay. Subsequent administrations will be based on the actual date of the previous dose. All 
required examinations and evaluations must be completed prior to each dose. The interval 
between two doses must not be less than 12 days. 
Some subjects may have temporary accelerated tumor growth in the first few months after 
starting immunotherapy, followed by response. Therefore, subjects are allowed to continue the 
treatment after the first PD. 
Accelerated tumor growth may include any of the following: 
 
Worsening of existing target lesions; 
 
Worsening of existing non-target lesions; 
 
Appearance of new lesions. 
If a subject develops PD as determined by RECIST v1.1, the investigator may decide whether 
treatment should be continued based on subject's overall clinical status, including performance 
status, clinical symptoms, and laboratory test results. Treatment can be continued when the 
subject is clinically stable, and a tumor evaluation should be performed again 4-6 weeks later. If 
non-PD is confirmed by both iRECIST and RECIST v1.1, the treatment will be continued, and 
otherwise, the treatment will be discontinued, unless the investigator believes the subject may 
continue benefiting from the study; the sponsor must be consulted to allow a subject with 
confirmed PD to continue the treatment. For subjects who are clinically unstable, treatment 
should be discontinued after the first PD, and the reevaluation is not required. 


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 Definition of clinically stable: No significant deterioration in subject's performance status, 
and no significant worsening of cancer-related symptoms; 
 No rapid progressive disease; 
 No progressive tumor requiring other urgent medical interventions at important anatomical 
sites (e.g., spinal cord compression); 
In repeated imaging evaluation, PD can be confirmed by the criteria listed below. 
 
Conditions for Confirming PD 
(Any of the following conditions) 
Conditions Unable to Confirm PD 
(Meet all of the following conditions) 
Target 
Lesion 
The absolute value of tumor burden increases by 
≥ 5 mm compared to the first episode of PD. 
The absolute value of tumor burden increases by  
< 5 mm compared to the first episode of PD. 
Non-Target 
Lesion 
Compared to the first episode of PD, non-target 
lesion shows clear and continued progression 
(qualitative). 
Compared to the first episode of PD, there is no 
clear progression (qualitative). 
New Lesion 
(1)  A new lesion occurs compared to the first 
episode of PD; 
(2)  A new lesion that has appeared before 
increases in size or other new lesion occurs. 
(1)  Compared to the first episode of PD, no other 
new lesion occurs; 
(2)  A new lesion that has appeared before is stable 
or decreases in size. 
For subjects who receive the first PD evaluation, the date of the initial progression assessed by 
the investigator will be used in all progression-involved statistical analyses, regardless of post-
progression treatment/discontinuation. 
5.1.6 
Dose modification and delay 
5.1.6.1 
Dose modification 
Adverse events related to SHR-1210 may be immune-related adverse events (irAEs), and may 
occur shortly after the first dose or several months after the last dose. SHR-1210 administration 
should be interrupted when events listed in Table 4 occur. During the study, the investigator 
must consult with the sponsor when, based on the benefit to risk ratio of subjects, SHR-1210 
administration should not be interrupted or resumed according to recommendations found in 
Table 4 or when the situation is not listed. 
 
 


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Table 4. 
SHR-1210 dose modifications 
Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades 
for Treatment 
Interruption 
Resumption 
Discontinuation 
Diarrhea/Colitis 
2-3 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
4 
Discontinuation 
Discontinuation 
AST, ALT, or Bilirubin 
Increased 
2 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent 
Do not resolve within 12 weeks 
from the last dose. 
3–4 
Discontinuation 
Discontinuation 
Hyperthyroidism 
3 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
4 
Discontinuation 
Discontinuation 
Hypothyroidism 
 
Treatment can be continued 
after starting thyroxine 
replacement therapy 
Treatment can be continued 
after starting thyroxine 
replacement therapy 
Pneumonia 
2 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
3–4 
Discontinuation 
Discontinuation 
Immune-Related 
Hypophysitis 
2-3 
Recovery to Grade 0-1; SHR-
1210 treatment can be 
continued after starting 
endocrine replacement therapy 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
4 
Discontinuation 
Discontinuation 
Type I Diabetes Mellitus 
(New Onset) or 
Hyperglycemia 
New type I 
diabetes mellitus 
or Grade 3-4 
hyperglycemia 
with evidence of 
β-cell failure 
After clinical and metabolic 
conditions are stable 
Continue SHR-1210 treatment. 


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Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades 
for Treatment 
Interruption 
Resumption 
Discontinuation 
Renal Failure or Nephritis 
2 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent. 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
3–4 
Discontinuation 
Discontinuation 
Infusion Reactions 
2 
Symptoms disappear 
Re-administer at 50% of the 
initial rate after symptoms 
resolve. Restore the original 
infusion rate (100%) if no 
complications occur within 
30 minutes. 
Closely monitor. If the 
symptoms recur, the 
administration of the current 
SHR-1210 dose will be 
discontinued. 
3–4 
Discontinuation 
Discontinuation 
Other Treatment-Related 
Adverse Events 
3 
Recovery to Grade 0-1 and 
corticosteroids reduction to  
≤ 10 mg of prednisone or 
equivalent. 
Do not resolve within 12 weeks 
from the last dose, or the dose 
of corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent within 
12 weeks. 
4 
Discontinuation 
Discontinuation 
Note: Treatment should be discontinued if any Grade 3 treatment-related AE recurs or any life-threatening event 
occurs. 
For subjects with liver metastasis and Grade 2 AST or ALT increased at baseline, the treatment should be 
discontinued when a ≥ 50% increase in AST or ALT from baseline persists for at least 1 week. 
For subjects with intolerable or persistent Grade 2 treatment-related AEs, the investigator may consider interrupting 
SHR-1210 treatment if appropriate. For subjects with persistent Grade 2 adverse reactions that fail to recover to 
Grade 0-1 within 12 weeks after the last dose, the treatment should be discontinued. 
5.1.7 
Dose tracking 
The study center should prepare the drugs and complete the documentation as per the Pharmacy 
Manual. The documentation system of the study center should include all relevant or required 
information with regards to preparation and administration. 
5.1.8 
Precautions for special drug delivery devices 
Not applicable. 


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5.2 
Dosing Regimen 
SHR-1210: intravenous infusion (premedication not required) at a fixed dose of 200 mg over 
30 min (no less than 20 min and no more than 60 min, including flushing), on D1 and D15 of 
each 4-week cycle. The treatment will continue until the occurrence of confirmed PD, intolerable 
toxicity, voluntary withdrawal by the subject, or treatment discontinuation determined by the 
investigator. 
5.3 
Drug Management, Dispensation and Retrieval 
Designated personnel in GCP pharmacies of the study centers are responsible for the 
management, dispensation, and retrieval of investigational drugs. The investigator must ensure 
that all investigational drugs are used by enrolled subjects only and the dose and method of 
administration are in compliance with the study protocol. Remaining investigational drug SHR-
1210 should be returned to the sponsor. Expired or remaining drugs must be disposed as per the 
standard for medical wastes. The investigational drugs must not be transferred to anyone who is 
not involved in this study. 
The investigational drugs must be stored according to the label. Duplicate drug receipt forms 
should be signed upon arrival at the study center, one for the study center and one for the 
sponsor. If there is a need for retrieving remaining drugs and empty boxes at the end of the study, 
a retrieval form will also be signed by both parties. The dispensation and return of every drug 
should be immediately documented on designated forms. 
The CRA is responsible for monitoring the supply, usage, and storage of the investigational 
drugs, and the management of remaining drugs. 
Used investigational drugs should be disposed by the sponsor after retrieval, or by the study 
center upon authorization. Before disposal at authorized study centers, the CRA must verify the 
medication disposal procedures of the centers and ensure that a certificate of disposal can be 
provided after disposal. 
5.3.1 
Disposal of investigational drugs 
The sponsor or authorized personnel is responsible for disposing the investigational drugs. Drug 
disposal should be well documented. 
5.4 
Concomitant Treatment 
Concomitant treatment refers to other treatment that is given for the benefit of subjects as 
determined by the investigator. 


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All concomitant medications and treatments within 30 days before the start of study treatment 
and during the study must be documented in the eCRF in strict accordance with the GCP. 
Antibiotic treatments within 3 months before medication and during the study period must be 
documented in detail. 
Once the study treatment is interrupted, concomitant medications within 90 days after the last 
dose should be documented. Only concomitant medications for treatment-related AEs should be 
documented 30 days after the end of treatment. 
5.4.1 
Other anti-tumor/cancer or study drugs 
5.4.1.1 
Permitted concomitant medications 
Topical use of corticosteroids such as ophthalmic, nasal, intra-articular, and inhaled is permitted. 
Subjects should be given optimal supportive care during the treatment. The use of existing 
hormone replacement therapy and bisphosphonates for bone metastases are permitted. 
Palliative treatment of local lesions that may cause significant 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 recommended to consult with the sponsor 
prior to starting palliative treatment.  
1. 
The investigator must assess whether there is PD in subjects who require local treatment 
due to symptom exacerbations during the study; 
2. 
Subjects with PD must meet the criteria for continuation of treatment beyond progression; 
3. 
The locally treated lesions cannot be the target lesions. 
All concomitant medications should be documented in the eCRF. Concomitant medications from 
30 days before the first dose to 90 days after the last dose will be documented; only concomitant 
medications for treatment-related AEs will be documented from 30 days after the end of 
treatment. Antibiotic use within 3 months before medication and during the study period must be 
documented in detail. 
5.4.1.2 
Prohibited concomitant medications 
 
Anti-tumor systemic chemotherapy and biological therapy; 
 
Modern TCM preparations approved by CFDA (now NMPA) for anti-cancer treatment 
(refer to Appendix III); 
 
Immunotherapy not specified in the protocol; 


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 
Immunomodulators with auxiliary anti-tumor effects, such as thymosin, lentinan, 
interleukin-12, etc. 
 
Vaccination of live vaccines within 4 weeks before the first dose and during the study. Live 
vaccines include, but not limited to, rubeola, epidemic parotitis, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid. Injections of inactivated influenza vaccine for seasonal 
influenza are permitted, but not live attenuated influenza vaccines for intranasal use; 
 
Physiological doses of systemic corticosteroids for purposes other than the relief of 
symptoms due to immunological causes may, after the consultation with the sponsor, be 
approved (inhaled steroids are permitted as a part of fixed treatment for asthma or chronic 
obstructive pulmonary disease). Corticosteroids may be used prophylactically to prevent 
allergic reactions (such as intravenous contrast agent); 
5.4.2 
Supportive care 
Subjects should receive appropriate supportive treatment measures deemed necessary by the 
investigator. Supportive treatment measures for managing immune-related adverse events 
(irAEs) are listed below, including oral or intravenous corticosteroids and other anti-
inflammatory medications when symptoms are not relieved after the use of corticosteroids. 
Corticosteroids may need to be tapered over several cycles since symptoms may worsen during 
dose reduction. Other reasons requiring other supportive treatments, such as metastatic disease or 
bacterial or viral infections, should be ruled out where possible. When the investigator is sure 
that the AE is related to SHR-1210, the supportive treatments listed below may be followed. 
Otherwise, the supportive treatments listed below are not required. 
1. 
Cutaneous capillary endothelial proliferation 
Subjects with cutaneous capillary endothelial proliferation should undergo biopsy and 
pathological examination whenever possible. Endoscopic and MRI examinations are 
recommended for subjects with relatively severe or long-lasting cutaneous capillary endothelial 
proliferation to confirm the involvement of internal organs and/or mucosa. For cutaneous 
capillary endothelial proliferation that occurs in areas prone to rubbing, surgical resection, laser, 
freezing or ligation is recommended. 
2. 
Diarrhea/colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, hematochezia or mucus stools, with or without pyrexia) and intestinal 
perforations (such as peritonitis and intestinal obstruction). 


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 
Subjects with diarrhea/colitis should drink an adequate amount of fluids. Fluids and 
electrolytes should be administered intravenously if adequate oral intake is not possible. GI 
consultation and endoscopy should be considered to confirm or rule out colitis for subjects 
with Grade 2 or greater diarrhea. 
 
Oral corticosteroids should be prescribed for Grade 2 diarrhea/colitis. 
 
Subjects with Grade 3 or 4 diarrhea/colitis should be treated with intravenous corticosteroids 
followed by oral high-dose corticosteroids. 
 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. Taper 
will last for no less than 4 weeks. 
3. 
AST, ALT, or bilirubin increased 
 
Subjects should receive intravenous or oral corticosteroids for Grade 2 events. Liver 
function should be monitored with an increased frequency until it/they return(s) to baseline 
(testing once a week considered). 
 
Corticosteroids via intravenous route for 24-48 h should be given for Grade 3-4 events. 
 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. Taper 
will last for no less than 4 weeks. 
4. 
Hyperthyroidism/hypothyroidism 
Thyroid disorder may occur at any time during the course of the treatment period. Monitor 
changes in subjects' thyroid function (when starting treatment, regularly during the treatment 
period) as well as clinical signs and symptoms of thyroid disorder. 
 
For subjects with Grade 2 hyperthyroidism, it is recommended to use non-selective beta-
blockers (such as propranolol) as initial treatment. 
 
Subjects with Grade 3-4 hyperthyroidism should receive intravenous corticosteroids 
followed by oral corticosteroids. Corticosteroids should begin to taper after symptoms 
improve to Grade 1 or lower. Taper will last for no less than 4 weeks. During the tapering 
process, appropriate hormone replacement therapy may be required. 
 
Thyroid hormone replacement therapy may be considered for Grade 2-4 hypothyroidism 
(such as levothyroxine). 
5. 
Pneumonia 
 
Subjects with Grade 2 pneumonia should receive systemic corticosteroids. Corticosteroids 
should begin to taper after symptoms improve to Grade 1 or lower. Taper will last for no less 
than 4 weeks. 
 
If long-term use of corticosteroids is acceptable, antibiotic prophylaxis should be used. 


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6. 
Immune-related hypophysitis 
 
Persistent corticosteroid treatment should be used for Grade 2 hypophysitis. Corticosteroids 
should begin to taper after symptoms improve to Grade 1 or lower. Taper will last for no less 
than 4 weeks. During the tapering process, appropriate hormone replacement therapy may be 
required. 
 
Subjects with Grade 3 or 4 hypophysitis should receive intravenous corticosteroids followed 
by oral corticosteroids. Corticosteroids should begin to taper after symptoms improve to 
Grade 1 or lower. Taper will last for no less than 4 weeks. During the tapering process, 
appropriate hormone replacement therapy may be required. 
7. 
Type I diabetes mellitus 
Insulin replacement therapy is recommended for T1DM and Grade 3-4 hyperglycemia 
accompanied by metabolic acidosis or ketonuria. Then, subjects' blood glucose, and full 
metabolic panel, urinary ketones, HbA1C, and C-peptide should be evaluated. 
8. 
Renal failure or nephritis 
 
Subjects with Grade 2 events should receive corticosteroids. 
 
Subjects with Grade 3-4 events should receive systemic corticosteroids. 
 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. Taper 
will last for no less than 4 weeks. 
9. 
Infusion reactions 
Table 5. 
Classification and clinical treatment recommendations for infusion reactions 
CTCAE 
Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade 1 
Mild and transient 
reactions 
Bedside observation and close monitoring until 
recovery. 
Pre-administration prophylactics are 
recommended for subsequent infusions: 50 mg 
of diphenhydramine or equivalent and/or 325-
1000 mg of acetaminophen at least 30 min 
before SHR-1210 being given. 
Continue 


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CTCAE 
Grade 
Clinical Symptoms 
Clinical 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) 
Intravenous administration of normal saline, 
50 mg of diphenhydramine IV or equivalent 
and/or 325-1000 mg of acetaminophen; bedside 
observation and close monitoring until 
recovery. Corticosteroids or bronchodilators 
can be considered based on clinical needs; the 
amount of investigational drug infused should 
be recorded in the original medical record; pre-
administration prophylactics are recommended 
for subsequent infusions: 50 mg of 
diphenhydramine or equivalent and/or 325-
1000 mg of acetaminophen at least 30 min 
before SHR-1210 is given. Corticosteroids 
(equivalent to 25 mg of hydrocortisone) can be 
used when necessary. 
Interruption. Re-administer at 
50% of the initial rate after 
symptoms resolve. Restore 
the original infusion rate 
(100%) if no complications 
occur within 30 minutes. 
Closely monitor. If the 
symptoms recur, the 
administration of the current 
SHR-1210 dose will be 
discontinued. 
≥ Grade 3 
Grade 3: Severe 
reactions with no 
rapid resolution after 
intervention and/or 
treatment 
interruption; 
symptom recurrence 
after resolution; 
sequelae requiring 
hospitalization. 
Grade 4: life-
threatening 
Immediately discontinue SHR-1210 infusion; 
Administer normal saline by intravenous drip. 
•  
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, and/or 
50 mg of diphenhydramine + 100 mg of 
methylprednisolone or equivalent by 
intravenous injection when necessary; 
•  
Based on the guidelines for anaphylaxis of 
the study center; 
Bedside observation and close monitoring until 
recovery. 
Discontinuation 
6 
STUDY PROCEDURES 
Before the study commences, the subjects must read and sign the current informed consent form 
approved by the ethics committee (EC). All examinations and study procedures will be carried 
out according to the schedule of activities, and will not be affected by the duration of drug 
interruption. However, it is allowed to change within the window period of test items due to 
holidays, weekends or other administrative reasons. 


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6.1 
Screening 
The screening period is the time from the signing of the informed consent form until 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 
before the start of study treatment. 
 
Signing the informed consent form; 
 
Collecting demographics: gender, date of birth, ethnicity, height, and weight. 
 
Tumor diagnosis: site of primary tumor, the date of pathological diagnosis, pathological 
staging, and the location of the metastatic lesion. 
 
History of cancer treatment 
 
Cancer surgery history: name of surgery, date of surgery, postoperative TNM staging, 
and date of postoperative recurrence; 
 
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; 
 
Rescue treatment: regimen, cycles, start and end dates, best overall response, time to 
tumor progression, and presence of changes in treatment due to tumor progression; 
 
History of concurrent diseases, past medications, and medication allergies; 
 
Serology (completed within 14 days before the first dose): HbsAg (if positive, HBV-
DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, HCV-
RNA test required), HIV-Ab, and EBV-DNA; 
 
Fresh (preferred) or archived tumor tissue specimens for PD-L1 testing. The following 
screening procedures should be completed within 7 days before the start of study 
treatment. A pregnancy test should be completed within 72 h before the start of study 
treatment. 
 
ECOG PS; 


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 
Vital signs: pulse, respiratory rate, body temperature, and blood pressure; 
 
Comprehensive physical examination: general condition, head and face, skin, lymph 
nodes, neck, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular 
system, abdomen, reproductive and urinary system, musculoskeletal system, nervous 
system, mental state, and others; 
 
Blood routine: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
 
Urinalysis: WBC, RBC, and urine protein. In case of a urine protein ≥ 2+, a 24-h urine 
protein test (quantitative) should be added; 
 
Fecal occult blood; 
 
Blood biochemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea 
nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, lactate 
dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
 
Thyroid function: TSH, FT3, and FT4; 
 
Coagulation function: APTT, PT, FIB, INR; 
 
Echocardiography: including LVEF assessment. Perform when clinically indicated. 
 
12-Lead ECG: additional necessary investigations required when an abnormality is 
seen as determined by the investigator; 
 
Pregnancy test: serum or urine (for women of childbearing potential); 
 
Imaging examination: CT or MRI of nasopharynx, neck, chest, upper and lower 
abdomen (including 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 administration and 
before informed consent may be used as long as they meet the RECIST 1.1. 
 
Adverse events: Documented from the signing of ICF. 
 
Concomitant medications: Concomitant medications within 30 days before the first dose will 
be documented in detail; antibiotic use within 3 months before enrollment will be 
documented. 


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6.2 
Enrollment 
 
Confirmation of inclusion/exclusion criteria. 
 
Administration to subjects. 
6.3 
Treatment Period 
 
All examinations and evaluations (except imaging evaluations) should be completed within 
3 days before administration. The following items should be examined/assessed before each 
administration in each cycle; items are not required for examination/assessment in the first 
cycle when they have been examined/assessed at screening within 7 days before the first 
administration. 
 
ECOG PS; 
 
Vital signs: pulse, respiratory rate, body temperature, and blood pressure; 
 
Physical examination: general condition, head and face, skin, lymph nodes, neck, eyes, 
ears, nose and throat, mouth, respiratory system, cardiovascular system, abdomen, 
reproductive and urinary system, musculoskeletal system, nervous system, mental state, 
and others; 
 
Blood routine: complete blood count with differential (white blood cells, red blood 
cells, lymphocytes, monocytes, neutrophils, basophils, eosinophils, and hemoglobin), 
platelet counts; 
 
Blood biochemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea 
nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, lactate 
dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
 
12-Lead ECG: additional necessary investigations required when an abnormality is 
seen as determined by the investigator; 
 
Concomitant medications: Concomitant medications will be documented; 
 
Adverse events: document AEs in detail; 
 
The following investigations should be completed before the administration on D1 of each 
cycle: 
 
Urinalysis: WBC, RBC, and urine protein. In case of a urine protein ≥ 2+, a 24-h urine 
protein test (quantitative) should be added; 
 
Fecal occult blood (before or after administration); 


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 
Thyroid function: TSH, FT3, and FT4 (T3 and T4 can be used instead if FT3 and FT4 
are unavailable); 
 
Concomitant medications: Concomitant medications will be documented; 
 
Adverse events: document AEs in detail; 
 
The following investigations should be completed every 2 cycles before administration 
 
EBV-DNA testing; 
 
Imaging evaluation: CT or MRI of the nasopharynx, neck, chest, and abdomen (including 
pelvic cavity); enhanced scanning with contrast is preferred if not contraindicated. Imaging 
examinations are performed every 8 weeks. For lesions of bone metastases, bone scans are 
only required when the evaluation result of other lesions is CR and it is necessary to confirm 
the presence of lesions of bone metastases or when clinically indicated. For subjects exiting 
the group for any reason, a tumor imaging evaluation should be performed at the time of 
exiting when an evaluation has not been carried out within 4 weeks before exiting. 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). 
Subjects who discontinue treatment for reasons other than imaging-confirmed PD must also 
undergo a tumor evaluation every 8 weeks until documentation of confirmed PD, start of a 
new anti-tumor treatment, lost to follow-up, or death. Time of imaging evaluation will not be 
adjusted due to dose delays. Subjects showing CR or PR for the first time (whichever comes 
first) should undergo imaging evaluation for confirmation at least 4 weeks (28 days) later, 
with a time window of + 7 days. 
Subjects who are clinically stable should have a confirmation scan 4-6 weeks after the first 
occurrence of PD based on iRECIST and RECIST (v1.1). The subsequent tumor evaluations will 
be performed at the pre-specified time point. 
 
Immunogenicity blood sampling: once before the C1D1, C2D1, C3D1, and C4D1 
administrations; once every 3 cycles after Cycle 4; and once before withdrawal from study. 
6.4 
Follow-Up 
Subjects should return to the study center for a follow-up 30 days after the last dose, and safety 
information can be obtained via telephone calls on D60 and D90 after the last dose (including 
AE outcome, new SAEs and AEs of special interest), with a time window of ± 7 days.  
When a subject starts a new anti-tumor treatment within 30 days after the last treatment, the visit 
should be completed before the new treatment is started. 


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 
Blood routine: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
 
Blood biochemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea 
nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, lactate 
dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
 
Thyroid function: TSH, FT3, and FT4; 
 
Immunogenicity: collect once before withdrawal from study. 
 
Adverse events: document AEs in detail; 
Concomitant medications: Concomitant medications within 90 days after the last treatment will 
be documented. Only concomitant medications for treatment-related AEs will be documented 
30 days after the last treatment. 
Survival follow-up visits will be conducted once a month after the last treatment via effective 
methods such as telephone. It is necessary to record whether the subjects have subsequently 
received a new anti-tumor treatment. When there is any new anti-tumor treatment, record the 
treatment regimen and start/end time of the treatment while completing the survival follow-up 
visit records. 
For subjects who withdraw from the group due to "non-PD" (such as intolerable AEs) reasons, it 
is recommended to conduct tumor progression follow-up visit in the frequency identical to that 
for response evaluation (every 8 weeks ± 7 days) until PD, death, or start of a new anti-tumor 
treatment. Follow-up information should be documented in eCRF. 
6.5 
Visit for Early Discontinuation of Treatment 
If relevant evaluations and examinations have not been performed within 7 days before the 
subject withdrawal, the following procedures should be followed: 
 
ECOG PS; 
 
Vital signs: pulse, respiratory rate, body temperature, and blood pressure; 
 
Comprehensive physical examination: general condition, head and face, skin, lymph 
nodes, neck, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular 
system, abdomen, reproductive and urinary system, musculoskeletal system, nervous 
system, mental state, and others; 
 
Blood routine: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 


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 
Urinalysis: WBC, RBC, and urine protein. In case of urine protein ≥ 2+, an additional 
24-h urine protein test (quantitative) is required. Blood biochemistry: ALT, AST, GGT, 
total bilirubin, direct bilirubin, AKP, BUN (preferred) or urea, total protein, albumin, 
creatinine, blood glucose, lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
 
Thyroid function: TSH, FT3, and FT4; 
 
EBV-DNA testing. 
 
ECG; 
 
Imaging evaluation: An imaging evaluation should be performed at the end of 
treatment/upon withdrawal when it has not been done within 4 weeks before 
withdrawal. Subjects who discontinue treatment for reasons other than imaging-
confirmed PD must also undergo a tumor evaluation every 8 weeks until documentation 
of confirmed PD, start of new anti-tumor treatment, or death. 
 
Adverse events: document AEs in detail; 
 
Concomitant medications: Concomitant medications will be documented; 
6.6 
Unscheduled Visits 
The following items should be documented during unscheduled visits if subjects develop AEs 
during the study and within 90 days after the last dose or within 90 days until the start of a new 
anti-tumor treatment: 
 Concomitant medications; 
 Adverse events; 
 All relevant examinations (including imaging evaluations, if any). 
7 
IMMUNOGENICITY STUDIES 
7.1 
Immunogenicity and Drug Trough Concentration Blood Sampling and Processing 
7.1.1 
Blood sampling time 
Once before the administration on C1D1, C2D1, C3D1, and C4D1, once every 3 cycles after 
Cycle 4, and once before withdrawal from study. 
7.1.2 
Processing and storage of blood samples 
At each of the above time points, 4-6 mL of venous blood samples will be collected into serum 
separation tubes to collect the serum, which will be then transferred to 4 cryotubes (aliquoted 
equally into 3 test tubes, 1 for ADA, 1 for drug trough concentration, and 1 for antibody 
neutralizing activity, and 1 backup tube). Refer to the "Laboratory Manual" for operation details 
and sample storage and transportation conditions. 


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7.1.3 
Shipping of clinical samples 
The samples in test tubes should be sent out first in dry ice storage state. The samples in the 
backup tubes will be sent out after the bioanalytical laboratory confirms the receipt of the test 
tube samples. Details of shipping frequency and other shipping information are described in the 
Laboratory Manual. 
8 
BIOMARKER TESTING 
 
Tissue PD-L1 testing: Tissue samples should be collected before enrollment. Fresh tissues 
are preferred. Archived samples of 5-8 paraffin embedded sections are also acceptable for 
PD-L1 testing when fresh tissue samples are not available. 
 
Testing of immune-related cells in the tumor microenvironment: T lymphocytes, B 
lymphocytes, macrophages, dendrites, and bone marrow-derived suppressor cells are analyzed 
using the remaining tissue samples after PD-L1 testing with multiple staining method. 
After the above tests are completed, the PD-L1 stained sections will be saved until being 
destroyed at the end of the study; the stained immune cells and remaining tissue sections will be 
destroyed after the staining analysis is completed. 
9 
EVALUATION 
9.1 
Efficacy Evaluation 
The primary efficacy endpoint for this study is the ORR assessed by IRC as per RECIST v1.1. 
The ORR will be evaluated using the RECIST v1.1, including the CR and PR cases. 
CR or PR must be confirmed at least 4 weeks (28 days) after the first evaluation. The objective 
response rate refers to the result obtained by dividing the number of subjects whose best overall 
response (BOR) is complete response (CR) or partial response (PR) by the total number of 
subjects. 
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. 
The same imaging technique should be used in subsequent tumor evaluations for the same type 
of lesions as at screening. Anti-tumor activity evaluation will be carried out during the screening 
period and treatment process through radiography according to the schedule of activities; the 
evaluation will 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). 


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Evaluation will be performed in accordance with the RECIST version 1.1 (Appendix IV). 
Documentation and radiographic data of all subjects must be accessible for source validation and 
peer review. 
9.2 
Safety Evaluation 
9.2.1 
Pregnancy test 
Female subjects of childbearing potential will receive a serum or urine pregnancy test within 
72 hours before the start of administration. When the pregnancy test shows negative during the 
screening period, appropriate contraceptive measures shall be taken. If the hCG test shows 
positive result, the subject should withdraw from the study. 
9.2.2 
Adverse events 
The incidence and severity of adverse events (AE) and serious adverse events (SAEs) will be 
assessed according to NCI-CTCAE V4.03. 
Incidence of treatment interruption and discontinuation due to AEs. 
AEs that occur during the study, including signs and symptoms at screening period, will be 
recorded in the eCRF. Treatment interruption and dose reduction as well as other modifications 
will be documented in the eCRF. 
9.2.3 
Laboratory safety evaluation 
All laboratory abnormalities that are clinically significant or meet the definition of AE/SAE 
should be recorded in the eCRF: 
Investigators are recommended to use clinical terms rather than laboratory terms (such as anemia 
instead of hemoglobin reduced) in reports. 
9.2.4 
Vital signs and physical examinations 
Vital sign measurement, physical examination, and body weight measurements will be 
performed according to the schedule of activities. 
A comprehensive physical examination is required during the screening period, and all test 
results should be recorded in the eCRF. A comprehensive physical examination is required 
during the treatment period, but only abnormal findings need to be documented in the eCRF. 
Repeated documentation is not required if there is no change from baseline. 
9.2.5 
12-Lead ECG 
All abnormal ECG results that are clinically significant or meet the definition of AE/SAE should 
be recorded in the eCRF. 


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10 ADVERSE EVENT REPORTING 
10.1 Adverse Event (AE) 
10.1.1 Definition of adverse event 
An adverse event (AE) refers to any untoward medical condition in a clinical trial subject who 
receives a pharmaceutical product, and the condition does not necessarily have a causality with 
the treatment. Safety information should be collected from the subject's signing of the informed 
consent form to 90 days after the last dose or the start of new anti-tumor treatment (if the anti-
tumor treatment starts within 30 days after the last dose, the subject should be followed up until 
at least 30 days after the last dose; if the tumor treatment starts beyond 30 days after the last 
dose, the subjects should be followed up until the start of the new anti-tumor treatment). An AE 
may be any untoward and unexpected symptom, vital sign, laboratory test abnormality, or 
disease, including the following: 
1) 
Worsening of pre-existing (prior to entering clinical study) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2) 
Any new AE: Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
3) 
Clinically significant abnormal laboratory values or results that are not caused by 
concomitant diseases. 
Any AEs should be recorded in detail, including name of events and description of all relevant 
symptoms, time of occurrence, severity, causes, correlation with investigational drug, duration, 
measures taken, and final results and outcomes. 
10.1.2 AE severity grading criteria 
Please refer to NCI CTCAE 4.03 for grading standards. Refer to the following criteria for AEs 
not listed in NCI-CTCAE 4.03: 
Grade 
Clinical Description of Severity 
1 
Mild; asymptomatic or mild clinical symptoms; clinical or laboratory test abnormality 
only; 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. 


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Grade 
Clinical Description of Severity 
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 
10.1.3 Causality assessment 
AEs will be collected and documented from signing the informed consent form until 90 days 
after the last study dose or the start of new anti-tumor treatments, regardless of whether the event 
is related to the investigational drug or whether the medication is administered. All subject 
complaints and abnormal changes in laboratory tests during the treatment period should be 
documented truthfully. The severity, duration, measures taken, and outcome of the AE shall be 
noted. The investigator should assess the relationship between the AE and the investigational 
drug, such as whether there is a plausible temporal relationship with the investigational drug, the 
characteristics of the investigational drug, the toxicological and pharmacological effects of the 
investigational drug, whether there are concomitant medications, the subject's underlying 
diseases, medical history, family history, as well as dechallenge and rechallenge, etc. 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. 
10.2 Serious Adverse Event (SAE) 
10.2.1 Definition of 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; 


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 
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). 
10.2.2 Hospitalization 
AEs resulting in hospitalization (even if for less than 24 h) or prolonged hospitalization during 
the clinical study are considered as 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.) 
Hospitalization or prolonged hospitalization unrelated to the worsening of an AE is not 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 
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 
AE, it should be reported as such. 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. 


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10.2.3 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 PD 
are not reported as SAEs. Death caused by the symptoms and signs of PD is reported as an SAE. 
10.2.4 Potential drug-induced liver injury 
Drug-induced liver injury is 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. 
Potential drug-induced liver injury is defined as follows: 
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 values 
≥ 3 × ULN; or AST or ALT ≥ 8 × ULN 
 
with TBIL increase ≥ 1 × ULN or values  
≥ 3 × ULN  
After being notified of the abnormal results, the subjects should return to the study center for an 
assessment where 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, 
acetaminophen, soft drugs, various supplements, family diseases, occupational exposure, sexual 
behavior, travel, contact with jaundice subjects, 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 the etiological 
tests of liver function. Potential drug-induced liver injury should be reported as an SAE. 


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10.2.5 Other anti-tumor treatments 
SAEs should be recorded from the signing of the informed consent form until 90 days after the 
last dose of the investigational drug. SAEs must be reported regardless of whether the patient 
starts a new anti-tumor treatment. 
10.2.6 SAE reporting 
The collection period for SAEs begins with the signing of the informed consent form until 90 
calendar days (inclusive) after the last study dose. In the event of an SAE, whether it is the first 
report or a follow-up report, the investigator must complete the "Serious Adverse Event Report 
Form" immediately, with a signature and date, and notify the sponsor within 24 h of knowing of 
the event. Relevant authorities must be informed of such SAE in a timely manner according to 
local regulatory requirements. 
The sponsor's email address for SAE reporting is: hengrui_drug_safety@hrglobe.cn 
SAEs that occur 90 days after the last study dose are generally not reported unless they are 
suspected to be related to the investigational drug. The symptoms, severity, relationship with the 
investigational drug, time of occurrence, treatment duration, measures taken, time and method of 
follow-up, and outcome should be documented in details in the SAE report. If the investigator 
believes that an SAE is unrelated to the investigational drug but potentially related to study 
conditions (such as the termination of the previous treatment, or comorbidities during the study), 
their relationship should be explained in the description section of the SAE report form. If the 
severity of an ongoing SAE or its relationship to the investigational drug changes, a follow-up 
report should be submitted immediately. If an error is found in a previously reported SAE, such 
an SAE may be revised, revoked, or downgraded in follow-up reports and reported in accordance 
with the SAE reporting procedure. 
10.2.7 Follow-up of AEs/SAEs 
All SAEs and treatment-related AEs should be followed up until recovery, returning to baseline 
or  ≤ Grade 1, reaching a steady state, or obtaining a reasonable explanation (e.g., lost to follow-
up, death). 
During each visit, the investigator should ask about the AEs/SAEs that occur after the last visit and 
whether there are new AE/SAEs, document relevant updated information including the outcome, 
and provide follow-up information in a timely manner based on the sponsor's query request. 


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10.3 Pregnancy 
During the study, if a female subject becomes pregnant, she will immediately discontinue the 
study treatment. The investigator will report it to the sponsor within 24 h and fill out the 
"Pregnancy Report/Follow-up Form for Hengrui Clinical Studies". 
During the study, if the partner of a male subject becomes pregnant, he may continue the study. 
The investigator will report it to the sponsor within 24 h and fill out the "Pregnancy 
Report/Follow-Up Form for Hengrui Clinical Studies". 
The investigator should follow up the outcome of the pregnancy until 1 month after delivery, and 
report the outcome to the sponsor. 
Pregnancy outcomes such as stillbirth, spontaneous abortion, and fetal malformation are 
considered SAEs and need to be reported according to the time requirements for SAEs. 
If a subject experiences any SAE during pregnancy, then "SAE Report Form" should be filled 
out and reported according to SAE reporting procedure. 
10.4 Adverse Events of Special Interest 
When an AE of special interest specified in the study protocol occurs, the investigator will fill 
out the "Report of Adverse Event of Special Interest for Hengrui Clinical Studies" and report it 
to the sponsor within 24 h of being notified. If the AE of special interest is also an SAE, the 
"Serious Adverse Event Report Form" should also be completed and submitted to the relevant 
authorities according to SAE reporting procedure. 
 
≥ Grade 3 infusion reactions; 
 
≥ Grade 2 diarrhea/colitis, uveitis, interstitial pneumonitis; 
 
Other ≥ Grade 3 immune-related adverse events (irAEs); 
 
Any events that meet Hy's Law (ALT/AST > 3 × ULN accompanied with total bilirubin > 
2 × ULN and without other causes);  
11 CLINICAL MONITORING 
The CRA must follow the GCP and SOP, make visits to the study center for clinical monitoring 
on a regular basis or according to the actual conditions, supervise the implementation and 
progress of the clinical study, check and confirm that all data recorded and entered into CRF are 
correct and intact and are consistent with source data, and ensure that the clinical study is 
implemented following the study protocol. The investigator should cooperate with the CRA 
actively. Specifically, the CRA is responsible for: 


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i. 
Confirming that the study center is qualified prior to starting the study, including 
personnel and training, a well-equipped and functional laboratory with various 
study-related test conditions, sufficient number of subjects, and study personnel's 
familiarity with the protocol requirements; 
ii. 
Monitoring how the investigator is implementing the study protocol during the 
course of the study, confirming that informed consent forms are obtained from all 
subjects before the study, the enrollment rate and progress of the study, as well as 
the eligibility of enrolled subjects; 
iii. Confirming the accuracy and integrity of documentations and reports, and ensuring 
accurate data entry of all case report forms and consistency with source data. All 
errors or omissions have been corrected or noted, signed and dated by the 
investigator. Dose modifications, treatment changes, concomitant medications, 
intercurrent diseases, lost to follow-up, and missing investigations should be 
confirmed and documented for each subject. Verifying that withdrawal and lost to 
follow-up of enrolled subjects are explained in the case report forms; 
iv. Confirming that all AEs have been recorded, and that SAEs have been recorded 
and reported within the specified time frame; verifying that the investigational 
drugs are supplied, stored, dispensed, and returned in accordance with relevant 
regulations, and corresponding documentation are made; 
v. 
Recording clearly and faithfully visits, tests, and examinations that the investigator 
has failed to perform, and whether errors or omissions have been corrected; 
vi. Completing a written monitoring report after each visit, which should state the date 
and time of the monitoring visit, the name of the CRA, and the findings of the 
visit. 
The Quality Assurance Unit of the sponsor may conduct audit on the study in the clinical 
research institution. The audit covers the supply of drugs, required study documents, 
documentation of the informed consent process, and consistency between case report forms and 
original documents. The content and scope of the audit may also be expanded according to the 
situation. The investigator agrees to participate at a reasonable time and in a reasonable way. 


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12 DATA ANALYSIS/STATISTICAL METHOD 
12.1 Sample Size 
Efficacy hypothesis 
According to study SHR-1210-101, the ORR of all dose groups (n = 93) of NPC subjects was 
29.0%, and the ORR of the 200 mg dose group (n = 68) was 36.8%. In the subgroup analysis, the 
ORR of all dose groups (n = 58) of subjects who had failed at least two lines of chemotherapy 
was 27.6%, and the ORR of the 200 mg dose group (n = 43) was 37.2%. Also, referring to the 
efficacy results of similar drugs, the intended study for registration will use a dose of 200 mg, 
and a conservative estimate of the upper limit of ORR is set at 26%. 
Pembrolizumab for the treatment of head and neck squamous cell carcinoma was approved by 
the FDA with an ORR of 16% in a single-arm study. Therefore, it is stipulated that the lower 
limit of the 95% confidence interval for the ORR for this study should not be less than 15%. 
Sample size calculation 
According to the above efficacy hypothesis (ORR = 26%), with a one-sided alpha = 0.025, 
enrolling 139 subjects can achieve a power of 90% that the lower limit of 95% confidence 
interval for ORR is not less than 15%. In order to ensure that the 139 subjects are included in the 
evaluation, assuming a dropout rate of 10%, 155 subjects should be enrolled. 
12.2 Statistical Analysis Plan 
In this study, SAS 9.4 or later will be used for data processing and analysis. 
Categorical data will be descriptively summarized using statistics including the frequency (n) 
and percentage (%), as well as the 95% confidence interval of the overall percentage when 
necessary. Continuous data will be descriptively summarized using statistics including the mean, 
standard deviation (SD), median, minimum, and maximum. 
For the analysis of the primary endpoint, the IRC-assessed ORR and its 95% confidence interval 
(Clopper-Pearson method) will be estimated. 
The detailed analysis plan and strategy will be described in the Statistical Analysis Plan (SAP). 
12.3 Statistical Hypothesis and Decision Rule 
The primary endpoint of this study is the ORR. The ORR of the investigational drug is compared 
with the ORR of 15% for the monotherapy (refer to the ORR in the single-arm study of 
pembrolizumab in the treatment of head and neck squamous cell carcinoma for which the drug is 
approved by the FDA). 


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Hypotheses 
H0: The ORR of the investigational drug = 15% 
H1: The ORR of the investigational drug ≠ 15% 
α level: 0.05 (two-sided). 
12.4 Analysis Population 
 
Full analysis set (FAS): all eligible subjects who have used the investigational drug after 
enrollment. The FAS is the primary analysis set for the efficacy analysis of this study. 
 
Per-protocol set (PPS): a subset of the FAS, excluding subjects with important protocol 
deviations which significantly impact study results. 
 
Safety analysis set (SS): enrolled subjects who have received at least one dose of 
investigational drug and have at least one safety assessment. 
 
Slice-testing biomarker analysis set: all enrolled subjects who have received at least one 
dose of investigational drug and have at least one slice-testing biomarker data for PD-L1. 
 
ADA analysis set: all enrolled subjects who have received at least one dose of 
investigational drug and have at least one ADA assessment data. 
12.5 Statistical Methods 
12.5.1 Basic methods 
This is a single-arm, open-label, multi-center phase II clinical study. Six months after the last 
subject in, the primary endpoints, secondary endpoints, and safety will be statistically analyzed. 
12.5.2 Primary efficacy endpoint analysis 
Primary endpoint will be analyzed based on the FAS. For the analysis of the primary endpoint, 
the IRC-assessed ORR and its 95% confidence interval (Clopper-Pearson method) will be 
estimated. 
Objective response rate (ORR): refers to the objective tumor response as per the RECIST1.1 
criteria and is obtained by dividing the number of subjects whose best overall response (BOR) is 
complete response (CR) or partial response (PR) by the number of subjects. 
The analysis on the PPS is similar to the analysis on the FAS in terms of detailed analytical 
methods. 


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12.5.3 Secondary efficacy endpoints analysis 
The investigator-assessed ORR, disease control rate (DCR), and their 95% confidence intervals 
(Clopper-Pearson method) will be estimated. 
The Kaplan-Meier method will be used to estimate the PFS, DoR, and OS and the corresponding 
95% confidence intervals will be calculated (Brookmeyer-Crowley method based on log-log 
transformation, with the standard error calculated using the Greenwood formula). 
TTR will be descriptively summarized using the mean, standard deviation, median, maximum, 
and minimum. 
Disease control rate (DCR): refers to the result obtained by dividing the number of subjects 
whose BOR is CR, PR, or stable disease (SD ≥ 8 weeks) by the number of subjects. 
Progression-free survival (PFS): refers to the time from the date of first dose to progressive 
disease or death, whichever occurs first. 
Duration of response (DoR): refers to the time from measurement criteria are first met for CR/PR 
(whichever is first recorded) to the first documentation of disease recurrence/progression or 
death (whichever comes first). 
Overall survival (OS): refers to the time from first study dose to death of any cause. 
Time to response (TTR): refers to the time from the date of the first dose to meeting the CR or 
PR criteria for the first time (whichever is measured first). 
The secondary endpoints will be analyzed based on the FAS and PPS. 
12.5.4 Handling of missing data 
In this study, the missing data of the efficacy endpoints will not be treated specially, and the 
missing values will not be estimated in the safety evaluation. 
12.5.5 Safety analysis 
The analysis will be performed based on SS. 
AEs that occur during the study will be coded according to MedDRA v21.0. The frequency and 
incidence of AEs will be summarized by system organ class and preferred term. The causality 
and severity of AEs will be further tabulated for description. Descriptive statistics will be used to 
summarize other safety endpoints. The incidences of AEs, adverse reactions, AEs resulting in 
withdrawal from study, AEs resulting in death, and the incidence of SAEs will be summarized. 
Severity of AEs and adverse reactions: For the same AE occurring multiple times in the same 
subject, the highest severity will be included in the analysis; for different AEs occurring in the 
same subject, the most severe AE will be included in the analysis. 


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Laboratory tests: Abnormal laboratory values will be summarized using descriptive statistics. 
Vital signs: Measured values and changes will be summarized using mean, maximum, minimum, 
median, and SD. 
Physical examination and 12-Lead ECG will be summarized descriptively. 
Baseline is defined as the most recent test data before the first dose. 
12.5.6 Exploratory analysis 
The relationship between PD-L1 expression and efficacy of SHR-1210 will be evaluated. 
The relationship between immune-related cells (T lymphocytes, B lymphocytes, macrophages, 
dendritic cells, and bone marrow-derived suppressor cells) in tumor microenvironment and 
efficacy of SHR-1210 will be evaluated. 
The generation of anti-SHR-1210 antibodies (ADAs) vs. time of measurement will be 
statistically described. 
13 DATA MANAGEMENT 
13.1 Data Recording 
Data will be collected and managed using the electronic case report form (eCRF). 
13.1.1 eCRF entry 
Clinical study data will be collected using the HRTAU EDC system. 
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 
study 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 error message prompt for questionable data. PI or CRC is permitted to 
modify or explain the problematic data. If necessary, multiple queries can be raised until the 
event of problematic data is resolved. 
13.1.2 eCRF review 
The investigator or designated personnel should fill out, review, and submit eCRF in a timely 
manner. The PI or CRC should promptly respond to queries raised by the CRA, data manager, 
and medical reviewer. After data cleaning is completed, the investigator will sign the completed 
eCRF for verification. 


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13.2 Data Monitoring 
Implemented by: CRA. 
Monitoring content: To confirm that the study protocol is adhered to; the records on CRF are 
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). 
13.3 Data Management 
13.3.1 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 using the system, 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.) 
13.3.2 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 guideline. After submitting the 
eCRF, the CRA, data manager, and medical reviewer should review the data. Questions during 
the review are 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. 
13.3.3 Data review and database locking 
After the clinical study is completed, the study director, sponsor, statistician, and data manager 
will conduct a joint data review before statistical analysis mainly to determine the analysis data 
set (including FAS, PPS, and SS) for each case, the judgment of missing values, and the handling 
of outliers. All decisions made under data review must not be modified, and any decision must 
be documented. 
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 as confirmed by the data review meeting. The data manager will export the 
data to the statistics department for data analysis. 


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13.3.4 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-ROMs, which will be archived by the sponsor 
and various institutions for auditing and/or inspection. 
All materials should be preserved and managed in accordance with GCP requirements, and 
necessary documents of clinical trials should be preserved until 2 years after the investigational 
drug is approved for marketing or 5 years after the termination of the clinical study. 
14 SOURCE DATA AND 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 the 
authorized representative of Jiangsu Hengrui Pharmaceuticals Co., Ltd. and regulatory 
authorities to inspect the clinical records (which may be copied if permissible by law) 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. 
15 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 investigational 
drugs, including receipt, storage, dispensing, return, and disposal (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. 


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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 correction and addition. 
The drug regulatory authorities, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), sponsor's CRA and/or auditor may carry out systemic inspection of clinical 
study-related activities or documents to assess whether the study is implemented based on the 
requirements of the study protocol, SOPs, and relevant regulations (such as Good Laboratory 
Practices (GLP) and Good Manufacturing Practices (GMP)), and whether the study data are 
recorded in a prompt, truthful, accurate, and complete manner. The audit should be performed by 
personnel not directly involved in this clinical study. 
16 REGULATIONS, ETHICS, INFORMED CONSENT, AND SUBJECT 
PROTECTION 
16.1 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 trial and the clinical trial can 
only be carried out after an approval is obtained. The clinical study approval number for SHR-
1210 is 2016L01455. 
The legal basis for the design of this study protocol is as follows: 
1) 
Provisions for Drug Registration 
2) 
Good Clinical Practice 
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 Ethical Guidelines 
4) 
Other applicable laws and regulations 
16.2 Ethical Standards 
This study protocol must first be reviewed and approved by the Ethics Committee of the Cancer 
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", CFDA's (now 
NMPA) "Good Clinical Practice (GCP)", and relevant regulations. Before the study is initiated, 
approval must be obtained from the IEC/IRB of the hospital. 


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The study protocol must not be unilaterally modified without approvals from both the sponsor 
and investigator. The investigator can modify or deviate from the study protocol before obtaining 
an approval from the IRB/IEC only when in purpose of eliminating direct and immediate harm to 
the subject. Besides, the deviation or change and the corresponding reason, and the recommended 
protocol modification should be submitted to the IRB/IEC 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 ethics committee. 
If necessary, corresponding changes should be simultaneously made to other study documents 
and submitted and/or be approved according to the pertinent requirements of the ethics 
committee. The investigator is responsible for submitting the interim reports regularly according 
to the pertinent requirements of the IEC/IRB. After the end of the study, the completion should 
be informed to the IEC/IRB. 
16.3 Independent Ethics Committee 
The protocol, ICF, recruitment material, and all subject materials must be reviewed and approved 
by the IEC/IRB. Subjects may be enrolled only after the protocol and ICF have been approved. 
Any revisions to the protocol must be reviewed and approved by the IEC/IRB prior to being 
implemented. All revisions to the ICF must be approved by the IEC/IRB, who will decide 
whether the subjects who have signed the previous version of the ICF are required to sign the 
new one. 
16.4 Informed Consent 
The ICF describes the investigational drug and study process in detail and fully explains the risks 
of the study to the subjects. Written ICFs must be obtained prior to screening. 
16.4.1 ICFs and other written information for subjects 
The following informed consent materials will be submitted along with the protocol: 
Informed consent form; 
Subject contact card; 
Recruitment advertisement. 
16.4.2 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 


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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. 
16.5 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 investigational drugs can 
examine all 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. 
The contact information of the subjects will be safely kept in each study center and only used 
internally during the study. At the end of the study, all the records will be kept in a secure place 
based on the time limit specified by local IRB and regulations. 
The study data of subjects collected for statistical analysis and scientific reports will be uploaded 
and stored in Sun Yat-Sen University Cancer Center. This should not include the contact 
information or identification information of subjects. 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 and Sun Yat-Sen University 
Cancer Center are all confidential and password-protected. At the end of the study, all 
identification information in the study database will be erased and archived in Sun Yat-Sen 
University Cancer Center. 
17 PUBLISHING 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 


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with the manuscript, abstract, or full text of all planned publications (poster, invited lectures, or 
guest lectures) at least 30 days prior to submission for publication or other forms of release. To 
protect the intellectual property rights that need to be patented, the investigator should agree to 
delay publications, and the delay period should not exceed 60 days. Before open publication, 
Hengrui can require the investigator to delete any previously unpublished confidential 
information (except for study results). If this study is part of a multicenter study, the investigator 
must agree that the first publication is an integrated result from all study 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. 
18 CLINICAL STUDY PROGRESS 
Estimated enrollment of the first subject: Jun. 2018 
Estimated enrollment of the last subject: Mar. 2019 
Estimated study completion: one year after the last subject's first dose, the subjects undergoing 
treatment will enter the expansion study of SHR-1210 for continued treatment and observation. 
19 REFERENCES 
1. 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence 
and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J 
Cancer. 2015;136(5):E359-86. 
2. 
Her C. Nasopharyngeal cancer and the Southeast Asian patient. Am Fam Physician. 2001; 
63(9):1776-82. 
3. 
Zhang L, Zhang Y, Huang PY, Xu F, Peng PJ, Guan ZZ. Phase II clinical study of 
gemcitabine in the treatment of subjects with advanced nasopharyngeal carcinoma after the 
failure of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2008;61(1):33-8. 
4. 
Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, et al. Co-expression of PD-1 and PD-L1 
predicts poor outcome in nasopharyngeal carcinoma. Med Oncol. 2015;32(3):86. 
5. 
Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, et al. Safety and Antitumor 
Activity of Pembrolizumab in Subjects with Programmed Death-Ligand 1-Positive 
Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 
2017;35(36):4050-6. 
6. 
An open-label, multicohort, phase I/II study to evaluate nivolumab in subjects with virus-
associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) 
nasopharyngeal carcinoma (NPC). ASCO abstract. 2017. [cited March 29, 2018]. Available from: 
https://meetinglibrary.asco.org/record/146861/abstract 
 


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Appendix I. 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. 
5 
Death. 
 
 


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Appendix II. Creatinine Clearance Calculation 
Creatinine Clearance Calculation Using the Cockcroft-Gault Formula 
Serum Creatinine (mg/dL): 
Creatinine Clearance in Males (mL/min) = 
(140 - Age) × (Weight) a 
72 × Serum Creatinine  
 
 
 
Creatinine Clearance in Females (mL/min) = 0.85 × (140 - Age) × (Weight) a 
72 × Serum Creatinine  
 
 
 
Serum Creatinine (μmol/L): 
Creatinine Clearance in Males (mL/min) = 
(140 - Age) × (Weight) a 
0.818 × Serum Creatinine  
 
 
 
Creatinine Clearance in Females (mL/min) = 0.85 × (140 - Age) × (Weight) a 
0.818 × Serum Creatinine  
 
 
 
a: The unit for age is year and for weight is kg. 
 
 


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Appendix III. Prohibited Traditional Chinese Medicine 
Prohibited Traditional Chinese Medicine 
Huatan Huisheng tablet 
Kangaiping pill 
Brucea Javanica oil soft 
capsule 
Fukang capsule 
Mandarin melon berry 
syrup 
Xiaoaiping 
Cantharidin 
Pingxiao capsule 
Cinobufotalin 
Pingxiao tablet 
Bufotoxin 
Shendan Sanjie capsule 
Kang'ai injection 
Ankangxin capsule 
Kanglaite injection 
Boshengaining 
Zhongjiefeng injection 
Zedoary turmeric oil and glucose injection 
Aidi injection 
Kanglixin capsule 
Awei Huapi ointment 
Cidan capsule 
 
 


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Appendix IV. 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) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
1 BACKGROUND 
Omitted 
2 PURPOSE 
Omitted 
3 MEASURABILITY OF TUMOR AT BASELINE 
3.1 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 nodule: pathologically enlarged and measurable, single lymph nodule must 
be ≥ 15 mm in short axis by CT scan (CT scan slice thickness 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. 
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. 


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Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of cutaneous 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both imaging and clinical examination, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end 
of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT, MRI: CT is currently the best available and reproducible method for efficacy evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g., for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm CR when biopsies are obtained, or to 
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 trials in ovarian cancer. 
Cytology/Histology: These techniques can be used to differentiate between PR and CR in certain 
cases specified in the protocol (e.g., residual benign tumor tissue is often present in the lesions of 
germ cell tumors). 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 


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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 subjects 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 subjects 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 ≥ 
15 mm by CT scan. Only the short axis of these nodes needs to be measured at baseline. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by tumor metastasis. Nodule size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smallest of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 


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recorded as the node measurement. Nodes with short axis ≥ 10 mm but < 15 mm should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions 
should be recorded as "present", "absent", or in rare cases "unequivocal progression". It is 
possible to record multiple target lesions involving the same organ as a single item on the case 
record form (e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
4.3 Response Criteria 
4.3.1 Evaluation of target lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
compared 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 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. 


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Target lesions that become too small to measure: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being "too small to 
measure". When this occurs it is important that a value be recorded on the CRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm could be assigned. (Note: It is less likely that this rule will be 
used for lymph 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 could be 
assigned in this circumstance as well). This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will prevent 
false evaluation based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. 
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). 
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. 


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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 quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable), a useful test that can be applied when assessing subjects 
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 
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. 


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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 assessments generally need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible new disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following process: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, PD 
is confirmed. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the imaging examination, this is not PD. 
4.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement for confirmation. On occasion a response 
may not be documented until after the end of treatment, so protocols should be clear if post-
treatment assessments are to be considered in the evaluation of best overall response. Protocols 
must specify how any new treatment introduced before progression will affect best response 
evaluation. The patient's best overall response evaluation will depend on the findings of both 
target and non-target diseases and will also take 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 trials where response is 
the primary endpoint, confirmation of PR or CR is needed to determine either one is the best 
overall response. 


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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 subjects 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, and NE = not 
evaluable 
If a 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 
efficacy evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 Missing assessments and inevaluable 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 a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 


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4.4.3 Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
Best response determination in trials where confirmation of complete or partial response is not 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at the last cycle 
has a best overall response of PR). When SD is believed to be best response, it must also meet 
the protocol specified minimum time calculated from baseline. If the minimum time is not met 
when SD is otherwise the best overall response, the patient's best overall response depends on the 
subsequent assessments. For example, a patient who has SD at cycle 1, PD at cycle 2 and does 
not meet minimum duration for SD, will have a best overall response of PD. The same patient 
lost to follow-up after the first SD assessment would be considered not evaluable. 
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 best overall response can be interpreted as in Table 3. 
Table 3. Best overall response when confirmation of CR and PR required 
Overall Response 
at First Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable. 
a: If a CR is truly met at first time point, then 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 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. 
 


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4.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodules decrease to a normal 
size of < 10 mm, they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodules are normal in order not to overstate progression should it be 
based on increase in size of the nodules. As noted earlier, this means that subjects with CR may 
not have "zero" recorded on the case report form (CRF). 
In trials where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/evaluations will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
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 disease 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 may be used to confirm a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be prospectively described in the protocol and supported by 
disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled evaluation. If at 
the next scheduled evaluation, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 


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


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


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Appendix V. The 2017 Chinese Staging of Nasopharyngeal Carcinoma (the 
2008 Revised Expert Consensus on Staging of Nasopharyngeal Carcinoma) 
T Staging 
Tx: The primary tumor cannot be evaluated 
T0: The tumor is not found, but with positive EBV and metastasis to lymph nodes on the neck  
T1: The tumor is in the nasopharynx, or has invaded the oropharynx and/or nasal cavity, but does 
not involve parapharyngeal space  
T2: The tumor has invaded the parapharyngeal space, and/or involved the adjacent soft tissues 
(internal pterygoid muscle, external pterygoid muscle, anterior vertebral muscle)  
T3: The tumor has invaded the bone structure of the skull base, cervical vertebrae, pterygoid 
structure, and/or paranasal sinuses  
T4: The tumor has invaded the skull, with involvement of cranial nerves, hypopharynx, orbits, and 
parotid glands, and/or extensive soft tissue invasion beyond the lateral edge of the pterygoid muscle 
N Staging 
Nx: Regional lymph nodes cannot be evaluated  
N0: No regional lymph node metastasis 
N1: Metastasis to lymph nodes of the neck of one side and/or postpharyngeal lymph nodes 
(regardless of the number of sides): maximum diameter ≤ 6 cm, and located above the lower 
edge of the cricoid cartilage 
N2: Metastasis to lymph nodes on both sides of the neck: maximum diameter ≤ 6 cm, and located 
above the lower edge of the cricoid cartilage  
N3: Metastasis to postpharyngeal lymph nodes (regardless of the number of sides): the largest 
diameter > 6 cm and/or located below the lower edge of the cricoid cartilage 
Clinical Stage 
Stage 0: TisN0M0 
Stage I: TiN0M0 
Stage II: T0-1N1M0, T2N0-1M0 
Stage III: T0-2N2M0, T3N0-2M0 
Stage IVA: T0-3N3M0 or T4N0-3M0 
Stage IVB: Any T and N plus M1 

SAP_001.pdf: 
Title: A single-arm, open-label, multi-center, phase II clinical study of anti-PD-1 
antibody SHR-1210 in recurrent/metastatic nasopharyngeal carcinoma subjects who 
have received previous at least two lines of chemotherapy   
Clinical trial registration number: NCT03558191 
Date: 2 Mar., 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SHR-1210-II-209 
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Statistical Analysis Plan 
 
1 
Translated from Original Document 
 
 
 
 
 
 
A Single-Arm, Open-Label, Multi-Center, Phase II Clinical Study of 
Anti-PD-1 Antibody SHR-1210 in Recurrent/Metastatic 
Nasopharyngeal Carcinoma Patients Who Have Received Previous 
at Least Two Lines of Chemotherapy 
Statistical Analysis Plan 
(SAP) 
 
Author: 
 
Company: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Version: 1.0 
Date: 2 Mar., 2020 
 
This SAP has been reviewed by the following personnel before being approved and effective. 
 
Functional Role 
Reviewer 
Senior Medical Director 
Qing Yang 
Associate Director of Statistics 
 
 
 


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ABBREVIATIONS 
Term 
Definition 
CR 
Complete response 
DCR 
Disease control rate 
DoR 
Duration of response 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PPS 
Per-protocol set 
SD 
Stable disease 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS ....................................................................................................................... 2 
1 
REVISION ............................................................................................................................. 6 
2 
INTRODUCTION ................................................................................................................ 6 
2.1 
Study Design ................................................................................................................ 6 
2.2 
Study Objectives .......................................................................................................... 7 
3 
STATISTICAL HYPOTHESIS ........................................................................................... 7 
4 
STUDY ENDPOINTS ........................................................................................................... 7 
4.1 
Primary Endpoint ......................................................................................................... 7 
4.2 
Secondary Endpoints ................................................................................................... 8 
4.2.1 
Efficacy ......................................................................................................... 8 
4.2.2 
Safety ............................................................................................................. 8 
4.3 
Exploratory Endpoints ................................................................................................. 8 
5 
STATISTICAL ANALYSIS ................................................................................................ 8 
5.1 
General Considerations ................................................................................................ 8 
5.1.1 
Analysis sets .................................................................................................. 8 
5.1.2 
General analytical method ............................................................................. 9 
5.1.3 
Covariates and subgroups ............................................................................ 10 
5.1.4 
Analysis window ......................................................................................... 10 
5.1.5 
Missing data ................................................................................................ 10 
5.1.5.1 
Medical history ............................................................................ 10 
5.1.5.2 
Adverse events ............................................................................ 11 
5.1.5.3 
Concomitant medication ............................................................. 11 
5.1.5.4 
Drug exposure ............................................................................. 12 
5.1.5.5 
Rules for imputing the last survival date and the start  
date of a new anti-tumor treatment ............................................. 12 
5.1.5.5.1 
Last survival date ................................................... 12 
5.1.5.5.2 
Date of death .......................................................... 13 
5.1.5.5.3 
Start date of a new anti-tumor treatment ................ 13 
5.2 
Sample Size................................................................................................................ 15 


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5.3 
Subject Description .................................................................................................... 15 
5.3.1 
Subject distribution ..................................................................................... 15 
5.3.2 
Demographics and other baseline characteristics ........................................ 15 
5.3.3 
Medical history and cancer surgery history ................................................ 16 
5.3.4 
History of anti-tumor treatment ................................................................... 16 
5.3.5 
History of drug allergy ................................................................................ 16 
5.3.6 
Past medication and concomitant medication ............................................. 16 
5.3.7 
Subsequent anti-tumor treatment ................................................................ 17 
5.3.8 
Protocol deviation ....................................................................................... 17 
5.4 
Compliance ................................................................................................................ 17 
5.5 
Efficacy Analysis ....................................................................................................... 18 
5.5.1 
Primary efficacy analysis ............................................................................ 18 
5.5.2 
Secondary efficacy analysis ........................................................................ 18 
5.5.3 
Subgroup analysis ....................................................................................... 20 
5.6 
Safety Analysis .......................................................................................................... 20 
5.6.1 
Drug exposure ............................................................................................. 20 
5.6.2 
Adverse events ............................................................................................ 21 
5.6.3 
Laboratory tests ........................................................................................... 24 
5.6.4 
ECOG (performance status assessment) ..................................................... 25 
5.6.5 
Vital signs .................................................................................................... 25 
5.6.6 
ECG ............................................................................................................. 26 
5.6.7 
Physical examination ................................................................................... 26 
5.6.8 
Other safety analyses ................................................................................... 26 
5.7 
Statistical analysis of PK ........................................................................................... 26 
5.8 
Statistical analysis of PD ........................................................................................... 26 
5.9 
Immunogenicity (ADA) Analysis .............................................................................. 26 
5.10 Other Analyses ........................................................................................................... 27 
6 
INTERIM ANALYSIS ....................................................................................................... 27 
7 
REFERENCES .................................................................................................................... 27 


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LIST OF TABLES 
Table 5.6.5-1. Criteria for determining clinically significant abnormalities of vital signs .......... 25 
Table 5.6.6-1. Classification criteria of PR and QTcF ................................................................. 26 
 
 


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1 
REVISION 
None 
2 
INTRODUCTION 
This is a phase II clinical study to investigate and evaluate the efficacy and safety of anti-PD-1 
antibody SHR-1210 in patients with recurrent/metastatic nasopharyngeal carcinoma who have 
failed at least two lines of chemotherapy. 
This statistical analysis plan is written based on the final version of its study protocol (version: 
1.0, version date: 20 Apr., 2018).  
The final draft of this plan will be completed before database locking and will be signed by 
various functional departments for confirmation. 
2.1 
Study Design 
This is a single-arm, open-label, multi-center phase II clinical study to investigate and evaluate 
the efficacy and safety of anti-PD-1 antibody SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma who have failed at least two lines of chemotherapy. A total of 155 subjects 
will be enrolled. 
After being fully informed and providing a written informed consent form, eligible subjects will 
receive SHR-1210 200 mg IV, q2w, in treatment cycles of 4 weeks. Treatment will continue until 
the criteria for treatment discontinuation as specified in the protocol are met. After the end of 
treatment, subjects will continue safety follow-ups and survival follow-ups. Subjects who 
discontinue the treatment due to reasons other than progressive disease will also be followed for 
progressive disease after discontinuation. SHR-1210 is an immune checkpoint inhibitor and, 
according to the experience of similar drugs, some subjects may experience delayed or early tumor 
pseudo progression after receiving immunotherapy drugs. Therefore, the benefits of 
immunotherapy drugs may be underestimated based on RECIST 1.1 only. As a result, it is 
suggested in this study to carry out imaging evaluation based on both RECIST 1.1 and iRECIST. 
For subjects who are clinically stable after the first occurrence of PD, the investigator may decide 
to allow the subjects to continue using SHR-1210 and undergo imaging examination again after 
4-6 weeks. If the subsequent imaging examination confirms PD, the subjects should discontinue 
SHR-1210 treatment unless the investigator believes that the subjects can continue to gain clinical 
benefit from the SHR-1210 treatment, which should be decided upon discussion with the sponsor. 
After subjects are enrolled in the study, safety follow-ups will be conducted before 
administration of SHR-1210 on D1 and D15 of each treatment cycle. After treatment begins, 
response will be assessed once every 2 cycles (8 weeks) until the end of treatment, withdrawal of 
informed consent, or death. 
The schedule of activities is detailed in the protocol. 


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2.2 
Study Objectives 
 
Primary objective: 
To evaluate the objective response rate (ORR) of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma who have failed at least two lines of chemotherapy by independent 
review committee (IRC). 
 
Secondary objective: 
To evaluate the efficacy and safety of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma who have failed at least two lines of chemotherapy. 
 
Exploratory objectives: 
To evaluate the relationship between PD-L1 expression in tumor tissues and efficacy of SHR-
1210; to evaluate the immunogenicity of SHR-1210 in subjects with recurrent/metastatic 
nasopharyngeal carcinoma; and to investigate the correlation between immunogenicity and 
efficacy/safety. 
3 
STATISTICAL HYPOTHESIS 
The primary endpoint of this study is the ORR. The ORR of the investigational drug is compared 
with the ORR of 15% for the monotherapy (refer to the ORR in the single-arm study of 
pembrolizumab in the treatment of head and neck squamous cell carcinoma for which the drug is 
approved by the FDA). The hypotheses are as follows: 
H0: The ORR of the investigational drug = 15% 
H1: The ORR of the investigational drug ≠ 15% 
α level: 0.05 (two-sided). 
If the lower limit of the 95% CI for the ORR of the investigational drug exceeds 15%, the 
investigational drug is considered effective compared with historical control data. 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
IRC-assessed ORR of SHR-1210 in subjects with recurrent/metastatic nasopharyngeal carcinoma 
who have failed at least two lines of chemotherapy. 


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4.2 
Secondary Endpoints 
4.2.1 Efficacy 
 
Investigator-assessed ORR 
 
Duration of response (DoR) 
 
Disease control rate (DCR) 
 
Time to response (TTR) 
 
Progression-free survival (PFS) as per RECIST 1.1 
 
Overall survival (OS) 
4.2.2 Safety 
The following safety data will be collected and summarized following the study protocol (see the 
study protocol for the endpoints and collection time in details). 
 
Adverse events 
 
Laboratory tests 
 
Vital signs 
 
12-Lead ECG 
 
Physical examination 
4.3 
Exploratory Endpoints 
 
To evaluate the relationship between PD-L1 expression and efficacy of SHR-1210 
 
To investigate the anti-SHR-1210 antibodies (ADAs) in subjects after injection of SHR-
1210 
5 
STATISTICAL ANALYSIS 
5.1 
General Considerations 
5.1.1 Analysis sets 
 
Full analysis set (FAS): all enrolled subjects who have received at least one dose of the 
investigational drug. The FAS is the primary analysis set for the efficacy analysis of this 
study. 
 
Per-protocol set (PPS): a subset defined in the FAS, excluding subjects with important 
protocol deviations that have a significant impact on efficacy. 


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 
Safety set (SS): all enrolled subjects who have received at least one dose of the 
investigational drug. 
 
Slice-testing biomarker analysis set (SBAS): all enrolled subjects who have received at least 
one dose of the investigational drug and have at least one slice-testing biomarker data for 
PD-L1. 
 
ADA analysis set (ADAS): all enrolled subjects who have received at least one dose of the 
investigational drug and have at least one ADA assessment data. 
5.1.2 General analytical method 
Baseline 
Unless otherwise stated, the "baseline" in this study is defined as the last non-missing 
measurement value obtained prior to the first use of the investigational drug, including the 
measurements taken on the day of and prior to the first dose. 
Study days 
The day of the first dose is defined as the start day of the study. Then, based on the start day of 
the study, the number of days of study corresponding to test or event is calculated by the 
following formulas: 
 
If an examination/event occurs before the start of the study, days = examination date - study 
start date; 
 
If an examination/event occurs after the start of the study, days = examination date - study 
start date + 1. 
General analysis 
Unless otherwise specified, the following descriptive statistics will be summarized by the type of 
variables: 
 
Measurement data will be summarized using number of subjects, mean, standard deviation, 
median, maximum, and minimum; 
 
Count data will be summarized using frequency and percentage; 
 
For time-to-event data, Kaplan-Meier method will be used to estimate the survival function 
and median time to event onset, and a survival curve will be plotted. 
Number of decimal places 
Unless otherwise specified, number of decimal places in the analysis report will be determined as 
per the following rules: 


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 
The decimal places of the minimum and maximum will remain the same as those of the raw 
data to be acquired. Mean and median should have one more decimal place than those of the 
raw data, and the standard deviation should have 2 more decimal places than that of the raw 
data. However, there can only be at most 4 decimal places. 
 
The percentage will be rounded to 1 decimal place. If the frequency is 0, the percentage is 
not displayed. 
 
The P value will retain 4 decimal places. If the P value is < 0.0001, it will be expressed as 
"< 0.0001"; if the P value is > 0.9999, it will be reported as "> 0.9999". 
 
The 95% CI, if being a decimal, will retain at least 2 decimal places, up to 4 decimal places. 
 
Time to event (in months) will be rounded to one decimal place. 
 
Hazard ratio will be rounded to two decimal places. 
Analysis software 
All statistical analyses will be conducted using SAS® 9.4 or above. 
5.1.3 Covariates and subgroups 
Subgroups include but are not limited to the following: gender (male/female), age (< 50 years old 
or ≥ 50 years old), baseline anti-tumor treatment (2 lines, 3 lines or more), baseline ECOG 
PS (0 and 1), number of organs with metastases (2 and ≥ 3), PD-L1 expression level in tumor 
tissues (< 1% and ≥ 1%, < 5% and ≥ 5%, or < 10% and ≥ 10%), and baseline EBV-DNA 
(negative or positive). 
5.1.4 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. 
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. 
5.1.5 Missing data 
Missing dates that are incalculable shall be imputed as follows. However, the listings are still 
presented with actual records. 
5.1.5.1 
Medical history 
For the missing dates of medical history (including the dates of first pathological diagnosis, 
progression/recurrence, and response prior to the first dose of the investigational drug), the rules 
for imputing data are as follows: 


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 
If the day is missing, it will be imputed with 1 of that month. 
 
If both month and day are missing while the year precedes the year of the first dose, the date 
will be imputed with 1 Jan. 
 
If both month and day are missing while the year is the same as the year of the first dose, the 
date will be imputed with 1 Jan. 
 
Completely missing dates will not be imputed. 
5.1.5.2 
Adverse events 
If the date related to an AE is missing, the rules for imputing are as follows: 
 
If the start date of an AE is completely missing, it will be imputed with the date of the first 
dose. 
 
If only the day of the start date of an AE is missing, while the year and month are the same 
as those of the first dose, the day will be imputed with the day of the first dose. 
 
If both month and day of the start date of an AE are missing, while the year is the same as 
that of the first dose, they will be imputed with the month and day of the first dose. 
 
In other cases when the month or day of the start date of an AE is missing, it will be 
imputed with 1. 
 
If only the day of the end date of an AE is missing, it will be imputed with the last day of 
the month (before the date of death). If the last day of the month is later than the date of 
death, the date will be imputed with the date of death. 
 
In other cases when the end date of an AE is missing, it will not be imputed. If the end date 
of an AE is later than the end date of study and if the outcome of the AE is ongoing, the end 
date of the study will be used as the end date of the AE. 
5.1.5.3 
Concomitant medication 
If the date related to the concomitant medication is missing, the rules for imputing are as follows: 
 
If the start date of the concomitant medication is completely missing, it will be imputed with 
the date of the first dose. 
 
If only the day of the start date of the concomitant medication is missing, while the year and 
month are the same as those of the first dose, the day will be imputed with the day of the 
first dose. 
 
If both month and day of the start date of the concomitant medication are missing, while the 
year is the same as that of the first dose, they will be imputed with the month and day of the 
first dose. 


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 
In other cases when the month or day of the start date of the concomitant medication is 
missing, it will be imputed with 1. 
 
If only the day of the end date of the concomitant medication is missing, it will be imputed 
with the last day of the month (before the date of death). If the last day of the month is later 
than the date of death, the date will be imputed with the date of death. 
 
In other cases when the end date of the concomitant medication is missing, it will not be 
imputed. 
5.1.5.4 
Drug exposure 
The date of the first dose will not be imputed. If the date of the last dose is unknown or partially 
missing, it will be imputed according to the following rules: 
 
If the date of the last dose is completely missing while the date of death and CRF page for 
treatment discontinuation are absent, the subject is considered to be under continuous 
administration and the date of the last dose will be imputed with the end date of the study. 
 
If the date of the last dose is completely or partially missing while the date of death or CRF 
page for treatment discontinuation is present (both are before the end date of the study), the 
date of the last dose will be imputed as follows: 
= 31-12-YYYY (if the year YYYY is known, and if YYYY < min (year) [date of treatment 
discontinuation, date of death]) 
= The last day of the month (if both the year and month are not missing, and if YYYY < min 
(year) [date of treatment discontinuation, date of death]) 
= The last day of the month (if both the year and month are not missing, and if YYYY = min 
(year) [date of treatment discontinuation, date of death], and MM < min (month) [date of 
treatment discontinuation, date of death]) 
= min (date of treatment discontinuation, date of death), other cases. 
5.1.5.5 
Rules for imputing the last survival date and the start date of a new anti-tumor 
treatment 
5.1.5.5.1 Last survival date 
If the investigator is not informed of subject death by the cutoff date of analysis, the latest complete date 
of the following data will be used as the last survival date: 
 
All dates of examinations and evaluations of the subjects (tumor response evaluation, blood 
tests (laboratory, PK), vital signs, physical examination, ECOG PS, pregnancy test, 
urinalysis, and routine stool test) 


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 
The start and end dates of a new anti-tumor treatment after the discontinuation of study 
treatment 
 
The start and end dates of AEs 
 
The date of the last known survival status of the subject on the survival follow-up page 
 
The start and end dates of study treatment 
 
Date of withdrawal of informed consent form 
 
Date of randomization 
 
The date on the study discontinuation page (if the reason for discontinuation is "lost to 
follow-up", the date of lost to follow-up will not be calculated) 
Only the date of actual examinations can be used to derive the last survival date. The dates of 
examinations and evaluations carried out after the cutoff date will not be used to derive the last 
survival date. 
5.1.5.5.2 Date of death 
If the date of death is completely or partially missing, the last survival date will be used to 
impute the date of death: 
 
If the date of death is completely missing, the last survival date + 1 day will be used as the 
date of death. 
 
If the day is missing or if both month and day are missing, the date of death = max (last 
survival date + 1, the date imputed below) 
- Day is missing:  
01-MM-YYYY 
- Month and day are missing:  
01-01-YYYY 
5.1.5.5.3 Start date of a new anti-tumor treatment 
If the start date of a new anti-tumor treatment is not completely missing, it will be imputed 
according to the following rules and used to derive the end date of the study treatment. The date 
of PD mentioned below is based on the radiographic assessment. 
 
If the end date of a new anti-tumor treatment is partially missing or not missing, it will be 
used to derive the start date of the new anti-tumor treatment. 
- 
If the month and day of the end date of the new anti-tumor treatment are missing while 
the year is not missing, 31 Dec. will be used as the end date of the new anti-tumor 
treatment. 


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- 
If only the day of the end date of the new anti-tumor treatment is missing, the last day 
of the month will be used as the end date of the new anti-tumor treatment. 
 
If the start date of a new anti-tumor treatment is completely missing or only the year is not 
missing, it will be derived and imputed according to the following rules: 
- 
If the start date of the new anti-tumor treatment is completely missing, the start date 
imputed = min [max (PD date + 1, date of last dose + 1), end date of new anti-tumor 
treatment] 
- 
Only the year (YYYY) of the start date of the new anti-tumor treatment is not missing 
1)  If YYYY < min (year) [max (PD date + 1, date of last dose + 1), end date of new 
anti-tumor treatment], the date will be imputed as 31-12-YYYY. 
2)  In other cases, if YYYY = min (year) [max (PD date + 1, date of last dose + 1), 
end date of new anti-tumor treatment], the date imputed = min [max (PD date + 1, 
date of last dose +1), end date of new anti-tumor treatment]. 
3)  In other cases, if YYYY > min (year) [max (PD date + 1, date of last dose + 1), 
end date of new anti-tumor treatment], the date imputed = 01-01-YYYY. 
 
The year (YYYY) and month (MM) of the start date of a new anti-tumor treatment are not 
missing 
- 
If YYYY = min (year) [max (PD date + 1, date of last dose + 1), end date of new anti-
tumor treatment], and if MM < min (month) [max (PD date + 1, date of last dose + 1), 
end date of new anti-tumor treatment], the date will be imputed with the last day of MM. 
- 
In other cases, if YYYY = min (year) [max (PD date + 1, date of last dose + 1), end 
date of new anti-tumor treatment], and MM = min (month) [max (PD date + 1, date of 
last dose + 1), end date of new anti-tumor treatment], then the date imputed = min [max 
(PD date + 1, date of last dose + 1), end date of new anti-tumor treatment]. 
- 
In other cases, if YYYY = min (year) [max (PD date + 1, date of last dose + 1), end 
date of new anti-tumor treatment], and MM > min (month) [max (PD date + 1, date of 
last dose + 1), end date of new anti-tumor treatment], then the date imputed = 01-MM-
YYYY. 
- 
In other cases, if YYYY < min (year) [max (PD date + 1, date of last dose + 1), end 
date of new anti-tumor treatment], the day imputed will be the last day of MM. 
- 
In other cases, if YYYY > min (year) [max (PD date + 1, date of last dose + 1), end 
date of new anti-tumor treatment], then the date imputed = 01-MM-YYYY. 


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5.2 
Sample Size 
Efficacy hypothesis: 
According to study SHR-1210-101, the ORR of all dose groups (n = 93) of NPC subjects was 
29.0%, and the ORR of the 200 mg dose group (n = 68) was 36.8%. In the subgroup analysis, the 
ORR of all dose groups (n = 58) of subjects who had failed at least two lines of chemotherapy 
was 27.6%, and the ORR of the 200 mg dose group (n = 43) was 37.2%. Also, referring to the 
efficacy results of similar drugs, the intended study for registration will use a dose of 200 mg, 
and a conservative estimate of the upper limit of ORR is set at 26%. 
Pembrolizumab for the treatment of head and neck squamous cell carcinoma was approved by 
the FDA with an ORR of 16% in a single-arm study. Therefore, it is stipulated that the lower 
limit of the 95% confidence interval for the ORR for this study should not be less than 15%. 
Sample size calculation: 
According to the above efficacy hypothesis (ORR = 26%), with a one-sided alpha = 0.025, 
enrolling 139 subjects can achieve a power of 90% that the lower limit of 95% confidence 
interval for ORR is not less than 15%. In order to ensure that the 139 subjects are included in the 
evaluation, assuming a dropout rate of 10%, 155 subjects should be enrolled. 
5.3 
Subject Description 
5.3.1 Subject distribution 
The descriptive statistics of the screening status of the subjects, including the number and 
percentage of subjects failing the screening, will be summarized based on the signing of 
informed consent form and categorized by the reasons for screening failure. The enrolled 
subjects receiving or not receiving the study treatment will be described, and the reasons for not 
receiving the study treatment or discontinuing the study treatment will be descriptively 
summarized with a detailed list. 
 Subjects included in each analysis set will be descriptively summarized, and the reasons for 
being excluded from the FAS, PPS, SS, SBAS, and ADAS will be listed in detail. 
5.3.2 Demographics and other baseline characteristics 
The gender, age, age stratification [< 50 years old and ≥ 50 years old] (those ≥ 50 years old can 
be further divided into ≥ 50 to < 65 vs. ≥ 65), ethnicity, height (cm), weight (kg), and body mass 
index BMI (kg/m2) of the subjects will be summarized using descriptive statistics. Demographic 
characteristics will be described based on the FAS. 
Formula of BMI calculation: Baseline weight (kg)/Baseline height (m2). 


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The tumor histological classification, metastasis, number of organs with distant metastases, 
location of metastases, clinical stage before enrollment, course of disease, and time from the date 
of last progression/recurrence to the randomization will be summarized. A detailed listing of 
subjects for tumor diagnosis will be provided. 
Course of disease (month) is defined as the time from the date of first pathological diagnosis to 
the date of first dose, and its formula of calculation is as follows: (Date of first dose - Date of 
first pathological diagnosis + 1)/30.4375. 
The calculation formula for the time (month) from the date of last progression/recurrence to the 
date of first dose is as follows: (Date of first dose - Date of last progression/recurrence + 1)/30.4375. 
Calculation of the number of organs with distant metastasis: the number of metastasis site 
checked in EDC (excluding the nasopharynx and neck; "other" is counted only once) 
5.3.3 Medical history and cancer surgery history 
If permitted, medical history and cancer surgery history will be coded per the latest version of 
MedDRA, categorized by PT and SOC, and summarized. In addition, a detailed list of medical 
history will also be provided. 
5.3.4 History of anti-tumor treatment 
For the history of anti-tumor treatment, the following descriptive statistics will be provided: 
 
Number of lines of previous anti-tumor treatment summarized by categorical variables 
 
Number and percentage of subjects who have received platinum-based medications 
 
Number and percentage of subjects who have received radiotherapy to the primary tumor 
lesion (nasopharynx) 
 
Summary of type of treatment (chemotherapy, targeted therapy, others) and purpose of 
treatment (neoadjuvant therapy, adjuvant therapy, others). 
A detailed listing will be provided for the history of anti-tumor treatment; a detailed listing will 
also be provided for the cancer surgery history, history of other surgeries, and history of 
radiotherapy. 
5.3.5 History of drug allergy 
A detailed listing of subjects with history of drug allergies will be provided. 
5.3.6 Past medication and concomitant medication 
Past medications are defined as drugs whose use has been completed before the first dose of the 
investigational drug. 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. 


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The past and concomitant medications will be classified and summarized according to ATC level 
2 and PT. In the summary description, if a subject uses the same drug (classified by ATC) more 
than once, it is counted only once. 
A listing of all past and concomitant medications will be provided. 
5.3.7 Subsequent anti-tumor treatment 
The number and percentage of subjects who have subsequently received new anti-tumor 
treatments will be summarized by the type and purpose of treatments, and a detailed listing will 
be provided. 
5.3.8 Protocol deviation 
Prior to database locking, the investigator and the sponsor will discuss and determine protocol 
deviations. Protocol deviations can be classified as "major" or "minor". 
Based on the FAS, all major protocol deviations will be descriptively summarized by type, and 
be tabulated for analysis. In addition, a detailed listing of protocol deviations will be provided. 
The listing will include all major and minor protocol deviations. 
5.4 
Compliance 
The descriptive statistics of treatment compliance will be analyzed based on SS. 
The duration of drug exposure, drug exposure, number of treatment cycles, frequency of doses, 
frequency of and reason for dose interruption, frequency of and reason for dose delay, and the 
compliance rate of the subjects receiving camrelizumab will be summarized using descriptive 
statistics. 
Since camrelizumab is administered twice in one treatment cycle, the treatment cycle is 
considered completed providing that at least one administration is completed in the cycle. 
The duration of exposure to the investigational drug (weeks) is defined as: (date of last dose - 
date of first dose + 1)/7. 
Drug exposure is defined as the cumulative amount of investigational drug received by the 
subject. 
Planned exposure to the investigational drug (mg) = (Date of last dose - Date of first dose + 14)/ 
14 × 200  
Compliance rate% = (Actual cumulative exposure (mg)/Planned cumulative exposure (mg)) × 100%.  
A detailed listing will be provided for the administration of camrelizumab. 
In addition, the follow-up time of the subjects and the number and percentage of subjects who 
continue camrelizumab medication after PD will be counted. 


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Follow-up time (months) = (Date of last contact or date of death (whichever occurs first) - date 
of first dose + 1)/12 
5.5 
Efficacy Analysis 
5.5.1 Primary efficacy analysis 
The primary endpoint is the IRC-assessed ORR, which will be analyzed based on the FAS. 
The ORR refers to the objective tumor response as per RECIST 1.1 and is obtained by dividing 
the number of subjects whose best overall response (BOR) during the trial is complete response 
(CR) or partial response (PR) by the number of subjects included in the FAS. Any CR or PR 
after the new anti-tumor treatment will not be included in the ORR calculation. 
The ORR will be estimated, and the two-sided 95% CI will be calculated using the Clopper-
Pearson method. 
The above analyses will be repeated in the PPS. 
5.5.2 Secondary efficacy analysis 
The secondary efficacy endpoints of this study include the investigator-assessed ORR, duration 
of response (DoR), disease control rate (DCR), time to response (TTR), progression-free survival 
(PFS), and overall survival. The secondary efficacy analysis will be based on the FAS only. The 
consistency between IRC-assessed and investigator-assessed PD/non-PD, BOR, and CR/PR will 
be analyzed using Amit's method. 
 
Investigator-assessed ORR 
Analyzed using the same method as that for the primary efficacy endpoint. In addition, the 
consistency between IRC-assessed and investigator-assessed PD/non-PD, BOR, and CR/PR will 
be analyzed using Amit's method based on the FAS. 
 
Duration of response (DoR) 
DoR refers to the time from the first PR or CR to the subsequent first PD or death. 
DoR will only be assessed in subjects with a BOR after treatment. The end date of tumor 
response must be consistent with the PD date of PFS or the date of death. The Kaplan-Meier 
product-limit method will be used to estimate the median survival, and its 95% CI will be 
calculated. If possible, the 6- and 12-month DoRs and their 95% CIs will be estimated. BOR of 
tumor response indicates CR or PR. The date of response is the date when response is first 
observed. The assessments by the investigator and the IRC will be analyzed separately. 
Note: For subjects with pseudo progression, such as subjects who have PR or SD after PD, the 
DoR event is the first PD after this PR. 


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Censoring rules: Follow the method for PFS (see PFS Analysis). 
 
Disease control rate (DCR) 
DCR refers to the proportion of subjects whose BOR is CR, PR, or SD (SD ≥ 8 weeks (± 7 days)). 
DCR is defined as a parameter of best response starting from the date of first dose to the date of 
objective documentation of PD or subsequent anti-tumor treatment (whichever occurs first). For 
subjects with no record of PD or subsequent anti-tumor treatment, the DCR will be determined 
based on all results of response assessment. 
DCR will be analyzed using the same method as that for ORR. The IRC- and investigator-
assessed results will be summarized separately. 
 
Time to response (TTR) 
TTR is the time from the first dose to the first occurrence of CR/PR. 
TTR will only be measured in subjects with a BOR after treatment. The date of response is the 
date of first documented response instead of the date of confirmation. TTR will be statistically 
described by the number of subjects, mean, standard deviation, median, minimum, and 
maximum. The assessments by the investigator and the IRC will be analyzed separately. 
 
Progression-free survival (PFS) 
PFS is the time from the first dose to the first occurrence of PD. 
The Kaplan-Meier method will be used to estimate the PFS, plot the survival curve, and estimate 
the median PFS, and its 95% CI will be calculated (using the Brookmeyer-Crowley method with 
log-log transformation). The IRC- and investigator-assessed PFS will be summarized separately. 
The censoring rules are as follows: 
 
If there is no baseline tumor assessment, the date of first dose will be censored. 
 
If there is no post-baseline objective tumor response evaluation or death, the date of first 
dose will be censored. 
 
If there is no PD or death as per RECIST 1.1, the date of the last objective tumor 
response evaluation will be censored. 
 
If there is no imaging PD or death before the start of any new anti-tumor treatment, then 
the date of the last objective tumor response assessment prior to the start of a new anti-
tumor treatment will be censored. 
 
If the subject misses ≥ 2 planned imaging assessments in a row before PD or death (i.e., 
the time between PD or death and prior tumor assessment is ≥ 126 days), the censoring 
date is the date of the last objective tumor imaging assessment carried out before the 


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missing imaging assessments; if no tumor assessments are carried out after the first 
dose, the time interval from the date of baseline tumor imaging assessment to the date of 
the event will be calculated. If it exceeds 126 days, it is recorded as censored data and is 
censored to the date of the first dose. 
Definition of the date of tumor PD/non-PD: 
 
For PD, it is the earliest of the dates of imaging examination of progression. 
 
For non-PD, it is the latest of the dates of imaging examination. 
 
Overall survival (OS) 
OS is defined as the time from the first dose to the death of the subject due to any cause. 
The Kaplan-Meier method will be used to estimate the OS, plot the survival curve, and estimate 
the median OS, and its 95% confidence interval will be calculated (Brookmeyer-Crowley 
method: log-log transformation, standard error calculated using the Greenwood formula). 
Censoring rules: 
 
If there is no death during the study, the survival will be censored on the date of the last 
survival follow-up. 
 
If a subject is lost to follow-up, the survival will be censored on the date of the last 
survival follow-up before lost to follow-up. 
5.5.3 Subgroup analysis 
The ORR, DoR, DCR, PFS, and OS will be analyzed according to the following factors 
(including but not limited to). 
Stratification factors: gender (male/female), age (< 50 years old or ≥ 50 years old), baseline anti-
tumor treatment (2 lines, 3 lines or more), baseline ECOG PS (0 and 1), number of organs with 
metastases (2 and ≥ 3), PD-L1 expression level in tumor tissues (< 1% and ≥ 1%, < 10% and ≥ 10%, 
or < 20% and ≥ 20%), and baseline EBV-DNA (negative or positive). 
If possible, a subgroup analysis will also be conducted on the ORR and PFS by the presence or 
absence of capillary hyperplasia. 
5.6 
Safety Analysis 
Safety analysis will be based on the safety set. Unless otherwise stated, safety will be 
summarized using descriptive statistics. 
5.6.1 Drug exposure 
See the Compliance section. 


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5.6.2 Adverse events 
Safety information should be collected from the subject's signing of the informed consent form to 
90 days after the last dose or the start of new anti-tumor treatments (if the anti-tumor treatment 
starts within 30 days after the last dose, the subject should be followed up until at least 30 days 
after the last dose; if the tumor treatment starts beyond 30 days after the last dose, the subjects 
should be followed up until the start of the new anti-tumor treatment). 
A treatment-emergent adverse event (TEAE) is defined as an AE that occurs on or after the first 
dose of the investigational drug but no later than 90 days after the last dose of the investigational 
drug (an AE that occurs more than 90 days after the last dose and is judged to be definitely or 
possibly related to the investigational drug will also be included in the analysis). Causality with 
the investigational drug consists of "definitely related, possibly related, and indeterminable"; if 
the causality is missing, the AE will be considered treatment-related for analysis. 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. See 
the protocol for the definition of AE of special interest. The immune-related AEs per the 
investigator's judgment are those whose CRF option for immune-related AEs is shown as yes, 
undeterminable, or missing. 
Attention should be paid to immune-related AEs, including immune-related pneumonia, 
immune-related diarrhea and colitis, immune-related hepatitis, immune-related myocarditis, 
immune-related nephritis, immune-related endocrine diseases, immune-related cutaneous 
adverse drug reactions, and infusion reactions. 
All AEs will be coded by the latest version of MedDRA 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. 
The incidence of AEs will be sorted from high to low based on their corresponding SOC and 
treatment groups, and the incidence of AEs in each SOC will be sorted from high to low based 
on their PT. If the incidences of ≥ 2 PT are equal, the AEs will be sorted alphabetically. 
TEAEs will be statistically described by frequency and percentage. These include but are not 
limited to: 
 
Overview of AEs (AEs/treatment-related AEs, Grade ≥ 3 AEs/treatment-related AEs, 
AEs/treatment-related AEs resulting in treatment interruption, AEs/treatment-related 
AEs resulting in treatment discontinuation, AEs/drug-related AEs resulting in death, 
SAEs/treatment-related SAEs, SAEs/treatment-related SAEs resulting in treatment 
interruption/discontinuation, SAEs/treatment-related SAEs resulting in death, AESIs, irAEs 
per the investigator's judgment, irAEs resulting in death per the investigator's judgment; 
subjects with the highest CTC Grade: 1-5) 


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 
AEs will be summarized by SOC, PT, and CTCAE grade 
 
Treatment-related AEs will be summarized by SOC, PT, and CTCAE grade 
 
Grade ≥ 3 AEs will be summarized by SOC and PT 
 
Grade ≥ 3 treatment-related AEs will be summarized by SOC and PT 
 
AEs with an incidence of ≥ 5% will be summarized by SOC and PT 
 
Treatment-related AEs with an incidence of ≥ 5% will be summarized by SOC and PT 
 
AEs resulting in treatment interruption will be summarized by SOC and PT 
 
Treatment-related AEs resulting in treatment interruption will be summarized by SOC and PT 
 
AEs resulting in treatment discontinuation will be summarized by SOC and PT 
 
Treatment-related AEs resulting in treatment discontinuation will be summarized by SOC 
and PT 
 
AEs resulting in death will be summarized by SOC and PT 
 
Treatment-related AEs resulting in death will be summarized by SOC and PT 
 
SAEs will be summarized by SOC and PT 
 
Treatment-related SAEs will be summarized by SOC and PT 
 
SAEs resulting in treatment interruption will be summarized by SOC and PT 
 
SAEs resulting in treatment discontinuation will be summarized by SOC and PT 
 
SAEs resulting in death will be summarized by SOC and PT 
 
Treatment-related SAEs resulting in death will be summarized by SOC and PT 
 
AESIs will be summarized by SOC and PT 
 
AESIs resulting in treatment interruption will be summarized by SOC and PT 
 
AESIs resulting in treatment discontinuation will be summarized by SOC and PT 
 
Outcomes and corrective treatment of AESIs will be summarized by SOC and PT 
 
irAEs per the investigator's judgment will be summarized by SOC and PT 
 
irAEs per the investigator's judgment resulting in treatment interruption will be summarized 
by SOC, PT, and CTCAE grade 
 
irAEs per the investigator's judgment resulting in treatment discontinuation will be 
summarized by SOC, PT, and CTCAE grade 


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 
irAEs per the investigator's judgment resulting in death will be summarized by SOC, PT, 
and CTCAE grade 
 
irAEs resulting in death will be summarized by the classification of irAEs and PT 
 
The number and percentage of subjects experiencing at least one irAE of special interest 
will be summarized by the classification of irAEs and PT; these irAEs will be summarized 
according to the highest CTCAE severity grade 
 
irAEs of special interest resulting in treatment interruption/discontinuation will be 
summarized by the classification of irAEs 
 
The number and percentage of subjects experiencing irAEs of special interest will be 
summarized by the classification of irAEs 
 
Reactive capillary endothelial proliferation will be summarized (including location, 
concomitance, infection, ulceration, pain, bleeding, treatment) 
All collected AEs, AEs resulting in treatment interruption, AEs resulting in treatment 
discontinuation, AEs resulting in death, SAEs, and reactive capillary endothelial proliferation 
will be listed. 
In addition, for irAEs of special interest (classified per irAEs), the time to the occurrence of AEs, 
the time to the occurrence of Grade ≥ 3 AEs, the duration of AEs, the duration of Grade ≥ 3 AEs, 
the response time of AEs, and the response time of Grade ≥ 3 AEs will be summarized. 
The time (day) to the occurrence of AE is defined as the time from the date of the first 
administration of investigational drug to the date of the first occurrence of the AE. If one subject 
has experienced multiple times of one AE, the date of the first occurrence of the AE will be used 
for calculation regardless of the AE grading. The formula is as follows: Start date of AE - Date 
of the first dose of investigational drug + 1. 
The time (day) to the occurrence of Grade ≥ 3 AE is defined as the time from the date of the first 
administration of investigational drug to the date of the first occurrence of the Grade ≥ 3 AE. The 
calculation method is similar to the time to the occurrence of AE. 
The response time of AE (day) is defined as the date from the start to the end of the AE, and the 
calculation formula is as follows: End date of AE - Start date of AE + 1. If one subject has 
experienced multiple times of one AE, the cumulative time of the AE will be calculated, but the 
time overlapping of multiple times of the AE should be avoided in the calculation. If an AE is 
not relieved by the cut-off point of analysis or the end of the study (the response of the AE will 
be judged by the last outcome information of the AE, and the responses include AE outcome of 
recovered/resolved, recovered/resolved with sequelae, and alleviated), the end date of the AE 
will be used for censoring. If the end date of the AE is missing, the date will be imputed 


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according to Section 5.1.5 before censoring. If one AE category (such as the category of 
immune-related AE) contains more than one AEs (by PT) and one of these AEs is not relieved, 
this AE category will be judged as not relieved. 
The duration of AE is defined similarly to the response time of AE, with the difference that the 
duration of AE does not need to consider the state of censoring. 
Time to the occurrence of AE, time to the occurrence of Grade ≥ 3 AE, response time of AE, and 
response time of Grade ≥ 3 AE will only be calculated for the population who have experienced 
AE, and the corresponding median time and 95% confidence interval will be estimated by the 
Kaplan-Meier product limit method. For duration of AE and duration of Grade ≥ 3 AE, a 
descriptive summary will be provided as measurement data. 
For irAEs of special interest (by irAEs), listing of subjects receiving high-dose corticosteroids 
(defined as at least one dose or a single daily dose of ≥ 40 mg of the equivalent dose of 
prednisone), the starting dose of corticosteroids, and the duration of dosing will also be provided. 
The dosage of different hormonal drugs will be converted into the equivalent dose of prednisone 
according to the following formula: 0.75 mg of dexamethasone = 5 mg of prednisone = 5 mg of 
prednisolone = 4 mg of methylprednisolone = 20 mg of hydrocortisone = 0.8 mg of 
betamethasone = 5 mg of prednison. 
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 AEs (by PT), this AE category will be treated as one AE when being summarized. 
When the starting 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. 
A detailed listing of AEs, SAEs, AEs resulting in treatment interruption/discontinuation, and 
deaths will be provided. 
5.6.3 Laboratory tests 
For blood routine, blood biochemistry, urinalysis, and thyroid function, a crossover table will be 
used to descriptively summarize the number and percentage of subjects showing most significant 
changes from baseline after the first administration. Among them, the statistics of the most 
severe grading will be calculated for indicators whose toxicity grading can be carried out by 
CTCAE. The statistics of the most severe clinical significance (grading of clinical severity: 
abnormal with clinical significance > abnormal with no clinical significance > normal) will also 
be provided for the above indicators. 


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In addition, for the judgment of clinical significance of blood routine, blood biochemistry, 
urinalysis, and thyroid function, a crossover table will be used to descriptively summarize the 
number and percentage of subjects showing changes from baseline. 
The judgment of clinical significance of test indicators such as blood routine, blood 
biochemistry, urinalysis, thyroid function, coagulation function, fecal occult blood, and virology 
will be provided with a detailed listing of various laboratory test items. The listing will include at 
least name of visit, date of sampling, number of days of study, measurement and unit (if 
applicable), and judgment of clinical significance (if applicable). 
5.6.4 ECOG (performance status assessment) 
ECOG PS will be treated as a categorical variable, and a crossover table will be used to 
summarize the number and percentage of subjects showing changes in the highest ECOG PS 
from baseline after the first dose according to treatment groups. In addition, a detailed listing of 
ECOG will also be provided. The listing will include at least name of visit, date of scoring, 
number of days of study, and ECOG PS. 
5.6.5 Vital signs 
The vital signs to be collected in this study will include body temperature, heart rate, respiration, 
diastolic blood pressure, and systolic blood pressure. The number and incidence of subjects with 
clinically significant abnormalities after the first administration will be descriptively summarized 
(refer to the following criteria for determining clinically significant abnormalities in vital signs), 
along with the results obtained at various time points. 
In addition, a detailed listing of vital signs will also be provided. The listing will include at least 
the name of the visit, the date of the examination, number of days of study, the results of various 
examination items of vital signs, and the signs of clinically significant abnormalities. 
Table 5.6.5-1. 
Criteria for determining clinically significant abnormalities of vital signs 
Test Item 
Unit 
Low 
High 
Body 
Temperature 
°C  
≤ 35 °C and change from baseline 
≤ -1.1 °C  
≥ 38.3 °C and change from baseline ≥ 1.1 °C 
Heart Rate 
bpm 
< 40 bpm 
> 120 bpm 
Respiration 
breaths/min < 12 breaths/min 
> 24 breaths/min 
Systolic Blood 
Pressure 
mmHg 
< 90 mmHg 
or 
change from baseline ≤ -30 mmHg 
change from baseline ≥ 30 mmHg 
Diastolic Blood 
Pressure 
mmHg 
< 50 mmHg 
or 
change from baseline ≤ -20 mmHg 
change from baseline ≥ 20 mmHg 


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5.6.6 ECG 
The descriptive statistics of the number and percentage of subjects based on the most severe cases 
after the first administration will be provided by clinical significance judgment, i.e., normal, 
abnormal with no clinical significance, and abnormal with clinical significance (grading of clinical 
severity: abnormal with clinical significance > abnormal with no clinical significance > normal). 
The clinical significance judgment will also be descriptively summarized by test time. 
For PR interval and QTcF, the incidence of each category defined in the table below after the 
first administration will be descriptively summarized. In addition, the incidence will be 
summarized by test time points. 
Table 5.6.6-1. 
Classification criteria of PR and QTcF 
Test Item 
Unit 
 
Criteria for Abnormality 
PR 
ms 
Absolute value 
max ≥ 300 
 
 
Change from baseline 
Baseline > 200 and change from baseline ≥ 25%, or baseline 
≤ 200 and change from baseline ≥ 50% 
QTcF 
ms 
Absolute value 
450 ≤ max < 480 
 
 
 
480 ≤ max < 500 
 
 
 
max ≥ 500 
 
 
Change from baseline 
30 ≤ max < 60 
 
 
 
max ≥ 60 
For ECG parameters such as heart rate, PR interval, QT interval, and QTcF, the results obtained 
at various time points will be descriptively summarized. 
The calculation formula for QTcF: QTcF = QT 
, where RR = 60/heart rate 
5.6.7 Physical examination 
Physical examinations will be listed only. 
5.6.8 Other safety analyses 
Other safety parameters will be listed only. 
5.7 
Statistical analysis of PK 
A descriptive statistical analysis will be performed on the drug concentration of concurrent 
immunogenic blood samples. 
5.8 
Statistical analysis of PD 
This study does not involve PD analysis. 
5.9 
Immunogenicity (ADA) Analysis 
The number and percentage of subjects with ADA positive at baseline, ADA negative at baseline 
and positive post baseline, and at least one ADA positive at baseline or post baseline will be 
summarized. 


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For the population with negative baseline results and positive post-baseline results, the following 
items will be analyzed: the time to the first positive ADA result (i.e., time to the first positive 
ADA result (days) = date of the first positive ADA result - date of first dose + 1), 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) will be summarized using 
descriptive statistics. 
In addition, the efficacy and safety of ADA-positive and negative subjects will be analyzed so as 
to investigate the effects of ADA on efficacy and 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. 
Immunogenicity raw data will be reported in the form of listing. 
5.10 
Other Analyses 
N/A 
6 
INTERIM ANALYSIS 
No routine interim analysis. 
7 
REFERENCES 
None