Clinical trial NCT03155425
Conditions: Hodgkin Lymphoma, Adult
Sponsor: Jiangsu HengRui Medicine Co., Ltd.
Start date: 2017-06-09; Completion date: 2020-09-30
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multicenter, non-randomized, phase 2 trial to evaluate efficacy and safety of SHR-1210 in patients with relapsed or refractory classic Hodgkin's lymphoma. The primary objective is to assess ORR of SHR-1210 in patients with relapsed or refractory classic Hodgkin's lymphoma.

Detailed description:
The primary objective of this phase 2 study is to assess objective response rate of SHR-1210 in patients with relapsed or refractory classic Hodgkin's lymphoma. The secondary objective is to observe the duration of response, progression free survival, time to response, overall survival and safety of SHR-1210 in relapsed or refractory classic Hodgkin's lymphoma. Pharmacokinetic index is also investigated in 12 patients.

Arms: arm 1: SHR-1210 injection, 200 mg/dose, intravenous infusion.
Interventions: intervention 1: SHR-1210
Intervention descriptions: intervention 1: A humanized monoclonal immunoglobulin

Protocol documents:
Prot_000.pdf: 
Title: An Open-Label, Single Arm, Multi-Center, Phase 2 Study of PD-1 Antibody 
SHR-1210 in Subjects with Relapsed or Refractory Classic Hodgkin's Lymphoma 
NCT number: NCT03155425 
Date: 19 Jul., 2017 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
1 
 
AN OPEN-LABEL, SINGLE ARM, MULTI-CENTER, 
PHASE 2 STUDY OF PD-1 ANTIBODY SHR-1210 
IN SUBJECTS WITH RELAPSED OR 
REFRACTORY CLASSIC HODGKIN'S 
LYMPHOMA 
Protocol No.: 
SHR-1210-II-204 
Study Phase: 
II 
Compound Code: 
SHR-1210 
Medical Director: 
 
Leading Site of Clinical Study: 
Beijing Cancer Hospital 
  
Jiangsu Cancer Hospital 
Principal Investigators: 
Prof. Jun Zhu, Prof. Jifeng Feng 
 
Version No.: 
3.0 
Version Date: 
19 Jul., 2017 
 
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. 
Translated from Original Document 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
2 
VERSION HISTORY/REVISION HISTORY 
Document 
Version Date 
Amendment Rationale and Summary of Changes 
Version 1.0 
25 Apr., 2017 
Not applicable 
Version 2.0 
6 May, 2017 
See separate document: Amendment Instructions of Protocol 
Version 2.0 
Version 3.0 
19 Jul., 2017 
See separate document: Amendment Instructions of Protocol 
Version 3.0 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
3 
Sponsor's Signature Page 
 
 
I have read and confirmed this clinical study protocol (protocol no.: SHR-1210-II-204, version 
no.: 3.0, version date:  
19 Jul., 2017). 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.  
 
 
 
 
  
 
 
Study Director (print) 
Study Director (signature) 
Signature Date 
(DD/MM/YYYY) 
 
 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
4 
Principal Investigator's Signature Page (Leading Site) 
 
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. 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 authority, 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, and submit it to the ethics committee and to the drug regulatory authority for 
filing purposes. 
 
Study Site: _____________________________________________ 
 
 
 
  
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
5 
Principal Investigator's Signature Page (Leading Site) 
 
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. 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 authority, 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, and submit it to the ethics committee and to the drug regulatory authority for 
filing purposes. 
 
Study Site: _____________________________________________ 
 
 
 
  
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
6 
Principal Investigator's Signature Page (Participating Site) 
 
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. 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 authority, 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, and submit it to the ethics committee and to the drug regulatory authority for 
filing purposes. 
 
Study Site: __________________________________________ 
 
 
 
  
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
7 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 7 
LIST OF TABLES ...................................................................................................................... 11 
LIST OF FIGURES .................................................................................................................... 11 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
SCHEDULE OF ACTIVITIES ................................................................................................. 22 
ABBREVIATIONS ..................................................................................................................... 27 
 KEY FUNCTIONAL ROLES ............................................................................................... 30 
 INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE ........................ 30 
2.1. Background ....................................................................................................................... 30 
2.2. Scientific Rationale ........................................................................................................... 32 
2.2.1. Study rationale ......................................................................................................... 32 
2.2.2. Rationale for drug development ............................................................................... 32 
2.2.3. Basis of dosing regimen ........................................................................................... 33 
2.3. Potential Risks and Benefits .............................................................................................. 33 
 OBJECTIVES AND ENDPOINTS ....................................................................................... 34 
3.1. Study Objectives ............................................................................................................... 34 
3.1.1. Primary objective ..................................................................................................... 34 
3.1.2. Secondary objectives ................................................................................................ 34 
3.2. Study Endpoints ................................................................................................................ 34 
3.2.1. Primary endpoint ...................................................................................................... 34 
3.2.2. Secondary endpoints ................................................................................................ 34 
 STUDY DESIGN ..................................................................................................................... 35 
 SELECTION AND WITHDRAWAL OF SUBJECTS ....................................................... 35 
5.1. Inclusion Criteria ............................................................................................................... 35 
5.2. Exclusion Criteria .............................................................................................................. 37 
5.3. Study Withdrawal Criteria ................................................................................................ 39 
5.4. Criteria for Treatment Discontinuation ............................................................................. 39 
5.5. Procedures for Withdrawal or Discontinuation ................................................................. 40 
5.6. Re-Screening Criteria for Subjects .................................................................................... 40 
5.7. Premature Termination or Suspension of Study ............................................................... 40 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
8 
 PHARMACOKINETIC STUDY DESIGN .......................................................................... 41 
6.1. Collection and Processing of Blood Samples ................................................................... 41 
6.1.1. Blood sampling time ................................................................................................ 41 
6.1.2. Processing and storage of blood samples ................................................................. 41 
6.2. Shipping of Clinical Samples ............................................................................................ 41 
 STUDY MEDICATION ......................................................................................................... 41 
7.1. Overview of Investigational Drug ..................................................................................... 41 
7.1.1. Access to investigational drug ................................................................................. 41 
7.1.2. Dosage form, packaging, and label of investigational drug ..................................... 41 
7.1.3. Storage and stability of investigational drug ............................................................ 42 
7.1.4. Preparation of investigational drug .......................................................................... 43 
7.1.5. Administration of investigational drug .................................................................... 43 
7.1.6. Dose modification and delay .................................................................................... 43 
7.2. Management, Dispensation, and Return of Investigational Drug ..................................... 45 
7.2.1. Disposal of investigational drug............................................................................... 45 
7.3. Concomitant Treatment ..................................................................................................... 45 
7.3.1. Permitted concomitant medications ......................................................................... 45 
7.3.2. Prohibited concomitant medications ........................................................................ 46 
7.4. Recommendations on the Handling of Immune-Related Adverse Events ........................ 46 
 STUDY PROCEDURES ........................................................................................................ 49 
8.1. Screening Period ............................................................................................................... 49 
8.2. Treatment Period ............................................................................................................... 51 
8.3. End of Treatment ............................................................................................................... 53 
8.4. Follow-Up Period .............................................................................................................. 54 
8.5. Unscheduled Visit ............................................................................................................. 56 
8.6. Criteria for Continuing Treatment Beyond Progression ................................................... 56 
 ASSESSMENTS ...................................................................................................................... 57 
9.1. Assessment of Efficacy ..................................................................................................... 57 
9.2. Assessment of Safety ........................................................................................................ 57 
9.2.1. Safety parameters ..................................................................................................... 57 
9.3. Assessment of Pharmacodynamics ................................................................................... 58 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
9 
 ADVERSE EVENT REPORTING ..................................................................................... 58 
10.1. Adverse Event (AE) ........................................................................................................ 58 
10.1.1. Definition of adverse event .................................................................................... 58 
10.1.2. AE severity grading criteria ................................................................................... 59 
10.1.3. Determination of the relationship between AEs and investigational drug ............. 59 
10.2. Serious Adverse Event (SAE) ......................................................................................... 60 
10.2.1. Definition of SAE .................................................................................................. 60 
10.2.2. Hospitalization ....................................................................................................... 60 
10.2.3. Progressive disease................................................................................................. 61 
10.2.4. Potential drug-induced liver injury ........................................................................ 61 
10.2.5. Other anti-tumor treatment ..................................................................................... 62 
10.2.6. SAE reporting ........................................................................................................ 62 
10.2.7. Follow-up of AEs/SAEs ......................................................................................... 63 
10.3. Pregnancy ........................................................................................................................ 63 
10.4. Adverse Event of Special Interest ................................................................................... 64 
 INDEPENDENT REVIEW .................................................................................................. 64 
 DATA ANALYSIS/STATISTICAL METHODS .............................................................. 65 
12.1. Sample Size Determination ............................................................................................. 65 
12.2. Statistical Analysis Plan .................................................................................................. 65 
12.3. Statistical Hypothesis and Decision Rules ...................................................................... 65 
12.4. Analysis Populations ....................................................................................................... 66 
12.5. Statistical Methods .......................................................................................................... 66 
12.5.1. General analysis ..................................................................................................... 66 
12.5.2. Basic analysis ......................................................................................................... 66 
12.5.3. Handling of missing data ....................................................................................... 67 
12.5.4. Efficacy endpoint analysis ..................................................................................... 67 
12.5.5. Safety analysis ........................................................................................................ 67 
12.5.6. Interim analysis ...................................................................................................... 68 
12.5.7. Subgroup analysis .................................................................................................. 68 
12.5.8. Multiple comparison/multiplicity........................................................................... 68 
12.5.9. Statistical analysis of PK ........................................................................................ 68 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
10 
 DATA MANAGEMENT ...................................................................................................... 68 
13.1. Data Recording ................................................................................................................ 68 
13.1.1. Filing of study medical records .............................................................................. 68 
13.1.2. eCRF entry ............................................................................................................. 69 
13.1.3. eCRF review .......................................................................................................... 69 
13.2. Data Monitoring .............................................................................................................. 69 
13.3. Data Management ........................................................................................................... 69 
13.3.1. EDC database establishment .................................................................................. 69 
13.3.2. Data entry and verification ..................................................................................... 70 
13.3.3. Database lock ......................................................................................................... 70 
13.3.4. Data archiving ........................................................................................................ 70 
13.3.5. Protocol deviation .................................................................................................. 70 
 SOURCE DATA AND DOCUMENTS ............................................................................... 71 
 QUALITY ASSURANCE AND QUALITY CONTROL .................................................. 71 
 REGULATORY ETHICS, INFORMED CONSENT, AND SUBJECT  
PROTECTION ...................................................................................................................... 72 
16.1. Regulatory Considerations .............................................................................................. 72 
16.2. Ethical Standards ............................................................................................................. 72 
16.3. Independent Ethics Committee ....................................................................................... 73 
16.3.1. Informed consent form and other written information for subjects ....................... 73 
16.3.2. Informed consent process and records ................................................................... 73 
16.4. Confidentiality of Subject Information ........................................................................... 73 
16.4.1. Use of samples, specimens, or data ........................................................................ 74 
 PUBLICATION OF STUDY RESULTS ............................................................................ 74 
 CLINICAL STUDY PROGRESS ....................................................................................... 74 
 REFERENCES ...................................................................................................................... 75 
APPENDIX I. ECOG PS ............................................................................................................ 77 
APPENDIX II. CREATININE CLEARANCE CALCULATION ......................................... 78 
APPENDIX III. STAGING OF HODGKIN'S LYMPHOMA ............................................... 79 
APPENDIX IV. INTERNATIONAL PROGNOSTIC SCORE (IPS) .................................... 80 
APPENDIX V. RESPONSE EVALUATION CRITERIA ...................................................... 81 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
11 
 
LIST OF TABLES 
Table 1. Summary of treatments for relapsed or refractory HL .................................................... 31 
Table 2. SHR-1210 dose modification criteria ............................................................................. 43 
Table 3. AE severity grading criteria ............................................................................................ 59 
Table 4. Contacts for SAE reporting ............................................................................................. 63 
LIST OF FIGURES 
None 
 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
12 
PROTOCOL SYNOPSIS 
Study Title 
An Open-Label, Single Arm, Multi-Center, Phase 2 Study of PD-1 Antibody 
SHR-1210 in Subjects with Relapsed or Refractory Classic Hodgkin's 
Lymphoma 
Protocol No. 
SHR-1210-II-204 
Version No. 
3.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Principal 
Investigators 
Prof. Jun Zhu, Prof. Jifeng Feng 
Participating 
Study Sites 
Approximately 15 sites 
Study 
Objectives 
Primary objective 
To evaluate the objective response rate (ORR) of PD-1 antibody SHR-1210 
in the treatment of relapsed or refractory classic Hodgkin's lymphoma. 
Secondary objectives 
 
To investigate and evaluate the duration of response (DoR), progression-
free survival (PFS), time to response (TTR), and overall survival (OS) of 
PD-1 antibody SHR-1210 in the treatment of patients with relapsed or 
refractory classic Hodgkin's lymphoma (cHL). 
 
To evaluate the safety of PD-1 antibody SHR-1210 in patients with 
relapsed or refractory classic Hodgkin's lymphoma (cHL). 
 
To evaluate the pharmacokinetic (PK) parameters of PD-1 antibody 
SHR-1210 in patients with relapsed or refractory classic Hodgkin's 
lymphoma (cHL) 
Study 
Endpoints 
Primary endpoint 
• 
Objective response rate (ORR) assessed by the independent review 
committee (IRC), including the proportion of complete response (CR) 
and partial response (PR) 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
13 
Secondary endpoints 
• 
Objective response rate (ORR) assessed by the investigators, including 
the proportion of complete response (CR) and partial response (PR) 
• 
Duration of response (DoR) 
• 
Progression-free survival (PFS) 
• 
Time to response (TTR) 
• 
Overall survival (OS) 
• 
Safety: adverse events (AEs), clinical laboratory measurements 
• 
Population estimates of pharmacokinetic (PK) parameters 
Study 
Population 
Chinese adult patients with refractory or relapsed cHL. 
Study Design 
This study is an open-label, single-arm, multi-center, phase II clinical study 
of PD-1 antibody SHR-1210 in the treatment of patients with refractory or 
relapsed classic Hodgkin's lymphoma. 
Investigational 
Drug 
SHR-1210 Injection 
Method of 
Administration 
All subjects will receive an intravenous infusion of SHR-1210 at 200 mg/dose 
over 30 min (not less than 20 min and not more than 60 min, including 
rinsing), once every two weeks (q2w), until the following conditions occur: 
progressive disease, intolerable toxicity, or other reasons specified in the 
protocol. 
Inclusion 
Criteria 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Age ≥ 18 years old, male or female; 
2. 
With histologically identified cHL; 
3. 
Have relapsed (confirmed progressive disease [PD] after the latest 
treatment) or refractory (failure to achieve complete response or partial 
response after the latest treatment) cHL, and must meet any of the 
following criteria: 
a) 
Have not reached response after autologous hematopoietic stem 
cell transplant or have progressed; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
14 
b) 
Have previously received at least 2 lines of systemic chemotherapy 
and not suitable for autologous stem cell transplant 
4. 
Have a measurable lesion. Measurable lesions are defined as: the 
longest diameter > 1.5 cm for lymph node lesions in CT cross-sectional 
images or the longest diameter > 1.0 cm for extranodal lesions; and the 
lesions should be FDG-PET positive; 
5. 
With an Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) of 0 or 1 
6. 
With a life expectancy of ≥ 12 weeks 
7. 
Patients must undergo all laboratory tests during the screening period as 
required by study protocol, and must complete such tests within 14 days 
before enrollment. Laboratory tests at screening must meet the 
following criteria: 
Hematology (without blood transfusion, G-CSF, or corrective treatment 
within 14 days prior to screening): 
1) Hb ≥ 80 g/L; 
2) ANC ≥ 1.0 × 109/L; 
3) PLT ≥ 75 × 109/L; 
Clinical chemistry: 
1) TBIL < 1.5 × upper limit of normal (ULN); 
2) ALT and AST ≤ 2.5 × ULN; 
3) Serum Cr ≤ 1.25 × ULN or endogenous CrCl ≥ 45 mL/min 
(Cockcroft-Gault formula) 
Coagulation function (unless the subject is receiving anticoagulant 
therapy and the coagulation parameters (PT/INR and APTT) at the time 
of screening are within the expected range of anticoagulant therapy): 
1) International normalized ratio (INR) ≤ 1.5 × ULN; 
2) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;  
8. 
Women of childbearing potential must have a negative serum pregnancy 
test result within 7 days prior to the first administration and be willing to 
take 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 female partners 
of childbearing potential must have undergone surgical sterilization or 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
15 
agree to take highly effective 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); 
9. 
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. 
With nodular lymphocyte predominant Hodgkin's lymphoma or gray 
zone lymphoma 
2. 
With known central nervous system (CNS) lymphoma 
3. 
Medical history and concurrent diseases 
1) 
With any active, known, or suspected autoimmune disease. Patients 
who are stable and do not require systemic immunosuppressive 
treatment may be enrolled; 
2) 
With a condition requiring systemic treatment with either 
corticosteroids (> 10 mg/day of prednisone or equivalent) or other 
immunosuppressive medications within 14 days before receiving 
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; 
3) 
Received tumor antigen vaccines or other immunostimulatory anti-
tumor treatments within 3 months before receiving the 
investigational drug; 
4) 
Prior treatment with anti-PD-1 antibodies, anti-PD-L1 antibodies, 
anti-PD-L2 antibodies, or anti-CTLA-4 antibodies (or any other 
antibody targeting T-cell co-stimulation or checkpoint pathways); 
5) 
Currently participating in another clinical study or less than 4 
weeks from the end of the last clinical study treatment; 
6) 
With a known history of interstitial pneumonia or highly suspected 
of interstitial pneumonia; or with conditions that may interfere with 
the testing or management of suspected treatment-related 
pulmonary toxicities; 
7) 
With other active malignant tumors requiring treatment at the same time; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
16 
8) 
With a history of malignant tumors, except for patients with skin 
basal cell carcinoma, superficial bladder cancer, cutaneous 
squamous cell carcinoma, or cervical carcinoma in situ who have 
undergone possible curative treatment and do not have disease 
recurrence within 5 years since starting the treatment 
9) 
Less than 4 weeks from prior cancer chemotherapy, radiotherapy, 
and immunotherapy, including local-regional treatment; patients 
whose anti-tumor treatment-related adverse reactions (except for 
alopecia) after previous systemic anti-tumor treatment have not 
recovered to NCI-CTCAE Grade ≤ 1 
10) Have received allogeneic hematopoietic stem cell transplant 
11) Have received autologous stem cell transplant within 90 days 
before the first dose 
12) Have undergone major surgery or have severe trauma, with the effects 
of surgery or trauma eliminated for less than 14 days before enrollment; 
13) Patients with active pulmonary tuberculosis (TB) should be 
excluded. Active TB should be ruled out in patients suspected of 
such condition, by chest X-ray, sputum test, and examinations of 
clinical symptoms and signs. Patients with a history of active TB 
infection within the past year should be excluded, despite being 
treated; patients with a history of active TB infection more than 
1 year ago should also be excluded, unless it is proven that the 
course and type of prior TB treatment are both appropriate; 
14) With severe acute or chronic infections requiring systemic 
treatment; 
15) With heart failure (New York Heart Association Class III or IV) 
and despite receiving appropriate pharmacological treatment, 
poorly controlled coronary artery disease or arrhythmia, or a 
history of myocardial infarction within 6 months before screening; 
16) Inoculated with live vaccine within 4 weeks before receiving the 
investigational drug. Injections of inactivated influenza vaccine for 
seasonal influenza are permitted, but not live attenuated influenza 
vaccines for intranasal use. 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
17 
4. 
Physical examination and laboratory tests 
1) 
With a known history of human immunodeficiency virus (HIV) 
seropositive status or acquired immunodeficiency syndrome 
(AIDS); 
2) 
With untreated active hepatitis (hepatitis B: HBsAg positive and 
HBV DNA ≥ 500 IU/mL; hepatitis C: HCV RNA positive with 
abnormal liver function); co-infection with hepatitis B and 
hepatitis C; 
5. 
The investigators determine that the patients may have other factors that 
may result in the premature termination of the study, such as other 
serious illnesses or serious laboratory abnormalities or family or social 
factors that could affect the safety of the subject, or study data and 
sample collection 
PK Study 
A PK study will be carried out in 12 subjects enrolled in this study (the PK 
study will only be carried out in Beijing Cancer Hospital, the leading site). 
1) There are 4 blood collection time points for the single dose in Cycle 1: 
within 0.5 h pre-administration on D1, within 5 min and at 2 h (± 10 min)  
after the end of administration on D1, and on D8 (± 60 min).  
2) In Cycles 2, 4, and 6, a total of 2 blood sampling time points: within 0.5 h 
pre-administration and 5 min post-administration on D1. 
The concentration of the parent drug in the blood sample will be 
determined, and the primary multiple-dose PK parameters will be 
investigated, mainly including: 
1) Cmax: maximum blood concentration; 
2) Cmin: minimum blood concentration; 
3) Tmax: time to the maximum concentration; 
4) Elimination half-life (t1/2z); 
5) Area under the concentration-time curve (AUC); 
6) Apparent volume of distribution (Vz); 
7) Systemic clearance (CLS); 
The above PK parameters of SHR-1210 in the human body will be calculated 
using the non-compartmental model. For multiple-dose pharmacokinetics, 
drug accumulation will be studied according to the maximum concentration 
and minimum concentration in multiple cycles. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
18 
Study 
Withdrawal 
Criteria 
1. Withdrawal of informed consent and refusal of further follow-ups by 
subjects; 
2. Continuing participation in the study is not in the best interests of the 
patient due to any clinical adverse reactions, laboratory abnormalities, or 
concurrent diseases, as assessed by the investigators; 
3. Other investigator-assessed reasons requiring withdrawal, such as the 
inability to provide voluntary consent due to imprisonment or 
quarantine; 
4. Lost to follow-up; 
5. Death; 
6. Study termination by the sponsor. 
Study 
Treatment 
Discontinuation 
Criteria 
The study treatment must be discontinued when any of the following occurs: 
1. Treatment discontinuation requested by subjects;  
2. Radiographic or clinical evidence of PD, unless the subject meets the 
criteria for continuing treatment after progression (see Section 8.6 for 
details); 
3. Occurrence of subject pregnancy during the study; 
4. Any clinical AEs, laboratory abnormalities, or other medical conditions 
indicating that the subject can no longer benefit from the treatment;  
5. Deterioration of the overall health suggesting treatment continuation 
impossible; 
6. Major protocol deviations such as ineligibility found after enrollment;  
7. Lost to follow-up; 
8. Study termination by the sponsor; 
9. Death; 
10. Other reasons as determined by the investigators. 
Determination 
of Sample Size 
This study uses a single-arm design. The primary objective is to evaluate the 
efficacy of SHR-1210 in the treatment of relapsed or refractory cHL. The 
study endpoint is ORR. By referring to historical research data and research 
results of similar products and given the current clinical practice 
requirements, the investigational drug can be judged as effective only when 
the lower limit of the 95% confidence interval for ORR obtained from the 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
19 
study data is greater than 40%. Therefore, the sample size for this study is 
determined based on the following 2 points: 1. the exact method (Clopper-
Pearson) is used to calculate the 95% confidence interval for ORR; 2. the 
lower limit of the confidence interval is greater than 40%. Assuming that the 
ORR of SHR-1210 in the treatment of relapsed or refractory cHL reaches 
65%, a power of 92.90% can be obtained with 50 subjects. Given a dropout 
rate of 20%, this study intends to enroll 60 subjects. 
Data Analysis/ 
Statistical 
Methods 
Analysis sets/populations 
This study will involve the following analysis sets or populations: 
 
Informed Consent Set (ICS):  
all subjects who have signed the informed consent form. 
 
Full Analysis Set (FAS):  
eligible subjects who have received the investigational drug. The 
FAS is the primary analysis set for efficacy analysis other than the 
primary efficacy endpoint. 
 
Evaluable Set (ES): 
a subset of the FAS, defined as subjects with at least one post-
baseline efficacy evaluation in the FAS. The ES is the primary 
analysis set for the primary efficacy endpoint ORR. 
 Per-Protocol Set (PPS):  
a subset of the FAS, defined as subjects in the FAS who have 
experienced no major protocol deviations. PPS is the secondary 
analysis set for efficacy analysis. Safety Set (SS): all enrolled 
subjects who have received the investigational drug and have post-
administration evaluable safety data. SS is the primary analysis set 
for safety analysis. 
 PK Set (PKS):  
all enrolled subjects who have received the investigational drug and 
have post-administration evaluable PK data (concentration and/or 
parameters). 
General analysis 
Unless otherwise specified, all data in this study will be summarized using 
descriptive statistics according to the data type. Measurement data will be 
summarized using mean, standard deviation (SD), median, minimum, and 
maximum; count data and rank data will be summarized using frequency and 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
20 
percentage; for time to event data, the Kaplan-Meier method will be used to 
estimate the median time and its overall 95% confidence interval will be 
calculated. 
Efficacy analysis 
For the objective response rate (ORR) based on the IRC's and investigators' 
assessment, point estimation will be performed, and the exact method 
(Clopper-Pearson) will be used to estimate the overall 95% confidence 
interval. 
For other secondary efficacy endpoints, including duration of response 
(DoR), progression-free survival (PFS), time to response (TTR), and overall 
survival (OS), the Kaplan-Meier method will be used to estimate their 
median times and the overall 95% confidence intervals will be calculated. 
The analysis of the primary efficacy endpoint will be based on the ES, and 
other efficacy analyses will be repeated based on the primary analysis set 
FAS and secondary analysis set PPS. 
Safety analysis 
The safety analysis will be summarized primarily using descriptive statistics. 
AEs, treatment-emergent AEs (TEAEs), SAEs, laboratory data, vital signs, 
and other data will be statistically summarized. Also, the exposure to the 
investigational drug (including treatment cycle, received total dose, and dose 
intensity) will be statistically summarized. The above data will be analyzed 
and summarized using Hengrui's current clinical study report standards. Such 
standards include but are not limited to the following: 
Summary of AEs (of all causes and treatment-related); 
Incidence and severity of AEs (of all causes and treatment-related); 
Correlation analysis between AEs and investigational drug; 
Analysis of outcomes of AEs; 
Analysis of SAEs; 
Descriptive statistical summary of laboratory measurements, vital sign data, 
and ECG data (post-baseline absolute values and post-baseline changes from 
baseline); 
Classified summary of post-baseline vital sign data and ECG. 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
21 
Statistical analysis of PK 
PK analyses will be based on the PKS, and PK concentration and PK 
parameters will be summarized using descriptive statistics. Apart from the 
statistics listed in the general analysis, PK concentration and PK parameter 
data will be also summarized descriptively using geometric mean (GM), 
coefficient of variation (CV%), and geometric CV% (GCV%). In addition, 
for PK concentration data, average and median blood concentration-time 
curves (concentration-time curves) on linear scale and semi-logarithmic scale 
can be plotted, and individual subjects' concentration-time curves (linear 
scale and semi-logarithmic scale) can be plotted at the same time. If PK 
statistical analysis is outsourced, the statistical analysis plan provided 
independently by the vendor shall prevail for the specific statistical analysis 
and method plan. 
Study Period 
Anticipated enrollment of the first subject: Jun. 2017 
Anticipated enrollment of the last subject: Nov. 2017 
Anticipated study end time: 24 months after the last subject receives the first 
administration (about Dec. 2019) 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
22 
SCHEDULE OF ACTIVITIES  
Item 
Screening Period[1] 
(-28 days) 
Treatment Cycle (14 days)[2] 
End of Treatment[3] 
Follow-Up Period 
D1 of Cycle 1 
D1 of Every Cycle  
(± 3 days)  
Safety  
Follow-Up[6] 
Survival 
Follow-Up[22] 
Enrollment Assessment 
 
 
 
 
 
 
Signing of Informed Consent 
√ 
 
 
 
 
 
Verification of Eligibility 
√ 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
Medical History 
√ 
 
 
 
 
 
History of Anti-Tumor 
Treatment 
√ 
 
 
 
 
 
Safety Evaluation 
 
 
 
 
 
 
ECOG PS 
√ 
√ 
√ 
√ 
√ 
 
Physical Examination[4] 
√ 
√ 
√ 
√ 
√ 
 
Vital Signs[5] 
√ 
√ 
√ 
√ 
√ 
 
Hematology 
√ 
 
√ 
√ 
√ 
 
Urinalysis[7] 
√ 
 
√ 
√ 
√ 
 
Fecal Occult Blood 
√ 
 
√ 
√ 
√ 
 
Hepatic and Renal 
Function[8] 
√ 
 
√ 
√ 
√ 
 
Blood Electrolytes[8] 
√ 
 
√ 
√ 
√ 
 
Coagulation Function[9] 
√ 
 
See Notes 
√ 
√ 
 
Thyroid Function[10] 
√ 
 
See Notes 
√ 
√ 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
23 
Item 
Screening Period[1] 
(-28 days) 
Treatment Cycle (14 days)[2] 
End of Treatment[3] 
Follow-Up Period 
D1 of Cycle 1 
D1 of Every Cycle  
(± 3 days)  
Safety  
Follow-Up[6] 
Survival 
Follow-Up[22] 
Fasting Blood Glucose 
√ 
 
√ 
√ 
√ 
 
Erythrocyte Sedimentation 
Rate 
√ 
 
 
 
 
 
LDH 
√ 
 
√ 
√ 
√ 
 
Virological Examination[11] 
√ 
 
See Notes 
√ 
√ 
 
Blood HCG Test[12] 
√ 
√ 
See Notes 
√ 
 
 
12-Lead ECG 
√ 
 
√ 
√ 
√ 
 
Echocardiography[13] 
√ 
 
 
 
 
 
Concomitant 
Medication/Treatment[18] 
√ 
√ 
√ 
√ 
√ 
 
Recording of AEs[19] 
√ 
√ 
√ 
√ 
√ 
 
Efficacy Evaluation 
 
 
 
 
 
 
Tumor CT or MRI 
Examination[14] 
√ 
 
See Notes 
See Notes 
√ 
√ 
Tumor FDG-PET 
Examination[15] 
√ 
 
See Notes 
 
 
 
Bone Marrow Aspiration and 
Biopsy[16] 
√ 
 
See Notes 
 
 
 
IPS Score 
√ 
 
 
 
 
 
B Symptom Assessment[17] 
√ 
√ 
See Notes 
√ 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
24 
Item 
Screening Period[1] 
(-28 days) 
Treatment Cycle (14 days)[2] 
End of Treatment[3] 
Follow-Up Period 
D1 of Cycle 1 
D1 of Every Cycle  
(± 3 days)  
Safety  
Follow-Up[6] 
Survival 
Follow-Up[22] 
PK Evaluation 
√ 
 
 
 
 
 
PK Blood Sampling [20]  
 
See Notes 
See Notes 
 
 
 
Study Treatment 
√ 
 
 
 
 
 
Injection of SHR-1210[21] 
 
√ 
√ 
 
 
 
Others 
 
 
 
 
 
 
Survival Information 
 
 
 
 
√ 
√ 
Subsequent Anti-Tumor 
Treatment 
 
 
 
 
√ 
√ 
Note: In addition to the examinations and time points shown in this table, the investigators may order additional tests at any time. Test results should be entered 
into the "Unscheduled Tests" sheet of the eCRF. 
[1] 
Screening period: physical examination, vital signs, laboratory tests (including hematology, urinalysis, fecal occult blood, Hepatic and Renal Function, 
LDH, erythrocyte sedimentation rate, blood electrolytes, fasting blood glucose, coagulation function, thyroxine, virological examination, etc.), ECG, 
echocardiography (including LVEF) are tested within 14 days before the start of the study treatment; tumor CT or MRI examination (chest, abdomen, 
pelvis, and other sites of known lesions), FDG-PET examination, and bone marrow aspiration and biopsy are performed within 28 days before the start of 
the study treatment; blood HCG test is performed within 7 days before the start of the study treatment. 
[2] 
Treatment cycle: In the event of a dose delay, the scheduled visit items at the same time point should be delayed accordingly to ensure consistency with 
the actual time of administration. Imaging evaluation (including CT or MRI examination, FDG-PET examination) should be carried out according to the 
scheduled time point and is not related to administration. 
[3] 
End of study treatment/withdrawal from study: Examinations are not required at this stage if tumor CT or MRI has been performed within 4 weeks and 
safety evaluation and B symptom assessment have been completed within 7 days prior to treatment discontinuation. 
[4] 
Physical examination: including height, weight, symptoms, and signs. Lymph node regions (for example, submandibular, cervical, supraclavicular, armpit, 
and groin) and abdominal organs (for example, liver and spleen) are checked within 72 h before each administration. 
[5] 
Vital signs: including body temperature, blood pressure, heart rate, and respiratory rate; measure within 72 h before each administration. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
25 
[6] 
Safety follow-up: until 90 days after the last dose. The first visit should be conducted 30 days (± 7 d ays) after the last dose or on the day of treatment 
discontinuation (if the date of treatment discontinuation is more than 84 days after the date of the last dose). The second visit is conducted approximately 
90 days (± 7 days) after the last dose. Both vi sits must be conducted at study sites. 
[7] 
Urinalysis: In case of a urine protein ≥ 2+ at screening, a 24-h urine protein quantitation should be added.  
[8] 
Hepatic and Renal Function: including ALT, AST, TBIL, ALP, BUN or serum urea level, creatinine, and albumin; blood electrolytes: including K+, Na+, 
Ca++, Mg++, and Cl-. 
[9] 
Coagulation function: When international normalized ratio (INR) is not available, prothrombin time (PT) will be used. Measure once every 2 cycles 
during treatment 
[10] 
Thyroid function: including TSH, FT3, and FT4. Measure once every 4 cycles during treatment 
[11] 
Virological examination: including HIV-Ab, HBV, and HCV infection testing. HBV testing requirements: HbsAg (qualitative), HbsAb (qualitative), 
HbcAb (qualitative), HbeAg (qualitative), and HbeAb (qualitative) should be tested at screening. If HBV infection is suspected, HBV-DNA should be 
tested (qualitatively; if positive, then quantitatively). HCV testing requirements: HCV-Ab is tested at screening to determine the presence of HCV 
infection. If positive, HCV-RNA will be tested (qualitatively; if positive, then quantitatively). For patients with hepatitis virus infection during the 
screening period, virological examination will be performed every 2 cycles during the treatment period, and the examination will be performed at the end 
of the treatment and during the safety follow-up; for patients with HBV infection, they will be tested for HBV-DNA (quantitative), and for patients with 
HCV infection, they will be tested for HCV-RNA (quantitative). 
[12] 
Blood HCG test: Only for women of child bearing potential (WOCBP); test within 7 days before the first dose, and at least once every 4 weeks (± 7 days) 
thereafter, regardless of the dosing cycle. 
[13] 
Echocardiography: Perform according to local standard practice when clinically indicated. 
[14] 
Tumor CT or MRI examination: Evaluate according to IWG2014 criteria, including CT scans with contrast of the chest, abdomen, pelvis, and any other 
sites of known lesions (such as neck). If the subject is allergic to contrast media or has bronchial asthma, kidney damage, or other diseases that make it 
difficult to perform contrast imaging, the subject can undergo chest CT without contrast + MRI scans of abdomen, pelvis, and any other sites of known 
lesions (such as neck). Evaluation will be carried out on D1 (± 7 days) of Weeks 9, 17, 25, 37, and 49 after the start of treatment, then every 16 weeks 
(± 14 days) until Week 97, and then every 26 weeks (± 21 days) until PD (for subjects who continue to receive the study treatment a fter radiographic 
progression, evaluation will be carried out until the investigational drug is discontinued), start of new anti-tumor treatment, or death. 
[15] 
Tumor FDG-PET examination: Perform on D1 (± 7 days) of Weeks 17 and 25 after the start of treatment. For subjects who have not obtained two 
negative FDG-PET results after Week 1 and until Week 49, it is necessary to add a tumor FDG-PET examination on D1 (± 7 days) of Week 49. If it is 
necessary to determine whether a radiographic CR is obtained at other unscheduled FDG-PET evaluation time points after the start of treatment, the FDG-
PET evaluation must be performed within 4 weeks after the CT evaluation. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
26 
[16] 
Bone marrow aspiration and biopsy: The subject can start the study treatment before obtaining the bone marrow biopsy result, but the result must be 
recorded in the subject's CRF. Patients with bone marrow involvement at baseline require bone marrow aspiration or biopsy to confirm CR status. Bone 
marrow aspiration and biopsy specimens are collected within 2 weeks after the CT scan. There is no need to perform bone marrow assessment after the 
bone marrow aspiration and biopsy result turns negative. 
[17] 
B symptom assessment: including pyrexia of > 38 °C of unknown cause; night sweats; weight loss of > 10% within 6 mont hs before the assessment. The 
evaluation will be conducted on D1 of Cycle 1, and every 2 cycles thereafter until the discontinuation of study treatment. In addition, the evaluation is 
performed when the subject obtains PR or CR for the first time; if the subject has obtained PR before CR, the evaluation should be performed again when 
CR is obtained. 
[18] 
Concomitant medication: Concomitant medications from 14 days before study treatment to 90 days after the last dose of study treatment will be collected. 
After the last dose, only concomitant medications for treatment-related AEs will be recorded. 
[19] 
AE: As per NCI CTCAE V4.03, all AEs that occur from the signing of the informed consent form to 90 days after the last dose or the start of new anti-
tumor treatment should be observed and documented. From 30 days after the last dose, for non-serious AEs, only those related to the investigational drug, 
including AEs of special interest, will be collected. All AEs should be followed up until Grade 0-1, recovery to baseline levels, or reasonably explained 
(e.g., lost to follow-up or death). 
[20] 
PK blood collection: In Cycle 1, within 0.5 h pre-administration and within 5 min and at 2 h (± 10 min) post-administration on D1, and on D8 (± 60 min). 
In Cycles 2, 4, and 6, within 0.5 h pre-administration and 5 min post-administration on D1 (only for subjects participating in the PK study). 
[21] 
SHR-1210 injection: Record the start and end time of the infusion of the investigational drug. 
[22] 
Survival follow-up: The survival follow-up period will start after the end of the safety follow-up period. Survival follow-up will be conducted once every 
3 months (± 14 days), either via telephone or in -person visit. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
27 
ABBREVIATIONS 
Abbreviation 
Full Name 
Ab 
Antibody 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
APTT 
Activated partial thromboplastin time 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CD-ROM 
Compact disc read-only memory 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
CFDA 
China Food and Drug Administration (now NMPA) 
cHL 
Classic Hodgkin's lymphoma 
CNS 
Central nervous system 
Cr 
Creatinine 
CR 
Complete response 
CRA 
Clinical research associate 
CRC 
Clinical research coordinator 
CRO 
Contract research organization 
CT 
Computed tomography 
CV 
Coefficient of variation 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GCV 
Geometric coefficient of variation 
GLP 
Good Laboratory Practices 
GM 
Geometric mean 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
28 
Abbreviation 
Full Name 
GMP 
Good Manufacturing Practices 
Hb 
Hemoglobin 
HbsAg 
Hepatitis B surface antigen 
HbcAb 
Hepatitis B core antibody 
HbeAg 
Hepatitis B e antigen 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HL 
Hodgkin's lymphoma 
ICH 
International Conference on Harmonization 
ICS 
Informed consent set 
INR 
International normalized ratio 
IPS 
International Prognostic Score 
irAE 
Immune-related adverse event 
IRB/IEC 
Institutional review board/independent ethics committee 
IRC  
Independent Review Committee 
LDH 
Lactate dehydrogenase 
Ldi 
Longest transverse diameter of a lesion 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
 
Standard deviation 
SDi 
Shortest axis perpendicular to the Ldi 
SDV 
Source data verification 
SOP 
Standard operating procedure 
SPD 
Sum of the product of the perpendicular diameters for multiple lesions 
TEAE 
Treatment-emergent adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PD-1 
Programmed death-1 
PD 
Progressive disease 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
29 
Abbreviation 
Full Name 
PPD  
Cross product of the Ldi and perpendicular diameter 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PLT 
Platelet 
PPS 
Per-protocol set 
PR 
Partial response 
PT 
Prothrombin time 
q2w 
Every 2 weeks 
RNA 
Ribonucleic acid 
SS 
Safety set 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
WOCBP 
Woman of childbearing potential 
 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
30 
 KEY FUNCTIONAL ROLES 
Principal Investigators 
Prof. Jun Zhu 
Contact: 
Beijing Cancer Hospital 
 
 
 
 
Prof. Jifeng Feng 
Contact: 
Jiangsu Cancer Hospital 
 
 
 
Sponsor's Medical 
Director 
, M.D., Clinical Medical Director 
Contact: 
 
 
 
 
 
Statistician 
, Ph.D., Director of Statistics 
Contact: 
 
 
 
 
 
 
 INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
2.1. Background 
Hodgkin's lymphoma (HL) is a tumor that originates from lymphocytes, and R-S cells are its 
characteristic pathological manifestation, while painless lymphadenopathy is its common clinical 
manifestation. WHO divides HL into classic Hodgkin's lymphoma (cHL) and nodular 
lymphocyte predominant Hodgkin's lymphoma (NLPHL). According to GLOBOCAN 2012, the 
number of new HL cases is 66,000 per year [1]. The National Cancer Institute of the United 
States estimated that the number of new HL cases in 2016 was about 8500, and the total number 
of HL patients in 2013 was 193,545 [2]. China lacks complete epidemiological data of HL, but 
the National Cancer Center of China estimated that there would be 88,200 new lymphoma 
patients in 2016 [3], and HL accounted for 8.54% of all lymphoma patients [4]. The cause of HL 
is still unknown. The etiology study of Epstein-Barr virus has received the most attention. The 
genome fragments of Epstein-Barr virus can be detected in the RS cells of about half of the 
patients. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
31 
The initial treatment of HL can achieve a high cure rate, but 5%-10% of patients are still resistant 
to the initial treatment, and 10%-30% of patients will relapse after a complete response (CR). 
High-dose chemotherapy combined with ASCT is the standard treatment for refractory or 
relapsed HL [5]. HL patients who relapse after ASCT usually have a poor prognosis. Studies 
have reported that the median time to progression (TTP) for treatment after ASCT failure was 
only 3.8 months, and the median overall survival (OS) was 26 months [6]. After ASCT failure, 
the treatment options are very limited. Among the cytotoxic drugs, only vinorelbine and 
gemcitabine show certain activity, but the duration of their effects is relatively short and 
complicated with obvious hematological toxicity. In recent years, some new drugs have also 
been explored in patients with relapsed or refractory HL. The detailed information can be seen in 
Table 1: 
Table 1. Summary of treatments for relapsed or refractory HL 
Drug Name 
Drug Classification 
Number of Subjects 
Past ASCT (%) 
ORR (%) 
Brentuxiamb Vedotin7 
ADC 
102 
100 
75 
Panobinostat8 
HADC Inhibitors 
129 
100 
27 
Mocetinostat9 
HADC Inhibitors 
51 
84 
27 
Lenalidomide10 
IMiDs 
38 
87 
19 
Everolimus11 
mTOR Inhibitors 
57 
58 
42 
In foreign countries, brentuximab vedotin has been approved for relapsed HL patients after 
ASCT, and the median OS is 22.4 months [12], while the median PFS of treatment after the 
failure of brentuximab vedotin is only 3.5 months [13]. 
The Science selected cancer immunotherapy as the most important scientific breakthrough in 
2013. In recent years, immune checkpoint inhibitors represented by PD-1/PD-L1 monoclonal 
antibodies have achieved great success in the field of cancer treatment, especially in the 
treatment of melanoma, non-small cell lung cancer, kidney cancer, head and neck cancer, and 
Hodgkin's lymphoma. In a phase Ib clinical study of PD-1 antibody nivolumab developed by 
BMS, among 23 patients with relapsed or refractory cHL who were given 3 mg/kg of nivolumab 
once every 2 weeks, the ORR was as high as 87% and the 24-week PFS rate was 86% [14]. In a 
subsequent phase II study, 80 patients with cHL who failed both ASCT and brentuximab vedotin 
were enrolled and were given 3 mg/kg of nivolumab once every 2 weeks, and the ORR was 
66.3%. The most common treatment-related AEs (≥ 15%) included asthenia (25%), injection 
related reaction (20%), and rash (16%). The most common treatment-related Grade 3/4 AEs 
were neutropenia (5%) and lipase concentration increased (5%). The most common SAE was 
fever [15]. Based on the results of these two trials, the FDA has approved nivolumab for the 
treatment of cHL after ASCT and brentuximab vedotin treatments. Pembrolizumab, a PD-1 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
32 
antibody from Merck, was investigated in 31 cHL patients who had failed brentuximab vedotin 
treatment in the phase I study, and the patients were given 10 mg/kg of pembrolizumab once 
every 2 weeks, achieving an ORR of 65% (CR 16%, PR 48%) [16]. In a subsequent phase II 
study, pembrolizumab 200 mg was used once every 3 weeks to treat a total of 210 patients with 
relapsed/refractory cHL, with an ORR of about 70% and an proportion of CR of about 20%. The 
FDA has also approved it for the treatment of relapsed or refractory cHL [17]. In China, ASCT 
has not been widely used, and no brentuximab vedotin or PD-1 antibodies have been approved 
for the treatment of HL. Therefore, Chinese HL patients urgently need effective treatment 
options after the failure of initial treatment. 
2.2. Scientific Rationale 
2.2.1. Study rationale 
Programmed death-1 (PD-1) is a protein receptor expressed on the surface of T cells. It binds to 
programmed death-ligand 1 (PD-L1) to transmit inhibitory signals and reduce the proliferation of 
T cells. Many human solid tumors express PD-L1, which is one of the reasons for their evasion 
of immune killing. The genetic variation at the 9p24.1 locus is a feature of malignant cells in 
classic Hodgkin's lymphoma and leads to the overexpression of PD-L1 and immune escape [18]. 
Epstein-Barr virus infection will also increase the expression of PD-L1 in EBV + Hodgkin's 
lymphoma [19]. The overexpression of PD-L1 in Hodgkin's lymphoma may indicate the 
sensitivity of this disease to PD-1 blockade. PD-1 antibodies nivolumab and pembrolizumab 
have shown good efficacy and safety in clinical studies of classic Hodgkin's lymphoma. 
2.2.2. Rationale for drug development 
Hengrui 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 studies, 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, an antibody with the highest activity, was 
selected for further development. Preclinical study data showed that SHR-1210 has in vivo and in 
vitro anti-tumor effects similar to those of nivolumab and pembrolizumab on the market. 
Moreover, 3 phase I clinical studies of SHR-1210 are being carried out in Chinese solid tumor 
patients, and the dose escalation phase has been completed. No dose-limiting toxicity was found, 
and the maximum tolerated dose (MTD) was not reached, indicating good tolerability. This study 
aims to further explore the efficacy and safety of SHR-1210 in classic Hodgkin's lymphoma with 
potential benefit. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
33 
2.2.3. Basis of dosing regimen 
PD-1 immune checkpoint inhibitors exert their effect on relieving immunosuppression by 
blocking the binding of PD-1/PD-L1. Therefore, the receptor occupancy of these inhibitors is the 
basic pharmacological mechanism that reflects the ultimate anti-tumor effects. Phase I PK 
studies showed that blood concentrations dropped to 1000 ng/mL or below on D15 after a single 
dose of 1 mg/kg and a fixed dose of 60 mg, and remained between 4000-9000 ng/mL after a 
single dose of 3 mg/kg and a fixed dose of 200 mg. Receptor occupancy assays suggested that a 
blood concentration of at least 2000 ng/mL is required to maintain the receptor saturation. 
Clinical results also suggested that a fixed dose of 200 mg every 2 weeks can maintain a 
saturated receptor occupancy. In phase I studies, the incidence of AEs did not increase with the 
dose, whether the drug was administered by weight or by dose fixed. Based on results from the 
studies described above and the convenience of clinical administration, a fixed dose of 200 mg 
every 2 weeks is selected as the treatment regimen for this study. 
2.3. Potential Risks and Benefits 
Relapsed or refractory HL lacks effective treatment drugs. In recent years, studies have found 
that PD-1 antibodies nivolumab and pembrolizumab have shown good efficacy in patients with 
classic Hodgkin's lymphoma, and both nivolumab and pembrolizumab have been approved by 
the FDA for the treatment of relapsed or refractory classic Hodgkin's lymphoma. SHR-1210 is 
a humanized PD-1 antibody independently developed by Hengrui. Preclinical data suggested that 
SHR-1210 has efficacy and anti-tumor effect similar to those of nivolumab and pembrolizumab. 
An ongoing phase I clinical study in China has found that SHR-1210 also shows certain efficacy 
in solid tumors of different types, and it has entered the phase III clinical study. The possible 
benefit for subjects enrolled in this study is partial or complete response. The maintenance of 
stable disease may also be a benefit for subjects with relapsed or refractory cHL. The treatment 
data of these subjects may guide the clinical treatment and development of SHR-1210 for cHL. 
The AEs with a high incidence in phase I studies were mainly reactive cutaneous capillary 
endothelial proliferation, rash, pyrexia, ALT increased, AST increased, and hypothyroidism, but 
most of them were Grade I-II and could be recovered without interrupting the continued use of 
the investigational drug. In addition, subjects undergoing biopsy may be at risk of bleeding and 
pain. For more detailed safety information, please refer to the second edition of SHR-1210 
Investigator's Brochure and Informed Consent Form. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
34 
 OBJECTIVES AND ENDPOINTS 
3.1. Study Objectives 
3.1.1. Primary objective 
To evaluate the efficacy, namely objective response rate (ORR), of PD-1 antibody SHR-1210 in 
the treatment of relapsed or refractory classic Hodgkin's lymphoma. 
3.1.2. Secondary objectives 
• 
To investigate and evaluate the duration of response (DoR), progression-free survival (PFS), 
time to response (TTR), and overall survival (OS) of PD-1 antibody SHR-1210 in the 
treatment of patients with relapsed or refractory classic Hodgkin's lymphoma (cHL). 
• 
To evaluate the safety of PD-1 antibody SHR-1210 in patients with relapsed or refractory 
classic Hodgkin's lymphoma (cHL). 
• 
To evaluate the pharmacokinetic (PK) parameters of PD-1 antibody SHR-1210 in patients 
with relapsed or refractory classic Hodgkin's lymphoma (cHL). 
3.2. Study Endpoints 
3.2.1. Primary endpoint 
• 
Objective response rate (ORR) assessed by the Independent Review Committee (IRC), 
including the proportion of complete response (CR) and partial response (PR) 
3.2.2. Secondary endpoints 
• 
ORR assessed by the investigators, including the proportion of CR and PR 
• 
Duration of response (DoR) 
• 
Progression-free survival (PFS) 
• 
Time to response (TTR) 
• 
Overall survival (OS) 
• 
Safety: adverse events (AEs), clinical laboratory measurements 
• 
Population estimates of pharmacokinetic (PK) parameters 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
35 
 STUDY DESIGN 
This study adopts an open-label, single-arm, and multi-center design to evaluate the efficacy and 
safety of SHR-1210 in patients with relapsed or refractory classic Hodgkin's lymphoma, and to 
evaluate the PK parameters of 12 subjects at the same time. Sixty subjects who meet the 
enrollment conditions will be enrolled and given SHR-1210 at 200 mg/dose on D1 of each 2-
week cycle, until the following conditions occur: progressive disease (PD), intolerable toxicity, 
or other reasons specified in the protocol. After treatment, the subjects will enter the follow-up 
period to receive safety follow-up or survival follow-up. 
SHR-1210 is an immune checkpoint inhibitor. According to the experience with similar drugs, 
some subjects may experience delayed or early pseudo progression after receiving the 
immunotherapy agents. Therefore, subjects with first PD are allowed to continue to receive 
treatment under the premise of no obvious clinical deterioration per the judgment of the 
condition by the investigators, until PD is still determined in the next imaging evaluation. 
The diagram of study design is shown as follows: 
 
 
 
 
 
 
 
 
 SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1) Age ≥ 18 years old, male or female; 
2) With histologically identified cHL; 
3) Have relapsed (confirmed progressive disease [PD] after the latest treatment) or refractory 
(failure to achieve complete response or partial response after the latest treatment) cHL, and 
must meet any of the following criteria: 
SHR-1210 200 mg, q2w, 
continuous administration 
until PD/intolerance, etc. 
Relapsed or refractory 
Classic Hodgkin's 
lymphoma 
N = 60 
Primary endpoint: 
ORR by IRC 
Secondary endpoints: 
· 
ORR by 
investigators 
· 
PFS, DoR 
· 
TTR, OS 
· 
Safety 
· 
PK parameters 
(12 subjects) 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
36 
a) Have not reached response after autologous hematopoietic stem cell transplant or have 
progressed 
b) Have previously received at least 2 lines of systemic chemotherapy and not suitable for 
autologous stem cell transplant 
4) Have a measurable lesion(s). Measurable lesion is defined as: the longest diameter > 1.5 cm 
for lymph node lesions in CT cross-sectional images or the longest diameter > 1.0 cm for 
extranodal lesions; and the lesions should be FDG-PET positive; 
5) With an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 
6) With a life expectancy of ≥ 12 weeks 
7) Patients must undergo all laboratory tests during the screening period as required by study 
protocol, and must complete such tests within 14 days before enrollment. Laboratory tests at 
screening must meet the following criteria: 
Hematology (without blood transfusion, G-CSF, or corrective treatment within 14 days prior 
to screening): 
A. Hb ≥ 80 g/L; 
B. ANC ≥ 1.0 × 109/L; 
C. PLT ≥ 75 × 109/L; 
Clinical chemistry: 
A. TBIL < 1.5 × upper limit of normal (ULN); 
B. ALT and AST ≤ 2.5 × ULN; 
C. Serum Cr ≤ 1.25 × ULN or endogenous CrCl ≥ 45 mL/min (Cockcroft-Gault formula) 
Coagulation function (unless the subject is receiving anticoagulant therapy and the 
coagulation parameters (PT/INR and APTT) at the time of screening are within the 
expected range of anticoagulant therapy): 
A. International normalized ratio (INR) ≤ 1.5 × ULN; 
B. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;  
9) 
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days prior to the first administration and be willing to take highly effective contraceptive 
measures during the study and within 60 days after the last dose of the investigational drug 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
37 
(around 5 half-lives of the drug + menstrual cycle). Male patients with female partners of 
childbearing potential must have undergone surgical sterilization or agree to take highly 
effective 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. 
5.2. Exclusion Criteria 
Patients meeting any of the following criteria will be excluded:  
1) With nodular lymphocyte predominant Hodgkin's lymphoma or gray zone lymphoma 
2) With known central nervous system (CNS) lymphoma 
3) Medical history and concurrent diseases 
a) With any active, known, or suspected autoimmune disease. Patients who are stable and 
do not require systemic immunosuppressive treatment may be enrolled; 
b) With a condition requiring systemic treatment with either corticosteroids (> 10 mg/day 
of prednisone or equivalent) or other immunosuppressive medications within 14 days 
before receiving 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; 
c) Received tumor antigen vaccines or other immunostimulatory anti-tumor treatments 
within 3 months before receiving the investigational drug; 
d) Prior treatment with anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, 
or anti-CTLA-4 antibodies (or any other antibody targeting T-cell co-stimulation or 
checkpoint pathways); 
e) Currently participating in another clinical study or less than 4 weeks from the end of the 
last clinical study; 
f) 
With a known history of interstitial pneumonia or highly suspected of interstitial 
pneumonia; or with conditions that may interfere with the testing or management of 
suspected treatment-related pulmonary toxicities; 
g) With other active malignant tumors requiring treatment at the same time; 
h) With a history of malignant tumors, except for patients with skin basal cell carcinoma, 
superficial bladder cancer, cutaneous squamous cell carcinoma, or cervical carcinoma in 
situ who have undergone possible curative treatment and do not have disease recurrence 
within 5 years since starting the treatment 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
38 
i) 
Less than 4 weeks from prior cancer chemotherapy, radiotherapy, and immunotherapy, 
including local-regional treatment; patients whose anti-tumor treatment-related adverse 
reactions (except for alopecia) after previous systemic anti-tumor treatment have not 
recovered to NCI-CTC AE Grade ≤ 1 
j) 
Have received allogeneic hematopoietic stem cell transplant 
k) Have received autologous stem cell transplant within 90 days before the first dose 
l) 
Have undergone major surgery or have severe trauma, with the effects of surgery or 
trauma eliminated for less than 14 days before enrollment; 
m) Patients with active pulmonary tuberculosis (TB) should be excluded. Active TB should 
be ruled out in patients suspected of such condition, by chest X-ray, sputum test, and 
examinations of clinical symptoms and signs. Patients with a history of active TB 
infection within the past year should be excluded, despite being treated; patients with 
a history of active TB infection more than 1 year ago should also be excluded, unless it 
is proven that the course and type of prior TB treatment are both appropriate; 
n) With severe acute or chronic infections requiring systemic treatment 
o) With heart failure (New York Heart Association Class III or IV) and despite receiving 
appropriate pharmacological treatment, poorly controlled coronary artery disease or 
arrhythmia, or a history of myocardial infarction within 6 months before screening; 
p) Inoculated with live vaccine within 4 weeks before receiving the investigational drug. 
Injections of inactivated influenza vaccine for seasonal influenza are permitted, but not 
live attenuated influenza vaccines for intranasal use. 
4) Physical examination and laboratory tests 
a) With a known history of human immunodeficiency virus (HIV) seropositive status or 
acquired immunodeficiency syndrome (AIDS); 
b) With untreated active hepatitis (hepatitis B: HBsAg positive and HBV DNA ≥ 500 IU/mL; 
hepatitis C: HCV RNA positive with abnormal liver function); co-infection with 
hepatitis B and hepatitis C; 
5) The investigators determine that the patients may have other factors that may result in the 
premature termination of the study, such as other serious illnesses or serious laboratory 
abnormalities or family or social factors that could affect the safety of the subject, or study 
data and sample collection 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
39 
5.3. Study Withdrawal Criteria 
Reasons for withdrawal may include: 
• 
Withdrawal of informed consent and refusal of further follow-ups by subjects; 
• 
Continuing participation in the study is not in the best interests of the patient due to any 
clinical adverse reactions, laboratory abnormalities, or concurrent diseases, as assessed 
by the investigators; 
• 
Other investigator-assessed reasons requiring withdrawal, such as the inability to 
provide voluntary consent due to imprisonment or quarantine; 
• 
Lost to follow-up; 
• 
Death; 
• 
Study termination by the sponsor. 
5.4. Criteria for Treatment Discontinuation 
Criteria for treatment discontinuation are as follows: 
The study treatment must be discontinued when any of the following occurs: 
1. Treatment discontinuation requested by subjects; 
2. Radiographic or clinical evidence of PD, unless the subject meets the criteria for continuing 
treatment after progression; 
3. Occurrence of subject pregnancy during the study; 
4. Any clinical AEs, laboratory abnormalities, or other medical conditions indicating that the 
subject can no longer benefit from the treatment;  
5. Deterioration of the overall health suggesting treatment continuation impossible; 
6. Major protocol deviations such as ineligibility found after enrollment;  
7. Lost to follow-up; 
8. Study termination by the sponsor; 
9. Death; 
10. Other reasons as determined by the investigators. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
40 
5.5. 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 investigators can 
recommend or provide new or alternative treatments to a subject based on the condition of the 
subject. Subjects showing no PD need to be continuously followed-up for imaging evaluation 
until the subjects begin new anti-tumor treatment or show PD. 
Subject's survival status should still be followed up even when the subject refuses to visit study 
sites, 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. 
5.6. Re-Screening Criteria for Subjects 
In this study, re-screening is allowed, i.e., subjects who have entered the screening process but 
have not met the enrollment conditions and have not started treatment may be re-enrolled. When 
re-screening, the informed consent form must be re-signed and a new subject number will be 
given. 
5.7. Premature Termination or Suspension of Study 
This study can be terminated prematurely or suspended if there are sufficient reasons. This may 
result from the decision of the regulatory authorities, changes in comments by the ethics 
committee (EC), efficacy or safety issues of the investigational drug, 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 
investigators, sponsor, and regulatory authorities in writing, documenting the reasons for 
suspension/termination. The investigators must immediately notify the EC and sponsor, and 
provide relevant reasons. 
The reasons for premature termination or suspension of the study may include: 
• 
Confirmed unexpected, major, or unacceptable risk to the subjects. 
• 
Existing efficacy data supporting premature study termination. 
• 
Poor protocol compliance. 
• 
Incomplete or undetectable measures. 
• 
Valueless study results. 
Once the aforementioned issues involving drug safety, protocol compliance, and data quality are 
resolved, the study can be continued upon approval from the sponsor, EC, or CFDA (now NMPA). 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
41 
 PHARMACOKINETIC STUDY DESIGN 
6.1. Collection and Processing of Blood Samples 
6.1.1. Blood sampling time 
A PK study will be carried out in 12 subjects enrolled in this study (in Beijing Cancer Hospital, 
the leading site). 
• 
There were 4 blood collection time points for the single dose in Cycle 1: within 0.5 h 
pre-administration on D1, within 5 min and at 2 h (± 10 min) after the end of 
administration on D1, and on D8 (± 60 min); 
• 
Within 0.5 h pre-administration and 5 min post-administration on D1 of Cycles 2, 4, 
and 6. 
6.1.2. Processing and storage of blood samples 
At each of the above time points, 4 mL of venous blood is collected into a serum separation tube 
to obtain the serum, which is then transferred into cryotubes (aliquoted equally into the test tubes 
and backup tubes). The cryotubes are stored in a low temperature freezer at ≤ -60 °C until they 
are transported to the central laboratory for PK testing. Please refer to the Laboratory Manual for 
specific operation details. 
6.2. Shipping of Clinical Samples 
The samples in test tubes should be sent out first in dry ice storage state. The samples in 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. 
 STUDY MEDICATION 
7.1. Overview of Investigational Drug 
7.1.1. Access to investigational drug 
SHR-1210 is manufactured by Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
7.1.2. Dosage form, packaging, and label of investigational drug 
Investigational drug: SHR-1210 Injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: lyophilized powder 
Strength: 200 mg in 20 mL vials 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
42 
Batch no.: see Certificate of Analysis 
Method of administration: intravenous drip infusion 
Shelf life: 2 years (tentative) from the date of manufacture 
Storage conditions: sealed, away from light, stored at 2-8 °C in medical refrigerator. Do not 
freeze. 
Label: refer to the pharmacy manual, and the actual label shall prevail 
7.1.3. Storage and stability of investigational drug 
The investigators 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. 
The investigational drug should be stored under the storage conditions listed in Section 7.1.2. 
Where the protocol differs from other information, SHR-1210 will be stored according to the 
storage conditions listed on the label. 
Daily maximum and minimum temperatures of all storage zones (such as cold storage) must be 
recorded by study sites. Documentation should begin with the receipt of the investigational drug 
until the last subject completes the last visit. Even if a continuous monitoring system is 
employed, a written log must be kept to ensure a correct record of storage temperature. The 
temperature monitoring and storage devices (such as refrigerator) should be regularly inspected 
to ensure proper operation. 
Any deviations related to the labeled conditions on the product should be immediately reported 
upon discovery. Study sites should take active measures to restore the investigational drug under 
the storage conditions described on the label, and the temperature deviation and the measures 
taken should 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 such case is not considered 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 study sites. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
43 
7.1.4. Preparation of investigational drug 
Drugs used in this study are all administered via intravenous drip infusion. Therefore, these 
drugs should be prepared by qualified or experienced study staff such as a study nurse. The 
investigational drug SHR-1210 does not contain preservatives, and must be prepared using 
aseptic technique. Refer to the pharmacy manual for drug preparation. 
7.1.5. Administration of investigational drug 
SHR-1210: 200 mg/dose, intravenous drip infusion over 30 min (not less than 20 min and not 
more than 60 min) on D1 of each 2-week cycle. The treatment will continue until the occurrence 
of confirmed PD, intolerable toxicity, or other reasons specified in the protocol. 
For Cycle 2 and subsequent cycles, the drug can be administered 3 days before or after the day of 
scheduled administration. Administration beyond 3 days after the scheduled dosing day will be 
considered as a dose delay. Subsequent dosing will be carried out based on the actual date of the 
previous dosing. All required examinations and evaluations must be completed prior to each 
dose. 
7.1.6. Dose modification and delay 
7.1.6.1. Dose modification 
AEs related to SHR-1210 may be immune-related AEs (irAEs), and may develop shortly after 
the first dose or months after the last dose. SHR-1210 should be interrupted if events listed in the 
following table occur. During the study, the investigators must consult with the sponsor if, based 
on the benefit to risk ratio of the subject, SHR-1210 should be interrupted or resumed instead of 
the recommendations found in Table 2 or when the situation is not listed. 
Table 2. SHR-1210 dose modification criteria 
Treatment-Related 
Immune-Related 
Adverse Event (irAE) 
Severity Grade 
for Treatment 
Interruption 
Resumption 
SHR-1210 Treatment 
Diarrhea/Colitis 
2-3 
Recovery to 
Grade 0-1 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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 
Treatment should be discontinued if the AE 
fails to resolve within 12 weeks after the 
last dose. 
3-4 
Discontinuation 
Discontinuation 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
44 
Treatment-Related 
Immune-Related 
Adverse Event (irAE) 
Severity Grade 
for Treatment 
Interruption 
Resumption 
SHR-1210 Treatment 
Hyperthyroidism 
3 
Recovery to 
Grade 0-1 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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-onset type I 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
accompanied with 
evidence of β-cell 
depletion 
After clinical and 
metabolic conditions 
are stabilized 
Continue SHR-1210 treatment. 
Renal Failure or 
Nephritis 
2 
Recovery to  
Grade 0-1 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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 Reaction 
2 
Symptoms 
disappeared 
Re-administer at 50% of the initial rate after 
symptoms resolve. If no reaction occurs 
within 30 min, restore the original infusion 
rate (100%). Closely monitor. If the 
symptoms recur, the administration of the 
current SHR-1210 dose will be 
discontinued. 
3-4 
Discontinuation 
Discontinuation 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
45 
Treatment-Related 
Immune-Related 
Adverse Event (irAE) 
Severity Grade 
for Treatment 
Interruption 
Resumption 
SHR-1210 Treatment 
Other Treatment-Related 
AEs 
3 
Recovery to  
Grade 0-1 
Treatment should be discontinued if the AE 
does not resolve within 12 weeks after 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 patients with metastasis to liver and Grade 2 AST or ALT increased at baseline, treatment should be 
discontinued if 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 investigators may consider interrupting 
SHR-1210 treatment if appropriate. For subjects with persistent Grade 2 adverse reactions that fail to return to Grade 
0-1 within 12 weeks after the last dose, treatment should be discontinued. 
7.2. Management, Dispensation, and Return of Investigational Drug 
Designated personnel are responsible for the management, dispensation, and return of 
investigational drugs. The investigators must ensure that all investigational drugs are used by 
enrolled subjects only and the dose and route of administration comply with Section 6.1.5. 
Remaining or expired drugs should be returned to the sponsor and may not be used for non-
participants. 
When the investigational drug is transported to study sites, a drug receipt form should be signed 
by both parties in duplicate, one copy for study sites and the other for the sponsor. When 
returning remaining drugs and empty packaging, both parties must sign the drug return form. The 
dispensation and return of every drug should be immediately documented on designated forms. 
The CRA is responsible for monitoring the supply, use, and storage of investigational drugs, and 
disposal of remaining drugs. 
7.2.1. Disposal of investigational drug 
The sponsor or authorized personnel is responsible for disposing investigational drugs. Drug 
disposal should be well documented. 
7.3. Concomitant Treatment 
7.3.1. Permitted concomitant medications 
• 
Topical use of corticosteroids, such as ophthalmic, nasal, intra-articular, and inhaled 
administrations, are permitted. 
• 
Use of immunosuppressive agents (such as prednisone of > 10 mg/d or an equivalent 
dose of glucocorticoids) to handle the AEs in the study. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
46 
• 
Prophylactic use of short-term glucocorticoids, such as for the prevention of contrast 
agent allergy; short-term glucocorticoids that are used to treat non-autoimmune 
diseases, such as delayed allergic reactions caused by exposure to allergens. 
• 
The use of inactivated seasonal influenza vaccines is allowed; the use of live attenuated 
vaccines needs to be decided upon discussion with the sponsor. 
7.3.2. Prohibited concomitant medications 
• 
Chemotherapy, radiotherapy, hormone therapy, or immunotherapy 
• 
Immunosuppressants; 
• 
Modern TCM preparations approved by the NMPA for anti-tumor treatment; 
• 
Inoculation of live vaccines within 4 weeks before the first dose and during the study. 
Live vaccines include but are not limited to, rubeola, epidemic parotitis, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid vaccines. Injections of inactivated 
influenza vaccine for seasonal influenza are permitted, but not live attenuated influenza 
vaccines for intranasal use; 
7.4. Recommendations on the Handling of Immune-Related Adverse Events 
Subjects should receive appropriate supportive treatment measures deemed necessary by the 
investigators. Supportive treatment measures for managing immune-related AEs (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 investigators are sure that the AE 
is related to SHR-1210, the supportive treatment listed below may be followed. Otherwise, the 
supportive treatment listed below is not required. 
1. 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). 
 
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. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
47 
 
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. 
2. 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 recover(s) to 
baseline (testing once per 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. 
3. 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 disease. 
 
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). 
4. 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 subjects receive long-term corticosteroids, antibiotic prophylaxis should be used. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
48 
5. 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. 
6. 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. 
7. 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. 
8. Infusion Reaction 
CTCAE Grade 
Clinical 
Symptom 
Clinical Management 
SHR-1210 Treatment 
Grade 1 
Mild and transient 
reactions 
Bedside observation and close monitoring 
until recovery. 
Premedications are recommended for 
subsequent infusion: diphenhydramine  
50 mg or equivalent, and/or acetaminophen 
325-1000 mg, given at least 30 min before 
SHR-1210 infusion. 
Continue  
Grade 2 
Moderate 
reactions 
requiring 
treatment or 
interruption; 
rapidly resolve 
after symptomatic 
treatment (such as 
antihistamines, 
non-steroidal 
Intravenous drip infusion of normal saline, 
IV of diphenhydramine 50 mg or equivalent 
and/or acetaminophen 325-1000 mg; 
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; 
Interrupt. Re-administer at 
50% of the initial rate after 
symptoms resolve. If no 
reaction occurs within 
30 min, restore the original 
infusion rate (100%). 
Closely monitor. If the 
symptoms recur, the 
administration of the current 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
49 
CTCAE Grade 
Clinical 
Symptom 
Clinical Management 
SHR-1210 Treatment 
antiphlogistics, 
anesthetics, 
bronchodilators, 
and intravenous 
fluids) 
Premedications are recommended for 
subsequent infusion: diphenhydramine  
50 mg or equivalent, and/or acetaminophen 
325-1000 mg, given at least 30 min before 
SHR-1210 infusion. Use corticosteroids 
(equivalent to hydrocortisone 25 mg) when 
necessary. 
SHR-1210 dose will be 
discontinued. 
Grade ≥ 3 
Grade 3: Severe 
reaction without 
rapid recovery 
with treatment 
and/or 
interruption; or 
symptoms recur 
after alleviation; 
or the subject 
develops sequelae 
that require 
hospitalization. 
Grade 4: life-
threatening 
Immediately discontinue SHR-1210; 
Administer normal saline by intravenous 
drip infusion. 
• Bronchodilators are recommended: 
subcutaneous injection of 1:1000 adrenaline 
solution 0.2-1 mg or slow intravenous 
infusion of 1:10,000 adrenaline solution 
0.1-0.25 mg, and/or diphenhydramine  
50 mg + methylprednisolone 100 mg or 
equivalent by intravenous injection when 
necessary; 
• Based on the guidelines for anaphylaxis of 
study sites; 
Bedside observation and close monitoring 
until recovery. 
Discontinuation 
 STUDY PROCEDURES 
8.1. Screening Period 
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 screening should be completed within 28 days before starting the 
investigational drug. 
• 
Obtain informed consent form signed by the subject. 
• 
Demographics: gender, date of birth, ethnicity, height, weight, etc. 
• 
Medical history collection: 
· Diagnosis: date of pathological diagnosis, pathological type, clinical stage, B 
symptoms, and IPS score 
· Treatment history: 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
50 
· History of radiotherapy: site, dose, and start and completion dates 
· History of chemotherapy: regimen, cycles, and start and completion dates 
· History of concomitant disease, prior medications, and drug allergies 
• 
Safety assessment (within 14 days prior to the first study dose): 
· ECOG PS; 
· Physical examination: including height, weight, symptoms, and signs. Lymph node 
regions (for example, submandibular, cervical, supraclavicular, armpit, and groin) 
and abdominal organs (for example, liver and spleen); 
· Vital signs: body temperature, blood pressure, heart rate, and respiratory rate; 
· Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil 
count, and lymphocyte count; 
· Urinalysis: WBCs, RBCs, and urine protein; if urine protein ≥ 2+, 24-h urine 
protein quantitation is required; 
· Fecal occult blood; 
· Hepatic and Renal Function: including ALT, AST, TBIL, ALP, BUN or serum urea 
level, creatinine, and albumin; 
· Blood electrolytes: including K+, Na+, Ca++, Mg++, and Cl-; 
· Coagulation function: When international normalized ratio (INR) is not available, 
prothrombin time (PT) will be used; 
· Thyroid function: including TSH, FT3, and FT; 
· Fasting blood glucose; 
· Erythrocyte sedimentation rate; 
· LDH; 
· Virological examination: including HIV-Ab, HBV, and HCV infection testing. 
HBV testing requirements: HbsAg (qualitative), HbsAb (qualitative), HbcAb 
(qualitative), HbeAg (qualitative), and HbeAb (qualitative) should be tested at 
screening. If HBV infection is suspected, HBV-DNA should be tested 
(qualitatively; if positive, then quantitatively). HCV testing requirements: HCV-Ab 
is tested at screening to determine the presence of HCV infection. If positive, HCV-
RNA will be tested (qualitatively; if positive, then quantitatively). 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
51 
· Blood HCG test: Only for women of childbearing potential (WOCBP); test within 
7 days before the first dose; 
· 12-lead ECG; 
· Echocardiography;  
· Concomitant medication/treatment: Concomitant medications within 14 days 
before the first dose will be recorded; 
· AEs: Document from the signing of informed consent form. 
• 
Efficacy Evaluation 
· Tumor CT or MRI examination: chest, abdomen, pelvis, and other sites of known 
lesions (perform within 28 days before starting treatment; results of imaging 
examination performed prior to signing informed consent may be used for tumor 
assessment at screening if the requirements are met). 
· Tumor FDG-PET examination: Perform within 28 days before starting treatment; 
results of imaging examination performed prior to signing informed consent may 
be used for tumor assessment at screening if the requirements are met. 
· Bone marrow aspiration and biopsy. Perform within 28 days before starting 
treatment; results of bone marrow aspiration and biopsy performed prior to signing 
informed consent may be used for tumor assessment at screening if the 
requirements are met. 
8.2. Treatment Period 
All examinations and evaluations during the treatment period should be completed prior to the 
administration. 
• 
ECOG PS: Perform within 72 h prior to each dose 
• 
Physical examination: including height, weight, symptoms, and signs. Lymph node 
regions (for example, submandibular, cervical, supraclavicular, armpit, and groin) and 
abdominal organs (for example, liver and spleen) are checked within 72 h before each 
administration; 
• 
Vital signs: including body temperature, blood pressure, heart rate, and respiratory rate; 
measure within 72 h before each administration; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
52 
• 
Blood HCG test: Only for women of childbearing potential (WOCBP); test within 
7 days before the first dose, and at least once every 4 weeks (± 7 days) thereafter, 
regardless of the dosing cycle; 
• 
B symptom assessment: including pyrexia of > 38 °C of unknown cause, night sweats, 
or weight loss of > 10% (the evaluation will be conducted on D1 of Cycle 1, and every 
2 cycles thereafter until the discontinuation of study treatment); 
• 
PK blood collection: In Cycle 1, within 0.5 h pre-administration and within 5 min and 
at 2 h (± 10 min) post-administration on D1, and on D8 (± 60 min). In Cycles 2, 4, and 
6, within 0.5 h pre-administration and within 5 min post-administration on D1 (only for 
subjects participating in the PK study); 
• 
Injection of SHR-1210: 
• 
Adverse event 
• 
Concomitant medication/treatment 
The following relevant examinations must be completed pre-administration in Cycle 2 and 
subsequent cycles (complete within 72 h pre-administration): 
• 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
• 
Urinalysis: WBCs, RBCs, and urine protein; if urine protein ≥ 2+, 24-h urine protein 
quantitation is required; 
• 
Fecal occult blood; 
• 
Hepatic and Renal Function: including ALT, AST, TBIL, ALP, BUN or serum urea 
level, creatinine, and albumin; 
• 
Blood electrolytes: including K+, Na+, Ca++, Mg++, and Cl-; 
• 
Coagulation function: When international normalized ratio (INR) is not available, 
prothrombin time (PT) will be used; once every 2 cycles; 
• 
Thyroid function: including TSH, FT3, and FT; once every 4 cycles 
• 
Fasting blood glucose; 
• 
LDH; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
53 
• 
Virological examination: Only for patients with hepatitis virus infection. Virological 
examination will be performed every 2 cycles during the treatment period; for patients 
with HBV infection, they will be tested for HBV-DNA (quantitative), and for patients 
with HCV infection, they will be tested for HCV-RNA (quantitative); 
• 
12-lead ECG; 
• 
Tumor CT or MRI examination: Evaluation will be carried out on D1 (± 7 days) of 
Weeks 9, 17, 25, 37, and 49 after the start of treatment, then every 16 weeks (± 14 days) 
until Week 97, and then every 26 weeks (± 21 days) until PD (for subjects who continue 
to receive study treatment after radiographic progression, evaluation will be carried out 
until the investigational drug is discontinued), start of new anti-tumor treatment, or 
death; 
• 
Tumor FDG-PET examination: Perform on D1 (± 7 days) of Weeks 17 and 25 after the 
start of treatment. For subjects who have not obtained two negative FDG-PET results 
after Week 1 and until Week 49, it is necessary to add a tumor FDG-PET examination 
on D1 (± 7 days) of Week 49. If it is necessary to determine whether a radiographic CR 
is obtained at other unscheduled FDG-PET evaluation time points after the start of 
treatment, the FDG-PET evaluation must be performed within 4 weeks after the CT 
evaluation; 
• 
Bone marrow aspiration and biopsy: Patients with bone marrow involvement at 
baseline require bone marrow aspiration and biopsy to confirm CR status. Bone marrow 
aspiration and biopsy specimens are collected within 2 weeks after the CT scan. There 
is no need to perform bone marrow assessment after the bone marrow aspiration and 
biopsy result turns negative. The subject can start the study treatment before obtaining 
the bone marrow biopsy result, but the result must be recorded in the subject's CRF. 
8.3. End of Treatment 
The following examinations are required if tumor CT or MRI has not been performed within 4 weeks 
and safety evaluation and B symptom assessment have not been completed within 7 days prior to 
discontinuing the study treatment: 
• 
ECOG PS: 
• 
B symptom assessment: including pyrexia of > 38 °C of unknown cause; night sweats; 
weight loss of > 10% (symptoms in the past 6 months are evaluated); 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
54 
• 
Physical examination: including height, weight, symptoms, and signs. Lymph node 
regions (for example, submandibular, cervical, supraclavicular, armpit, and groin) and 
abdominal organs (for example, liver and spleen); 
• 
Vital signs: body temperature, blood pressure, heart rate, and respiratory rate; 
• 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
• 
Urinalysis: WBCs, RBCs, and urine protein; if urine protein ≥ 2+, 24-h urine protein 
quantitation is required; 
• 
Fecal occult blood; 
• 
Hepatic and Renal Function: including ALT, AST, TBIL, ALP, BUN or serum urea 
level, creatinine, and albumin; 
• 
Blood electrolytes: including K+, Na+, Ca++, Mg++, and Cl-; 
• 
Coagulation function: When international normalized ratio (INR) is not available, 
prothrombin time (PT) will be used; 
• 
Thyroid function: including TSH, FT3, and FT; 
• 
Fasting blood glucose; 
• 
LDH; 
• 
Virological examination: Only for patients with hepatitis virus infection. For patients 
with HBV infection, they will be tested for HBV-DNA (quantitative), and for patients 
with HCV infection, they will be tested for HCV-RNA (quantitative); 
• 
12-lead ECG; 
• 
Blood HCG test: for women of childbearing potential (WOCBP) only; 
• 
Tumor CT or MRI examination. 
8.4. Follow-Up Period 
Subjects enter the follow-up period after the end of treatment. The first visit should be conducted 
30 days (± 7 days) after the last dose or on the day of treatment discontinuation (if the date of 
treatment discontinuation is more than 42 days after the date of the last dose). The second visit is 
conducted approximately 90 days (± 7 days) after the last dose. Both visits must be conducted at 
study sites. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
55 
• 
ECOG PS: 
• 
Physical examination: including height, weight, symptoms, and signs. Lymph node 
regions (for example, submandibular, cervical, supraclavicular, armpit, and groin) and 
abdominal organs (for example, liver and spleen); 
• 
Vital signs: including body temperature, blood pressure, heart rate, and respiratory rate; 
measure within 72 h before each administration; 
• 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
• 
Urinalysis: WBCs, RBCs, and urine protein; if urine protein ≥ 2+, 24-h urine protein 
quantitation is required; 
• 
Fecal occult blood; 
• 
Hepatic and Renal Function: including ALT, AST, TBIL, ALP, BUN or serum urea 
level, creatinine, and albumin; 
• 
Blood electrolytes: including K+, Na+, Ca++, Mg++, and Cl-; 
• 
Coagulation function: When international normalized ratio (INR) is not available, 
prothrombin time (PT) will be used; 
• 
Thyroid function: including TSH, FT3, and FT; 
• 
Fasting blood glucose; 
• 
LDH; 
• 
Virological examination: Only for patients with hepatitis virus infection. For patients 
with HBV infection, they will be tested for HBV-DNA (quantitative), and for patients 
with HCV infection, they will be tested for HCV-RNA (quantitative); 
• 
AEs: All AEs should be collected until 90 days after the last dose or the start of new 
anti-tumor treatment. From 30 days after the last dose, for non-serious AEs, only those 
related to the investigational drug, including AEs of special interest, will be collected. 
Each recorded AE should be followed up until recovered to baseline level or Grade 0-1, 
stabilized, or reasonably explained (such as lost to follow-up and death). 
• 
Concomitant medications: collect until 90 days after the last dose of study treatment. 
After the last dose, only concomitant medications for treatment-related AEs will be 
recorded. 
• 
Survival follow-up: 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
56 
· Subjects who discontinue study treatment due to "PD" will begin survival follow-up, 
which will be conducted every 3 months (± 14 days), either via telephone or in-person 
visit. 
· Subjects who discontinue the study treatment due to reasons other than "PD" will 
enter the tumor progression follow-up, and continue to receive tumor evaluation in 
accordance with the efficacy evaluation visit frequency (tumor CT or MRI 
examination, tumor FDG-PET examination) as stipulated in the protocol, until PD, 
start of new anti-tumor treatment, or death; after tumor progression, the survival 
follow-up will be carried out once every 3 months (± 14 days), either via telephone 
or in-person visit. 
8.5. Unscheduled Visit 
The following items should be documented at unscheduled visits for subjects developing AEs 
during the study: 
• 
Results of relevant examinations 
• 
AEs 
• 
Concomitant medications 
8.6. Criteria for Continuing Treatment Beyond Progression 
Some subjects receiving immunotherapy can still benefit clinically after radiographic 
progression. The study treatment may be continued after PD defined per Lugano 2014 criteria for 
subjects who meet the criteria below: 
• 
The investigators deem that it is in the best interest of the subject to continue treatment, 
and subject is not required to start other anti-tumor treatment immediately; 
• 
The subject is able to tolerate continued study treatment 
• 
No significant deterioration in subject's performance status, and no significant 
worsening of cancer-related symptoms 
• 
Before continuing the study treatment, it must be reviewed and approved by the 
medical monitor 
If it is decided that the subject will continue the study treatment after progression, the subject 
should continue to be treated, evaluated, and followed up according to the protocol requirements. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
57 
Subjects should withdraw from study treatment if further progression is observed at the next 
assessment. The initial date of investigator-assessed progression should be used for all statistics 
analyses involving progression, regardless of whether the subject continues the study treatment 
beyond progression. 
If the subject discontinues treatment due to deterioration of the general condition without 
objective evidence for PD, the progression will be reported as "general deterioration". More 
objective evidences (such as imaging confirmation) of progression of these subjects should be 
obtained after treatment discontinuation.  
For subjects who withdraw from the study due to intolerable toxicity without radiographic PD 
observed, the imaging examination should be performed at the same frequency, until PD or start 
of other anti-tumor treatment. The radiographic evidence of PD of these subjects must be 
obtained whenever possible. 
 ASSESSMENTS 
9.1. Assessment of Efficacy 
The Lugano 2014 criteria are used to evaluate the objective response rate (ORR), including the 
CR and PR cases. 
ORR: Defined as the proportion of subjects whose best response reaches CR or PR from the first 
dose to the occurrence of PD or the start of new anti-tumor treatment, whichever comes first 
PFS: Defined as the time from the date of the first dose to the first documented PD or all-cause 
death, whichever occurs first. If the subject has not had PD or died by the data cut-off date, the 
cut-off date is the date of the subject's last efficacy evaluation. If the subject has not received 
tumor evaluation, the cut-off date is the date of the first dose, and PFS lasts for 1 day. 
DoR: Defined as the time from the date of the first CR or PR to the date of initial assessment of 
PD or all-cause death, whichever comes first. If the subject has not had PD or died by the data 
cut-off date, the censoring date is the date of the subject's last efficacy evaluation. Only 
applicable to subjects with CR/PR. 
TTR: Defined as the time from D1 of administration to the first evaluation of PR or CR, 
whichever comes first. Only applicable to subjects with CR/PR. 
9.2. Assessment of Safety 
9.2.1. Safety parameters 
Safety parameters for this study include clinical symptoms, vital signs, physical examination, 
and laboratory tests (hematology, urinalysis, blood biochemistry, thyroid function, coagulation 
function, etc.). 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
58 
AEs are evaluated according to NCI CTCAE V4.03, including type, incidence, severity, start and 
end date, whether it is an SAE, correlation with the investigational drug, and outcome. 
AEs that occur during the study, including signs and symptoms at screening, will be recorded in 
the AE page of the electronic case report form (eCRF). 
The latest version of MedDRA is used to medically code the collected AEs, which are finally 
presented in the form of listing. 
9.3. Assessment of Pharmacodynamics 
PK assessment is conducted by measuring the concentration of the parent drug in the blood 
sample, and the PK parameters of SHR-1210 in the human body will be calculated using the 
non-compartmental model. For multiple-dose pharmacokinetics, drug accumulation will be 
studied according to the maximum concentration and minimum concentration in multiple cycles. 
The primary multiple-dose PK parameters will be investigated, mainly including: 
1) Cmax: maximum blood concentration; 
2) Cmin: minimum blood concentration; 
3) Tmax: time to the maximum concentration; 
4) Elimination half-life (t1/2z); 
5) Area under the concentration-time curve (AUC); 
6) Apparent volume of distribution (Vz); 
7) Systemic clearance (CLS). 
 ADVERSE EVENT REPORTING 
10.1. Adverse Event (AE) 
10.1.1. Definition of adverse event 
An AE refers to any untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. In this study, all AEs occurring from signing the informed consent form to 90 days 
after the last dose will be collected. From 30 days after the last dose, for non-serious AEs, only 
those related to the investigational drug will be collected. 
AEs can include any unfavorable and unintended symptoms, signs, laboratory abnormalities, or 
diseases, including the following: 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
59 
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 laboratory abnormalities. 
All AEs should be collected in detail by the investigators, including: the name of the AE and 
description of all relevant symptoms, onset time, severity, correlation with the investigational 
drug, duration, measures taken, as well as final results and outcomes. 
10.1.2. AE severity grading criteria 
Please refer to NCI-CTC AE V4.03 for grading criteria. Refer to the following criteria for AEs 
not listed in NCI-CTC AE V4.03: 
Table 3. AE severity grading criteria 
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; limiting age-appropriate 
instrumental activities of daily living (ADL), e.g., cooking, shopping, using the telephone, counting 
money, etc. 
3 
Severe or medically significant symptoms but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. Self-care ADL: refer to 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Leading to death 
10.1.3. Determination of the relationship between AEs and investigational drug 
AEs will be collected from the signing of the informed consent form to 90 days after the last 
study dose or the start of new anti-tumor treatment, regardless of whether the event is related to 
the investigational drug or whether any medication is taken against the AE. From 30 days after 
the end of treatment, for non-serious AEs, only those related to the investigational drug will be 
collected. Any discomforts complained by the subject or changes in objective laboratory 
measurements during the treatment period should be faithfully recorded. The severity, duration, 
measures taken, and outcome of AEs should also be documented. The study physician should 
comprehensively assess the relationship between the AE and the investigational drug by 
considering the temporal relationship between the administration of investigational drug and the 
occurrence of AE, the characteristics of the investigational drug, the toxicological and 
pharmacological effects of the investigational drug, concomitant medications, underlying 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
60 
diseases, medical history, family history, as well as dechallenge and rechallenge. The causality 
assessment will be provided using the following five categories: "related, possibly related, 
unlikely related, not related, and unassessable". Events that are assessed to be "related", 
"possibly related", and "unassessable" will be listed as adverse drug reactions. When calculating 
the incidence of AEs, the total of these three categories will be used as the numerator and the 
total number of subjects for safety assessments will be used as the denominator. 
10.2. Serious Adverse Event (SAE) 
10.2.1. Definition of SAE 
An SAE refers to a medical occurrence during the study that results in hospitalization, prolonged 
hospitalization, disability, incapacity, life-threatening or death, or congenital malformation. The 
following medical events are included: 
 
Events leading to death; 
 
Life-threatening events (defined as when the subject is at immediate risk of death at the 
time of the event); 
 
Events leading to hospitalization or prolonged hospitalization; 
 
Events leading to 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 leading to hospitalization (even if for less than 24 h) or prolonged hospitalization during the 
clinical study should be 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.) 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
61 
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 or aggravation of the 
pre-existing disease (e.g., hospitalization to examine laboratory abnormalities that have 
persisted from before the study until now); 
 
Hospitalization for management reasons (e.g., annual physical examination); 
 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to worsening of AEs (e.g., elective surgery); 
 
Scheduled treatment or surgery that should be documented throughout the entire study 
protocol and/or in the subjects' individual baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) and non-invasive procedures should not be 
reported as AEs. However, when a condition resulting in such procedures meets the definition of 
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 should be recorded as the 
treatment of the AE. 
10.2.3. Progressive disease 
PD 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 
lesions relative to the primary tumor, or progression of the previous lesions, are recognized as 
PD. Life-threatening events, hospitalization or prolonged hospitalization, or events leading to 
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 will be reported as an SAE. 
10.2.4. Potential drug-induced liver injury 
Drug-induced liver injury will be considered if AST and/or ALT levels are abnormal 
accompanied with abnormal elevation of TBIL, 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. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
62 
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 TBIL ≥ 3 × ULN 
After being notified of the abnormal results, the subjects should return to study sites for an 
assessment as soon as possible (preferably within 48 h). Assessments include 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 patients, surgery, blood transfusion, hepatic diseases, and 
allergies. Further tests may include the testing for acute hepatitis A, B, C, and E, and hepatic 
imaging (such as biliary tract). If the above laboratory criteria are confirmed upon re-
examination, the possibility of potential drug-induced liver injury should be considered in the 
absence of any other causes of abnormal liver function, without waiting for all liver function test 
results. Potential drug-induced liver injury should be reported as an SAE. 
10.2.5. Other anti-tumor treatment 
SAEs should be collected from the signing of the informed consent form until 90 days after the 
last dose of the investigational drug. Within 90 days after the last dose, SAEs that occur after the 
start of new anti-tumor treatment should also be reported. 
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 case of an SAE, whether it is an initial 
report or a follow-up report, the investigators must complete the "NMPA Serious Adverse Event 
Report Form" promptly with signature and date provided. The SAE must be reported to the 
provincial, autonomous regional, and municipal drug regulatory authorities, NMPA, and health 
administrations within 24 h of knowing the event. In addition, the sponsor should be notified and 
the event should be reported to the EC in time. The contact information for reporting is shown in 
Table 5. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
63 
SAEs that occur after 90 days post the last study dose are generally not reported unless they are 
suspected to be related to the investigational drug. The symptoms, severity, correlation with the 
investigational drug, time of onset, time of treatment, measures taken, time and method of 
follow-up, and outcome should be documented in detail in the SAE report. If the investigators 
believe that an SAE is not related to the investigational drug but potentially related to study 
conditions (such as the termination of the previous treatment, or comorbidities during the study), 
this causality should be explained in the description section of the SAE report form. If the 
severity of an ongoing SAE or its relationship to the investigational drug changes, a follow-up 
report should be submitted immediately. If an error is found in a previously reported SAE, such 
SAE may be revised, revoked, or downgraded in follow-up reports and reported in accordance 
with the SAE reporting procedure. 
Table 4. Contacts for SAE reporting 
Institution 
Contact 
Fax/Tel./Address 
Hospital 
Ethics Committee 
Tel./Fax:  
Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. 
Drug Safety Group 
(SAE), Oncology 
Business Unit 
Email: hengrui_drug_safety@shhrp.com 
Division of Drug Research Supervision, 
Department of Drug and Cosmetics 
Registration, China Food and Drug 
Administration (now NMPA)  
 
Address: Building 2, No. 26 Xuanwumen 
West Street, Xicheng District, Beijing, China 
Postal code: 100053 
Tel.: 010-88330732 
Fax: 010-88363228 
Medical Administration Bureau, Health 
Administration 
 
Address: No. 38 North Lishi Road, Xicheng 
District, Beijing, China (100810) 
Tel.: 010-68792201 
Fax: 010-68792734 (preferred) 
Food and Drug Administration of 
Provinces, Autonomous Regions, and 
Municipalities 
Refer to the reporting requirements of the drug administration of 
corresponding province, autonomous region, or municipality 
10.2.7. Follow-up of AEs/SAEs 
All AEs/SAEs should be followed up until they are resolved, return to baseline levels or Grade ≤ 1, 
reach a stable state, or are reasonably explained (e.g., lost to follow-up or death). 
10.3. Pregnancy 
During the study, if a female subject becomes pregnant, she will immediately discontinue the 
study treatment. The investigators will report it to the sponsor within 24 h and fill out the 
"Pregnancy Report/Follow-Up Form for Hengrui Clinical Studies". 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
64 
During the study, if the partner of a male subject becomes pregnant, the subject can continue in 
the study. The investigators must report to the sponsor within 24 h and fill out the "Pregnancy 
Report/Follow-Up Form for Hengrui Clinical Studies". 
The investigators 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 the subject also experiences an SAE during the pregnancy, the "NMPA Serious Adverse Event 
Report Form" should also be filled out and reported according to the SAE reporting procedure. 
10.4. Adverse Event of Special Interest 
When an AE of special interest specified in the study protocol occurs, the investigators must fill 
out the "Report Form of Adverse Events of Special Interest for Hengrui Clinical Studies" and 
report to the sponsor within 24 h of being notified. If the AE of special interest is also an SAE, 
the "NMPA Serious Adverse Event Report Form" should also be completed and submitted to the 
relevant authorities according to the SAE reporting procedure. 
• 
Grade ≥ 3 infusion reaction; 
• 
Grade ≥ 2 diarrhea/colitis, uveitis, and interstitial pneumonia; 
• 
Other Grade ≥ 3 immune-related AEs; 
• 
Any events that meet Hy's Law (ALT/AST > 3 × ULN accompanied with TBIL > 2 × 
ULN and without other causes). 
 INDEPENDENT REVIEW 
On-site imaging review will be performed at each study site, and the independent review 
committee (IRC) will perform central review on the primary efficacy endpoint, ORR. 
On-site imaging review will be performed by an experienced and qualified study physician 
designated by each study site. All the imaging data related to efficacy assessment should be 
archived on CD and sent by each study site to the IRC for evaluation at regular intervals. 
Central review will be performed blindly by two independent radiologists. In the event of 
disagreement between these two independent radiologists, a third radiologist should make the 
final judgment. Refer to the IRC Charter for details. 
Radiographic efficacy evaluations will be performed at each study site and by independent 
radiologists according to Lugano 2014 criteria. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
65 
 DATA ANALYSIS/STATISTICAL METHODS 
Data analysis will be completed by Hengrui. Data analysis will be carried out without distinction 
of study sites (Data from all participating study sites will be combined). The primary analysis 
will be performed when the last subject has been treated for 6 months. 
Patients who have failed the screening (those who do not receive any treatment despite signing 
informed consent) will not be included in any analysis. However, they will be reported in 
a separate listing. 
Reasons for withdrawal will be summarized and listed. The listing should include: date of first 
and last administration, duration of investigational drug exposure, and date of withdrawal. 
12.1. Sample Size Determination 
This study uses a single-arm design. The primary objective is to evaluate the efficacy of SHR-
1210 in the treatment of relapsed or refractory cHL. The study endpoint is ORR. By referring to 
historical research data and research results of similar products and given the current clinical 
practice requirements, the investigational drug can be judged as effective only when the lower 
limit of the 95% confidence interval for ORR obtained from the study data is greater than 40%. 
Therefore, the sample size for this study is determined based on the following 2 points: 1. the 
exact method (Clopper-Pearson) is used to calculate the 95% confidence interval for ORR; 2. the 
lower limit of the confidence interval is greater than 40%. Assuming that the ORR of SHR-1210 
in the treatment of relapsed or refractory cHL reaches 65%, a power of 92.90% can be obtained 
with 50 subjects. Given a dropout rate of 20%, this study intends to enroll 60 subjects. 
12.2. Statistical Analysis Plan 
Statistical summaries and analytical methods of data collected from this study will be detailed in 
another individual statistical analysis plan (SAP). The finalized SAP will be kept by the sponsor. 
This SAP may contain revisions to the relevant contents in the protocol. However, when the 
revised content involves the main and/or key factors in the protocol, such as the definition of 
endpoints and the corresponding analysis, such a revision should be reflected in the protocol 
amendment version. 
12.3. Statistical Hypothesis and Decision Rules 
The alternative hypothesis of this study is that the ORR of SHR-1210 for relapsed or refractory 
cHL is greater than 40%. A lower limit of the 95% confidence interval for overall ORR greater 
than 40% estimated from the study data indicates that the investigational drug is effective 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
66 
12.4. Analysis Populations 
This study will involve the following analysis sets or populations: 
 
Informed Consent Set (ICS): all subjects who have signed the informed consent form. 
 
Full Analysis Set (FAS): eligible subjects who have received the investigational drug. 
The FAS is the primary analysis set for efficacy analysis other than the primary efficacy 
endpoint. 
 
Evaluable Set (ES): 
a subset of the FAS, defined as subjects with at least one post-baseline efficacy 
evaluation in the FAS. The ES is the primary analysis set for the primary efficacy 
endpoint ORR 
 
Per-Protocol Set (PPS): a subset of the FAS, defined as subjects in the FAS who have 
experienced no major protocol deviations. PPS is the secondary analysis set for efficacy 
analysis. 
 
Safety Set (SS): all enrolled subjects who have received the investigational drug and 
have post-administration evaluable safety data. SS is the primary analysis set for safety 
analysis. 
 
PK Set (PKS): all enrolled subjects who have received the investigational drug and 
have post-administration evaluable PK data (concentration and/or parameters). 
12.5. Statistical Methods 
The content and methods of analysis in this study will be explained in the following sections 
hierarchically. 
12.5.1. General analysis 
Unless otherwise specified, all data in this study will be summarized using descriptive statistics 
according to the data type. Measurement data will be summarized using mean, standard 
deviation (SD), median, minimum, and maximum; count data and rank data will be summarized 
using frequency and percentage; for time to event data, the Kaplan-Meier method will be used to 
estimate the median time and its overall 95% confidence interval will be calculated. 
12.5.2. Basic analysis 
The basic analysis will be based on the FAS. The analysis will include but is not limited to the 
following: 
 
Subject disposition and populations; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
67 
 
Subjects' basic characteristics (including demographics, life history, medical history, 
and medication history); 
 
The analysis of dose interruption, dose reduction, and study withdrawal of subjects as 
well as corresponding reasons. 
Descriptive summary will be made in the form of listing or using the statistical methods listed in 
Section 12.5.1. 
12.5.3. Handling of missing data 
Except for missing dates in this study, missing data will not be processed. PFS and other time to 
event data will be judged according to Hengrui's censoring rules and the censoring time will be 
calculated. Missing date will be processed according to Hengrui's missing date imputation 
criteria. 
12.5.4. Efficacy endpoint analysis 
For the objective response rate (ORR) based on the IRC's and investigators' assessment, point 
estimation will be performed, and the exact method (Clopper-Pearson) will be used to estimate 
the overall 95% confidence interval as its primary analysis. 
For other secondary efficacy endpoints, including duration of response (DoR), progression-free 
survival (PFS), time to response (TTR), and overall survival (OS), the Kaplan-Meier method will 
be used to estimate their median times and the overall 95% confidence intervals will be 
calculated. 
The analysis of the primary efficacy endpoint will be based on the ES, and other efficacy 
analyses will be repeated based on the primary analysis set FAS and secondary analysis set PPS. 
12.5.5. Safety analysis 
The safety analysis will be summarized primarily using descriptive statistics. AEs, treatment-
emergent AEs (TEAEs), SAEs, laboratory data, vital signs, and other data will be statistically 
summarized. Also, the exposure to the investigational drug (including treatment cycle, received 
total dose, and dose intensity) will be statistically summarized. The above data will be analyzed 
and summarized using Hengrui's current clinical study report standards. Such standards include 
but are not limited to the following: 
Summary of AEs (of all causes and treatment-related); 
Incidence and severity of AEs (of all causes and treatment-related); 
Correlation analysis between AEs and investigational drug; 
Analysis of outcomes of AEs; 
Analysis of SAEs; 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
68 
Descriptive statistical summary of laboratory measurements, vital sign data, and ECG data (post-
baseline absolute values and post-baseline changes from baseline); 
Classified summary of post-baseline vital sign data and ECG. 
12.5.6. Interim analysis 
This study does not involve an interim analysis. 
12.5.7. Subgroup analysis 
As a supporting analysis for the primary endpoint ORR, this study will analyze the following 
subgroups based on the FAS: age (≤ 45 vs. > 45 years), IPS score (≤ 3 vs. > 4), and baseline 
disease status (relapsed vs. refractory). The analytical method is the same as that of ORR. If 
necessary, the results will be presented with a forest plot. 
12.5.8. Multiple comparison/multiplicity 
This study does not involve conventional hypothesis testing, and the main results will be 
presented in the form of confidence intervals, without involving the issue of multiplicity. 
12.5.9. Statistical analysis of PK 
PK analyses will be based on the PKS, and PK concentration and PK parameters will be 
summarized using descriptive statistics. Apart from the statistics listed in the general analysis, 
PK concentration and PK parameter data will also be summarized descriptively using geometric 
mean (GM), coefficient of variation (CV%), and geometric CV% (GCV%). In addition, for PK 
concentration data, average and median blood concentration-time curves (concentration-time 
curves) on linear scale and semi-logarithmic scale can be plotted, and individual subjects' 
concentration-time curves (linear scale and semi-logarithmic scale) can be plotted at the same 
time. If PK statistical analysis is outsourced, the statistical analysis plan provided independently 
by the vendor shall prevail for the specific statistical analysis and method plan. 
 DATA MANAGEMENT 
13.1. Data Recording 
Data will be collected and managed using the electronic case report form (eCRF). 
13.1.1. Filing of study medical records 
As source documents, the medical records should be completely retained. The investigators 
should be responsible for filling and keeping the study medical record. The subject information 
on the cover of the medical record should be checked each time before filling the record. The 
medical record should be written in a neat and legible way so that the sponsor's CRA could 
verify the data with eCRF during each monitoring visit. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
69 
13.1.2. 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 eCRF should be filled out, 
with no blank or omission. 
Modification: 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 clinical research 
coordinator (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. 
13.1.3. eCRF review 
The investigators or designated personnel should fill out, review, and submit the eCRF in a 
timely manner. The investigators or clinical research coordinator (CRC) should promptly 
respond to queries raised by CRA, data manager, and medical reviewer. After data cleaning is 
completed, the investigators will sign the completed eCRF for verification. 
13.2. Data Monitoring 
Implemented by: clinical research associate (CRA). 
Monitoring content: To confirm that whether the study protocol is adhered to; whether the 
records in eCRF are correct and complete, and consistent with the source documents such as 
study medical records and laboratory test reports, 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 use, all EDC users should receive adequate training and get the corresponding account to 
log into the system. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
70 
13.3.2. Data entry and verification 
The investigators or CRC should input data into the EDC system in accordance with the 
requirements of the visit procedures and the eCRF completion guide. After submitting the eCRF, 
the CRA, data manager, and medical personnel should review the data. Questions during the 
review will be submitted to the investigators or CRC in the form of queries. After data cleaning 
is completed, the investigators should sign the completed eCRF for verification. 
13.3.3. Database lock 
After SDV is completed by CRA, data manager and medical reviewer will conduct the final 
quality control of all data in the database, summarize all protocol deviations during the study, 
and hold a data verification meeting. The database will be locked after quality requirements are 
met. The data manager will export the data to the statistics department for data analysis. 
13.3.4. Data archiving 
After the study is completed, subjects' eCRFs in PDF format must be generated from the EDC 
system and kept in CD-ROMs. These CD-ROMs 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 
essential documents of clinical studies should be preserved until 2 years after the investigational 
drug is approved for marketing or 5 years after the termination of the clinical study. 
13.3.5. Protocol deviation 
Protocol deviation refers to any practice that does not comply with study protocol or GCP. This 
non-compliance may occur in the subject and may also occur in the investigators or other study 
personnel. Study sites should prepare corresponding corrective measures and implement them 
immediately if a protocol deviation occurs. 
Study sites have the responsibility to maintain constant vigilance, complete the identification of 
protocol deviations in a timely manner, and complete the actions required by the protocol, to 
identify and report protocol deviations in a timely manner. All protocol deviations must be 
documented in the source documents. Protocol deviations must be submitted to local IRB in 
accordance with local ethical regulations. The principal investigators or study personnel of study 
sites are responsible for understanding and complying with local ethical standards. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
71 
 SOURCE DATA AND DOCUMENTS 
According to ICH E6, relevant regulations, and requirements for subject's personal information 
protection of study sites, each study site must properly keep all the treatment and scientific 
records related to this study. As a part of the study that Hengrui sponsors or participates in, each 
study site must allow the authorized representative of Hengrui 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. 
 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure study quality, the sponsor and the investigators 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 sites must comply with the SOPs for the management of the investigational drug, 
including receipt, storage, dispensation, return, and destruction (if applicable). 
According to the GCP guidelines, necessary measures must be taken at the design and 
implementation phases of the study to ensure that all collected data are accurate, consistent, 
intact, and reliable. All observed results and abnormal findings in the clinical study must be 
verified and recorded in a timely manner to ensure data reliability. All devices, equipment, 
reagents, and standards used in various tests in the study must have stringent specifications and 
be operated under normal conditions. 
The investigators 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 site personnel for 
necessary revision and addition. 
The drug regulatory authorities, institutional review board (IRB)/independent ethics committee 
(IEC), sponsor's CRA and/or auditor may carry out systematic inspection of study-related 
activities and documents to assess whether the study is implemented based on the study protocol, 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
72 
SOPs, and relevant regulations (such as Good Laboratory Practices [GLP] and Good 
Manufacturing Practices [GMP]) and whether the study data is recorded in a prompt, faithful, 
accurate, and complete manner. The audit should be performed by personnel not directly 
involved in this clinical study. 
 REGULATORY 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 NMPA before starting a new drug study and the study can only be carried out 
after approval is obtained. The clinical approval number for SHR-1210 is 2016L01455. 
The legal basis for the design of this protocol is as follows: 
1) Provisions for Drug Registration 
2) Good Clinical Practice 
3) Technical Guidelines for Clinical Pharmacokinetic Study of Chemical Drugs 
4) Consensus on ethical principles based on international ethics guidelines, including the 
Declaration of Helsinki and the Council for International Organizations of Medical Sciences 
(CIOMS) International Ethics Guidelines 
5) ICH Guidelines 
6) Other applicable laws and regulations 
16.2. Ethical Standards 
The investigators will ensure that this study is fully implemented in accordance with the 
requirements for fully protection of the safety and rights of the subjects. 
This study protocol must first be reviewed and approved in writing by the EC of the hospital 
before being implemented. The study protocol, protocol amendments, informed consent form, 
and other relevant documents such as recruitment advertisements should be submitted to the EC. 
This clinical study must be conducted in accordance with the Declaration of Helsinki, NMPA's 
Good Clinical Practice (GCP), and applicable laws and regulations. Before the study is initiated, 
approval must be obtained from the EC of the hospital. 
The study protocol must not be unilaterally modified without approvals from both the sponsor 
and investigators. The investigators can modify or deviate from the study protocol before 
obtaining an approval from the EC/IRB only when in purpose of eliminating direct and 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
73 
immediate harm to the subject. Besides, the deviation or change and the corresponding reason, 
and the recommended protocol amendment should be submitted to the EC/IRB for review. The 
investigators must provide explanations and document any protocol deviation. 
During the study, any changes to this study protocol must be submitted to the EC. If necessary, 
corresponding changes should be simultaneously made to other study documents and be 
submitted and/or approved according to the pertinent requirements of the EC. The investigators 
are responsible for submitting the interim reports regularly according to the pertinent 
requirements of the EC. After the end of the study, the completion should be informed to the EC. 
16.3. Independent Ethics Committee 
The protocol, informed consent form, recruitment material, and all subject materials must be 
reviewed and approved by the EC. Subjects may be enrolled only after the protocol and informed 
consent form have been approved. Any revisions to the protocol must be reviewed and approved 
by the EC prior to being implemented. All revisions to the informed consent form must be 
approved by the EC.  
16.3.1. Informed consent form and other written information for subjects 
The informed consent form describes the investigational drug and study process in detail and 
fully explains the risks of the study to the subjects. Written documentation of informed consent 
must be obtained before starting any study-related procedures. 
16.3.2. 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 legally acceptable 
representatives. Subjects will be asked to read and review the informed consent form that has 
been approved by the EC. The investigators will explain the clinical study to the subjects and 
answer any questions posed by the subjects. Subjects can only participate in the study after they 
have signed the informed consent forms. During the clinical study, subjects can withdraw the 
informed consents at any time. One copy of the signed informed consent form 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. 
16.4. Confidentiality of Subject Information 
The confidentiality of subject information will be strictly enforced by the investigators, 
participated study personnel, and sponsor and its representative. In addition to the clinical 
information, confidentiality also simultaneously covers biological samples and genetic tests of 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
74 
the subjects. Therefore, the study protocol, documentation, 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 drug can 
examine all the documents and records that are maintained by the investigators, including but not 
limited to medical records and subject's administration records. Study sites should allow access 
to these records. 
The contact information of the subjects will be safely kept in each study site and only used 
internally during the study. When the study is ended, all the records will be kept in a secure place 
based on the time limit specified by local IRB and regulations. 
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 study sites should 
be confidential and password-protected. 
16.4.1. Use of samples, specimens, or data 
This section should include the following: 
• 
Planned use: The samples and data collected in accordance with the protocol will be 
used for the detection of biomarkers and will not be used for any unrelated purposes. 
• 
Storage: Samples and data will be numbered for storage in this study. The data in the 
computer will also be password-protected. Only the study personnel can have access to 
these samples and data. 
 PUBLICATION OF STUDY RESULTS 
The study results belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd. If the investigators plan to 
publish any research-related data and information, Hengrui should be provided with the 
manuscript, abstract, or full text of all planned publications (poster, invited lectures, or guest 
lectures) at least 30 days prior to the submission of documents for publication or other forms of 
publication. 
 CLINICAL STUDY PROGRESS 
Anticipated enrollment of the first subject: Jun. 2017 
Anticipated enrollment of the last subject: Nov. 2017 
Anticipated study completion: Dec. 2019 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
75 
 REFERENCES 
1. Jacques Ferlay et al. Cancer incidence and mortality worldwide: Sources, methods and 
major patterns in GLOBOCAN 2012. Int. J. Cancer: 136, E359-E386 (2015). 
2. https://seer.cancer.gov/statfacts/html/hodg.html 
3. Wanqing Chen et al. Cancer Statistics in China, 2015. CA Cancer J Clin 2016; 66: 115-132. 
4. Xiaoqiu Li. Distribution pattern of lymphoma subtypes in China: A nationwide multicenter 
study of 10002 cases. Journal of Diagnostics Concepts & Practice, 2012, 11(2): 111-115. 
5. Stephen M. Ansell. CME Information: Hodgkin lymphoma: 2014 Update. Am. J. Hematol. 
89: 772-779, 2014. 
6. T Kewalramani et al. Progressive disease following autologous transplantation in patients 
with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-
Hodgkin's lymphoma. Bone Marrow Transplantation (2003) 32, 673-679. 
7. Younes A, Gopal AK, Smith SE, et al. Results of apivotal phase II study of brentuximab 
vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 2012; 30: 
2183-2189. 
8. Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory 
Hodgkin's lymphoma after autologous stem-cell transplantation: Results of a phase II study. 
J Clin Oncol 2012; 30: 2197-2203. 
9. Younes A, Oki Y, Bociek RG, et al. Mocetinostat for relapsed classical Hodgkin's 
lymphoma: An open-label, single-arm, phase 2 trial. Lancet Oncol 2011; 12: 1222-1228. 
10. Fehniger TA, Larson S, Trinkaus K, et al. A phase 2 multicenter study of lenalidomide in 
relapsed or refractory classical Hodgkin lymphoma. Blood 2011; 118: 5119-5125. 
11. Johnston PB, Pinter-Brown L, Rogerio J, et al. Everolimus for Relapsed/Refractory Classical 
Hodgkin Lymphoma: Multicenter, Open-Label, Single-Arm, Phase 2 Study. 54th ASH 
Annual Meeting; Blood 2012; 20, abstract 2740 
12. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab 
vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 2012; 30: 
2183-89.  
13. Cheah CY, Chihara D, Horowitz S, et al. Patients with classical Hodgkin lymphoma 
experiencing disease progression after treatment with brentuximab vedotin have poor 
outcomes. Ann Oncol 2016; 27: 1317-23. 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
76 
14. Stephen M. Ansell etal. PD-1 Blockade with Nivolumab in Relapsed or Refractory 
Hodgkin's Lymphoma. N Engl J Med 2015; 372: 311-9. 
15. Anas Younes et al. Nivolumab for classical Hodgkin's lymphoma after failure of both 
autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, 
single-arm phase 2 trial. Lancet Oncol 2016; 17: 1283-94. 
16. Philippe Armand et al. Programmed Death-1 Blockade With Pembrolizumab in Patients 
With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol 34: 
3733-3739. 
17. Craig H. Moskowitz etal. Hodgkin Lymphoma and T/NK Cell Lymphoma - Clinical Studies: 
Emerging Immunotherapy Approaches in Hodgkin Lymphoma. 58th ASH, abs 1107. 
18. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 
amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular 
sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 
116: 3268-77. 
19. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection 
induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: 
implications for targeted therapy. Clin Cancer Res 2012; 18: 1611-8. 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
77 
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 self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, 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. 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
78 
APPENDIX II. CREATININE CLEARANCE CALCULATION 
Creatinine Clearance Calculation Using the Cockcroft-Gault Formula 
 
Serum Creatinine Concentration (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 Concentration (mol/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 
Age in years, weight in kg. 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
79 
APPENDIX III. STAGING OF HODGKIN'S LYMPHOMA 
Stage I 
Single lymph node involvement (I) or local involvement of a single extralymphatic 
organ or site (IE). 
Stage II 
Involvement of two or more lymph node regions (II) on the same side of the 
diaphragm or localized involvement of a single extralymphatic organ or site in 
association with regional lymph node involvement, with or without involvement of 
other lymph node regions on the same side of the diaphragm (IIE). 
Note: The number of involved lymph node regions can be represented by subscripts 
(for example, II3). 
Stage III Involvement of lymph node regions above or below the diaphragm (III); involvement 
of lymph node groups above and below the diaphragm and outside of the lymph 
nodes in a nearby organ or site (IIIE); involvement of lymph node groups above and 
below the diaphragm and in the spleen (IIIS); or involvement of lymph node groups 
above and below the diaphragm, outside the lymph nodes in a nearby organ or site, 
and in the spleen (IIIE+S). 
Stage IV Diffuse (multiple sites) involvement of one or more extralymphatic organs with or 
without related lymph node involvement or involvement of solitary extralymphatic 
organs with involvement of distant lymph nodes (non-lymphatic areas). 
A Absence of systemic symptoms 
B 
Pyrexia of > 38 °C of unknown cause; night sweats; weight loss of > 10% (within 6 months 
before diagnosis) 
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
80 
APPENDIX IV. INTERNATIONAL PROGNOSTIC SCORE (IPS) 
1 point for each of the following factors: 
Albumin < 4 g/dL  
Hemoglobin < 10.5 g/dL  
Male 
Age ≥ 45 years old 
Stage IV lesion 
WBC increased (WBC count of at least 15000/mm3)  
Lymphocyte decreased (lymphocyte count less than 8% of total WBCs, and/or lymphocyte count 
less than 600/mm3)  
 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
81 
APPENDIX V. RESPONSE EVALUATION CRITERIA 
Lugano 2014 Revised Criteria for Response Assessment of Lymphoma 
Response and Site 
Metabolic Response (PET-CT) 
Radiologic Response (CT) 
CR 
CMR (complete metabolic response) 
CRR (complete radiologic response) 
Lymph nodes and 
extranodal sites 
Score 1, 2, or 3 with or without a residual 
mass on PET 5-point scale. It is recognized 
that in Waldeyer's ring or extranodal sites 
with high physiologic uptake or with 
activation within spleen or marrow (e.g., 
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In 
this circumstance, complete metabolic 
response may be inferred if uptake at sites 
of initial involvement is no greater than 
surrounding normal tissue even if the tissue 
has high physiologic uptake. 
Target nodes/nodal masses must regress to 
≤ 1.5 cm in LDi 
No extranodal sites of disease 
Nonmeasured lesions 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if indeterminate, 
IHC negative 
PR 
PMR (partial metabolic response) 
PRR (partial radiologic response) 
Lymph nodes and 
extranodal sites 
Score 4 or 5 with reduced uptake compared 
with baseline and residual mass(es) of any 
size. 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings indicate 
residual disease 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites; 
when a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value; when no longer visible, 0 × 0 mm; 
for a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement for 
calculation; 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in 
length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of 
a nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan. 
Not applicable 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
82 
Lugano 2014 Revised Criteria for Response Assessment of Lymphoma 
Response and Site 
Metabolic Response (PET-CT) 
Radiologic Response (CT) 
SD 
No metabolic response 
SD 
Lymph nodes and 
extranodal sites 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment.  
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
Nonmeasured lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
PD 
Metabolic progression 
Radiologic progression 
Individual target 
nodes/nodal masses and 
extranodal lesions 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment.  
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm; 
In the setting of splenomegaly, the splenic 
length must increase by > 50% of the 
extent of its prior increase beyond baseline 
(e.g., a 15-cm spleen must increase to  
> 16 cm); if no prior splenomegaly, must 
increase by at least 2 cm from baseline; 
New or recurrent splenomegaly. 
Nonmeasured lesions 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered 
A new node > 1.5 cm in any axis; a new 
extranodal site > 1.0 cm in any axis; if  
< 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma; 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease;  
SPD: sum of the product of the perpendicular diameters for multiple lesions; PPD: cross product of the LDi and 
perpendicular diameter; LDi: longest transverse diameter of a lesion; SDi: shortest axis perpendicular to the LDi 
 


Compound Name: SHR-1210 
Protocol No.: SHR-1210-II-204 
Version 3.0, Version Date: 19 Jul., 2017 
 
 
Hengrui Confidential 
83 
PET 5-Point Scale 
Score 
PET/CT Examination Result 
1 
No uptake above background 
2 
Uptake ≤ mediastinum 
3 
Uptake > mediastinum but ≤ liver 
4 
Uptake moderately > liver 
5 
Uptake markedly higher than liver and/or new lesions 
 
 

SAP_001.pdf: 
Title: An Open-Label, Single Arm, Multi-Center, Phase 2 Study of PD-1 Antibody 
SHR-1210 in Subjects with Relapsed or Refractory Classic Hodgkin's Lymphoma 
NCT number: NCT03155425 
Date: 30 Aug., 2020 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
1 
Translated from Original Document 
 
 
 
 
 
AN OPEN-LABEL, SINGLE ARM, MULTI-CENTER, PHASE II STUDY OF 
PD-1 ANTIBODY SHR-1210 IN SUBJECTS WITH RELAPSED OR 
REFRACTORY CLASSIC HODGKIN'S LYMPHOMA 
 
Statistical Analysis Plan 
(SAP) 
 
Author: 
  
Company: Jiangsu Hengrui Pharmaceuticals Co., Ltd.  
Version: 3.0/Revision 
Date: 30 Aug., 2020 
This SAP has been reviewed by the following personnel before being approved and effective. 
Functional Role 
Reviewer 
Medical Science 
 
Statistics 
 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
2 
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 
PE 
Physical examination 
PFS 
Progression-free survival 
PR 
Partial response 
PPS 
Per-protocol set 
SD 
Stable disease 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
TTP 
Time to progression 
TTR 
Time to response 
 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
3 
TABLE OF CONTENTS 
ABBREVIATIONS ....................................................................................................................... 2 
1. 
REVISION ............................................................................................................................. 5 
2. 
INTRODUCTION ................................................................................................................ 6 
2.1. Study Design ................................................................................................................. 6 
2.2. Study Objectives ........................................................................................................... 6 
2.2.1. 
Primary objective ............................................................................................. 6 
2.2.2. 
Secondary objectives ........................................................................................ 6 
2.3. Sample Size ................................................................................................................... 6 
3. 
STATISTICAL HYPOTHESES......................................................................................... 7 
4. 
STUDY ENDPOINTS .......................................................................................................... 7 
4.1. Efficacy Endpoints ........................................................................................................ 7 
4.2. Safety Endpoints ........................................................................................................... 7 
4.2.1. 
Adverse events ................................................................................................ 8 
4.2.2. 
Laboratory test ................................................................................................ 8 
4.2.3. 
Vital signs ........................................................................................................ 8 
4.2.4. 
Electrocardiogram (ECG) .............................................................................. 8 
4.2.5. 
Physical examination ...................................................................................... 8 
4.2.6. 
Other safety endpoints .................................................................................... 8 
4.3. Pharmacokinetic Endpoints .......................................................................................... 9 
4.4. Pharmacodynamic Endpoints ....................................................................................... 9 
4.5. Other Endpoints ............................................................................................................ 9 
5. 
STATISTICAL ANALYSIS ................................................................................................ 9 
5.1. General Considerations ................................................................................................ 9 
5.1.1. 
Analysis sets .................................................................................................... 9 
5.1.2. 
General rule and analysis ............................................................................. 10 
5.1.3. 
Derived variables .......................................................................................... 11 
5.1.4. 
Covariates and subgroups ............................................................................ 11 
5.1.5. 
Analysis window ........................................................................................... 11 
5.1.6. 
Missing data .................................................................................................. 12 
5.2. Study Subjects ............................................................................................................. 12 
5.2.1. 
Disposition of subjects ................................................................................. 12 
5.2.2. 
Demographics and baseline characteristics ................................................ 12 
5.2.3. 
Medical history ............................................................................................. 12 
5.2.4. 
Prior therapy and concomitant medication ................................................. 13 
5.2.5. 
Protocol deviations ....................................................................................... 13 
5.3. Treatment Compliance................................................................................................ 13 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
4 
5.4. Efficacy Analysis ........................................................................................................ 13 
5.4.1. 
Exploratory analyses .................................................................................... 14 
5.4.2. 
Subgroup analysis ......................................................................................... 14 
5.4.3. 
Other analysis ................................................................................................ 14 
5.5. Safety Analyses ........................................................................................................... 14 
5.5.1. 
Extent of exposure ........................................................................................ 14 
5.5.2. 
Adverse events .............................................................................................. 14 
5.5.3. 
Laboratory evaluations ................................................................................. 15 
5.5.4. 
Vital signs ...................................................................................................... 16 
5.5.5. 
Electrocardiogram (ECG) ............................................................................ 16 
5.5.6. 
Physical examination .................................................................................... 16 
5.5.7. 
Other safety measures................................................................................... 16 
5.6. Pharmacokinetic Analysis .......................................................................................... 16 
5.7. Pharmacodynamics Analysis ...................................................................................... 16 
5.8. Other Analysis ............................................................................................................. 16 
6. 
INTERIM ANALYSIS ....................................................................................................... 16 
7. 
REFERENCES..................................................................................................................... 17 
8. 
APPENDIX ........................................................................................................................... 17 
 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
5 
1. REVISION 
Updated to Version 3.0 on 30 Aug. 2020. Formulated with reference to the protocol No. 
SHR-1210-II-204 (Version 3.0, 19 Jul., 2017). 
Content 
Before 
After 
Cover 
1. The version number is 2.0 
2. The version date is 4 Apr., 2018 
1. The version number is 3.0 
2. The version date is 30 Aug., 2020 
Definition of 
FAS 
Full Analysis Set (FAS): eligible subjects who have 
received the investigational drug and meet the 
following requirements. 
(1) Subjects who have received rescue autologous 
stem cell transplant after chemotherapy, and then 
have recurrence or progression; 
(2) Subjects who have not received autologous 
stem cell transplant are required to have received 
the following treatment: 
The first-line chemotherapy must be systemic 
multi-drug combination chemotherapy. For 
subsequent chemotherapy, it is required that at least 
one line of chemotherapy is systemic multi-drug 
combination chemotherapy. 
Patients with refractory disease are patients who 
did not achieve PR after ≥ 2 treatment cycles or CR 
after ≥ 4 treatment cycles, or patients who 
developed progressive disease, regardless of 
number of treatment cycles. 
Patients with relapsed disease are patients who 
were recently treated with at least second-line 
chemotherapy prior to recurrence. 
Full Analysis Set (FAS): eligible subjects 
who have received the investigational 
drug. 
5.1.4 Covariates 
and subgroups 
Subjects who received the highest number of lines 
of prior chemotherapy or autologous stem cell 
transplant but achieved non-CR/non-PR are 
classified as subjects with refractory diseases, and 
others are classified as subjects with relapsed 
diseases. 
Relapsed: Best overall response to the 
last chemotherapy/transplant is CR or 
PR, and time from the end of 
chemotherapy/transplant to progression 
is > 6 months. 
Refractory: 1. Best overall response to 
the last chemotherapy/transplant is CR, 
PR, or not evaluated, and time from the 
end of chemotherapy/transplant to 
progression is ≤ 6 months. Or, 2. Best 
overall response to the last 
chemotherapy/transplant is PD or SD. 
Missing: Response to the last 
chemotherapy/transplant is not evaluated, 
and time from the end of last 
chemotherapy/transplant to progression 
is > 6 months. 
 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
6 
2. INTRODUCTION 
This study is a phase II clinical study evaluating the efficacy and safety of SHR-1210 in the 
treatment of patients with refractory or relapsed classic Hodgkin's lymphoma. 
2.1. 
Study Design 
This study adopts a multi-center, open-label, single-arm design to evaluate the efficacy and 
safety of SHR-1210 in patients with relapsed or refractory classic Hodgkin's lymphoma and the 
PK parameters of 12 subjects at the same time. Sixty subjects who meet the eligibility criteria 
will be enrolled and given SHR-1210 at 200 mg/dose on day 1 of each 2-week cycle, until the 
following condition occurs: progressive disease (PD), intolerable toxicity, or other reasons 
specified in the protocol. After treatment, the subjects entered the follow-up period would 
receive safety follow-up or survival follow-up. 
2.2. 
Study Objectives 
2.2.1. 
Primary objective 
To evaluate the efficacy, namely objective response rate (ORR), of PD-1 antibody SHR-1210 in 
the treatment of relapsed or refractory classic Hodgkin's lymphoma. 
2.2.2. 
Secondary objectives 
• 
To observe and evaluate the duration of response (DoR), progression-free survival (PFS), 
time to response (TTR), and overall survival (OS) of PD-1 antibody SHR-1210 in the 
treatment of patients with relapsed or refractory classic Hodgkin's lymphoma (cHL). 
• 
To evaluate the safety of PD-1 antibody SHR-1210 in patients with relapsed or 
refractory classic Hodgkin's lymphoma (cHL). 
2.3. 
Sample Size 
This study adopts a single-arm design. The primary objective is to evaluate the efficacy of 
SHR-1210 in the treatment of relapsed or refractory cHL. The study endpoint is ORR. Based on 
historical research data and research results of similar products, combined with current clinical 
practice requirements, only when the lower limit of the 95% confidence interval for ORR 
obtained from the study is greater than 40%, it can be considered as effective. Therefore, the 
sample size for this study is determined based on the following 2 points: 1. the exact method 
(Clopper-Pearson) is used to calculate the 95% confidence interval for ORR; 2. the lower limit of 
the confidence interval is greater than 40%. Assume that the ORR of SHR-1210 in the treatment 
of relapsed or refractory cHL reaches 65%, a power of 92.90% can be obtained with 50 subjects. 
Combined with a dropout rate of 20%, this study intends to enroll 60 subjects. 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
7 
3. STATISTICAL HYPOTHESES 
Hypotheses of ORR are as follows:  
H0: ORR = 40% 
Ha: 
ORR ≠ 40% 
 = 0.05 (two-sided) 
4. STUDY ENDPOINTS 
4.1. 
Efficacy Endpoints 
Primary efficacy endpoint: 
Objective response rate (ORR) assessed by the independent review committee (IRC), including 
the proportion of complete response (CR) and partial response (PR). 
Secondary efficacy endpoints: 
• 
Objective response rate (ORR) assessed by the investigators, including the proportion 
of complete response (CR) and partial response (PR) 
• 
Duration of response (DoR) 
• 
Progression-free survival (PFS): The date of first PD documented after CR, PR, or SD 
is used as the date of progression; if the subject does not achieve CR, PR, or SD 
following PD, then the date of initial PD is used as the date of progression. 
• 
Time to response (TTR) 
• 
Overall survival (OS) 
• 
Time to progression (TTP) 
4.2. 
Safety Endpoints 
The following safety data will be collected and summarized according to the study protocol: 
• 
Adverse events 
• 
Laboratory test data 
• 
Vital signs data 
• 
Electrocardiography (ECG) 
• 
Physical examination 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
8 
4.2.1. 
Adverse events 
Including any AE occurring after signing the informed consent form (ICF) and being enrolled in 
the study. 
Any AE occurring after the treatment or occurring prior to the treatment but worsening after the 
treatment will be considered as a treatment-emergent AE (TEAE). Including but not limited to 
the followings: 
• 
Worsening of pre-existing (prior to start of study treatment) medical 
conditions/diseases after the start of investigational drug administration. 
• 
Any new AE occurring after the start of study treatment. 
• 
Clinically significant abnormal laboratory findings or results occurring after the start of 
study treatment. 
If an event occurs during non-treatment period (e.g., treatment interruption or follow-up period 
after treatment discontinuation), then this event will still be considered to be treatment emergent 
and attributed to previous therapy. 
4.2.2. 
Laboratory test 
Laboratory measurements including hematology, hepatic and renal function, urinalysis and fecal 
occult blood, blood electrolytes, coagulation function, and thyroid function will be collected at 
the visit time points specified in the study protocol. 
4.2.3. 
Vital signs 
Vital signs such as blood pressure, heart rate, body temperature, and respiratory rate will be 
collected at time points predetermined in the study protocol. 
4.2.4. 
Electrocardiogram (ECG) 
Heart rate, PR, and QTc will be collected at time points predetermined in the study protocol. 
4.2.5. 
Physical examination 
Physical examination includes general condition, head and face, skin, lymph nodes, eyes, ears, 
nose, throat, oral cavity, respiratory system, cardiovascular system, abdomen, 
reproductive-urinary system, musculoskeletal system, nervous system, mental state, and others. 
These data will be collected at protocol-specified visit/time points. 
4.2.6. 
Other safety endpoints 
Assessment of B symptoms, IPS score, and ultrasound ECG. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
9 
4.3. 
Pharmacokinetic Endpoints 
Not included in this SAP. See "PK Statistical Analysis Plan" provided by the vendor. 
4.4. 
Pharmacodynamic Endpoints 
None. This study does not involve PD endpoints. 
4.5. 
Other Endpoints 
None. 
5. STATISTICAL ANALYSIS 
5.1. 
General Considerations 
5.1.1. 
Analysis sets 
This study will involve the following analysis sets or populations: 
• 
Informed Consent Set (ICS) 
All subjects who have signed the informed consent form. 
• 
Full Analysis Set (FAS) 
Eligible subjects who have received the investigational drug. 
• 
Per-Protocol Set (PPS) 
A subset of the FAS, defined as subjects in the FAS who have experienced no 
important protocol deviations. 
• 
Safety Set (SS) 
All enrolled subjects who have received the investigational drug and have 
post-administration safety evaluation. The SS is the primary analysis set for safety analysis. 
Table 1. Analysis sets and corresponding endpoints. 
Endpoint 
Analysis Sets 
FAS 
PPS 
SS 
ORR (%)* 
X 
X 
 
TTR (Month) 
X 
 
 
TTP (Month) 
X 
 
 
PFS (Month) 
X 
 
 
DoR (Month) 
X 
 
 
DCR (%) 
X 
 
 
OS (Month) 
X 
 
 
Safety (AE, LAB, VS, ECG, and PE) 
 
 
X 
*: Assessed by the investigator and independent review committee, respectively. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
10 
5.1.2. 
General rule and analysis 
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 formula: 
• 
Study days = examination date - start date of the study, if the date of an 
examination/event is before the start date of study; 
• 
Study days = examination date - start date of the study + 1, if the date of an 
examination/event is on or after the start day of study. 
General analysis 
Unless otherwise specified, the following descriptive statistics will be summarized by the type of 
variables: 
• 
Continuous variables will be summarized using mean, standard deviation, median, 
maximum, and minimum. 
• 
Categorical variables will be summarized using frequency and percentage; 
• 
For time-to-event variables, 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: 
• 
The decimal places of the minimum and maximum will remain the same as that of raw 
data to be acquired; there should be one additional decimal place for the mean and 
median, and 2 additional decimal places for standard deviation, up to 4 decimal places. 
• 
The percentage will be rounded to 2 decimal places. If the frequency is 0, the 
percentage is not displayed. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
11 
• 
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. 
Analysis software 
All statistical analyses will be conducted using SAS® 9.4 or above. 
5.1.3. 
Derived variables 
Compliance (%) of subjects = (actual number of doses/scheduled number of doses) × 100%  
Time from initial pathological diagnosis to enrollment (month) = (date of enrollment - date of 
initial pathological diagnosis + 1)/30.44 
Time from final dose to enrollment (month) = (date of enrollment - last date of any previous 
anti-tumor therapy + 1)/30.44 
Duration of drug exposure (month) = (date of last dose +14 - date of first dose + 1)/30.44 
5.1.4. 
Covariates and subgroups 
This study includes the following subgroups: 
• 
Age (≤ 45 years old and > 45 years old) 
• 
IPS score (≤ 3 points and > 3 points) 
• 
Baseline Disease Status (Relapsed and Refractory): 
- 
Relapsed: Best overall response to the last chemotherapy/transplant is CR or PR, 
and time from the end of chemotherapy/transplant to progression is > 6 months. 
- 
Refractory: 1. Best overall response to the last chemotherapy/transplant is CR, PR, or 
not evaluated, and time from the end of chemotherapy/transplant to progression is ≤ 6 
months. Or, 2. Best overall response to the last chemotherapy/transplant is PD or SD. 
- 
Missing: Response to the last chemotherapy/transplant is not evaluated, and time 
from the end of last chemotherapy/transplant to progression is > 6 months. 
5.1.5. 
Analysis window 
Data obtained from post-baseline visits will be summarized by protocol visits shown in eCRF. 
There is no need to consider whether the visit window specified by the protocol has been 
exceeded. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
12 
When a planned visit is missing, or one of the test items in the planned visit is missing or its 
results are invalid, the unplanned visit closest to the planned visit will be considered as the 
protocol visit. If the time of two unplanned visits is equally close to the time of planned visit, the 
later unplanned visit will be selected as the protocol visit. All visits in the protocol will be sorted 
chronologically. In addition, once an unplanned visit is defined in one protocol, it will no longer 
be defined in other protocols. 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. 
5.1.6. 
Missing data 
If the missing date and month needs to be imputed, they will be imputed in accordance with the 
imputation rules of Hengrui date-type data. If not recorded in events, the time-event data will be 
right-censored. See appendix for information on how to judge censoring and calculate censored 
date. Other missing data will not be handled. 
5.2. 
Study Subjects 
Demographics and baseline characteristics will be analyzed based on FAS, and medical history 
and prior therapy will be analyzed based on SS. 
5.2.1. 
Disposition of subjects 
The number of screened subjects, number of enrolled subjects, number and percentage of treated 
subjects, number and percentage of subjects in the analysis sets, number of subjects who 
discontinue study/treatment, and number and percentage of corresponding subjects to the reasons 
for discontinuation. 
5.2.2. 
Demographics and baseline characteristics 
Age, gender, ethnicity, height, IPS score, B symptoms, and the occurrence of pulmonary 
involvement and mediastinal lesions of the subjects are summarized using descriptive statistics, 
respectively. Continuous variables such as age and body height are summarized using descriptive 
statistics, such as number of evaluable subjects (n), mean and standard deviation, median, min 
and max. Categorical variables such as gender and ethnicity will be summarized using 
descriptive statistics, including number of evaluable subjects per category and corresponding 
percentage in total population. 
5.2.3. 
Medical history 
The analysis of tumor diagnosis includes time to first pathological diagnosis, pathological 
classification, and Ann Arbor staging. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
13 
5.2.4. 
Prior therapy and concomitant medication 
The analyses of previous therapies include time from the last dose to enrollment (< 3 months, 3–
6 months, > 6 months), previous therapies (brentuximab vedotin, autologous stem cell transplant, 
and radiotherapy), and analysis of chemotherapy history (chemotherapy and autologous stem cell 
transplant) which includes the number of therapy line (1, 2, 3, 4, ≥ 5) and baseline disease status 
(relapsed/refractory). These analyses will be summarized using frequency and percentage. The 
number of therapy line (continuous variable) and time from the last dose to enrollment (month) will 
be summarized using descriptive statistics, such as mean, standard deviation, median, min, and max. 
All prior concomitant medications, concomitant medications, and concomitant non-drug therapy 
will be listed. 
5.2.5. 
Protocol deviations 
Before database lock, data of all subjects on CRF will be checked for important protocol 
deviations. All potential important protocol deviations will be reviewed and evaluated by the 
investigator and the sponsor. 
All important protocol deviations will be summarized and described by type and tabulated for 
analysis. 
Important protocol deviations include but are not limited to the following:  
• 
Serious violation of the inclusion/exclusion criteria;  
• 
Meeting the withdrawal criteria but the subject did not withdraw from the study; 
• 
Use of medication prohibited by the protocol. 
5.3. 
Treatment Compliance 
The use of investigational drug during the treatment period is summarized using descriptive 
statistics by cycles. All study drugs will be listed by subject code, treatment stage, dosing date, 
and use of medications. 
5.4. 
Efficacy Analysis 
Primary efficacy analysis 
The primary efficacy endpoint of the study is IRC-assessed ORR. Analysis will be based on results 
assessed by IRC and the investigator, respectively. The primary analysis of ORR is based on IRC 
assessment. ORR will be calculated and the 95% confidence interval will be calculated using the 
Clopper-Pearson method. The analysis will be based on FAS and PPS (mainly on the FAS). 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
14 
In addition, the consistency between IRC-assessed and investigator-assessed PD and non-PD, 
CR + PR, and non-CR + PR will be analyzed using Amit's method based on the FAS. 
Secondary efficacy analysis 
Identical to the primary efficacy analysis, the secondary efficacy analysis will be performed 
based on IRC-assessed and investigator-assessed results, respectively. However, the secondary 
efficacy analysis will be based on FAS only. 
Among the secondary efficacy endpoints in this study, time-event endpoints such as DoR, PFS, 
TTP, and OS will be analyzed using the Kaplan-Meier method, and TTR will be summarized 
using descriptive statistics. Survival curves could be plotted if needed. 
The secondary efficacy endpoint of DCR will be analyzed using the same statistical method as 
for ORR. 
In addition, best overall response will be summarized using descriptive statistics. 
5.4.1. 
Exploratory analyses 
None. 
5.4.2. 
Subgroup analysis 
The ORR analysis will be based on FAS. The ORR in subgroups and the corresponding 95% 
confidence interval will be analyzed. See 5.1.4 for subgroups and the definitions. 
5.4.3. 
Other analysis 
None. 
5.5. 
Safety Analyses 
All safety analyses will be conducted based on SS. 
5.5.1. 
Extent of exposure 
Duration of drug exposure and number of doses received will be summarized. 
5.5.2. 
Adverse events 
TEAE is any adverse event after treatment with the investigational drug. AEs will be 
summarized using descriptive statistics according to Hengrui's Statistical Analysis Reporting 
Standards, including but not limited to: 
• 
Overview of AEs (of all causes and treatment-related); 
• 
Summary of SAEs; 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
15 
• 
Incidence and severity of AEs (of all-cause and treatment-related); 
• 
Causality assessment of AEs; 
• 
Analysis of adverse events of special interest (AESIs). 
AESIs mainly include the following: 
- Haemangioma (time to onset and duration) 
- Grade ≥ 3 infusion reaction 
- Grade ≥ 2 diarrhoea/colitis, uveitis, interstitial pneumonia 
- Grade ≥ 3 other immune-related adverse events: skin, digestive tract, lungs, 
endocrine (by system organ class) 
- Hepatic enzyme abnormalities: ALT, AST and total bilirubin are abnormal against 
baseline 
- Grade 4 amylase or lipase increased. 
For AEs occurring after the start of study treatment, treatment-related AEs include those whose 
causality with the investigational drug is related, possibly related, unlikely related, or 
unassessable; if the causality assessment is missing, then the AE will be deemed 
treatment-related for analysis. 
5.5.3. 
Laboratory evaluations 
The baseline is defined as the last measurement before the first dose. Data will be summarized 
using descriptive statistics according to Hengrui Statistical Analysis Reporting Standards, 
including but not limited to: 
• 
Incidence of abnormal measurements and parameters; 
• 
Shift tables and listings of changes in measurements, visits, and parameters from 
baseline (normal/abnormal). 
• 
Shift tables of CTCAE grades before and after treatment. 
Listings of abnormal laboratory will be provided. 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
16 
5.5.4. 
Vital signs 
The baseline is defined as the last measurement before the first dose. Data will be summarized 
using descriptive statistics according to Hengrui Statistical Analysis Reporting Standards, 
including but not limited to: descriptive statistics and categorical analysis of absolute values and 
changes from baseline at scheduled visits in the protocol. Blood pressure and heart rate will be 
summarized. See Appendix B for classification criteria. 
5.5.5. 
Electrocardiogram (ECG) 
ECG results will be listed. 
5.5.6. 
Physical examination 
Data will be summarized using descriptive statistics according to Hengrui Statistical Analysis 
Reporting Standards, including but not limited to: descriptive statistics of absolute values at 
scheduled visits in the protocol. 
5.5.7. 
Other safety measures 
Baseline ECOG PS and post-baseline changes will be summarized by visit. B symptom scores 
will be summarized by visit and analyzed using frequency and percentages (according to 
categorical variables). 
Echocardiography results will be listed. 
5.6. 
Pharmacokinetic Analysis 
PK analysis is provided by the vendor and not included in this SAP. 
5.7. 
Pharmacodynamics Analysis 
Not involved. 
5.8. 
Other Analysis 
None. 
6. INTERIM ANALYSIS 
No routine interim analysis. 
 


SHR-1210-II-204 
3.0/Revision, 30 Aug., 2020 
Statistical Analysis Plan 
17 
7. REFERENCES 
None. 
8. APPENDIX 
Appendix 1.1. Definition of progression-free survival (PFS). 
No. 
Situation 
Date of Progression/ 
Censoring 
Handling 
1 
No baseline assessment 
Date of first dose 
Censoring 
2 
No post-baseline assessment, and no death 
Date of first dose 
Censoring 
3 
Any death (except #5) 
Date of death 
Event 
4 
Progressive disease during study (including 
after missing one assessment) 
Date of progressive 
disease 
Event 
5 
Death or progressive disease after 2 consecutive 
missing tumor assessments 
Date of last tumor 
assessment before missing 
Censoring 
6 
Withdrawal from the study due to toxicity or 
other reasons without PD or death record 
Date of last tumor 
assessment before study 
withdrawal 
Censoring 
7 
No progressive disease or death recorded before 
the initiation of new anti-cancer treatment 
Date of last recorded 
objective tumor 
assessment as no PD 
before the initiation of 
new anti-tumor treatment 
Censoring