Clinical trial NCT03711279
Conditions: Sarcoma
Keywords: Sarcoma SHR-1210 Apatinib
Sponsor: Jiangsu HengRui Medicine Co., Ltd.
Start date: 2018-11-22; Completion date: 2021-06-21
Enrollment: 99 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the efficacy of SHR-1210 plus Apatinib versus AMD plus IFO in participants with soft tissue sarcoma.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: SHR-1210 plus Apatinib intervention 2: ADM plus IFO or IFO alone
Intervention descriptions: intervention 1: SHR-1210 200 mg q3w+ Apatinib 500 mg qd intervention 2: ADM 60 mg/m2 D1 + IFO 2 g/m2 D1-D4 q3w；if the cumulative doses of ADM were beyond 450 mg/m2, the monotherapy of IFO (2 g/m2 D1-D5 q3w) would be used.

Protocol documents:
Prot_000.pdf: 
Title: A multicenter, randomized, open-label phase II clinical study of anti-PD-1 
antibody SHR-1210 combined with apatinib mesylate vs. doxorubicin combined with 
ifosfamide in treatment of soft tissue sarcoma 
NCT number: NCT03711279 
Date: 25 Feb., 2019 


SHR-1210, Apatinib 
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Translated from Original Document 
 
A MULTICENTER, RANDOMIZED, OPEN-LABEL PHASE II 
CLINICAL STUDY OF ANTI-PD-1 ANTIBODY SHR-1210 COMBINED 
WITH APATINIB MESYLATE 
VS. DOXORUBICIN COMBINED WITH IFOSFAMIDE IN 
TREATMENT OF SOFT TISSUE SARCOMA 
Protocol No.: 
SHR-1210-II-212 
Study Phase: 
II 
Compound: 
Camrelizumab for injection (SHR-1210), Apatinib 
Mesylate Tablets 
Medical Director: 
 
Leading Center of Clinical Study: 
Shanghai Sixth People's Hospital 
Principal Investigator: 
Prof. Yang Yao 
 
 
Version No.: 
3.0 
Version Date: 
25 Feb., 2019 
 
 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
 
No. 7 Kunlunshan Road, Lianyungang Economic and 
Technological Development Zone, Jiangsu 222047, China 
 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for use by clinical 
investigators only. Any disclosure is not permitted unless requested by current laws or regulations. 
The copyright is owned by Jiangsu Hengrui Pharmaceuticals Co., Ltd. or its subsidiaries. Any 
copy or distribution of information herein to any individuals not participating in this clinical study 
is not allowed, unless a confidentiality agreement has been signed with Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. or its subsidiaries. 


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VERSION HISTORY/REVISION HISTORY 
Document 
Version Date 
Amendment Rationale and Summary of Changes 
Initial version 
25 Jul., 2018 
Not applicable 
Version 2.0 
5 Sep., 2018 
Page 40, revised adverse events based on the latest CDE 
dossier submission 
Version 3.0 
25 Feb., 2019 
Added imaging assessments for tumor lesions of other 
sites; added exploratory endpoints: investigator-assessed 
PFS (as per iRECIST) and corresponding evaluation 
criteria; modified the dose of apatinib; SHR-1210 
administration may be delayed for up to 7 days after the 
specified time point. 


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Sponsor's Signature Page 
I have read and confirmed this clinical study protocol (protocol No.: SHR-1210-II-212, version 
No.: 3.0, version date: 25 Feb., 2019). 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) 
 
 
 
 


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Principal Investigator's Signature Page (Leading Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. I have received the Investigator's 
Brochure for the study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. I agree to fulfill my duties in accordance with Chinese laws, the 
Declaration of Helsinki, the Chinese GCP, and this study protocol. I agree that any modifications 
to the protocol must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the ethics committee, unless measures must be taken to protect the safety, rights, and 
interests of the subjects. It is my responsibility to make clinically relevant medical decisions to 
ensure appropriate and timely treatments in subjects experiencing adverse events during the study 
period, and to document and report such adverse events in accordance with relevant state 
regulations. I will document all data in a truthful, accurate, complete and timely manner. I agree to 
be monitored and audited by the clinical research associate or auditor assigned by the sponsor, and 
to be inspected by the drug regulatory authorities, to ensure the quality of the clinical study. I will 
keep the personal information of and matters related to the subjects confidential. I agree to disclose 
my full name and occupation to the sponsor, and the expenses related to the clinical study upon 
request. I agree not to engage in any commercial and economic activities related to this study. I 
agree for the study results to be used for drug registration and publication. I will provide a resume 
before the start of the study, submit it to the ethics committee, and to the drug regulatory authority 
for filing purposes. 
 
 
Study Center: Shanghai Sixth People's Hospital 
 
 
 
Yang Yao 
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


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Principal Investigator's Signature Page (Participating Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. I have received the Investigator's 
Brochure for the study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. I agree to fulfill my duties in accordance with Chinese laws, the 
Declaration of Helsinki, the Chinese GCP, and this study protocol. I agree that any modifications 
to the protocol must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the ethics committee, unless measures must be taken to protect the safety, rights, and 
interests of the subjects. It is my responsibility to make clinically relevant medical decisions to 
ensure appropriate and timely treatments in subjects experiencing adverse events during the study 
period, and to document and report such adverse events in accordance with relevant state 
regulations. I will document all data in a truthful, accurate, complete and timely manner. I agree to 
be monitored and audited by the clinical research associate or auditor assigned by the sponsor, and 
to be inspected by the drug regulatory authorities, to ensure the quality of the clinical study. I will 
keep the personal information of and matters related to the subjects confidential. I agree to disclose 
my full name and occupation to the sponsor, and the expenses related to the clinical study upon 
request. I agree not to engage in any commercial and economic activities related to this study. I 
agree for the study results to be used for drug registration and publication. I will provide a resume 
before the start of the study, submit it to the ethics committee, and to the drug regulatory authority 
for filing purposes. 
 
Study Center: __________________________________________ 
 
 
 
 
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 6 
LIST OF TABLES ...................................................................................................................... 11 
LIST OF FIGURES .................................................................................................................... 11 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
1 
FLOW DIAGRAM OF EXPERIMENT — INVESTIGATIONAL  
TREATMENT GROUP (SHR-1210 COMBINED WITH APATINIB) ........................ 20 
2 
FLOW DIAGRAM OF EXPERIMENT — CONTROL GROUP  
(DOXORUBICIN + IFOSFAMIDE OR IFOSFAMIDE MONOTHERAPY) .............. 25 
3 
SCHEDULE OF ACTIVITIES — CROSSOVER TREATMENT (SHR-1210 + 
APATINIB AFTER PROGRESSION FOLLOWING DOXORUBICIN + 
IFOSFAMIDE OR IFOSFAMIDE MONOTHERAPY) ................................................. 29 
4 
ABBREVIATIONS ............................................................................................................. 34 
5 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE .................... 36 
5.1 
Background ................................................................................................................... 36 
5.1.1 Introduction to soft tissue sarcoma ................................................................... 36 
5.1.2 Introduction to SHR-1210 ................................................................................. 37 
5.1.3 Introduction to apatinib ..................................................................................... 39 
5.1.4 Progress in the clinical studies of SHR-1210 plus apatinib .............................. 40 
5.2 
Scientific Rationale ...................................................................................................... 40 
5.3 
Potential Risks and Benefits ......................................................................................... 42 
6 
OBJECTIVES AND ENDPOINTS ................................................................................... 43 
6.1 
Study Objectives ........................................................................................................... 43 
6.1.1 Primary objective .............................................................................................. 43 
6.1.2 Secondary objectives ......................................................................................... 43 
6.1.3 Exploratory objectives ...................................................................................... 44 
6.2 
Study Endpoints ............................................................................................................ 44 
6.2.1 Primary endpoints ............................................................................................. 44 
6.2.2 Secondary endpoints ......................................................................................... 44 
6.2.3 Exploratory endpoints ....................................................................................... 45 
7 
STUDY DESIGN ................................................................................................................. 45 
7.1 
Overview of Study Design ........................................................................................... 45 


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8 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 47 
8.1 
Inclusion Criteria .......................................................................................................... 47 
8.2 
Exclusion Criteria ......................................................................................................... 49 
8.3 
Withdrawal from Study or Treatment Discontinuation ................................................ 51 
8.3.1 Study withdrawal criteria .................................................................................. 51 
8.3.2 Criteria for treatment discontinuation ............................................................... 51 
8.3.3 Criteria for continuing treatment beyond progression (investigational  
treatment group) ................................................................................................ 52 
8.3.4 Criteria for crossover treatment of subjects in control group after  
radiographic progression ................................................................................... 53 
8.4 
Definition of End of Study ........................................................................................... 56 
8.5 
Termination or Suspension of Study ............................................................................ 56 
9 
COLLECTION AND PROCESSING OF PHARMACOKINETIC AND 
IMMUNOGENIC BLOOD SAMPLES ............................................................................ 57 
9.1 
Collection and Processing of Blood Samples ............................................................... 57 
9.1.1 Blood sampling time ......................................................................................... 57 
9.1.2 Processing and storage of blood samples .......................................................... 57 
9.1.3 Blood sample submission .................................................................................. 57 
10 STUDY MEDICATION ..................................................................................................... 58 
10.1 Overview of Study Drugs ............................................................................................. 58 
10.1.1 Access to drugs ................................................................................................. 58 
10.1.2 Dosage form, packaging, and storage of study drugs ....................................... 58 
10.1.3 Storage and stability of drugs ............................................................................ 59 
10.1.4 Preparation of study drugs ................................................................................ 60 
10.1.5 Administration of study drugs ........................................................................... 60 
10.1.6 Dose modifications and delay ........................................................................... 61 
10.2 Drug Management, Dispensation and Return .............................................................. 66 
10.2.1 Disposal of study drugs ..................................................................................... 66 
10.3 Concomitant Medications ............................................................................................. 67 
10.3.1 Other anti-tumor/cancer or study drugs ............................................................ 67 
10.3.2 Medications to be used with caution in subjects receiving apatinib ................. 68 
10.3.3 Hematopoietic growth factor ............................................................................. 69 


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10.3.4 Dexrazoxane ...................................................................................................... 69 
10.3.5 Mesna ................................................................................................................ 69 
10.3.6 Treatment for vomiting ..................................................................................... 69 
10.3.7 Anti-inflammatory treatment ............................................................................ 69 
10.3.8 Corticosteroids .................................................................................................. 69 
10.3.9 Surgery .............................................................................................................. 70 
10.4 Subject Compliance ...................................................................................................... 70 
11 STUDY PROCEDURES .................................................................................................... 70 
11.1 Screening ...................................................................................................................... 70 
11.2 Treatment Period .......................................................................................................... 72 
11.2.1 Treatment period for the investigational treatment group ................................. 72 
11.2.2 Treatment period for the control group ............................................................. 74 
11.3 Follow-Up Period ......................................................................................................... 75 
11.3.1 Safety follow-up for the investigational treatment group ................................. 75 
11.3.2 Safety follow-up for the control group.............................................................. 77 
11.3.3 Survival follow-up ............................................................................................ 78 
11.4 Criteria for Crossover Treatment of Control Group ..................................................... 78 
11.4.1 Screening Period ............................................................................................... 78 
11.4.2 Treatment period ............................................................................................... 79 
11.4.3 Follow-up period ............................................................................................... 79 
11.5 Unscheduled Visit ........................................................................................................ 80 
12 EVALUATIONS ................................................................................................................. 80 
12.1 Efficacy Evaluation ...................................................................................................... 80 
12.2 Safety Evaluation .......................................................................................................... 81 
12.2.1 Pregnancy test ................................................................................................... 81 
12.2.2 Adverse event .................................................................................................... 81 
12.2.3 Laboratory safety assessment ............................................................................ 81 
12.2.4 Vital signs and physical examination ................................................................ 82 
12.2.5 12-Lead electrocardiography (ECG) ................................................................. 82 
12.2.6 Echocardiography ............................................................................................. 82 
 
 


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12.3 Collection and Processing of Immunogenicity and Drug Trough Concentration  
Blood Samples ............................................................................................................. 82 
12.4 Independent Data Monitoring Committee .................................................................... 83 
13 ADVERSE EVENTS REPORTING ................................................................................. 83 
13.1 Adverse Events (AEs) .................................................................................................. 83 
13.1.1 Definition of adverse event ............................................................................... 83 
13.1.2 AE severity grading criteria .............................................................................. 83 
13.1.3 Determination of the relationship between AEs and the study drug ................. 84 
13.2 Serious Adverse Event (SAE) ...................................................................................... 84 
13.2.1 Definition of SAE ............................................................................................. 84 
13.2.2 Hospitalization .................................................................................................. 85 
13.2.3 Progressive disease ............................................................................................ 86 
13.2.4 Potential drug-induced liver injury ................................................................... 86 
13.2.5 SAE reporting.................................................................................................... 87 
13.2.6 Time limit for collection and follow-up of AEs/SAEs ..................................... 87 
13.3 Pregnancy ..................................................................................................................... 88 
13.4 Adverse Events of Special Interest ............................................................................... 88 
14 DATA ANALYSIS/STATISTICAL METHODS ............................................................ 88 
14.1 Sample Size .................................................................................................................. 88 
14.2 Statistical Analysis Plan ............................................................................................... 89 
14.3 Analysis Population ...................................................................................................... 89 
14.4 Statistical Methods ....................................................................................................... 90 
14.4.1 Basic methods ................................................................................................... 90 
14.4.2 Primary efficacy endpoint analysis ................................................................... 90 
14.4.3 Secondary efficacy endpoint analysis ............................................................... 91 
14.4.4 Handling of missing data .................................................................................. 91 
14.4.5 Safety analysis ................................................................................................... 91 
14.4.6 Interim analysis ................................................................................................. 92 
14.4.7 Subgroup analysis ............................................................................................. 92 
14.4.8 Multiple comparison/multiplicity ...................................................................... 93 
14.4.9 Exploratory analysis .......................................................................................... 93 


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15 DATA MANAGEMENT .................................................................................................... 94 
15.1 Data Recording ............................................................................................................. 94 
15.1.1 Source documents and records .......................................................................... 94 
15.1.2 eCRF entry ........................................................................................................ 94 
15.1.3 eCRF review...................................................................................................... 94 
15.2 Data Monitoring ........................................................................................................... 94 
15.3 Data Management ......................................................................................................... 95 
15.3.1 EDC database establishment ............................................................................. 95 
15.3.2 Data entry and verification ................................................................................ 95 
15.3.3 Database lock .................................................................................................... 95 
15.3.4 Data archiving ................................................................................................... 95 
16 SOURCE DATA AND DOCUMENTS ............................................................................. 95 
17 QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 96 
18 REGULATORY ETHICS, INFORMED CONSENT, AND SUBJECT  
PROTECTION .................................................................................................................... 97 
18.1 Regulatory Considerations ........................................................................................... 97 
18.2 Ethical Standards .......................................................................................................... 97 
18.3 Independent Ethics Committee ..................................................................................... 98 
18.4 Informed Consent ......................................................................................................... 98 
18.4.1 ICF and other written information for subjects ................................................. 98 
18.4.2 Informed consent process and records .............................................................. 98 
18.5 Confidentiality of Subject Information ........................................................................ 98 
18.5.1 Use of samples, specimens, or data ................................................................... 99 
19 PUBLICATION OF STUDY RESULTS .......................................................................... 99 
20 CLINICAL STUDY PROGRESS ................................................................................... 100 
21 REFERENCES .................................................................................................................. 100 
Appendix 1. The WHO Soft Tissue Tumor Classification (2013 Edition) ........................... 101 
Appendix 2. Common Soft Tissue Sarcomas with Poor Chemotherapy Sensitivity .......... 106 
Appendix 3. Dose Conversion of Anthracyclines[7-8] .............................................................. 107 
Appendix 4. ECOG PS ............................................................................................................. 108 
Appendix 5. Cockroft-Gault Formula (for Calculating Creatinine Clearance) ................. 109 


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Appendix 6. Response Evaluation Criteria in Solid Tumors ................................................ 110 
Appendix 7. Management Principles for Immune Related Adverse Events ....................... 124 
Appendix 8. Percent Bone Marrow Content in Human Skeleton ........................................ 129 
Appendix 9. Prohibited Traditional Chinese Medicines During the Study Period ............ 130 
Appendix 10. EORTC QLQ-C30 Scale ................................................................................... 131 
Appendix 11. iRECIST Response Evaluation Criteria in Solid Tumors ............................. 133 
 
LIST OF TABLES 
Table 1. Binding affinity of SHR-1210 to human, monkey, and rat PD-1 antigens ................... 37 
Table 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 ......................................................... 37 
Table 3. Anti-tumor and immunomodulatory effects of SHR-1210 and apatinib in a  
mouse model of intestinal carcinoma ........................................................................... 41 
Table 4. Criteria for SHR-1210 dose modifications ................................................................... 61 
Table 5. Treatment recommendations for infusion reactions related to SHR-1210 ................... 64 
Table 6. Recommended dose modification of apatinib............................................................... 65 
Table 7. Recommended dose modification of doxorubicin/ifosfamide ...................................... 65 
Table 8. Dose modification of doxorubicin/ifosfamide .............................................................. 66 
Table 9. Laboratory tests ............................................................................................................. 82 
Table 10. CTC-AE severity grading criteria ................................................................................. 84 
Table 11. Principles of AE/SAE collection and follow-up ........................................................... 87 
Table 12. Termination criteria and α spending in the interim analysis and final  
analysis of PFS .............................................................................................................. 92 
 
LIST OF FIGURES 
Figure 1. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab ........................ 38 
Figure 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab ................................ 38 
 
 


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PROTOCOL SYNOPSIS 
Study Title 
A multicenter, randomized, open-label phase II clinical study of anti-PD-1 antibody SHR-1210 
combined with apatinib mesylate vs. doxorubicin combined with ifosfamide in treatment of 
soft tissue sarcoma 
Protocol No. 
SHR-1210-II-212 
Version No. 
3.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
Principal 
Investigators 
Professor Yang Yao 
Participating Study 
Centers 
Approximately 30 sites 
Study Objectives 
Primary objective 
 
To evaluate whether SHR-1210 combined with apatinib is better than doxorubicin 
combined with ifosfamide in the treatment of soft tissue sarcoma based on the progression 
free survival (PFS). 
Secondary objectives 
 
To evaluate and compare the overall survival (OS), objective response rate (ORR), 
duration of response (DoR), and disease control rate (DCR) in subjects with soft tissue 
sarcoma after treatment with SHR-1210 combined with apatinib vs. doxorubicin 
combined with ifosfamide; 
 
To evaluate and compare the safety of SHR-1210 combined with apatinib vs. doxorubicin 
combined with ifosfamide in the treatment of soft tissue sarcoma; 
 
To evaluate and compare the quality of life scores in subjects with soft tissue sarcoma after 
treatment with SHR-1210 combined with apatinib vs. doxorubicin combined with 
ifosfamide. 
Exploratory objectives: 
 
To explore the correlation between the immunogenicity and the efficacy/safety of 
SHR-1210; 
 
To explore the correlation between the concentrations of SHR-1210 and apatinib and the 
efficacy/safety; 
 
To evaluate the investigator-assessed PFS, ORR, DoR and DCR (as per iRECIST) in the 
SHR-1210 plus apatinib group; 
 
To evaluate the PFS (as per RECIST v1.1 and iRECIST) of subjects in the doxorubicin 
plus ifosfamide group after crossover treatment; 
 
To evaluate the ORR, DoR, and DCR (as per RECIST v1.1 and iRECIST), OS, safety, and 
quality of life scores of subjects in the doxorubicin plus ifosfamide group after crossover 
treatment. 


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Study Endpoints 
Primary endpoints 
 
PFS assessed by the independent review committee (as per RECIST v1.1) 
Secondary endpoints 
 
PFS assessed by the investigator (as per RECIST v1.1) 
 
OS 
 
ORR assessed by the investigator and independent review committee (as per RECIST 
v1.1) 
 
DoR assessed by the investigator and independent review committee (as per RECIST 
v1.1) 
 
DCR assessed by the investigator and independent review committee (as per RECIST 
v1.1) 
 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), 
abnormalities in vital signs, ECG, and laboratory tests 
 
Quality of life score (EORTC QLQ-C30) 
Exploratory endpoints: 
 
Anti-drug antibody and neutralizing antibody levels of SHR-1210 
 
Serum concentration of SHR-1210 and plasma concentration of apatinib 
 
Investigator-assessed PFS, ORR, DoR, and DCR (as per iRECIST) of the investigational 
treatment group 
 
PFS of subjects in the doxorubicin plus ifosfamide group after crossover treatment (as per 
RECIST v1.1 and iRECIST); 
 
ORR, DoR, and DCR (as per RECIST v1.1 and iRECIST), OS, safety, and quality of life 
scores of subjects in the doxorubicin plus ifosfamide group after crossover treatment 
Study Population 
Subjects with soft tissue sarcoma who have not received any prior systemic therapy or have 
sensitive relapse after chemotherapy (sensitive relapse refers to recurrence more than 6 months 
after the last chemotherapy). 
Study Design 
This study is a multicenter, randomized, open-label phase II clinical study, with a total of 292 
subjects planned to be enrolled. 
Qualified subjects with soft tissue sarcoma will be randomized in a 1:1 ratio into the SHR-1210 
plus apatinib group (investigational treatment group) and the doxorubicin plus 
ifosfamide/ifosfamide monotherapy group (control group). Stratification factors include: 1) 
ECOG PS, > 0 or not; 2) Whether the pathological type of the tumor has poor sensitivity to 
chemotherapy (see Appendix 2. Common Soft Tissue Sarcomas with Poor Chemotherapy 
Sensitivity); 3) Whether subjects have previously undergone chemotherapy. The administration 
regimens for investigational treatment group and control group are as follows: 
 
Investigational treatment group: SHR-1210 200 mg q3w (up to 2 years of treatment) 
+ apatinib 500 mg qd. 
 
 


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 
Control group: doxorubicin 60 mg/m2 on D1 + ifosfamide 2 g/m2/d on D1-D4, in 
3-week cycles (i.e., the total dose per cycle shall be 8 g/m2); 6 cycles are 
recommended. If the investigator judges that the subject benefits from doxorubicin 
+ ifosfamide chemotherapy, additional chemotherapy cycles may be administered. 
When the subject's anthracyclines have reached the recommended maximum 
cumulative dose of doxorubicin (see Appendix 3. Dose Conversion of 
Anthracyclines), the chemotherapy regimen should be adjusted to ifosfamide 
monotherapy, 2 g/m2/d on D1-D5, in 3-week cycles (i.e., the total dose per cycle 
shall be 10 g/m2). Similarly, when the investigator judges that the subject can benefit 
from ifosfamide monotherapy, the number of chemotherapy cycle can be increased. 
In this study, the screening period should be no more than 28 days. After completing screening 
examinations and assessments, eligible subjects will enter the treatment period and receive the 
study treatment and study visits according to the protocol. Among them, tumor imaging 
assessment will be performed once in every 2 cycles during the first 16 cycles and once every  
4 cycles thereafter. The independent review adjudication committee (IRaC) will review the 
imaging evaluation results of each study center. The safety follow-up period of subjects in the 
investigational treatment group starts after the last dose, and the subjects will be followed up 
once every 30 days until 90 days after the last dose. Among them, the first safety follow-up will 
be carried out at the study center; the second and the third follow-up visits will be made via 
phone calls. For subjects in the control group, if they do not receive SHR-1210 + apatinib 
treatment, their safety follow-up period will be 21 days after the last dose; otherwise, the same 
arrangement as that in the investigational treatment group will be used. The survival follow-up 
period will start after the end of the safety follow-up period. The survival follow-up period will 
end upon the subject's death, lost to follow-up, withdrawal of informed consent, or study 
termination by the sponsor. During this period, a follow-up shall be conducted every 2 months 
via phone calls or other effective methods to collect information on subject survival and 
subsequent anti-tumor treatment. 
Study Drugs and 
Method of 
Administration 
Investigational treatment group: SHR-1210 + Apatinib 
 
SHR-1210 for injection, 200 mg, will be administered via intravenous drip infusion 
(total time of drip infusion including tube flushing shall be no less than 20 min and 
no more than 60 min) once every 3 weeks; the longest duration of treatment shall 
not exceed 2 years. 
 
Apatinib mesylate tablets, 500 mg, will be administered orally once daily. 
Administered with warm water approximately half an hour after meals 
(administration time should be the same in each day whenever possible). 
Control group: doxorubicin + ifosfamide or ifosfamide monotherapy 
 
Doxorubicin 60 mg/m2 on D1, ≤ 2 h of intravenous drip infusion; once every 3 weeks. 
 
Ifosfamide 2 g/m2/d on D1-D4, 4-6 h of intravenous drip infusion, in 3-week cycles 
(i.e., the total dose per cycle is 8 g/m2). 
Or 
 
Ifosfamide monotherapy: 2 g/m2/d on D1-D5, once every 3 weeks (i.e., the total 
dose per cycle is 10 g/m2). 


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Inclusion Criteria 
Patients must meet all of the following criteria to be eligible. 
1. 
Aged 16-70 years, male or female. 
2. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; the 
criterion can be relaxed to 2 points for amputation subjects. 
3. 
Life expectancy of ≥ 3 months. 
4. 
Patients with distant metastasis or locally advanced soft tissue sarcoma that render 
the patient not suitable for surgical treatment as per the investigator's judgment 
(pathologically or cytologically diagnosed, except gastrointestinal stromal tumors, 
osteochondroma, embryonic/acinar rhabdomyosarcoma, Ewing's sarcoma, and 
intermediate soft tissue tumors without extensive metastasis, such as 
dermatofibrosarcoma protuberans and inflammatory myofibroblastic sarcoma, see 
Appendix 1. The WHO Soft Tissue Tumor Classification (2013 Edition) for details). 
5. 
Patients who have not received previous chemotherapy for soft tissue sarcoma, or 
have benefited from chemotherapy but have recurrence or metastasis more than 
6 months after drug discontinuation. 
6. 
With measurable lesion as per RECIST v1.1. 
7. 
All acute toxicities due to previous anti-tumor treatments must have resolved to 
Grade 0-1 (as per NCI CTCAE 4.03) or to the level specified in the 
inclusion/exclusion criteria before C1D1 (except for toxicities such as alopecia that 
are deemed by the investigator as not posing safety risks to the patient). 
8. 
With adequate organs and bone marrow functions, as defined below: 
Hematology (without blood transfusion, G-CSF, or medication correction within 
14 days prior to screening) 
 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
 
Blood platelet count (PLT) ≥ 100,000/mm3 (100 × 109/L); 
 
Hemoglobin (Hb) ≥ 9 g/dL (90 g/L); 
Blood Biochemistry 
 
Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN), or creatinine 
clearance (Cockroft-Gault formula) ≥ 60 mL/min; 
 
Total bilirubin (TBIL) ≤ 1.5 × ULN; 
 
Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 × ULN; for 
patients with liver metastasis, ALT and AST should be ≤ 5 × ULN; 
Coagulation Function 
 
International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and 
activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; 
Urinalysis 
 
Urine protein < 2+; If urine protein is ≥ 2+, then the 24-hour urine protein must 
be ≤ 1 g; 
 
 


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Thyroid Function 
 
Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, FT3 (T3) and FT4 
(T4) levels should be examined, and the subject can be enrolled if FT3 (T3) 
and FT4 (T4) levels are normal. 
9. 
Female subjects of childbearing potential must have a negative serum pregnancy 
test within 7 days prior to C1D1, and be willing to use a recognized effective 
contraceptive measure (such as: intra-uterine contraceptive devices, contraceptive 
pills, or condoms) during the study and within 3 months after the last dose of the 
study drug; male subjects with partners of childbearing potential must either be 
surgically sterilized or agree to take effective contraceptive measures during the 
study and within 3 months after the last dose of the study drug. 
10. Subjects must agree and have signed the informed consent form, be willing and able 
to follow the scheduled visits, study treatment, laboratory tests, and other study 
procedures. 
Exclusion Criteria 
Patients meeting any one of the followings are not eligible to participate in this study: 
1. 
Those who have received the following treatments within 4 weeks prior to C1D1: 
 
Previously received radiotherapy, surgery, chemotherapy, immune or 
molecular targeted therapy for tumors; 
 
Received other investigational drug of clinical studies; 
 
Inoculated with a live attenuated vaccine. 
2. 
Subjects who previously received anti-PD-1/PD-L1/CTLA4 antibodies, or VEGFR 
single target/multiple target inhibitors. 
3. 
Those who plan to receive surgical treatment and/or radiation therapy for soft tissue 
sarcoma during the study period. 
4. 
Presence of tumor lesions in the central nervous system confirmed by imaging 
diagnosis. 
5. 
Having been treated by immunosuppressive drugs within 14 days prior to C1D1, 
excluding intranasal and inhaled corticosteroids or systemic steroids of 
physiological doses (i.e., no more than 10 mg/d of prednisolone or equivalent 
physiological doses of other corticosteroids). 
6. 
Any active autoimmune disease, history of autoimmune disease (the subject with 
vitiligo or asthma that has completely resolved during childhood and currently does 
not require medical intervention can be included), or known history of allogeneic 
organ transplantation or allogeneic hematopoietic stem cell transplantation. 
7. 
Complicated with severe infection (such as one requiring intravenous drip infusion 
of antibiotics, antifungals, or antivirals) within 4 weeks prior to C1D1, or any 
unexplained fever of > 38.5 °C during screening/prior to the first dose. 
8. 
Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
 
 


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9. 
Patients with clinically significant bleeding symptoms or a clear bleeding tendency 
within 3 months prior to C1D1, such as hemorrhage of digestive tract, stomach ulcer 
with hemorrhage, fecal occult blood ++ and above, or vasculitis; or arterial/venous 
thrombus events, such as cerebrovascular accidents (including transient ischemic 
attack, cerebral hemorrhage, and cerebral infarction), deep vein thrombus, 
pulmonary embolism, etc. within 6 months before C1D1; or requiring long-term 
anticoagulation therapy with warfarin or heparin, or requiring long-term antiplatelet 
therapy (aspirin of ≥ 300 mg/d or clopidogrel of ≥ 75 mg/d). 
10. Active heart diseases within 6 months before C1D1, including myocardial 
infarction, severe/unstable angina, etc. Left ventricular ejection fraction < 50% as 
revealed by echocardiography and poorly controlled arrhythmia (including QTcF 
interval > 450 ms in males and > 470 ms in females). 
11. Having been diagnosed with any other malignancies within 3 years before C1D1, 
excluding adequately treated basal cell carcinoma and squamous cell skin cancer, 
and cervical carcinoma in situ. 
12. Known allergies to the study drug or their excipients; severe allergic reactions to 
other monoclonal antibodies. 
13. With human immunodeficiency virus (HIV) infection, or active hepatitis B (positive 
hepatitis B surface antigen and HBV DNA ≥ 500 IU/mL) or hepatitis C (positive for 
hepatitis C antibody, and HCV-RNA higher than the lower limit of detection of the 
analytical method). 
14. Presence of accompanying diseases (such as poorly controlled hypertension, severe 
diabetes, neurological or mental illness, etc.) or any other situation that may pose 
serious risks to the safety of the subjects, confuse the research results, or affect the 
ability of the subjects to complete the study as judged by the investigator. 
Pharmacokinetic/ 
Immunogenicity 
Studies 
Subjects receiving the combination therapy of SHR-1210 and apatinib shall undergo blood 
sampling for the pharmacokinetics and immunogenicity study of SHR-1210, as well as the 
pharmacokinetics study of apatinib. 
Blood sampling time points for pharmacokinetics and immunogenicity study of SHR-1210: 
within 0.5 h pre-administration on C1D1, C2D1, C4D1, C6D1, C9D1 and once every 4 cycles 
thereafter, with 4-6 mL of peripheral venous blood collected at each time point; 4-6 mL of 
peripheral venous blood shall be collected once at 30 days after the last dose. 
Blood sampling time points for pharmacokinetics study of apatinib: within 0.5 h 
pre-administration and 4 h (± 10 min) post-administration on C1D1, C2D1, C4D1, and C6D1, 
with 2-4 mL of peripheral venous blood collected at each time point. The time interval between 
the administration of apatinib on the day of blood sampling and the previous administration 
should be no less than 20 h. 
Study Withdrawal 
Criteria 
Reasons for withdrawal may include: 
1. 
Withdrawal of informed consent and refusal of further follow-ups by subjects; 
2. 
Other investigator-assessed reasons requiring withdrawal, such as the inability to 
provide voluntary consent due to imprisonment or quarantine; 
3. 
Lost to follow-up; 
4. 
Death; 
5. 
Study termination by the sponsor. 


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Criteria for 
Treatment 
Discontinuation 
Criteria for treatment discontinuation are as follows: 
1. 
Treatment discontinuation requested by subjects;  
2. 
Radiographic or clinical features indicate progression, except for the following two 
situations: 1) The subject in the investigational treatment group meet the criteria for 
treatment beyond progression (see 8.3.3 for details); 2) The subject in the control 
group who had radiographic progression and meet the inclusion/exclusion criteria 
may be cross over to receive the SHR-1210 + apatinib treatment (see 8.3.4 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. 
General deterioration of health status and inability to continue study participation; 
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 investigator. 
Determination of 
Sample Size 
In this study, IRC-assessed PFS (as per RECIST v1.1) will be used as the primary endpoint for 
superiority test with the control group. An interim analysis will be performed to determine the 
efficacy of the drugs and to determine whether to terminate or continue the study. The 
parameters for sample size calculation are as follows: 
Enrollment rate = 13 subjects/month (156 subjects/year), enrollment time = 20 months (the 
overall time will be 26 months) 
Randomization in a 1:1 ratio; one-sided α = 0.025; the power of the test is 90%; 
Hazard ratio (investigational treatment group/control group [HR]) = 0.64 (estimated median 
PFS is 4.5 months in the control group and 7.0 months in the investigational treatment group) 
An interim analysis will be performed when 67% of PFS events are collected to determine the 
safety and efficacy of the drug by IDMC. 
Based on the above parameters, at least 214 PFS events shall be collected according to the 
log-rank test for PFS comparison in the two groups and the O'Brien & Fleming spending 
function (EAST 6.4.1) in the α spending function method proposed by Lan-DeMets, i.e., 
approximately 262 subjects are needed. Considering a 10% dropout rate, 292 subjects are 
finally required for enrollment. 
Data Analysis/ 
Statistical Methods 
This study plans to conduct an interim analysis for efficacy and a final analysis. The interim 
analysis will be carried out when 67% of PFS events (approximately 143 subjects) are collected 
to determine whether the drug is effective and whether to terminate or continue the study. The 
final analysis will be performed when the number of PFS events reaches 214. 
◼ 
General analysis 
For this study, efficacy data will be summarized in accordance with the following general 
principles using descriptive statistics, unless otherwise stated. 


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Two-category and multi-category data will be summarized using frequency and percentage. 
Measurement data will be summarized using mean, standard deviation, median, maximum, and 
minimum. 
Time-event data will be analyzed using the Kaplan-Meier method, so as to estimate the survival 
function of both groups and plot the survival curves. 
All statistical analyses will be performed using SAS version 9.4 or later. 
◼ 
Efficacy analysis 
In addition to the general principles of efficacy analysis described above, the analysis of 
primary and secondary efficacy indicators also includes: 
ORR and DCR: The Clopper-Pearson method will be used to calculate the 95% confidence 
interval of the ORR. 
PFS and OS: The Kaplan-Meier method will be used to plot the survival curve, and the 
Brookmeyer Crowley method will be used to calculate the 95% confidence interval of the 
median survival. In addition, the Cox regression model will be used to estimate the hazard ratio 
between the two groups and its 95% confidence interval (95% CI). 
The general analysis principle also applies to DoR analysis, but whenever necessary, the 95% 
confidence interval of the median survival will be calculated to estimate and plot the survival 
curve. 
◼ 
Safety analysis 
The AEs, SAEs, and adverse drug reactions will be analyzed mainly using descriptive statistics. 
Laboratory tests that are normal before the study but become abnormal after starting treatment 
will be described. 
Interim Analysis 
In this study, one interim analysis will be carried out for the primary efficacy endpoint PFS. In 
order to control the overall type I error, the O'Brien-Fleming spending function in the α 
spending function method will be used to evaluate the efficacy of the drugs and to determine 
whether the study shall end early when 67% of PFS events (143 subjects) are collected. When 
the z-score of PFS based on the log-rank test result exceeding the unbound effective boundary 
is -2.506 (P-value [one-sided] < 0.006), the study will end early because it is effective. If the 
efficacy is not established, the study will continue. If, in the interim analysis, the actual number 
of observed events does not reach or exceed 143, the boundary should be timely monitored and 
adjusted using EAST (e.g., using IM tool for monitoring). The final analysis will be performed 
when 214 PFS events are collected. The results of interim analysis will be reviewed by the 
IDMC, which will recommend whether to continue the study. 
Study Period 
Anticipated enrollment of the first subject: Sep. 2018 
Anticipated enrollment of the last subject: Dec. 2020 
Anticipated study completion: Sep. 2022 
 


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1 FLOW DIAGRAM OF EXPERIMENT — INVESTIGATIONAL 
TREATMENT GROUP (SHR-1210 COMBINED WITH APATINIB) 
STUDY 
PROCEDURES 
Screening 
Period 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Safety Follow-Up[24] 
Survival 
Follow- 
Up[25] 
D-28 
to D-1 
D-7 to 
D-1 
D1 
D1 
D1 
(once per cycle) 
30 days 
after the 
last dose 
60 and 90 
days after 
the last 
dose 
Once every  
2 months 
Time Window 
 
 
 
± 3  
± 3  
± 5  
± 5  
± 5  
Signing of Informed 
Consent Form[1] 
× 
 
 
 
 
 
 
 
Demographics, 
Medical History, 
and Treatment 
History[2] 
× 
 
 
 
  
 
 
 
Inclusion/ 
Exclusion  
Criteria and 
Randomization 
 
× 
(Eligibility for 
randomization) 
 
 
 
 
 
ECOG PS[3] 
 
× 
 
× 
× 
× 
 
 
Vital Signs[4] 
 
× 
 
× 
× 
× 
 
 
Physical 
Examination[5] 
 
× 
 
× 
× 
× 
 
 
Virology [6] 
× 
 
 
 
 
 
 
 
Hematology[7] 
 
× 
 
× 
× 
× 
 
 
Urinalysis[8] 
 
× 
 
 
× (once every  
2 cycles) 
× 
 
 
Fecal Occult 
Blood[9] 
 
× 
 
× 
× 
× 
 
 
Blood 
Biochemistry[10] 
 
× 
 
× 
× 
× 
 
 
Coagulation 
Function[11] 
 
× 
 
 
× (once every  
2 cycles) 
× 
 
 
Thyroid 
Function[12] 
 
× 
 
 
× (once every  
2 cycles) 
× 
 
 
Myocardial 
Zymogram[13] 
 
× 
 
 
 
 
 
 
12-Lead ECG[14] 
 
× 
 
× 
× 
× 
 
 
Echocardiography[15] 
× 
 
 
 
 
 
 
 
Pregnancy Test [16] 
 
× 
 
 
× (once every  
2 cycles) 
 
 
 
Tumor Imaging 
× 
 
 
 
× (once every  
× 
 
 


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STUDY 
PROCEDURES 
Screening 
Period 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Safety Follow-Up[24] 
Survival 
Follow- 
Up[25] 
D-28 
to D-1 
D-7 to 
D-1 
D1 
D1 
D1 
(once per cycle) 
30 days 
after the 
last dose 
60 and 90 
days after 
the last 
dose 
Once every  
2 months 
Examination[17] 
2 cycles or once 
every 4 cycles) 
Dispensation/Retrie
val of Drugs and 
Study Treatment[18] 
 
 
× 
× (D -3 to 
D+7) 
× (D -3 to D+7) 
 
 
 
Adverse Events[19] 
× 
× 
× 
× 
× 
× 
× 
 
Concomitant 
Medications/ 
Treatments[20] 
× 
× 
× 
× 
× 
× 
× 
 
PK and 
Immunogenicity 
Blood Sampling[21] 
 
 
× 
×[21] 
×[21] 
× 
 
 
Quality of Life 
Questionnaires [22] 
 
× 
 
 
× (once every  
2 cycles or once 
every 4 cycles) 
× 
 
 
Subject Diary Card 
Dispensing, 
Retrieval, and 
Filling[23] 
 
 
×[23] 
×[23] 
×[23] 
 
 
 
Subsequent 
Anti-Tumor 
Treatment and 
Survival Status 
 
 
 
 
 
× 
× 
× 
Note: In addition to the examinations and time points listed in the table, the investigator may add visits and other 
examinations if needed. 
[1] Subjects who have failed screening may be screened again in this study, but the informed consent form must be 
re-signed and a new subject number should be given for re-screening. If the re-screening fails, no further 
screening will be performed. Data from virology, echocardiography, and imaging assessment (tested at this study 
center only) performed prior to the signing of informed consent for clinical needs may be used if they are within 
the specified window period. 
[2] Demographics, medical history, and treatment history: including date of birth, gender, ethnicity, tumor history 
(tumor diagnosis, surgery, radiotherapy, chemotherapy history, etc.), other concurrent diseases and 
corresponding treatments. Among them, the tumor history should include: the time of initial diagnosis, 
pathological diagnosis, clinical staging, etc. 
[3] ECOG PS scoring: Performed within 7 days before the first dose, on day 1 of each cycle from cycle 2 onwards, 
and at 30 days after the last dose. 


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[4] Vital signs: pulse, respiratory rate, temperature, and blood pressure. Performed within 7 days before the first 
dose, on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. 
[5] Physical examination: Performed within 7 days before the first dose, on day 1 of each cycle from cycle 2 onwards, and 
at 30 days after the last dose; comprehensive examinations (height, weight, general condition, head and face, 
neck, chest, abdomen, perineum, extremities, etc.) will be performed; height will be measured only once 
within 7 days before the first dose and weight will be measured at each visit point (except for C1D1); a targeted 
physical examination will be performed when clinically indicated. 
[6] Virology: HBsAg (quantitative HBV DNA test if positive); HCV-Ab (quantitative HCV-RNA test if positive) 
and HIV-Ab: within 28 days before the first dose. 
[7] Hematology: red blood cell count (RBC), hemoglobin (Hb), blood platelet count (PLT), white blood cell count 
(WBC), absolute neutrophil count (ANC), and lymphocyte count (LYM); tested within 7 days before the first 
dose, on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. 
[8] Urinalysis: WBC, RBC, and urine protein; tested within 7 days before the first dose, on day 1 of every 2 cycles 
from cycle 3 onwards, and at 30 days after the last dose. If urine protein is ≥ 2+, then a quantitative 24-h urine 
protein test should be added. 
[9] Fecal occult blood: performed within 7 days before the first dose, on day 1 of each cycle from cycle 2 onwards, 
and at 30 days after the last dose. 
[10] Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (AKP), blood urea 
nitrogen (BUN) or urea, total protein (TP), albumin (ALB), creatinine (Cr), blood glucose (GLU), serum 
potassium (K+), serum natrium (Na+), serum calcium (Ca2+), serum magnesium (Mg2+), and blood chloride (Cl-); 
tested within 7 days before the first dose, on day 1 of each cycle from cycle 2 onwards, and at 30 days after the 
last dose. 
[11] Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time 
(TT), fibrinogen (FIB), and international normalized ratio (INR); tested within 7 days before the first dose, on 
day 1 of every 2 cycles from cycle 3 onwards, and at 30 days after the last dose. 
[12] Thyroid function: serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine 
(FT4); if FT3 and FT4 are not available, T3 and T4 are allowed for substitution; tested within 7 days before the 
first dose, on day 1 of each cycle from cycle 2, and at 30 days after the last dose. 
[13] Myocardial zymogram: lactate dehydrogenase (LDH), creatine kinase (CK), and hybrid creatine kinase 
(CK-MB); tested within 7 days before the first dose. 
[14] 12-Lead ECG: Attentions should be paid to QT, QTcF, and P-R intervals. Performed within 7 days before the first 
dose, on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. QTcF can be calculated as: 
QTcF = QT/(60/heart rate)0.33. 
[15] Echocardiography: within 28 days before the first dose. 
[16] Pregnancy test: Serum pregnancy test will be performed for women of childbearing potential. Performed 
within 7 days before the first dose and on day 1 of every 2 cycles from cycle 3 onwards. 


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[17] Tumor imaging evaluation: CT or MRI of lesions in the head, chest, abdomen, pelvis, and other sites. Sites with 
bone metastasis as shown by bone scans, PET-CT, or clinical indications must also be reexamined by CT or MRI 
at baseline but no longer undergo bone scan or PET-CT for efficacy follow-up. CT or MRI follow-ups of lesions 
in the head, chest, abdomen, pelvis, and other sites will be performed at each response evaluation. The CT/MRI 
examination methods and techniques for a subject shall remain the same throughout the study period. 
✓ 
At screening, tumor evaluations (at this study center only) up to 4 weeks before the first dose and before 
signing the informed consent may be used as long as they meet the requirements. 
✓ 
Study treatment period: The imaging examination cycles will start from C1D1. In the first 16 treatment 
cycles, imaging examinations will be performed once every 2 cycles (the first assessment will be on 
C3D1), and once every 4 cycles thereafter. If radiographic progression is noted and pseudoprogression has 
been ruled out, imaging examinations will no longer be performed; subjects who discontinue the study 
treatment for reasons other than radiographic progression will still be followed up according to the 
established cycle. If the previous imaging examination does not show progression and no imaging 
examination is performed within 4 weeks before the 30-day visit after the last dose, an imaging 
examination must be performed at the 30-day visit after the last dose. The time window for tumor 
evaluation is ± 7 days. Additional tumor evaluations may be performed if PD is suspected (for example, 
worsening of symptoms). 
[18] Dispensation/retrieval of drugs and study treatment: SHR-1210 200 mg, intravenous drip infusion, once every 
3 weeks starting from C1D1; if SHR-1210 administration of the current cycle cannot be performed due to 
adverse events, it can be delayed for up to 7 days from the scheduled administration point. SHR-1210 will not be 
administered in this cycle if the scheduled administration is delayed for more than 7 days. Apatinib 500 mg, 
continuous oral administration, once daily. Each treatment cycle lasts for 21 days. The first dose of apatinib will 
be dispensed on C1D1 or one day in advance; subsequent apatinib tablets are allowed to be dispensed at the 
scheduled time point within ± 3 days; remaining apatinib must be retrieved before each dispensation. For dose 
interruption due to AEs or other reasons, unscheduled drug dispensation and retrieval are permitted. 
[19] Adverse events: Recorded from the date of signing the informed consent form to the end of the safety follow-up 
period or the start of a new anti-tumor treatment. See Table 11. Principles of AE/SAE collection and follow-up 
for details. 
[20] Concomitant medication/treatment: Recorded from 28 days before the first dose of study treatment to the end of 
the safety follow-up period; If a new anti-tumor treatment is started during this period, only concomitant 
medications for treatment-related adverse events will be recorded thereafter. After the safety follow-up period, 
only concomitant medications/treatments for adverse events are required to be recorded. 
[21] Pharmacokinetics/immunogenicity test: Blood sampling time points for pharmacokinetics and immunogenicity 
study of SHR-1210: within 0.5 h pre-administration on C1D1, C2D1, C4D1, C6D1, C9D1, and every 4 cycles 
thereafter, with 4-6 mL of peripheral venous blood collected at each time point; 4-6 mL of peripheral venous 
blood will be collected once at 30 days after the last dose. Blood sampling time points for pharmacokinetics study 
of apatinib: within 0.5 h pre-administration and 4 h (± 10 min) post-administration on C1D1, C2D1, C4D1, and 
C6D1, with 2-4 mL of peripheral venous blood collected at each time point. The time interval between the 
administration of apatinib on the day of blood sampling and the previous administration should be no less than 20 h. 
[22] Quality of life scoring: Performed within 7 days before the first dose, on day 1 of every 2 cycles from cycle 
3 onwards, on day 1 of every 4 cycles from cycle 17 onwards, and at 30 days after the last dose. 


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[23] Diary card dispensing, retrieval, and filling: The subjects will measure blood pressure by themselves or others 
during the treatment period, and shall fill out the diary card every day to record blood pressure and other 
discomforts. 
[24] Safety follow-up: performed on days 30, 60, and 90 after the last dose. The first safety follow-up visit (day 30) 
will be carried out at the study center, where the evaluations specified in the protocol will be completed. The 
second (day 60) and the third (day 90) follow-ups will be performed via phone calls. Information on new 
anti-tumor treatment, survival, concomitant medications/treatments, and adverse events will be collected. 
[25] Survival follow-up: At the end of the safety follow-up period, the subjects will enter the survival follow-up 
period until death, lost to follow-up, withdrawal of informed consent or termination of the clinical study by the 
sponsor. During this period, follow-up will be conducted via phone calls or other effective methods once every 
2 months to collect information on subject survival and subsequent treatments (if the subjects start a new 
anti-tumor treatment, the therapeutic regimen and the start and end time should be recorded). 


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2 FLOW DIAGRAM OF EXPERIMENT — CONTROL GROUP 
(DOXORUBICIN + IFOSFAMIDE OR IFOSFAMIDE 
MONOTHERAPY) 
STUDY 
PROCEDURES 
Screening 
Period 
Cycle 1 
Cycles 2-6 
Cycles 7-16 Cycle 17 and 
beyond 
Safety 
Visit[22] 
Survival 
Follow- 
Up[23] 
D-28 
to D-1 
D-7 to 
D-1 
D1 
D1 
(once every  
1 cycle) 
D1 
(once every 
2 cycles) 
D1 
(once every  
4 cycles) 
21 days 
after the 
last dose 
Once 
every  
2 months 
Time Window 
 
 
 
± 3  
± 7  
± 7  
± 5  
± 5  
Signing of Informed 
Consent Form[1] 
× 
 
 
 
 
 
 
 
Demographics, Medical 
History, and Treatment 
History[2] 
× 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria and 
Randomization 
 
× 
(Eligibility for 
randomization) 
 
 
 
 
 
ECOG PS[3] 
 
× 
 
× 
 
 
× 
 
Vital Signs[4] 
 
× 
 
× 
 
 
× 
 
Physical Examination[5] 
 
× 
 
× 
 
 
× 
 
Virology[6] 
× 
 
 
 
 
 
 
 
Hematology[7] 
 
× 
 
× 
 
 
× 
 
Urinalysis[8] 
 
× 
 
× 
 
 
× 
 
Fecal Occult Blood 
Test[9] 
 
× 
 
× 
 
 
× 
 
Blood Biochemistry[10] 
 
× 
 
× 
 
 
× 
 
Coagulation Function[11] 
 
× 
 
× 
 
 
× 
 
Thyroid Function[12] 
 
× 
 
 
 
 
× 
 
Myocardial 
Zymogram[13] 
 
× 
 
× 
 
 
× 
 
12-Lead ECG[14] 
 
× 
 
× 
 
 
× 
 
Echocardiography[15] 
× 
 
 
× 
 
 
× 
 
Pregnancy Test [16] 
 
× 
 
× (once 
every  
2 cycles 
from cycle  
3 onwards) 
 
 
× 
 


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STUDY 
PROCEDURES 
Screening 
Period 
Cycle 1 
Cycles 2-6 
Cycles 7-16 Cycle 17 and 
beyond 
Safety 
Visit[22] 
Survival 
Follow- 
Up[23] 
D-28 
to D-1 
D-7 to 
D-1 
D1 
D1 
(once every  
1 cycle) 
D1 
(once every 
2 cycles) 
D1 
(once every  
4 cycles) 
21 days 
after the 
last dose 
Once 
every  
2 months 
Tumor Imaging 
Examination[17] 
× 
 
 
× 
(once every 
2 cycles 
from cycle  
3 onwards) 
× 
× 
× 
 
Study Treatment[18] 
 
 
× 
× 
 
 
 
 
Adverse Events[19] 
× 
× 
× 
× 
× 
× 
× 
 
Concomitant 
Medications/ 
Treatments[20] 
× 
× 
× 
× 
× 
× 
× 
 
Quality of Life Score[21] 
 
× 
 
× 
(once every 
2 cycles 
from cycle  
3 onwards) 
× 
× 
× 
 
Subsequent Anti-Tumor 
Treatment and Survival 
Status 
 
 
 
 
 
 
× 
× 
Note: In addition to the examinations and time points listed in the table, the investigator may add visits and other 
examinations if needed. Subjects crossed over for SHR-1210 combined with apatinib will be followed up according to 
the crossover treatment flow chart. 
[1] Subjects who have failed previous screening may be screened again in this study. The informed consent form 
must be re-signed and a new subject number should be given for re-screening. If the re-screening fails, no further 
screening will be performed. Data from virology, echocardiography, and imaging assessment (tested at this study 
center only) performed prior to the signing of informed consent for clinical needs may be used if they are within 
the specified window period. 
[2] Demographics, medical history, and treatment history: including date of birth, gender, ethnicity, tumor history 
(tumor diagnosis, surgery, radiotherapy, chemotherapy history, etc.), other concurrent diseases and 
corresponding treatments. Among them, the tumor history should include: the time of initial diagnosis, 
pathological diagnosis, clinical staging, etc. 
[3] ECOG PS scoring: Performed within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 
21 days after the last dose. 
[4] Vital signs: pulse, respiratory rate, temperature, and blood pressure. Performed within 7 days before the first 
dose, on day 1 of each cycle in cycles 2-6, and at 21 days after the last dose. 
[5] Physical examination: Performed within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 
21 days after the last dose; comprehensive examinations (height, weight, general condition, head and face, neck, 
chest, abdomen, perineum, extremities, etc.) will be performed; height will be measured only once within 7 days 
before the first dose and weight will be measured at each visit point; a targeted physical examination will be 
performed when clinically indicated. 


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[6] Virology: HBsAg (quantitative HBV DNA test if positive); HCV-Ab (quantitative HCV-RNA test if positive) 
and HIV-Ab. 
[7] Hematology: red blood cell count (RBC), hemoglobin (Hb), blood platelet count (PLT), white blood cell count 
(WBC), absolute neutrophil count (ANC), and lymphocyte count (LYM); tested within 7 days before the first 
dose, on day 1 of each cycle in cycles 2-6, and at 21 days after the last dose. 
[8] Urinalysis: WBC, RBC, and urine protein. If urine protein is ≥ 2+, then a quantitative 24 h urine protein test 
should be added; performed within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 
21 days after the last dose. 
[9] Fecal occult blood: performed within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 
21 days after the last dose. 
[10] Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (AKP), blood urea 
nitrogen (BUN) or urea, total protein (TP), albumin (ALB), creatinine (Cr), blood glucose (GLU), serum 
potassium (K+), serum natrium (Na+), serum calcium (Ca2+), serum magnesium (Mg2+), and blood chloride (Cl-); 
tested within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 21 days after the last dose. 
[11] Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time 
(TT), fibrinogen (FIB), and international normalized ratio (INR); tested within 7 days before the first dose, on 
day 1 of each cycle in cycles 2-6, and at 21 days after the last dose. 
[12] Thyroid function: serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine 
(FT4); if FT3 and FT4 are not available, T3 and T4 are allowed for substitution; tested within 7 days before the 
first dose, and at 21 days after the last dose. 
[13] Myocardial zymogram: lactate dehydrogenase (LDH), creatine kinase (CK), and hybrid creatine kinase 
(CK-MB); tested within 7 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 21 days after the 
last dose. 
[14] 12-Lead ECG: Attentions should be paid to QT, QTcF, and P-R intervals. Performed within 7 days before the first 
dose, on day 1 of each cycle in cycles 2-6, and at 21 days after the last dose. Investigators may decide whether to 
perform additional ECGs and/or myocardial zymographic tests if the subject complains of symptoms such as 
chest pain or palpitations. QTcF can be calculated as: QTcF = QT/(60/heart rate)0.33. 
[15] Echocardiography: performed within 28 days before the first dose, on day 1 of each cycle in cycles 2-6, and at 
21 days after the last dose. Additional echocardiography may be performed if the subject complains of symptoms 
such as chest pain or palpitations. 
[16] Pregnancy test: Serum pregnancy test will be performed for women of childbearing potential. Performed 
within 7 days before the first dose, on day 1 of every 2 cycles in cycles 3-6, and at 21 days after the last dose. 
[17] Tumor imaging evaluation: CT or MRI of lesions in the head, chest, abdomen, pelvis, and other sites. Sites with 
bone metastasis as shown by bone scans, PET-CT, or clinical indications must also be reexamined by CT or MRI 
at baseline but no longer undergo bone scan or PET-CT for efficacy follow-up. CT or MRI follow-ups of lesions 
in the head, chest, abdomen, pelvis, and other sites will be performed at each response evaluation. The CT/MRI 
examination methods and techniques for a subject shall remain the same throughout the study period. 
✓ 
At screening, tumor evaluations (at this study center only) up to 4 weeks before the first dose and before 
signing the informed consent may be used as long as they meet the requirements. 


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✓ 
Study treatment period: The imaging examination cycles will start from C1D1. In the first 16 treatment 
cycles, imaging examinations will be performed once every 2 cycles (the first assessment will be on 
C3D1), and once every 4 cycles thereafter. Imaging examinations will no longer be performed in case of 
radiographic progression; subjects who discontinue the study treatment for reasons other than radiographic 
progression will still be followed up according to the established cycle. If the previous imaging 
examination does not show progression and no imaging examination is performed within 4 weeks before 
the 21-day visit after the last dose, an imaging examination must be performed at the 21-day visit after the 
last dose. The time window for tumor evaluation is ± 7 days. Additional tumor evaluations may be 
performed if PD is suspected (for example, worsening of symptoms). 
[18] Study treatment: (doxorubicin + ifosfamide/ifosfamide monotherapy): doxorubicin 60 mg/m2, on D1, ifosfamide 
2 g/m2/d, on D1-D4, q3w, and 6 cycles are recommended; if the investigator considers that the subject benefits 
from the chemotherapy, additional chemotherapy cycles may be administered; the content of visits in subsequent 
treatment cycles will be the same as those in cycles 2-6. If intolerability is noted, the investigator may delay the 
administration of this cycle or the chemotherapy drug, and adjust the administration time of the next cycle to 
21 days after the administration of the previous cycle. If the maximum cumulative dose of doxorubicin is 
reached, the treatment will be switched to ifosfamide monotherapy 2 g/m2/d on D1-D5 q3w. 
[19] Adverse events: Recorded from the date of signing the informed consent form to the end of the safety follow-up 
period or the start of a new anti-tumor treatment. See Table 11. Principles of AE/SAE collection and follow-up 
for details. 
[20] Concomitant medication/treatment: Recorded from 28 days before the first dose of study treatment to the end of 
the safety follow-up period; If a new anti-tumor treatment is started, only concomitant medications for 
treatment-related adverse events will be recorded thereafter. After the safety follow-up period, only concomitant 
medications/treatments for adverse events are required to be recorded. Subjects crossed over for SHR-1210 + 
apatinib treatment will be followed up according to the procedures after crossover. 
[21] Quality of life scoring: Performed within 7 days before the first dose, on day 1 of every 2 cycles in cycles 3-6, on 
day 1 of every 2 cycles in cycles 7-16, on day 1 of every 4 cycles from cycle 17 onwards, and at 21 days after the 
last dose. 
[22] Safety visit: Subjects shall go to the study center for safety visit at 21 days after the last dose in accordance with 
protocol requirements. 
[23] Survival follow-up: At the end of the safety follow-up period, the subjects will enter the survival follow-up 
period until death, lost to follow-up, withdrawal of informed consent or termination of the clinical study by the 
sponsor. During this period, follow-up will be conducted via phone calls or other effective methods once every 
2 months to collect information on subject survival and subsequent treatments (if the subject starts a new 
anti-tumor treatment, the therapeutic regimen and the start and end time should be recorded). 


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3 SCHEDULE OF ACTIVITIES — CROSSOVER TREATMENT 
(SHR-1210 + APATINIB AFTER PROGRESSION FOLLOWING 
DOXORUBICIN + IFOSFAMIDE OR IFOSFAMIDE MONOTHERAPY) 
STUDY 
PROCEDURES 
Screenin
g Period 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Safety Follow-Up[22] 
Survival 
Follow- 
Up[23] 
D-7 to 
D-1 
D1 
D1 
D1 (once per 
cycle) 
30 days 
after the last 
dose 
60 and 90 
days after 
the last 
dose 
Once 
every  
2 months 
Time Window 
 
 
 
± 3  
± 5  
± 5  
± 5  
Signing of Informed 
Consent and Verification 
of Eligibility[1] 
× 
 
 
 
 
 
 
ECOG PS[2] 
× 
 
× 
× 
× 
 
 
Vital Sign[3] 
× 
 
× 
× 
× 
 
 
Physical Examination[4] 
× 
 
× 
× 
× 
 
 
Virology[5] 
× 
 
 
 
 
 
 
Hematology[6] 
× 
 
× 
× 
× 
 
 
Urinalysis[7] 
× 
 
 
× (once every 
2 cycles) 
× 
 
 
Fecal Occult Blood[8] 
× 
 
× 
× 
× 
 
 
Blood Biochemistry[9] 
× 
 
× 
× 
× 
 
 
Coagulation Function[10] 
× 
 
 
× (once every 
2 cycles) 
× 
 
 
Thyroid Function[11] 
× 
 
 
× (once every 
2 cycles) 
× 
 
 
12-Lead ECG[12] 
× 
 
× 
× 
× 
 
 
Echocardiography[13] 
× 
 
 
 
 
 
 
Pregnancy Test[14] 
× 
 
 
× (once every 
2 cycles) 
 
 
 
Tumor Imaging 
Examination[15] 
× (within 
28 days) 
 
 
× (once every 
2 cycles or 
once every  
4 cycles) 
× 
 
 
Dispensation/Retrieval 
of Drugs and Study 
Treatment[16] 
 
× 
× (D -3 to 
D+7) 
× (D -3 to 
D+7) 
 
 
 


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STUDY 
PROCEDURES 
Screenin
g Period 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
Safety Follow-Up[22] 
Survival 
Follow- 
Up[23] 
D-7 to 
D-1 
D1 
D1 
D1 (once per 
cycle) 
30 days 
after the last 
dose 
60 and 90 
days after 
the last 
dose 
Once 
every  
2 months 
Adverse Events[17] 
× 
× 
× 
× 
× 
× 
 
Concomitant 
Medications/ 
Treatments[18] 
× 
× 
× 
× 
× 
× 
 
Pharmacokinetics/Immu
nogenicity Blood 
Sampling[19] 
 
× 
×[19] 
×[19] 
× 
 
 
Quality of Life Score[20] 
× 
 
 
× (once every 
2 cycles or 
once every  
4 cycles) 
× 
 
 
Diary Card Dispensing, 
Retrieval, and Filling[21] 
 
×[21] 
×[21] 
×[21] 
 
 
 
Subsequent Anti-Tumor 
Treatment and Survival 
Status 
 
 
 
 
× 
× 
× 
Note: In addition to the examinations and time points listed in the table, the investigator may add visits and other 
examinations if needed. 
[1] Subjects in the control group who develop radiographically confirmed progressive disease may be crossed over 
to receive SHR-1210 + apatinib. There should be at least a 3-week interval between the first dose of SHR-1210 + 
apatinib and the last dose of the previous standard chemotherapy. The first dose and subsequent visits will be 
carried out according to the schedule of activities of crossover treatment. Subjects should sign an informed 
consent form for the crossover treatment. Examination results within 7 days before the first dose of the subject 
may be used to evaluate whether the inclusion and exclusion criteria of crossover treatment are met (see 8.3.4). If 
the criteria are met, the subject will receive crossover treatment, i.e., SHR-1210 + apatinib. If the inclusion and 
exclusion criteria are not met, the subject may receive supportive treatment for adjustment. But during this 
period, anti-tumor treatment must not be performed. If, at the reexamination 2 months after progressive disease, 
the inclusion and exclusion criteria for crossover treatment are still not met, crossover to receive SHR-1210 + 
apatinib will not be permitted. 
[2] ECOG PS scoring: Performed within 7 days before the first dose (*), on day 1 of each cycle from cycle 2 onwards, 
and at 30 days after the last dose. 
[3] Vital signs: pulse, respiratory rate, temperature, and blood pressure. Performed within 7 days before the first dose 
(*), on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. 


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[4] Physical examination: Performed within 7 days before the first dose (*), on day 1 of each cycle from cycle 2 onwards, 
and at 30 days after the last dose; comprehensive examinations (height, weight, general condition, head and face, 
neck, chest, abdomen, perineum, extremities, etc.) will be performed; height will be measured only once 
within 7 days before the first dose and weight will be measured at each visit point (except C1D1); a targeted 
physical examination will be performed when clinically indicated. 
[5] Virology: HBsAg (quantitative HBV DNA test if positive); HCV-Ab (quantitative HCV-RNA test if positive) 
and HIV-Ab. 
[6] Hematology: red blood cell count (RBC), hemoglobin (Hb), blood platelet count (PLT), white blood cell count 
(WBC), absolute neutrophil count (ANC), and lymphocyte count (LYM); tested within 7 days before the first 
dose (*), on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. 
[7] Urinalysis: WBC, RBC, and urine protein. If urine protein is ≥ 2+, then a quantitative 24-h urine protein test 
should be added; performed within 7 days before the first dose (*), on day 1 of every 2 cycles from cycle 3 onwards, 
and at 30 days after the last dose. 
[8] Fecal occult blood: performed within 7 days before the first dose (*), on day 1 of each cycle from cycle 2 onwards, 
and at 30 days after the last dose. 
[9] Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (AKP), blood urea 
nitrogen (BUN) or urea, total protein (TP), albumin (ALB), creatinine (Cr), blood glucose (GLU), serum 
potassium (K+), serum natrium (Na+), serum calcium (Ca2+), serum magnesium (Mg2+), and blood chloride (Cl-); 
tested within 7 days before the first dose, on day 1 of each cycle from cycle 2 onwards, and at 30 days after the 
last dose. 
[10] Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time 
(TT), fibrinogen (FIB), and international normalized ratio (INR); tested within 7 days before the first dose (*), on 
day 1 of every 2 cycles from cycle 3 onwards, and at 30 days after the last dose. 
[11] Thyroid function: serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine 
(FT4); if FT3 and FT4 are not available, T3 and T4 are allowed for substitution; tested within 7 days before the 
first dose (*), on day 1 of every 2 cycles from cycle 3 onwards, and at 30 days after the last dose. 
[12] 12-Lead ECG: Attentions should be paid to QT, QTcF, and P-R intervals. Performed within 7 days before the first 
dose (*), on day 1 of each cycle from cycle 2 onwards, and at 30 days after the last dose. Investigators may decide 
whether to perform additional ECGs, echocardiography, or myocardial zymographic tests if the subject 
complains of symptoms such as chest pain or palpitations. QTcF can be calculated as: QTcF = QT/(60/heart 
rate)0.33. 
[13] Echocardiography: within 7 days before the first dose (*). 
[14] Pregnancy test: Serum pregnancy test will be performed for women of childbearing potential. Performed 
within 7 days before the first dose (*) and on day 1 of every 2 cycles from cycle 3 onwards. 
[15] Tumor imaging evaluation: CT or MRI of lesions in the chest, abdomen, pelvis, and other sites. Brain MRI or CT 
should be performed for suspected or confirmed brain metastases. MRI or CT confirmation should be performed 
for bone metastases radiographically or clinically indicated. CT or MRI follow-ups of lesions in the head, chest, 
abdomen, pelvis, and other sites will be performed at each response evaluation. The CT/MRI examination 
methods and techniques for a subject shall remain the same throughout the study period. 


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✓ 
Screening period: tumor evaluations within up to 4 weeks before the first dose and before signing the informed 
consent may be used as long as they meet the requirements. 
✓ 
Study treatment period: Treatment period starting from C1D1 of crossover treatment: The imaging 
examination cycles will start from C1D1. In the first 16 treatment cycles, imaging examinations will be 
performed once every 2 cycles (the first assessment will be on C3D1), and once every 4 cycles thereafter. If 
radiographic progression is noted and pseudoprogression has been ruled out, imaging examinations will no 
longer be performed; subjects who discontinue the study treatment for reasons other than radiographic 
progression will still be followed up according to the established cycle. If the previous imaging 
examination does not show progression and no imaging examination is performed within 4 weeks before 
the 30-day visit after the last dose, an imaging examination must be performed at the 30-day visit after the 
last dose. The time window for tumor evaluation is ± 7 days. Additional tumor evaluations may be 
performed if PD is suspected (for example, worsening of symptoms). 
[16] Dispensation/retrieval of drugs and study treatment: SHR-1210 200 mg, intravenous drip infusion, once every 
3 weeks starting from C1D1; if SHR-1210 administration of the current cycle cannot be performed due to 
adverse events, it can be delayed for up to 7 days from the scheduled administration point. SHR-1210 will not be 
administered in this cycle if the scheduled administration is delayed for more than 7 days. Apatinib 500 mg, 
continuous oral administration, once daily. Each treatment cycle lasts for 21 days. The first dose of apatinib is 
dispensed on C1D1 or one day in advance; subsequent apatinib tablets are allowed to be dispensed at the 
scheduled time point ± 3 days; remaining apatinib must be retrieved before each dispensation. For dose 
interruption due to AEs or other reasons, unscheduled drug dispensation and retrieval are permitted. 
[17] Adverse events: Recorded from the date of signing the informed consent form to the end of the safety follow-up 
period or the start of a new anti-tumor treatment. See Table 11. Principles of AE/SAE collection and follow-up 
for details. 
[18] Concomitant medication/treatment: Recorded from 28 days before the first dose of study treatment to the end of 
the safety follow-up period; If a new anti-tumor treatment is started, only concomitant medications for 
treatment-related adverse events will be recorded thereafter. After the safety follow-up period, only concomitant 
medications/treatments for adverse events are required to be recorded. 
[19] Pharmacokinetics/immunogenicity test: Blood sampling time points for pharmacokinetics and immunogenicity 
study of SHR-1210: within 0.5 h pre-administration on C1D1, C2D1, C4D1, C6D1, C9D1, and every 4 cycles 
thereafter, with 4-6 mL of peripheral venous blood collected at each time point; 4-6 mL of peripheral venous 
blood will be collected once 30 days after the last dose. Blood sampling time points for pharmacokinetics study 
of apatinib: within 0.5 h pre-administration and 4 h (± 10 min) post-administration on C1D1, C2D1, C4D1, and 
C6D1, with 2-4 mL of peripheral venous blood collected at each time point. The time interval between the 
administration of apatinib on the day of blood sampling and the previous administration should be no less than 20 h. 
[20] Quality of life scoring: Performed within 7 days before the first dose (*), on day 1 of every 2 cycles from cycle 
3 onwards, on day 1 of every 4 cycles from cycle 17 onwards, and at 30 days after the last dose. 
[21] Diary card dispensing, retrieval, and filling: The subjects will measure blood pressure by themselves or others 
during the treatment period, and shall fill out the diary card every day to record blood pressure and other 
discomforts. 


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[22] Safety follow-up: performed on days 30, 60, and 90 after the last dose. The first safety follow-up visit (day 30) 
will be carried out at the study center, where the evaluations specified in the protocol will be completed. The 
second (day 60) and the third (day 90) follow-ups will be performed via phone calls. Information on new 
anti-tumor treatment, survival, concomitant medications/treatments, and adverse events will be collected. 
[23] Survival follow-up: At the end of the safety follow-up period, the subjects will enter the survival follow-up 
period until death, lost to follow-up, withdrawal of informed consent or termination of the clinical study by the 
sponsor. During this period, follow-up will be conducted via phone calls or other effective methods once every 
2 months to collect information on subject survival and subsequent treatments (if the subjects start a new 
anti-tumor treatment, the therapeutic regimen and the start and end time should be recorded). 
(*) For the control group, if the examinations of the visit at 21 days after the last dose of chemotherapy are 
qualified, the results may be used for the visit within 7 days before the first dose of crossover treatment. 


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4 ABBREVIATIONS 
Abbreviations 
Full Name 
12-Lead ECG 
12-Lead electrocardiogram 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
Cl- 
Blood chlorine 
Cr 
Creatinine 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CTLA-4 
Cytotoxic T lymphocyte antigen 4 
D 
Day 
DC 
Dendritic cell 
DCR 
Disease control rate 
DoR 
Duration of response 
EC 
Ethics Committee 
ER 
Estrogen receptor 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
h 
Hour 
Hb 
Hemoglobin 
HR 
Hazard ratio 
HUVEC 
human vascular endothelial cells 
IB 
Investigator's brochure 
IC50 
Half maximal inhibitory concentration 
irAE 
Immune-related adverse event 
IU 
International unit 
K+ 
Serum potassium 
kg 
Kilogram 


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Abbreviations 
Full Name 
LDH 
Lactate dehydrogenase 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
MTD 
Maximum tolerated dose 
Na+ 
Plasma sodium 
NEUT 
Neutrophil 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PDGFR 
Platelet-derived growth factor receptors 
PFS 
Progression free survival 
PPS 
Per-protocol set 
PR 
Partial response 
PLT 
Blood platelet 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
sec 
Second 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SS 
Safety set 
TBIL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
UA 
Uric acid 
URBC 
Urine red blood cell 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell count 


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5 INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
5.1 
Background 
5.1.1 
Introduction to soft tissue sarcoma 
Soft tissue sarcoma is a group of malignant tumors originating from connective tissues such as 
mucus, fiber, fat, smooth muscle, synovium, striated muscle, mesothelium, blood vessels, and 
lymphatic vessels, including nerve tissue tumors originating in neuroectoderm, but does not 
include those originate from bone, cartilage, and lymphoid hematopoietic tissue. The incidence of 
soft tissue sarcoma is approximately 1.28-1.72/100,000 (approximately 17,600-23,700), 
accounting for 0.73-0.81% of malignant tumors in adults and 6.5% of malignant tumors in children 
under 15 years old. The incidence is higher in men than women[1-2]. Soft tissue sarcoma is 
classified into several pathological types. The World Health Organization (WHO) classifies the 
disease into more than 50 subtypes. Common subtypes include liposarcoma, leiomyosarcoma, 
angiosarcoma, synovial sarcoma, fibrosarcoma, pleomorphic undifferentiated sarcoma, and 
malignant schwannoma[3]. Soft tissue sarcoma can occur in almost any part of the body, 50-60% of 
which occurs in the limbs; at least 80% are potentially malignant, of which 50% are prone to 
distant metastasis, and 50% are prone to local recurrence[4]. The most common metastatic site of 
limb sarcoma is the lungs, while retroperitoneal and gastrointestinal sarcomas most often 
metastasize to the liver. If metastasis occurs, the 5-year survival period is still less than 10% 
despite active treatment [5]. At present, the systemic treatment of non-specific soft tissue sarcoma 
is mainly based on anthracycline and ifosfamide chemotherapy. The median progression free 
survival period is approximately 4.5 months. Alveolar soft tissue sarcoma, well-differentiated 
liposarcoma/atypical lipomatous tumor, clear cell sarcoma, and other subtypes are generally 
considered poorly sensitive to chemotherapy[6]. 
In recent years, with the continuous deepening of research, targeted therapy and immunotherapy 
have exhibited impressive efficacy in the treatment of many types of malignant tumors. In soft 
tissue sarcoma, targeted therapy has also shown satisfactory efficacy and has been included in the 
diagnosis and treatment guidelines. For example, the NCCN guidelines recommend pazopanib for 
the treatment of non-specific soft tissue sarcoma after the failure of previous chemotherapy, as 
well as imatinib, sunitinib, and regorafenib for the alternative treatment of gastrointestinal stromal 
tumors. However, there is still a lack of high-grade evidence-based clinical drugs for some soft 
tissue sarcomas (such as alveolar soft tissue sarcoma). Therefore, it is of great clinical significance 
to explore effective therapeutic drugs. 
This study is a clinical study on the inhibitor targeting the VEGF-VEGFR pathway combined with 
anti-PD-1 monoclonal antibody for the treatment of advanced soft tissue sarcoma. The goal is to 
lay a solid foundation for new combination therapies urgently needed in clinical practice. The 
present study has important clinical and academic significance. 


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5.1.2 Introduction to SHR-1210 
PD-1 is a protein receptor expressed on the surface of T cells and is involved in the apoptosis 
process. PD-1 is a member of the CD28 family and has a 23% consistency in amino acid sequence 
with cytotoxic T lymphocyte antigen 4 (CTLA-4). However, different from CTLA-4, it is 
primarily expressed on activated T cells, B cells, and myeloid cells. PD-1 has two ligands, PD-L1 
and PD-L2. PD-L1 is primarily expressed on T cells, B cells, macrophages, and dendritic cells 
(DCs), and is up-regulated on activated cells. In contrast, the expression of PD-L2 is mainly 
restricted to antigen presenting cells, such as activated macrophages and DCs. Humanized 
anti-PD-1 mAb can specifically bind to PD-1, blocking the interaction between PD-1 and its 
ligands, and restore T cell immune response against tumor cells. 
This study involves recombinant humanized anti-programmed death-l (anti-PD-1) monoclonal 
antibody injection (SHR-1210), a new class 1 therapeutic biological product developed by Jiangsu 
Hengrui Pharmaceuticals Co., Ltd. that has not been marketed either in China or abroad. 
Preclinical studies have shown that SHR-1210 has comparable in vivo pharmacological and safety 
profiles to those of drugs of the same class abroad, and may have a better clinical potential for 
anti-tumor treatment. 
Studies on the binding affinity of SHR-1210 antibody to human, monkey and rat antigens (Table 1) 
showed that the affinities of SHR-1210 to human and monkey PD1 antigens were quite close, 
being 6.9 nM and 4.1 nM, respectively, but no binding was detected with rat PD-1 antigens. In 
another study, the affinity of SHR-1210 for the antigen (human PD-1) was 3.0 nM, which was 
comparable to those of control antibodies nivolumab and pembrolizumab (Table 2). 
Table 1. Binding affinity of SHR-1210 to human, monkey, and rat PD-1 antigens 
Stationary Phase 
Mobile Phase 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
6.9 
SHR-1210 
Murine PD-1 antigen 
Extremely weak signals, no binding 
detected 
Monkey PD-1 antigen (-hFc) 
SHR-1210 
4.1 
Table 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 
Antibody 
Antigen 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
Pembrolizumab 
Human PD-1 antigen 
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Experimental results from inhibition of PD-1/PD-L1 binding by SHR-1210 showed that (Figure 1 
and Figure 2) in vitro binding inhibition activity of SHR-1210 was similar to those of nivolumab 
and pembrolizumab, with IC50 being 0.70 nM/0.79 nM and 0.79 nM/0.77 nM, respectively. 
 
Figure 1. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab 
 
 
Figure 2. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab 


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Since 2015, Jiangsu Hengrui Pharmaceuticals Co., Ltd. has initiated 15 clinical studies of 
SHR-1210 at multiple centers in Australia and China, which preliminarily validated the safety, 
tolerability, and efficacy of SHR-1210 in patients with advanced solid tumors. As of 25 Aug., 
2017, 624 subjects had received SHR-1210 treatment. 
Four phase I clinical studies showed that different doses of SHR-1210 (1 mg/kg, 3 mg/kg, 6 mg/kg, 
10 mg/kg and fixed doses of 60 mg, 200 mg, and 600 mg) were well tolerated. No DLT was 
observed in any of the dose groups during the tolerability observation period, i.e., the maximum 
tolerated dose (MTD) was greater than 10 mg/kg or 600 mg (refer to the IB for the 
pharmacokinetics data). 
5.1.3 Introduction to apatinib 
Apatinib is a highly effective and selective inhibitor of VEGFR-2. The activity assay showed that 
its inhibitory effect against VEGFR-2 is stronger than that of drugs of same class (sorafenib, 
sunitinib, pazopanib, etc.); its selectivity for VEGFR-2 is ≥ 30 times stronger than that of other 
targets (VEGFR-1/PDGFR, SRC, etc.). Apatinib can effectively inhibit the in vitro lumen 
formation of Human Umbilical Vein Endothelial Cells (HUVEC) and the formation of arterial ring 
capillaries in rats, and has a strong inhibitory effect against neovascularization. 
The efficacy and safety of apatinib in the treatment of advanced gastric cancer were evaluated in a 
multicenter, randomized, double-blind, placebo-controlled phase III clinical study. A total of 267 
subjects with advanced gastric cancer, including gastroesophageal junction adenocarcinoma, who 
had failed second-line therapy (definition of treatment failure: intolerable toxic and side effects, 
progressive disease during treatment, or recurrence after the end of treatment) were enrolled in the 
study. The median age of subjects treated with apatinib was 58 years old, and 75% were male; 27% 
had an ECOG PS of 0 and 73% had an ECOG PS of 1; about 60% of the subjects had once received 
radical surgery, including about 22% with total gastrectomy and 35% with gastrectomy; 68% of 
the primary lesions were GC, and 22% were GEJ adenocarcinoma; 21% of the subjects had more 
than 2 organs affected by metastases cumulatively, and 56% of the subjects had liver metastases; 
92% of the subjects were clinically classified as stage IV; 66% of the subjects had once received at 
least 2 types of systemic chemotherapy; the basic drugs used in first-line chemotherapy included 
fluorouracil, platinum, paclitaxel, and doxorubicin; the second-line chemotherapy is primarily 
based on irinotecan. The investigational treatment group and the placebo group were comparable 
in baseline features and demographics of subjects. The subjects were randomized in a 2:1 ratio to 
receive either apatinib tablet 850 mg once daily (n = 176) or placebo once daily (n = 91) in 28-day 
cycles. The mean chemotherapy cycles were 2.9 in the investigational treatment group, with 72% 
of the subjects receiving 2 or more cycles of treatment. 


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The primary efficacy endpoint was overall survival (OS). The secondary efficacy endpoints 
included progression free survival (PFS), disease control rate (DCR), and objective response rate 
(ORR). The median overall survival in the investigational treatment group was prolonged 
compared with the placebo group, while the death risk was reduced by about 30%. The secondary 
endpoints PFS and DCR were also higher in the treatment group than those in the placebo group. 
Generally, no symptoms specific to advanced GC or deterioration of health-related life quality 
were caused. In the investigational treatment group and the placebo group, the incidences of 
adverse drug reactions were 92.05% and 71.43%, respectively; the incidences of Grade 3/4 
adverse drug reactions were 51.70% and 24.18%, respectively. Among the common adverse drug 
reactions (incidence ≥ 5%), the ones that were statistically different between the two groups in 
incidence included hematologic toxicities (WBC decreased, granulocytopenia, and platelets 
decreased) and non-hematologic toxicities (proteinuria, hypertension, hand-and-foot syndrome, 
asthenia, and hoarse voice). The incidences of serious adverse drug reactions in the investigational 
treatment group and the control group were 6.25% and 6.59%, respectively. The common serious 
adverse drug reaction was upper gastrointestinal hemorrhage in both groups. 
Based on the phase III study, in Oct. 2014, apatinib was approved for treating patients with 
refractory or recurrent advanced gastric adenocarcinoma or gastroesophageal junction 
adenocarcinoma who had been treated with at least 2 systemic chemotherapies, with the 
requirement that patients undergoing the treatment must be in good general conditions. 
5.1.4 Progress in the clinical studies of SHR-1210 plus apatinib 
As of Jun. 2018, 7 clinical studies on SHR-1210 combined with apatinib are in progress, involving 
three dose groups of SHR-1210 combined with apatinib, i.e., 250 mg, 375 mg, and 500 mg. More 
than 200 subjects in the 7 studies received SHR-1210 combined with apatinib. 
5.2 
Scientific Rationale 
Tumor immune escape is a great challenge in cancer immunotherapy. Cancer cells' suppressive 
effect on the immune system promotes uncontrolled tumor growth. There is an extremely complex 
relationship between the immune escape mechanism of tumors and the body's immune response. 
Specific killer T cells have certain biological activities in the early stage of the cancer 
development, but they lose their cytotoxicity in the late stage of tumor growth. Cancer 
immunotherapy aims to maximize a patient's own immune response against the tumor. It not only 
activates the original immune response in the body, but also maintains the duration and intensity of 
the immune responses, which is the key to the cancer immunotherapy. 


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Although the anti-PD-1 antibody monotherapy has achieved obvious efficacy in some tumor 
types, it is one of the main study directions at this moment as how to further enhance the 
anti-tumor efficacy of anti-PD-1 antibody monotherapy by using other drugs in combination. 
Related study results showed that the VEGF-VEGFR pathway may have a huge impact on the 
immune response of tumor patients. VEGFA expressed by tumor cells can inhibit DC cell 
maturation, induce PD-L1 expression, up-regulate Treg cells, inhibit the differentiation of 
hematopoietic precursor cells, and cause immunosuppression. While, in a mouse model of 
intestinal carcinoma, apatinib significantly regulated the environment of tumor immune response 
(such as by down-regulating Treg cells), thereby up-regulating the immune response and further 
enhancing the anti-tumor efficacy of SHR-1210 (Table 3). 
Table 3. Anti-tumor and immunomodulatory effects of SHR-1210 and apatinib in a mouse 
model of intestinal carcinoma 
Group 
Administration Average 
Tumor 
Volume  
(mm3) D21 
Tumor 
Growth 
Inhibition 
(%) D21 
CD8+ in 
CD3+ (%) 
CD4+ in 
CD3+ (%) 
Treg in 
CD4+ (%) 
CD8+: 
Treg 
Vehicle 
Q2D ×  
8/QD × 21 
1467.7 ± 218.2 ---- 
38.7 
39.3 
5.5 
22.1 
Apatinib 
100 mg/kg 
QD × 21 
539.1 ± 126.4 63.3* 
40.8 
43.5 
0.5 
189.5 
SHR-1210 3 mg/kg Q2D × 8 
917.0 ± 204.0 37.5 
37.2 
33.9 
0.4 
409.9 
SHR-1210  
3 mg/kg + 
Apatinib 
100 mg/kg 
Q2D ×  
8/QD × 21 
186.2 ± 90.5 
87.3 
41.4 
35.4 
0.4 
565.1 
In fact, VEGFR inhibitors combined with PD-1/PD-L1 antibodies have also achieved many 
successes in clinical studies. "Avelumab (anti-PD-L1 antibody) + axitinib (axitinib) in the first-line 
treatment of advanced renal cell carcinoma" and "pembrolizumab (anti-PD-1 antibody) + lenvatinib in 
the first-line treatment of advanced renal cell carcinoma" obtained FDA designation of breakthrough 
therapy in Dec. 2017 and Jan. 2018, respectively. In addition, "pembrolizumab (anti-PD-1 antibody) + 
axitinib (axitinib) vs. sunitinib in the first-line treatment of advanced renal cell carcinoma 
(KEYNOTE-426 study)", "atezolizumab (PD-L1 card antibody) + PC (paclitaxel + carboplatin) ± Bev 
(bevacizumab) vs. PC (paclitaxel + carboplatin) + Bev (bevacizumab) in the first-line treatment of 
NSCLC (IMPOWER150 study)" also proved the advantages of combination therapy. 
Based on the above evidence and the current treatment status of soft tissue sarcoma, VEGFR 
inhibitor SHR-1210 combined with apatinib may also exert considerable synergistic effect in the 
treatment of soft tissue sarcoma, providing a novel and effective non-chemotherapy treatment for 
patients with soft tissue sarcoma. 


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5.3 
Potential Risks and Benefits 
Any investigational drug or treatment may have unpredictable or even serious side effects. 
Among the 258 subjects, 256 subjects (99.2%) experienced at least one treatment-related adverse 
event. Treatment-related AEs with an incidence ≥ 10% mainly included: skin and subcutaneous 
tissue disorders: cutaneous capillary endothelial proliferation (81.8%), pruritus (22.1%), rash 
(16.3%); systemic symptoms: asthenia (37.6%), fever (20.9%); investigations: aspartate 
aminotransferase increased (21.7%), alanine aminotransferase increased (18.6%), conjugated 
bilirubin increased (16.7%), white blood cell count decreased (14.7%), serum natrium decreased 
(14.3%), blood bilirubin increased (12.0%); gastrointestinal disorders: diarrhea (11.2%), nausea 
(10.5%); respiratory, thoracic, and mediastinal disorders: cough (19.0%); metabolism and 
nutrition disorders: hypoproteinemia (19.4%); blood and lymphatic system disorders: anemia 
(27.5%); kidney and urinary tract disorders: proteinuria (22.1%); infection and infestations: upper 
respiratory tract infection (10.1%); endocrine disorders: hypothyroidism (19.8%). 
Investigator-assessed immune-mediated AEs were predominantly skin toxicities (such as rash and 
capillary proliferation). Most immune-mediated AEs were grade 1-2 in severity. The above data 
was compared with adverse drug reactions reported for other approved anti-PD-1 antibodies - 
nivolumab from BMS and pembrolizumab from Merck. The incidence and severity were both low. 
Overall, the adverse drug reactions of this product are expected to be similar to those of nivolumab 
and pembrolizumab. Recommended management of common side effects and protocol-specified 
dose modifications have been established for this study, so that, in the presence of clinical benefit, 
subjects may continue the SHR-1210 treatment. 
All monotherapies using anti-PD-1 antibodies outperformed conventional chemotherapy and 
targeted therapy in terms of adverse drug reactions on the whole. However, immune-related 
adverse drug reactions still require special attention, mainly including immune-related interstitial 
pneumonia, rash, thyroiditis, as well as those with lower incidence (≤ 1%), such as vitiligo, colitis, 
nephritis, hepatitis, uveitis, adrenal insufficiency, and nerve paralysis. These immune-related 
adverse drug reactions are mostly mild and manageable. Very few are SAEs or potentially 
life-threatening. Thanks to established procedures for toxicity management, the majority of 
immune-mediated AEs can be adequately controlled. 
Subjects receiving macromolecular protein monoclonal antibody drugs may also encounter other 
risks including infusion reactions, which prominently manifest as chilliness, shivers, facial and 
peripheral cyanosis, followed by fever and probably accompanied by nausea, vomiting, headache, 
dizziness, dysphoria, delirium, etc. In severe cases, there may be coma, fall in blood pressure, and 
symptoms such as shock and respiratory failure, etc. These risks may arise due to various factors 
during intravenous infusion, such as pyrogens, drugs, impurities, low temperature of drug 
formulation, high concentration of drug, and high rate of infusion, etc. SHR-1210 is a fully humanized 
monoclonal antibody. Its reported infusion reactions were low in incidence and mild in severity. 


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Refer to the latest version of the investigator's brochure for the updates of new adverse events of 
SHR-1210. 
Doxorubicin and ifosfamide are common cytotoxic chemotherapy drugs. Apatinib is a marketed 
anti-angiogenic drug. Their adverse events have been well understood. Refer to the package insert 
for details. 
As mentioned earlier, soft tissue sarcoma is a common malignant tumor, seriously threatening 
human health and lives. Many patients with soft tissue sarcoma have already missed the optimal 
surgical timing at the time of diagnosis. They usually have poor life quality and heavy disease 
burden. Despite an active combination chemotherapy, the median survival of patients with these 
soft tissue sarcomas is only about 1 year. It is expected that subjects with soft tissue sarcoma may 
benefit from the combination therapy of PD-1 inhibitor and apatinib, may gain prolonged survival, 
but they also may not benefit. 
6 OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
6.1.1 
Primary objective 
• 
To evaluate whether SHR-1210 combined with apatinib is better than doxorubicin 
combined with ifosfamide in the treatment of soft tissue sarcoma based on the 
progression free survival (PFS). 
6.1.2 
Secondary objectives 
• 
To evaluate and compare the overall survival (OS), objective response rate (ORR), 
duration of response (DoR), and disease control rate (DCR) in subjects with soft tissue 
sarcoma after treatment with SHR-1210 combined with apatinib vs. doxorubicin 
combined with ifosfamide; 
• 
To evaluate and compare the safety of SHR-1210 combined with apatinib vs. 
doxorubicin combined with ifosfamide in the treatment of soft tissue sarcoma; 
• 
To evaluate and compare the quality of life scores in subjects with soft tissue sarcoma 
after treatment with SHR-1210 combined with apatinib vs. doxorubicin combined with 
ifosfamide. 


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6.1.3 
Exploratory objectives 
 
To explore the correlation between the immunogenicity and the efficacy/safety of 
SHR-1210; 
 
To explore the correlation between the concentrations of SHR-1210 and apatinib and the 
efficacy/safety; 
 
To evaluate the investigator-assessed PFS, ORR, DoR and DCR (as per iRECIST) in the 
SHR-1210 plus apatinib group; 
 
PFS after crossover treatment of subjects in the doxorubicin plus ifosfamide group (as 
per RECIST v1.1 and iRECIST); 
 
To evaluate the ORR, DoR, and DCR (as per RECIST v1.1 and iRECIST), OS, safety, 
and quality of life scores of subjects in the doxorubicin plus ifosfamide group after 
crossover treatment. 
6.2 
Study Endpoints 
6.2.1 
Primary endpoints 
• 
PFS assessed by the independent review committee (as per RECIST v1.1) 
6.2.2 
Secondary endpoints 
• 
PFS assessed by the investigator (as per RECIST v1.1) 
• 
OS 
• 
ORR assessed by the investigator and independent review committee (as per 
RECIST v1.1) 
• 
DoR assessed by the investigator and independent review committee (as per 
RECIST v1.1) 
• 
DCR assessed by the investigator and independent review committee (as per 
RECIST v1.1) 
• 
Incidence and severity of AEs and SAEs, vital signs, ECG, and laboratory abnormalities. 
• 
Quality of life score (EORTC QLQ-C30) 


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6.2.3 
Exploratory endpoints 
 
Anti-drug antibody and neutralizing antibody levels of SHR-1210 
 
Serum concentration of SHR-1210 and plasma concentration of apatinib 
 
Investigator-assessed PFS, ORR, DoR, and DCR (as per iRECIST) of the investigational 
treatment group; 
 
PFS of subjects in the doxorubicin plus ifosfamide group after crossover treatment (as 
per RECIST v1.1 and iRECIST) 
 
ORR, DoR, DCR (as per RECIST v1.1 and iRECIST), OS, safety, and quality of life 
scores of subjects in the doxorubicin plus ifosfamide group after crossover treatment 
7 
STUDY DESIGN 
7.1 
Overview of Study Design 
This study is a multicenter, randomized, open-label phase II clinical study, with a total of 292 
subjects planned to be enrolled. 
Qualified subjects with soft tissue sarcoma will be randomized in a 1:1 ratio into the SHR-1210 + 
apatinib group (investigational treatment group) and the doxorubicin + ifosfamide/ifosfamide 
monotherapy group (control group). Stratification factors include: 1) ECOG PS, 0 vs. 1-2; 2) 
Whether the pathological type of the tumor had poor sensitivity to chemotherapy (see Appendix 2. 
Common Types of Soft Tissue Sarcoma with Poor Chemotherapy Sensitivity); 3) Whether 
subjects have previously undergone chemotherapy. The administration regimens for 
investigational treatment group and control group are as follows: 
• 
Investigational treatment group: SHR-1210 200 mg q3w (up to 2 years of treatment) + 
apatinib 500 mg qd. 
• 
Control group: doxorubicin 60 mg/m2 on D1 + ifosfamide 2 g/m2/d on D4, in 3-week 
cycles (i.e., the total dose per cycle shall be 8 g/m2), 6 cycles are recommended. If the 
investigator judges that the subject benefits from doxorubicin + ifosfamide 
chemotherapy, additional chemotherapy cycles may be administered. When the subject's 
anthracyclines have reached the recommended maximum cumulative dose of doxorubicin 
(see Appendix 3. Dose Conversion Table for Anthracycline), the chemotherapy regimen 
should be adjusted to ifosfamide monotherapy, 2 g/m2/d on D1-D5, in 3-week cycles (i.e., 
the total dose per cycle shall be 10 g/m2). Again, if the investigator judges that the subject 
benefits from ifosfamide chemotherapy, additional chemotherapy cycles may be 
administered.


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PD/intolerability 
Main Subject Characteristics 
• Metastatic or locally advanced 
unresectable soft tissue sarcoma  
(except Ewing's sarcoma, embryonic 
rhabdomyosarcoma, osteochondroma, and 
intermediate tumors without extensive 
metastasis) 
• Have not received any prior systemic 
therapy or have sensitive relapse after 
chemotherapy (sensitive relapse refers to 
recurrence more than 6 months after the 
last chemotherapy) 
Stratification factors 
• ECOG PS: 0 or 1-2 
• Received any prior chemotherapy:  
Yes or No 
• Chemotherapy sensitivity: Poor sensitivity 
to chemotherapy or other 
SHR-1210 200 mg q3w[1] 
+ 
Apatinib 500 mg qd 
Radiological PD+ subjects meeting 
inclusion/exclusion criteria can be 
crossed over to receive the treatment for 
investigational treatment group 
Doxorubicin 60 mg/m2 on D1 + 
Ifosfamide 2 g/m2 on D1-D4 
q3w, routinely for 6 cycles[2] 
Primary endpoint: 
・Progression free survival (PFS) 
(IRC-assessed) 
Secondary endpoints: 
・Overall survival (OS) 
・Objective response rate (ORR) 
・Duration of response (DOR) 
・Disease control rate (DCR) 
・Safety endpoints 
Exploratory endpoints: 
・Tumor tissue biomarkers 
・ADA and concentration of SHR-1210
・Concentration of apatinib 
・PFS assessed as per iRECIST in the 
investigational treatment group 
・PFS and other endpoints after 
crossover treatment 
1. The treatment duration of SHR-1210 should be no more than 2 years; interruption of one drug does not require the interruption of the other; 2. If anthracycline 450 mg/m2 is 
used for the control group, the chemotherapy regimen will be adjusted to ifosfamide monotherapy, 2 g/m2 on D1-D5, q3w; more than 6 chemotherapy cycles may be 
administered. 


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In this study, the screening period should be no more than 28 days. After completing screening 
examinations and assessments, eligible subjects will enter the treatment period and receive the study 
treatment and study visits according to the protocol. Among them, tumor imaging assessment will be 
performed once in every 2 cycles during the first 16 cycles and once every 4 cycles thereafter. The 
independent review committee (IRC) will review the imaging evaluation results of each study center. 
The safety follow-up period of subjects in the investigational treatment group starts after the last dose, 
and the subjects will be followed up once every 30 days until 90 days after the last dose. Among them, 
the first safety follow-up will be carried out at the study center; the second and the third follow-up 
visits will be made via phone calls. For subjects in the control group, if they do not receive SHR-1210 
+ apatinib treatment, their safety follow-up period will be 21 days after the last dose; otherwise, the 
same arrangement as that in the investigational treatment group will be used. The survival follow-up 
period will start after the end of the safety follow-up period. The survival follow-up period will end 
upon the subject's death, lost to follow-up, withdrawal of informed consent, or study termination by 
the sponsor. During this period, a follow-up shall be conducted every 2 months via phone calls or other 
effective methods to collect information on subject survival and subsequent anti-tumor treatment. 
8 SELECTION AND WITHDRAWAL OF SUBJECTS 
The enrollment of eligible subjects is critical to ensure the outcome of the study. Subjects must 
meet the following criteria to be allowed to participate in this study. Any medical or non-medical 
conditions of a subject are considered for his/her eligibility. 
Before the subject's enrollment in the study, the investigator should review, confirm, and 
document whether the subject is suitable for participating in the study. 
8.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible. 
1. Aged 16-70 years, male or female. 
2. With an Eastern Cooperative Oncology Group (ECOG) PS of 0-1. The criterion can be 
relaxed to 2 points for amputation subjects. 
3. Life expectancy of ≥ 3 months. 
4. Patients with distant metastasis or locally advanced soft tissue sarcoma that render the 
patient not suitable for surgical treatment as per the investigator's judgment 
(pathologically or cytologically diagnosed, except gastrointestinal stromal tumors, 
osteochondroma, embryonic/acinar rhabdomyosarcoma, Ewing's sarcoma, and 
intermediate soft tissue tumors without extensive metastasis, such as 
dermatofibrosarcoma protuberans and inflammatory myofibroblastic sarcoma, see 
Appendix 1. The WHO Soft Tissue Tumor Classification (2013 Edition) for details). 


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5. Patients who have not received previous chemotherapy for soft tissue sarcoma, or have 
benefited from chemotherapy but have recurrence or metastasis more than 6 months after 
drug discontinuation. 
6. With measurable lesion(s) as per RECIST v1.1. 
7. All acute toxicities due to previous anti-tumor treatments or surgeries must have resolved 
to Grade 0-1 (as per NCI CTCAE 4.03) or to the level specified in the inclusion/exclusion 
criteria before C1D1 (except for toxicities such as alopecia that are deemed by the 
investigator as not posing safety risks to the patient). 
8. With adequate organs and bone marrow functions, as defined below: 
Hematology (without blood transfusion, G-CSF, or medication correction within 14 days 
prior to screening) 
 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
 
Blood platelet count (PLT) ≥ 100,000/mm3 (100 × 109/L); 
 
Hemoglobin (Hb) ≥ 9 g/dL (90 g/L); 
Blood Biochemistry 
 
Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance 
(Cockroft-Gault formula) ≥ 60 mL/min; 
 
Total bilirubin (TBIL) ≤ 1.5 × ULN; 
 
Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 × ULN; for 
patients with liver metastasis, ALT and AST should be ≤ 5 × ULN; 
Coagulation Function 
 
International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and activated 
partial thromboplastin time (APTT) ≤ 1.5 × ULN; 
Urinalysis 
 
Urine protein < 2+; If urine protein is ≥ 2+, then the 24-hour urine protein must be 
≤ 1 g; 
Thyroid function 
 
Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, FT3 (T3) and FT4 (T4) 
levels should be examined, and the subject can be enrolled if FT3 (T3) and FT4 (T4) 
levels are normal. 


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9. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to C1D1, and be willing to use a recognized effective contraceptive 
measure (such as: intra-uterine contraceptive devices, contraceptive pills, or condoms) 
during the study and within 3 months after the last dose of the study drug; male subjects 
with partners of childbearing potential must either be surgically sterilized or agree to take 
effective contraceptive measures during the study and within 3 months after the last dose 
of the study drug. 
10. Subjects must agree and have signed the informed consent form, be willing and able to 
follow the scheduled visits, study treatment, laboratory tests, and other study procedures. 
8.2 
Exclusion Criteria 
Patients meeting any one of the followings are not eligible to participate in this study: 
1. Those who have received the following treatments within 4 weeks prior to C1D1: 
 
Previously received radiotherapy, surgery, chemotherapy, immune or molecular 
targeted therapy for tumors; 
 
Received other investigational drug of clinical studies; 
 
Inoculated with a live attenuated vaccine. 
2. Subjects who previously received anti-PD-1/PD-L1/CTLA4 antibodies, or VEGFR 
single target/multiple target inhibitors. 
3. Those who plan to receive surgical treatment and/or radiation therapy for soft tissue 
sarcoma during the study period. 
4. Presence of tumor lesions in the central nervous system confirmed by imaging diagnosis. 
5. Having been treated by immunosuppressive drugs within 14 days prior to C1D1, 
excluding intranasal and inhaled corticosteroids or systemic steroids of physiological 
doses (i.e., no more than 10 mg/d of prednisolone or equivalent physiological doses of 
other corticosteroids). 
6. Presence of any active autoimmune diseases or a history of autoimmune diseases 
(including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, 
enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; 
adult patient with vitiligo or completely relieved childhood asthma may be enrolled if 
they do not require any intervention), or known history of allogeneic organ 
transplantation or allogeneic hematopoietic stem cell transplantation. 


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7. Complicated with severe infection (such as one requiring intravenous drip infusion of 
antibiotics, antifungals, or antivirals) within 4 weeks prior to C1D1, or any unexplained 
fever of > 38.5 °C during screening/prior to the first dose.  
8. Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
9. Patients with clinically significant bleeding symptoms or a clear bleeding tendency 
within 3 months prior to C1D1, such as hemorrhage of digestive tract, stomach ulcer with 
hemorrhage, fecal occult blood ++ and above at baseline, or vasculitis; or arterial/venous 
thrombus events, such as cerebrovascular accidents (including transient ischemic attack, 
cerebral hemorrhage, and cerebral infarction), deep vein thrombus, pulmonary 
embolism, etc. within 6 months before C1D1; or requiring long-term anticoagulation 
therapy with warfarin or heparin, or requiring long-term antiplatelet therapy (aspirin 
≥ 300 mg/d or clopidogrel ≥ 75 mg/d). 
10. Active heart diseases within 6 months before C1D1, including myocardial infarction, 
severe/unstable angina, etc. Left ventricular ejection fraction < 50% as revealed by 
echocardiography and poorly controlled arrhythmia (including QTcF interval > 450 ms 
in males and > 470 ms in females). 
11. Having been diagnosed with any other malignancies within 3 years before C1D1, 
excluding adequately treated basal cell carcinoma and squamous cell skin cancer, and 
cervical carcinoma in situ. 
12. Known allergies to the study drug or their excipients; severe allergic reactions to other 
monoclonal antibodies. 
13. With human immunodeficiency virus (HIV) infection, or active hepatitis B (positive 
hepatitis B surface antigen and HBV DNA ≥ 500 IU/mL) or hepatitis C (positive for 
hepatitis C antibody, and HCV-RNA higher than the lower limit of detection of the 
analytical method). 
14. Presence of accompanying diseases (such as poorly controlled hypertension, severe 
diabetes, neurological or mental illness, etc.) or any other situation that may pose serious 
risks to the safety of the subjects, confuse the research results, or affect the ability of the 
subjects to complete the study as judged by the investigator. 


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8.3 
Withdrawal from Study or Treatment Discontinuation 
8.3.1 
Study withdrawal criteria 
Reasons for withdrawal may include: 
• 
Withdrawal of informed consent and refusal of further follow-ups by subjects; 
• 
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. 
8.3.2 
Criteria for treatment discontinuation 
The study treatment must be discontinued when any of the following occurs: 
1. 
Treatment discontinuation requested by subjects; 
2. 
Radiographic (assessed by the investigator as per RECIST v1.1) or clinical progression, 
except for the following two situations: 1) The subjects in the investigational treatment 
group meet the criteria for continuing treatment beyond progression (see 8.3.3 for 
details); 2) The subject in the control group who had radiographic progression and meet 
the inclusion/exclusion criteria may be crossed over to receive the SHR-1210 + apatinib 
treatment (see 8.3.4 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. 
General deterioration of health status and inability to continue study participation; 
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 investigator. 


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8.3.3 
Criteria for continuing treatment beyond progression (investigational treatment 
group) 
Some subjects receiving immunotherapy or anti-angiogenesis therapy can still benefit from 
continuing treatment after radiographic progression. The tumor of some subjects may be enlarged, 
but remarkable necrosis, denaturation, or infiltration of immune cells may occur inside the tumor, 
with CT showing decreased internal density of the tumor lesion. It is generally considered to be 
beneficial to subjects under this circumstance. A subject meeting the following criteria may 
continue the treatment after progressive disease (PD, as per the investigator's judgment) based on 
RECIST v1.1: 
• 
The investigator deems that it is in the best interest of the subject to continue treatment, 
and subject is not required to start other anti-tumor treatment immediately; 
• 
The subject is able to tolerate continued study treatment; 
• 
No obvious deterioration in subject's performance status, and no marked worsening of 
cancer-related symptoms; 
• 
Subjects must sign the informed consent form prior to continuing study treatment, in 
which potential risks, discomforts, and other treatment options shall be included; 
• 
Continued study treatment must be reviewed and approved by the principal investigator 
of the study center. 
The assessment of clinical benefit must consider whether the subject has clinical exacerbations and 
whether the subject can benefit from continuing treatment. It is recommended that the investigator 
should discuss with the sponsor whether the subject should continue treatment beyond progression. 
If it is decided that the subject will continue the study treatment after progression, the subject 
should continue to be treated and followed up according to the protocol requirements. 
Investigators at the study center will perform subsequent imaging evaluations as per iRECIST (see 
Appendix 11) (independent imaging evaluations will still be performed as per RECIST v1.1). 
Subjects should withdraw from the study if the subject has iRECIST-confirmed PD (iCPD) in the 
subsequent tumor evaluation. The initial date of investigator-assessed progression should be used 
for the statistical analysis of PFS in secondary endpoints, regardless of whether the subject 
continues the study treatment beyond progression. 
If the subject discontinues treatment due to deterioration of the general condition without objective 
evidence for progressive disease, the progression will be reported as "general deterioration". More 
objective evidences (e.g., imaging confirmation) of progressive disease of these subjects should be 
obtained whenever possible after treatment discontinuation. 


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8.3.4 
Criteria for crossover treatment of subjects in control group after radiographic 
progression 
In a subject in the control group is found to have PD during or after chemotherapy, the safety visit 
will be conducted. After completing relevant examinations, subjects who are willing to and 
eligible for crossover treatment may be crossed over to receive the treatment of SHR-1210 
combined with apatinib. 
If the inclusion and exclusion criteria are not met, the subject may receive supportive treatment for 
adjustment. But during this period, anti-tumor treatment must not be performed. If, at the 
reexamination 2 months after progressive disease, the inclusion and exclusion criteria are still not 
met, crossover to receive SHR-1210 combined with apatinib will not be permitted. 
For the schedule of activities for the crossover treatment period and subsequent follow-ups of the 
control group, please refer to "3. Schedule of activities - crossover treatment" for details. 
8.3.4.1 
Inclusion criteria for crossover treatment 
1. With an Eastern Cooperative Oncology Group (ECOG) PS of 0-1. The criterion can be 
relaxed to 2 points for amputation subjects. 
2. Life expectancy of ≥ 3 months. 
3. All acute toxicities due to previous anti-tumor treatments or surgeries must have resolved 
to Grade 0-1 (as per NCI CTCAE 4.03) or to the level specified in the inclusion/exclusion 
criteria before C1D1 (except for toxicities such as alopecia that are deemed by the 
investigator as not posing safety risks to the patient). 
4. With adequate organs and bone marrow functions, as defined below: 
Hematology: (without blood transfusion within 14 days prior to screening, or G-CSF or other 
medication within 7 days prior to screening) 
 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
 
Blood platelet count (PLT) ≥ 100,000/mm3 (100 × 109/L); 
 
Hemoglobin (Hb) ≥ 9 g/dL (90 g/L); 
Blood Biochemistry 
 
Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance 
(Cockroft-Gault formula) ≥ 60 mL/min; 
 
Total bilirubin (TBIL) ≤ 1.5 × ULN; 
 
Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 × ULN; for 
patients with liver metastasis, ALT and AST should be ≤ 5 × ULN; 


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Coagulation Function 
 
International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) and activated 
partial thromboplastin time (APTT) ≤ 1.5 × ULN; 
Urinalysis 
 
Urine protein < 2+; If urine protein is ≥ 2+, then the 24-hour urine protein must be 
≤ 1 g; 
Thyroid function 
 
Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, FT3 (T3) and FT4 (T4) 
levels should be examined, and the subject can be enrolled if FT3 (T3) and FT4 (T4) 
levels are normal. 
5. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to C1D1, and be willing to use a recognized effective contraceptive 
measure (such as: intra-uterine contraceptive devices, contraceptive pills, or condoms) 
during the study and within 3 months after the last dose of the study drug; male subjects 
with partners of childbearing potential must either be surgically sterilized or agree to take 
effective contraceptive measures during the study and within 3 months after the last dose 
of the study drug. 
6. Subjects must agree and have signed the informed consent form, be willing and able to 
follow the scheduled visits, study treatment, laboratory tests, and other study procedures. 
8.3.4.2 
Exclusion criteria for crossover treatment 
1. Those who have received the following treatments within 4 weeks prior to C1D1: 
 
Previously received radiotherapy, surgery, immune or molecular targeted therapy 
for tumors; 
 
Received other investigational drug of clinical studies; 
 
Inoculated with a live attenuated vaccine. 
2. Those who have received the following treatments within 3 weeks prior to C1D1: 
3. Subjects who previously received anti-PD-1/PD-L1/CTLA4 antibodies, or VEGFR 
single target/multiple target inhibitors. 
4. Those who plan to receive surgical treatment and/or radiation therapy for soft tissue 
sarcoma during the study period. 
5. Presence of tumor lesions in the central nervous system confirmed by imaging diagnosis. 


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6. Having been treated by immunosuppressive drugs within 14 days prior to C1D1, 
excluding intranasal and inhaled corticosteroids or systemic steroids of physiological 
doses (i.e., no more than 10 mg/d of prednisolone or equivalent physiological doses of 
other corticosteroids). 
7. Presence of any active autoimmune diseases or a history of autoimmune diseases 
(including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, 
enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; 
adult patient with vitiligo or completely relieved childhood asthma may be enrolled if 
they do not require any intervention), or known history of allogeneic organ 
transplantation or allogeneic hematopoietic stem cell transplantation. 
8. Complicated with severe infection (such as one requiring intravenous drip infusion of 
antibiotics, antifungals, or antivirals) within 4 weeks prior to C1D1, or any unexplained 
fever of > 38.5 °C during screening/prior to the first dose. 
9. Hypertension uncontrolled by antihypertensives (systolic pressure > 140 mmHg or 
diastolic pressure > 90 mmHg). 
10. Patients with clinically significant bleeding symptoms or a clear bleeding tendency 
within 3 months prior to C1D1, such as hemorrhage of digestive tract, stomach ulcer with 
hemorrhage, fecal occult blood ++ and above at baseline, or vasculitis; or arterial/venous 
thrombus events, such as cerebrovascular accidents (including transient ischemic attack, 
cerebral hemorrhage, and cerebral infarction), deep vein thrombus, pulmonary 
embolism, etc. within 6 months before C1D1; or requiring long-term anticoagulation 
therapy with warfarin or heparin, or requiring long-term antiplatelet therapy (aspirin 
≥ 300 mg/d or clopidogrel ≥ 75 mg/d). 
11. Active heart diseases within 6 months before C1D1, including myocardial infarction, 
severe/unstable angina, etc. Left ventricular ejection fraction < 50% as revealed by 
echocardiography and poorly controlled arrhythmia (including QTcF interval > 450 ms 
in males and > 470 ms in females). 
12. Having been diagnosed with any other malignancies within 3 years before C1D1, 
excluding adequately treated basal cell carcinoma and squamous cell skin cancer, and 
cervical carcinoma in situ. 
13. Known allergies to the study drug or their excipients; severe allergic reactions to other 
monoclonal antibodies. 


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14. With human immunodeficiency virus (HIV) infection, or active hepatitis B (positive 
hepatitis B surface antigen and HBV DNA ≥ 500 IU/mL) or hepatitis C (positive for 
hepatitis C antibody, and HCV-RNA higher than the lower limit of detection of the 
analytical method). 
15. Presence of accompanying diseases (such as poorly controlled hypertension, severe 
diabetes, neurological or mental illness, etc.) or any other situation that may pose serious 
risks to the safety of the subjects, confuse the research results, or affect the ability of the 
subjects to complete the study as judged by the investigator. 
8.4 
Definition of End of Study 
Study completion is defined as 12 months after reaching the 214 events required for the analysis of 
the primary endpoint (IRC-assessed PFS) or completion of collection of all OS data. 
At the end of the study, all subjects who did not progress may continue treatment with the 
investigational drug after a new informed consent is signed. The drugs may be provided through 
charity donations or other forms as determined by the sponsor. 
8.5 
Termination or Suspension of Study 
This study can be terminated early or suspended if there are sufficient reasons. This may result 
from the decision of the regulatory authorities, changes in comments by the Ethics Committee, 
efficacy or safety issues of the study medications, or the judgment of the sponsor. In addition, 
Hengrui reserves the right to terminate the research and development of SHR-1210 and apatinib at 
any time. The party who decides to suspend/terminate the study should notify the investigator, 
sponsor, and regulatory authorities in writing, documenting the reasons for 
suspension/termination. The investigator must immediately notify the ethics committee and 
sponsor, and provide relevant reasons. 
The reasons for termination or suspension of the study may include: 
• 
Confirmed unexpected, major, or unacceptable risk to the subjects. 
• 
Existing efficacy data supporting study termination. 
• 
Poor protocol compliance. 
• 
Incomplete or undetectable measures. 
• 
Valueless study results. 
The study may continue once that issues related to drug safety, protocol compliance, and data 
quality have been resolved and approved by the sponsor, ethics committee, or CFDA (now 
NMPA). 


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9 COLLECTION AND PROCESSING OF PHARMACOKINETIC AND 
IMMUNOGENIC BLOOD SAMPLES 
9.1 
Collection and Processing of Blood Samples 
9.1.1 
Blood sampling time 
Subjects receiving the combination therapy of SHR-1210 and apatinib shall undergo blood 
sampling for the pharmacokinetics and immunogenicity study of SHR-1210, as well as the 
pharmacokinetics study of apatinib. 
Pharmacokinetics/immunogenicity blood sampling time points of SHR-1210: within 0.5 h 
pre-administration on C1D1, C2D1, C4D1, C6D1, C9D1, and every 4 cycles thereafter, with 4-6 mL 
of peripheral venous blood collected at each time point. If SHR-1210 medication is interrupted at 
the above time points, immunogenicity blood samples of SHR-1210 shall still be collected within 
the time windows of the corresponding time points. At 30 days after the last dose, 4-6 mL of 
peripheral venous blood will also be collected. 
Pharmacokinetics blood sampling time points of apatinib: within 0.5 h pre-administration and 4 h 
(± 10 min) on C1D1, C2D1, C4D1, and C6D1, with 2 -4 mL of peripheral venous blood collected at 
each time point. 
The time interval between the administration of apatinib on the day of blood sampling and the 
previous administration should be no less than 20 h. If the administration of apatinib is interrupted 
at the above sampling time point, there is no need to collect the blood sample related to the 
pharmacokinetics of apatinib. 
9.1.2 
Processing and storage of blood samples 
Please refer to the Laboratory Manual for operation details and sample storage and transportation 
conditions. 
9.1.3 
Blood sample submission 
The samples in test tubes should be sent out first in dry ice storage state. The samples in the backup 
tubes will be sent out after the bioanalytical laboratory confirms the receipt of the test tube 
samples. Details of shipping frequency and other shipping information are described in the 
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10 STUDY MEDICATION 
10.1 Overview of Study Drugs 
10.1.1 Access to drugs 
The study drugs are uniformly packaged, tested, and provided by the sponsor (see corresponding 
Certificate of Analysis). 
10.1.2 Dosage form, packaging, and storage of study drugs 
Investigational drug: SHR-1210 for injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: lyophilized powder. 
Strength: 200 mg (proposed) in 20-mL vials. 
Batch No.: see Certificate of Analysis 
Route of administration: intravenous infusion. 
Shelf life: 2 years (tentative) from the date of manufacture. 
Storage conditions: sealed, away from light, stored at 2-8 °C in refrigerator. Do not freeze.  
Apatinib mesylate tablets 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
Dosage form: tablet. 
Strength: 250 mg/tablet; 375 mg/tablet 
Batch No.: see Certificate of Analysis 
Route of administration: oral administration after meals (best to take the two drugs at the same 
time each day). 
Shelf life: 2 years. 
Storage conditions: away from light, sealed, stored below 25°C.  
Adriamycin hydrochloride for injection (doxorubicin) 
Manufacturer: Hisun-Pfizer Pharmaceuticals Co., Ltd. 
Dosage form: injection. 
Strength: 10 mg 
Batch No.: see Certificate of Analysis 


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Route of administration: intravenous infusion. 
Shelf life: 24 months (tentative). 
Storage conditions: kept away from light, sealed, in a cool condition (≤ 20 °C). 
Cyclophosphamide for injection 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
Dosage form: injection. 
Strength: 1 g; 0.5 g 
Batch No.: see Certificate of Analysis 
Route of administration: intravenous infusion. 
Shelf life: 36 months. 
Storage conditions: kept away from light, sealed, in a cool condition (2-8 °C).  
10.1.3 
Storage and stability of drugs 
The investigator or his/her authorized representative (e.g. pharmacist) shall ensure that all study 
drugs are stored in a safe zone with qualified storage conditions and controlled access. The storage 
must be in compliance with regulatory requirements. 
Study drugs should be stored under the storage conditions listed in Section 10.1.2. Where the 
protocol and other information differ, store according to the storage conditions listed on the label. 
Daily maximum and minimum temperatures of all storage areas (such as freezer, refrigerator, and 
room temperature) must be recorded by the study center. The documented period shall begin with 
the receipt of the study drug until the last subject completes the last visit. Even if a continuous 
monitoring system is employed, a written log must be kept to ensure a correct record of storage 
temperature. The temperature monitoring and storage devices (such as refrigerator) should be 
regularly inspected to ensure proper operation. 
Any deviations related to the labeled conditions on the product should be immediately reported 
upon discovery. The study center shall take active measures to restore the study drugs under the 
storage conditions described on the label, and the temperature deviation and the measures taken 
shall be reported to the sponsor. 
Study drugs affected by the temperature deviation should be isolated temporarily and may only be 
used after approval by the sponsor and if it is not a protocol deviation. The use of affected 
investigational drugs without the approval of the sponsor is considered a protocol deviation. The 
sponsor will provide a detailed procedure on reporting temperature deviations to the study center. 


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10.1.4 Preparation of study drugs 
Some drugs used in this study are administered via intravenous infusions. Therefore, the drugs 
should be prepared by a 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 brochure for drug preparation. 
10.1.5 Administration of study drugs 
SHR-1210 
Administered via intravenous drip infusion at 200 mg/dose (not less than 20 min and not more than 
60 min) on day 1 of each 3-week cycle for a period of up to 2 years. 
Apatinib Mesylate Tablets 
Administered orally at 500 mg/day once daily with warm water at approximately half an hour after 
meals (administration time should be the same in each day whenever possible) in 3-week cycles. 
Doxorubicin 
Administered via intravenous drip infusion at 60 mg/m2 within 2 h on day 1 of each 3-week cycle. 
Six cycles are recommended. 
If a subject has received more than 450 mg/m2 of anthracyclines, doxorubicin will no longer be used. 
Doxorubicin will also be discontinued if the subject experiences a decrease in LVEF from baseline 
by at least 5% to an absolute value of < 55% with symptoms of chronic heart failure, or a decrease in 
LVEF from baseline by at least 10% to an absolute value of < 55% without symptoms or signs. 
If the subject has received anthracycline treatment before the study, refer to Appendix 3. Dose 
Conversion of Anthracyclines for the conversion. In the course of the study, if the remaining 
available dose of doxorubicin (450 mg/m2 minus the cumulative dose used previously) is 
≥ 51 mg/m2 (i.e., 85% of the initial dose) in a certain cycle, then the doxorubicin + ifosfamide 
regimen is still used this time. If the remaining available dose of doxorubicin is less than 
51 mg/m2, the ifosfamide monotherapy regimen is used directly. 
The body surface area is calculated using the Stevenson's formula: body surface area (m2) = 
0.0061 × height (cm) + 0.0128 × weight (kg) - 0.1529. The final dose should be 95-105% of the 
calculated dose. 
Ifosfamide 
Combination with doxorubicin: Ifosfamide 2 g/m2/d on D1-D4, intravenous drip infusion within 
4-6 h, in 3-week cycles (i.e., the total dose per cycle shall be 8 g/m2). Six cycles are recommended. 
Ifosfamide monotherapy: 2 g/m2/ d on D1-D5, intravenous drip infusion within 4-6 h, in 3-week 
cycles (i.e., the total dose per cycle shall be 10 g/m2). Six cycles are recommended. 


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If the above infusion rate is not tolerated by the subject, the investigator may consider adjusting the 
ifosfamide infusion rate. 
The body surface area is calculated using the Stevenson's formula: body surface area (m2) = 
0.0061 × height (cm) + 0.0128 × weight (kg) - 0.1529. The final dose should be 95-105% of the 
calculated dose. 
10.1.6 
Dose modifications and delay 
10.1.6.1 Dose modifications for SHR-1210 
Adverse events related to SHR-1210 may be immune-related (irAE), and may develop shortly 
after the first dose or months after the last dose. SHR-1210 should be interrupted if events listed in 
Table 4 occur. During the study, the investigator 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 4 or when the situation is not listed. 
When SHR-1210 is discontinued and apatinib is well tolerated, the subject may receive apatinib 
monotherapy. 
Table 4. Criteria for SHR-1210 dose modifications 
Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades for 
Treatment 
Interruption 
Resumption 
Discontinuation 
Diarrhea/Colitis 
2-3 
Recovered to Grade 0-1 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
4 
Discontinuation 
Discontinuation 
AST, ALT, or bilirubin 
increased 
2 
Recovered to Grade 0-1 Fail to resolve within 12 weeks 
from the last dose. 
3-4 
Discontinuation 
Discontinuation 
Hyperthyroidism 
3 
Recovered to Grade 0-1 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
4 
Discontinuation 
Discontinuation 
Hypothyroidism 
2-4 
Treatment can be 
continued after starting 
thyroxine replacement 
therapy 
Treatment can be continued after 
starting thyroxine replacement 
therapy 


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Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades for 
Treatment 
Interruption 
Resumption 
Discontinuation 
Pulmonitis 
2 
Recovered to Grade 0-1 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
3-4 
Discontinuation 
Discontinuation 
Immune-Related Hypophysitis 
2-3 
Recovered to Grade 
0-1; SHR-1210 
treatment can be 
resumed after starting 
hormone replacement 
therapy 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
4 
Discontinuation 
Discontinuation 
Type I diabetes mellitus (new 
onset) or hyperglycemia 
New-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 
Recovered to Grade 0-1 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
3-4 
Discontinuation 
Discontinuation 
Infusion reactions 
2 
Symptoms 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 
Other Treatment-Related 
Adverse Events 
3 
Recovered to Grade 0-1 
Fail to resolve within 12 weeks 
from the last dose, or the dose of 
corticosteroids cannot be reduced 
to ≤ 10 mg of prednisone or 
equivalent within 12 weeks. 
4 
Discontinuation 
Discontinuation 
Note: Treatment should be discontinued if any Grade 3 treatment-related AE recurs or any life-threatening event 
occurs. 


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For subjects 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 investigator may 
consider interrupting SHR-1210 treatment if appropriate. For subjects with persistent Grade 2 
adverse drug reactions that fail to recover to Grade 0-1 within 12 weeks after the last dose, the 
treatment should be discontinued. 
For subjects with hypertension with a blood pressure not more than 140/90 mmHg whose AE is 
considered as Grade 3-4 only because of the administration of multiple antihypertensive drugs, 
treatment interruption is not required. 
10.1.6.2 Treatment for Common Adverse Drug Reactions Related to SHR-1210 
10.1.6.2.1 Immune-related adverse reactions 
Adverse events caused by immuno-oncology (I-O) drugs are different from those of other 
anti-tumor drugs, especially in terms of severity and duration. SHR-1210 is one such drug, and 
therefore, early identification and management of adverse events is required to reduce the 
incidence of severe toxicities. The safety management procedures of similar approved drugs 
provide references to assist the investigator in assessing and dealing with adverse events involving 
the following systems: GI tract, kidneys, lungs, liver, endocrine, skin, and nervous system. Safety 
management rules for immuno-oncology drugs are presented in Appendix 7. Management 
Principles for Immune Related Adverse Events. 
10.1.6.2.2 Infusion reactions 
During the course of this study, the investigator should pay close attention to potential infusion 
and/or allergic reactions, especially acute immune-mediated adverse reactions (including cytokine 
storms). 
SHR-1210 is a fully humanized monoclonal antibody with little potential for infusion or allergic 
reactions, and thus, in general, no prophylactic medications are required prior to SHR-1210 
infusion. Based on published relevant information, allergic reactions/events are most likely to 
occur within 24 h after infusion. If an allergic reaction/event occurs, the infusion should be slowed 
or interrupted based on the subject's condition, and supportive treatment should be given. In 
addition, prophylactics should be given before further administration. Possible allergic reactions 
include fever, chills, shiver, headache, rash, arthralgia, hypotension/hypertension, and 
bronchospasm. 
Management of allergic reactions should be based on the medical practice and guidelines of the 
study center. The treatment recommendations for infusion reactions are shown below for reference. 


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Table 5. Treatment recommendations for infusion reactions related to SHR-1210 
CTCAE 
Grade 
Clinical Symptoms 
Recommended Management 
SHR-1210 
Treatment 
Grade 1 
Mild and transient 
reactions 
Bedside observation and close monitoring until 
recovery. Pre-dose prophylactics are recommended for 
subsequent administration: 50mg of diphenhydramine 
or equivalent, and/or 325-1000 mg of acetaminophen 
can be given at least 30 minutes before the 
administration of SHR-1210. 
Continued use 
Grade 2 
Moderate reactions 
requiring treatment or 
interruption; rapidly 
resolve after 
symptomatic 
treatment (such as 
antihistamines, 
non-steroidal 
antiphlogistics, 
anesthetics, 
bronchodilators, 
intravenous fluids, 
etc.) 
Intravenous administration of normal saline, 50 mg of 
diphenhydramine IV or equivalent and/or 325-1000 mg 
of acetaminophen; bedside observation and close 
monitoring should be given until recovery. 
Corticosteroids or bronchodilators can be considered 
based on clinical needs; 
The amount of study drug infused should be recorded in 
the original medical record; 
Pre-dose prophylactics are recommended for 
subsequent administration: 50mg of diphenhydramine 
or equivalent, and/or 325-1000 mg of acetaminophen 
can be given at least 30 minutes before the 
administration of SHR-1210. Corticosteroids 
(equivalent to 25 mg of hydrocortisone) can be used 
when necessary. 
Interrupt. 
Re-administer at 50% 
of the initial rate after 
symptoms resolve. 
Restore the original 
infusion rate if no 
complications occur 
within 30 minutes. 
Closely monitor. If the 
symptoms recur, no 
more infusion shall be 
given. 
Grade ≥ 3 
Grade 3: Severe 
reaction without rapid 
recovery with 
treatment and/or 
interruption; or 
symptoms recur after 
alleviation; or the 
subject develops 
sequelae that requires 
hospitalization. 
Grade 4: 
Life-threatening. 
Immediately discontinue SHR-1210; 
Administer normal saline by intravenous infusion. 
Bronchodilators are recommended. Subcutaneous 
injection of 0.2-1 mg of 1:1000 adrenaline solution or 
slow intravenous infusion of 0.1-0.25 mg of 1:10,000 
adrenaline solution is recommended. Intravenous 
infusion of diphenhydramine 50 mg and 
methylprednisolone 100 mg (or equivalent dose) can be 
given if necessary. 
Medical practices and guidelines for treating allergic 
reactions at the study center are followed. Bedside 
observation and close monitoring until recovery. 
Discontinuation 
10.1.6.3 
Apatinib Dose Modification 
Dose modifications due to apatinib-related toxicity include: dose delay (for up to 28 days), dose 
reduction (first dose modification: 375 mg qd, second dose modification: 250 mg qd), and 
permanent treatment discontinuation. 
In case of Grade ≥ 3 apatinib-related toxicity, administration should be delayed until recovery, and 
then the original dose should be resumed or the dose should be reduced by one dose level. The 
minimum dose allowable is 250 mg/d. If the dose is still intolerable at the reduced dose of 
250 mg/d, apatinib should be permanently discontinued (refer to Table 6 for the recommended 
dose modification method). When apatinib is discontinued and SHR-1210 is well tolerated, the 
subject may receive SHR-1210 monotherapy. 


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In case of Grade ≥ 3 AEs unrelated to apatinib, the investigator shall decide on dose delay based on 
the actual situation. 
If apatinib causes Grade 2 ALT or AST increased for ≥ 7 days, the investigator can interrupt the 
apatinib treatment as appropriate. 
Dose increase of apatinib is not allowed during the study period. 
For subjects with hypertension with a blood pressure not more than 140/90 mmHg whose AE is 
considered as Grade 3-4 only because of the administration of multiple antihypertensive drugs, 
treatment interruption is not required. 
Table 6. Recommended dose modification of apatinib 
Apatinib 
Treatment-related 
toxicity 
Grade 
Dose delay 
Criteria for 
resuming 
Dose Modification 
Method 
Criteria for 
Discontinuation 
Hematologic 
Toxicity 
Grade 1-2 No 
— 
— 
— 
Grade 3-4 Yes 
Toxicity returns to 
Grade ≤ 2 
At the original dose or 
at a reduced dose level 
Apatinib interruption 
for more than 28 days 
Non-Hematologic 
Toxicity 
Grade 1-2 No 
— 
— 
— 
Grade 3-4 Yes 
Toxicity returns to 
Grade ≤ 1 
At the original dose or 
at a reduced dose level 
Apatinib interruption 
for more than 28 days 
10.1.6.4 Dose modification of doxorubicin/ifosfamide 
For subjects receiving doxorubicin combined with ifosfamide, dose modification can be made 
based on toxicities. 
Table 7. Recommended dose modification of doxorubicin/ifosfamide 
Chemotherapy-related 
toxicity 
Grade 
Dose delay Criteria for 
resuming 
Dose Modification 
Method 
Criteria for 
Discontinuation 
Hematologic Toxicity 
Grade 1-2 No 
— 
— 
— 
Grade 3-4 Yes 
Toxicity returns to 
Grade ≤ 1 
At the original dose 
or at a reduced dose 
level 
Chemotherapy 
interruption for more 
than 6 weeks 
Non-Hematologic 
Toxicity 
Grade 1-2 No 
— 
— 
— 
Grade 3-4 Yes 
Toxicity returns to 
Grade ≤ 1 
At the original dose 
or at a reduced dose 
level 
Chemotherapy 
interruption for more 
than 6 weeks 
For non-severe or non-fatal toxicities (e.g., alopecia, appetite change and nail discoloration), dose 
modification may not be necessary as judged by the investigator. 
Dose modification caused by toxicities of a single drug in the combination therapy will not affect 
the usage of other drugs according to the plan. 


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For subjects with hypertension with a blood pressure not more than 140/90 mmHg whose AE is 
considered as Grade 3-4 only because of the administration of multiple antihypertensive drugs, 
treatment interruption is not required. 
Table 8. Dose modification of doxorubicin/ifosfamide 
Drug 
Initial Dose 
Next Dose 
(85% of the initial dose) 
Dose after the Next 
Dose 
Doxorubicin 
60 mg/m2, q3w 
51 mg/m2, q3w 
Discontinuation 
Ifosfamide 
2 g/m2 on D1-D4 q3w for 
combined medication 
or 2 g/m2 on D1-D5 q3w for 
monotherapy 
1.7 g/m2 on D1-D4 q3w for 
combined medication 
or 1.7 g/m2 on D1-D4 q3w for 
monotherapy 
Discontinuation 
Chemotherapy-related toxicities cannot resolve within the same treatment cycle. Thus, the 
administration of doxorubicin/ifosfamide can be delayed for no more than 6 weeks (± 3 days). If 
the toxicities still do not resolve by 6 weeks, the chemotherapy will be discontinued, unless the 
investigator considers that the subjects can benefit from continued chemotherapy. 
10.2 Drug Management, Dispensation and Return 
The management, dispensation, and retrieval of study drugs should be the responsibility of 
designated study staff. The investigator must ensure that all study drugs are used for subjects 
participating in this clinical study. The dosage and administration are shown in Section 10.1.5. 
Remaining or expired drugs should be returned to the sponsor and may not be used for 
non-participants. 
When the drug is transported to the sub-center, a drug receipt form shall be signed in duplicate, one 
copy for the study center and one copy for the sponsor. When returning remaining drugs and empty 
packaging, both parties must sign the drug retrieval form. The dispensation and return of every 
drug should be immediately documented on designated forms. 
The CRA is responsible for monitoring the supply, use, and storage of study drugs, and disposal of 
remaining medications. 
10.2.1 Disposal of study drugs 
The sponsor or his/her authorized personnel will provide guidance on the destruction of unused 
study drugs. If the study center is authorized to destroy the study drugs, the investigator must 
ensure that the destruction of the study drugs complies with applicable environmental regulations 
and company policies, and provide relevant procedures for destruction. The investigator should 
record all destruction activities. 


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10.3 Concomitant Medications 
Concomitant medications refer to any drugs/treatments that are given for the interest of subjects as 
determined by the investigator. 
All concomitant medications, blood products, and non-drug interventions (e.g., paracentesis) that 
are given to the subjects from 28 days prior to the first dose to the end of the safety visit must be 
strictly documented in the CRF according to GCP requirements. If a subject starts a new 
anti-tumor therapy during the safety follow-up period, only concomitant medications used for 
treatment-related AEs will be collected. 
Prohibited medications and vaccines specified in the study protocol are strictly prohibited during 
the entire course of study. If the subject develops a comorbidity requiring treatment with a 
prohibited drug, the investigator should consult with the sponsor before discontinuing the study 
treatment or using the prohibited drug. Whether the subject will continue the study treatment or 
receive a prohibited drug should be jointly decided by the investigator, the sponsor, and the 
subject. 
In addition to the following contents, for subjects who receive apatinib, doxorubicin, and 
ifosfamide, the latest package insert of marketed drugs or medical practices regarding 
contraindications and precautions shall also be taken for reference. 
10.3.1 Other anti-tumor/cancer or study drugs 
Other anti-tumor treatments not specified in the protocol are not permitted while subjects are 
receiving study treatment, including CDFA (NMPA)-approved Chinese herbal preparations for 
anti-tumor treatments (see Appendix 9. Prohibited Traditional Chinese Medicines During the 
Study Period) and immunomodulators (including but not limited to interferon, interleukin-2, and 
thymosin). 
Participation in other drug/medical device clinical studies is not permitted. 
Subjects can receive bisphosphonates for the treatment of bone metastases. If systemic treatment 
or local analgesia is not effective in controlling painful lesions of bone metastases, a small area of 
palliative radiotherapy (the area of the radiotherapy must be < 5% of the bone marrow region, and 
the percent bone marrow in human is shown in Appendix 8. Percent Bone Marrow Content in 
Human Skeleton) is allowed. Except for the above-mentioned treatments for bone metastases, 
other anti-tumor treatments such as chemotherapy, molecular targeted therapy, hormone therapy, 
immunotherapy, biological therapy, radiotherapy, and surgical treatment are not permitted. 


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10.3.2 Medications to be used with caution in subjects receiving apatinib 
10.3.2.1 Drugs that may have interactions with apatinib mesylate 
In vitro metabolic enzymes studies have shown that apatinib is mainly metabolized by CYP3A4. 
When apatinib is used concomitantly with strong inhibitors of CYP3A4 (itraconazole, 
clarithromycin, voriconazole, telithromycin, saquinavir, and ritonavir), the plasma concentration 
of apatinib may rise. When apatinib is used concomitantly with CYP3A4 inducers 
(dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, and rifapentine), the 
plasma concentration of apatinib may decrease. When other combined medications are needed, it 
is recommended to choose alternative drugs that do not inhibit or induce CYP3A4. If a strong 
inducer or inhibitor of CYP3A4 enzyme must be used concomitantly, it is necessary to consider 
whether to modify the dose based on clinical observation. 
10.3.2.2 
Drugs that prolong the QT interval of the heart 
As tinib drugs may cause toxicities of prolonged QT interval in clinical applications, drugs that 
may prolong the QT interval should be used with caution during the study. These mainly include, 
but are not limited to, the following categories of drugs: 
 
Antibiotics: fluoroquinolones: sparfloxacin, gatifloxacin, levofloxacin, moxifloxacin, 
ofloxacin, ciprofloxacin; macrolides: erythromycin, clarithromycin, telithromycin, 
azithromycin, roxithromycin, and metronidazole. 
 
Antiarrhythmics: quinidine, procainamide, disopyramide, flecainide, propafenone, 
amiodarone, dronedarone, sotalol, dofetilide, and ibutilide. 
 
Drugs used to relieve angina: ranolazine and ivabradine. 
 
Antipsychotics: risperidone, fluphenazine, droperidol, haloperidol, thioridazine, 
pimozide, olanzapine, and clozapine. 
 
Antifungal drugs: voriconazole and posaconazole. 
 
Antimalarial drugs: mefloquine and chloroquine. 
 
Antihistamines: terfenadine, astemizole, and hydroxyzine. 
 
Gastrointestinal drugs: antiemetics: ondansetron, granisetron, dolasetron, droperidol 
(0.625-1.25 mg may be a safe dose), and hydroxyzine; prokinetics: cisapride, 
domperidone, and metoclopramide. 
 
Antidepressants: amitriptyline, imipramine, clomipramine, dosulepin, and doxepin. 


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10.3.3 Hematopoietic growth factor 
According to the current edition of the "American Society of Clinical Oncology Clinical Practice 
Guideline", granulocyte colony stimulating factor is used as prophylaxis for neutropenia. 
The probability that doxorubicin + ifosfamide causes febrile neutropenia is ≥ 20%, and it is 
recommended to use recombinant human granulocyte stimulating factor (such as 
mecapegfilgrastim) for prophylaxis. Whether to continue to use recombinant human granulocyte 
stimulating factor (such as mecapegfilgrastim) in the future depends on the outcome of 
previous use. 
10.3.4 
Dexrazoxane 
Dexrazoxane is recommended when the cumulative dose of doxorubicin reaches 300 mg/m2, but is 
not recommended when the cumulative dose has not reached 300 mg/m2, so as not to affect the 
efficacy. 
10.3.5 Mesna 
The toxicity of acrolein, a degradation product of ifosfamide, to the urinary system is mainly 
hemorrhagic cystitis, while Mesna reacts with acrolein and becomes non-toxic products that are 
excreted in the urine, reducing the incidence of hemorrhagic cystitis. The recommended dose for 
single-dose injection of Mesna is 20% (w/w) of ifosfamide, injected at the start of ifosfamide 
infusion, at 4 h after the infusion, and at 8 h after the infusion (the total dose is 60%). The 
recommended infusion time is the scheduled time ± 10 min.  
The recommended dose of ifosfamide in the protocol is 2 g/m2, and the recommended dose of 
mesna is 400 mg/m2 per injection (the actual dose should not be less than the recommended dose). 
10.3.6 Treatment for vomiting 
Chemotherapy with anthracycline and ifosfamide may pose a risk of vomiting. The investigator 
shall determine the prophylactic drugs to be used. 
The use of antiemetic drugs as a primary prevention method is not allowed for the investigational 
treatment group. 
10.3.7 Anti-inflammatory treatment 
Anti-inflammatory medications or narcotic analgesics can be given if there are no known or 
foreseeable drug interactions and if these drugs are not prohibited in the protocol. 
10.3.8 Corticosteroids 
Long-term, systemic use of corticosteroids for palliative or supportive treatment are prohibited. 
Emergency use, topical application, inhalation, eye drops, or local injections of corticosteroids are 
permitted. 


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10.3.9 
Surgery 
Any non-therapeutic tumor surgery conducted during the study period shall have its theoretical 
basis and necessity. The interval between the surgery and the treatment with study drug must not 
affect the recovery of the wound and the investigation on hemorrhage of unknown cause. An 
interruption of study treatment 1 week before the surgery is recommended. Re-initiation of study 
treatment after surgery will be determined on the basis of clinical assessment of wound healing and 
postoperative recovery. 
10.4 Subject Compliance 
Subjects in the investigational treatment group will be required to return or count all study drugs 
that have not been administered in the previous cycle before the start of the next cycle. The 
corresponding number of apatinib tablets will be documented and archived. The medication 
information in the subject's diary card will also be checked for consistency. 
For SHR-1210, doxorubicin, and ifosfamide, the study center shall prepare the drugs complete the 
documentation as per the product brochure or package insert. The documentation system of the 
study center should include all relevant or required information with regards to preparation and 
administration. 
11 STUDY PROCEDURES 
Before the start of the study, subjects must read and sign the current version of ICF approved by 
the independent ethics committee/institutional review board (IEC/IRB). All the study procedures 
must be completed within the time window specified in the study schedule. The informed consent 
form shall be signed within 28 days before C1D1. Subjects who have failed previous screening 
may be screened again in this study. The informed consent form must be re-signed and a new 
subject number should be given for re-screening. If the re-screening fails, no further screening will 
be performed. Data from virology, echocardiography, and imaging assessment (tested at this study 
center only) performed prior to the signing of informed consent for clinical needs may be used if 
they are within the specified window period. 
11.1 Screening 
Unless otherwise stated, the following procedures must be completed within 28 days prior to the 
start of study treatment during at the screening visit (Day-28 to Day-1): 
• 
Obtain informed consent form signed by the subject. 
• 
Collecting demographics: gender, date of birth, ethnicity, etc. 


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• 
Tumor diagnosis: the location of the primary lesion, the date of pathological diagnosis, 
the pathological diagnosis (must be consistent with the term of the 2013 version of the 
WHO guidelines on soft tissue tumors), the time of progressive disease or recurrence, 
and the progressive disease (locally advanced, unresectable, or distantly metastatic). 
• 
History of cancer treatment 
✓ History of tumor surgery: type, name, and date of surgery; 
✓ History of radiotherapy: site, total dose, and start and end dates; 
✓ History of neoadjuvant chemotherapy or chemotherapy: chemotherapy regimen, 
cycle, start and end dates, best response, reason for discontinuation of chemotherapy, 
whether recurrence happens within 6 months, and cumulative total dose of 
doxorubicin; 
✓ History of adjuvant chemotherapy: chemotherapy regimen, cycle, start and end dates, 
reason for discontinuation of chemotherapy, whether recurrence happens within 6 months, 
and cumulative total dose of doxorubicin; 
 
Medical history, surgical history, medication history (concomitant medications within 
28 days before C1D1), history of drug or alcohol abuse, history of drug allergy, etc.; 
• 
Virology: HBsAg (quantitative HBV DNA test if positive); HCV-Ab (quantitative 
HCV-RNA test if positive) and HIV-Ab: within 28 days before the first dose. 
• 
Echocardiography: Including left ventricular ejection fraction (LVEF) assessment. 
Echocardiography will be performed once within 28 days prior to the first dose, and 
performed if clinically indicated thereafter. 
• 
Imaging evaluation: CT or MRI of lesions in the head, chest, abdomen, pelvis, and other 
sites. Sites with bone metastasis as shown by bone scans, PET-CT, or clinical indications 
must also be reexamined by CT or MRI at baseline. 
• 
Collection of adverse events: Collect adverse events starting from the signing of ICF. 
• 
Concomitant medications/treatments: Concomitant medications/treatments within 28 days 
prior to the first dose of the study drug should be documented. 
The following screening procedures should be completed within 7 days before the start of 
study treatment: 
• 
ECOG PS. 
• 
Vital signs: pulse, respiratory rate, temperature, and blood pressure. 


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• 
Comprehensive physical examination: height, weight, general condition, head and face, 
neck, chest, abdomen, perineum, extremities, etc. 
• 
Hematology: Red blood cell count (RBC), hemoglobin (Hb), blood platelet count (PLT), 
white blood cell count (WBC), absolute neutrophil count (ANC), and lymphocyte count 
(LYM). 
• 
Urinalysis: WBC, RBC, and urine protein. If urine protein is ≥ 2+, then a quantitative 
24-h urine protein test should be added. 
• 
Fecal occult blood (OB): within 7 days before the first dose. 
• 
Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), 
alkaline phosphatase (AKP), blood urea nitrogen (BUN) or urea, total protein (TP), 
albumin (ALB), creatinine (Cr), blood glucose (GLU), serum potassium (K+), serum 
natrium (Na+), serum calcium (Ca2+), serum magnesium (Mg2+), and blood chloride 
(Cl-). 
• 
Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time 
(PT), thrombin time (TT), fibrinogen (FIB), and international normalized ratio (INR). 
• 
Thyroid function: Including serum thyroid stimulating hormone (TSH), free 
triiodothyronine (FT3), and free thyroxine (FT4). If FT3 and FT4 cannot be obtained, T3 
and T4 are allowed for substitution; 
• 
Myocardial zymogram: lactate dehydrogenase (LDH), creatine kinase (CK), and hybrid 
creatine kinase (CK-MB) 
• 
12-Lead ECG: Attentions should be paid to heart rate, QT, QTcF, and PR intervals. The 
investigator may decide to add other investigations if the results are abnormal. 
• 
Pregnancy test (serum pregnancy test will be performed for women of childbearing 
potential). 
• 
Quality of life score. 
11.2 Treatment Period 
11.2.1 Treatment period for the investigational treatment group 
The treatment period for the investigational treatment group will start from the first dose of the 
subject. The first dose of the study drugs should be given as close as possible to the time of 
completing the screening examinations and confirming the subjects' eligibility for the study. Each 
treatment cycle lasts for 21 days. 


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◆ The following should be completed on C1D1: 
 
Dispensation of study drugs in the investigational treatment group: Apatinib tablets 
are permitted to be dispensed on the day before or on the day of administration. 
 
Treatment with SHR-1210 and apatinib 
 
Pharmacokinetics and immunogenicity test for the investigational treatment group: 
Approximately 4-6 mL of peripheral venous blood will be collected within 0.5 h 
before the administration of SHR-1210 on C1D1 for 
pharmacokinetics/immunogenicity test of SHR-1210; Approximately 2-4 mL of 
peripheral venous blood will be collected within 0.5 h before and at 4 h (± 10 min) 
after the administration of apatinib on C1D1 for pharmacokinetics test of apatinib. 
 
Adverse event 
 
Recording of concomitant medications and concomitant treatments 
 
Dispensation and filling in of the subject diary card 
◆ The following should be completed on day 1 of each cycle from cycle 2 onwards: 
 
ECOG PS 
 
Vital signs 
 
Physical examination 
 
Hematology 
 
Fecal occult blood 
 
Blood biochemistry 
 
12-Lead ECG 
 
Dispensation and retrieval of study drugs of the investigational treatment group: 
Apatinib tablets are allowed to be dispensed at the scheduled time point within ± 
3 days; remaining apatinib must be retrieved before each dispensation. Unscheduled 
drug dispensation and retrieval are permitted. 
 
Pharmacokinetics/immunogenicity test: Within 0.5 h pre-administration on C2D1, 
C4D1, C6D1, C9D1 and every 4 cycles thereafter, with 4-6 mL of peripheral venous 
blood collected at each time point for pharmacokinetics/immunogenicity studies of 
SHR-1210; 4-6 mL of peripheral venous blood will be collected once 30 days after 
the last dose. Approximately 2-4 mL of peripheral venous blood will be collected 
within 0.5 h before and at 4 h (± 10 min) after the administration of apatinib on 
C2D1, C4D1, and C6D1 for pharmacokinetics study of apatinib. 


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 
Collection of AEs 
 
Documentation of concomitant medications/concomitant treatments 
 
Dispensation and filling in of the subject diary card 
◆ The following should be completed on day 1 of every 2 cycles from cycle 3 onwards: 
 
Urinalysis 
 
Coagulation function 
 
Thyroid function 
 
Blood pregnancy test 
 
Tumor imaging examination: Imaging examinations will be performed once every 
2 cycles (6 weeks) in the first 16 treatment cycles of the study treatment period and 
once every 4 cycles (12 weeks) thereafter. Imaging conditions should be the same as 
those at baseline (including slice thickness and contrast agent). The time window for 
imaging examination is ± 7 days. Additional imaging evaluations may be performed 
if PD is suspected (e.g., worsening of symptoms) 
 
Quality of life score 
11.2.2 Treatment period for the control group 
The treatment period will start from the first dose of the subject in the control group. The first dose 
of the study drugs should be given as close as possible to the time of completing the screening 
examinations and confirming the subjects' eligibility for the study. Each treatment cycle lasts for 
21 days. 
◆ The following should be completed on C1D1: 
 
Treatment with doxorubicin + ifosfamide or ifosfamide monotherapy 
 
Adverse event 
 
Recording of concomitant medications and concomitant treatments 
◆ The following should be completed on day 1 of each cycle from cycle 2 onwards 
(additional chemotherapy cycles may be administered if deemed beneficial by the 
investigator): 
 
ECOG PS 
 
Vital signs 
 
Physical examination 


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 
Hematology 
 
Urinalysis 
 
Fecal occult blood 
 
Blood biochemistry 
 
Coagulation function 
 
Myocardial zymogram 
 
12-Lead ECG 
 
Echocardiography 
 
Blood pregnancy test: Once every 2 cycles from cycle 3 onwards 
 
Treatment with doxorubicin + ifosfamide or ifosfamide monotherapy 
 
Collection of AEs 
 
Documentation of concomitant medications/concomitant treatments 
 
Tumor imaging examination: Imaging examinations will be performed once every 
2 cycles (6 weeks) in the first 16 treatment cycles of the study treatment period and 
once every 4 cycles (12 weeks) thereafter. Imaging conditions should be the same as 
those at baseline (including slice thickness and contrast agent). The time window for 
tumor evaluation is ± 7 days. Additional tumor evaluations may be performed if PD 
is suspected (for example, worsening of symptoms). 
 
Quality of life score: Quality of life scoring will be performed once every 2 cycles in 
the first 16 treatment cycles from cycle 3 onwards and once every 4 cycles from 
cycle 17 onwards. 
11.3 Follow-Up Period 
11.3.1 Safety follow-up for the investigational treatment group 
The safety follow-up for the combined medication of SHR-1210 and apatinib will start from the 
last dose of study treatment. Follow-ups will be performed once every 30 days (± 5 days) until 
90 days after the last dose. 
The first safety follow-up (30 ± 5 days) will be carried out at the study center where the evaluations 
specified in the protocol are completed. The second (60 ± 5 days) and the third (90 ± 5 days) 
follow-up will be made via phone calls. The information on new anti-tumor treatment, survival, 
concomitant medications/concomitant treatments, and adverse events will be collected. 


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◆ At the first safety follow-up (30 ± 5 days), subjects should return to the study center to 
complete the following assessments: 
 
ECOG PS 
 
Vital signs 
 
Physical examination 
 
Hematology 
 
Urinalysis 
 
Fecal occult blood 
 
Blood biochemistry 
 
Thyroid function 
 
Coagulation function 
 
Myocardial zymogram 
 
12-Lead ECG 
 
Imaging examination: Subjects who discontinue the study treatment for reasons 
other than radiographic progression will still be followed up according to the 
established cycle. If no imaging examination is performed within 4 weeks before the 
last dose, an imaging examination must be performed within 30 days after the 
last dose. 
 
Pharmacokinetics and immunogenicity test: 4-6 mL of peripheral venous blood will 
be collected 30 days (± 5 days) after the last dose for pharmacokinetics and 
immunogenicity tests of SHR-1210. 
 
Adverse events: Recorded from the date of signing the informed consent form to the 
end of the safety follow-up period. If a new anti-tumor treatment is initiated during 
this period, only treatment-related AEs will be collected after the start of the new 
anti-tumor treatment. 
 
Concomitant medications/treatments 
 
New anti-tumor treatment 
 
Quality of life score 
◆ For the second (60 days after the last dose) and the third safety follow-ups (90 days after 
the last dose), the subjects' subsequent anti-tumor treatment, survival, adverse events, 
and concomitant medications/treatments will be collected via phone interviews. 


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11.3.2 Safety follow-up for the control group 
The safety follow-up period for the combined medication of doxorubicin and ifosfamide will start 
from 21 days (± 5 days) after the last dose.  
◆ At the safety follow-up (21 ± 5 days), subjects should return to the study center to 
complete the following assessments: 
 
ECOG PS 
 
Vital signs 
 
Physical examination 
 
Hematology 
 
Urinalysis 
 
Fecal occult blood 
 
Blood biochemistry 
 
Thyroid function 
 
Coagulation function 
 
Myocardial zymogram 
 
12-Lead ECG 
 
Echocardiography 
 
Imaging examination: Subjects who discontinue the study treatment for reasons 
other than radiographic progression will still be followed up according to the 
established cycle if no imaging assessment is performed within 4 weeks before the 
last dose. An imaging examination must be performed within 21 days after the last 
dose. 
 
Adverse events: Recorded from the date of signing the informed consent form to the 
end of the safety follow-up period. If a new anti-tumor treatment is initiated during 
this period, only treatment-related AEs will be collected after the start of the new 
anti-tumor treatment 
 
Concomitant medication/treatments: Those within 28 days before the first dose of 
study medication to the new anti-tumor treatment will be documented; afterward, 
only concomitant medications for treatment-related AEs are documented. 
 
New anti-tumor treatment 
 
Quality of life score 


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11.3.3 Survival follow-up 
The survival follow-up period starts after the end of the safety follow-up period. The survival 
follow-up period ends upon the subject's death, lost to follow-up, withdrawal of informed consent, 
or study termination by sponsor. During this period, an effective follow-up such as telephone 
follow-up will be conducted once every 2 months to collect information on subject survival and 
subsequent treatments (if the subject has started a new anti-tumor treatment, the therapeutic 
regimen and the start and end time should be recorded). 
11.4 Criteria for Crossover Treatment of Control Group 
Subjects who are willing to and eligible for crossover treatment may be crossed over to receive the 
treatment of SHR-1210 combined with apatinib. 
11.4.1 Screening Period 
Unless otherwise stated, the following procedures must be completed within 7 days prior to the 
start of study treatment during at the screening visit (Day-7 to Day-1): 
• 
Obtain informed consent form signed by the subject. 
• 
Virology: HBsAg (quantitative HBV DNA test if positive); HCV-Ab (quantitative 
HCV-RNA test if positive) and HIV-Ab: within 28 days before the first dose. 
• 
Echocardiography: Including left ventricular ejection fraction (LVEF) assessment. 
Echocardiography will be performed once within 28 days prior to the first dose, and 
performed if clinically indicated thereafter. 
• 
Imaging evaluation: CT or MRI of lesions in the head, chest, abdomen, pelvis, and other 
sites. Sites with bone metastasis as shown by bone scans, PET-CT, or clinical indications 
must also be reexamined by CT or MRI at baseline but no longer undergo bone scan or 
PET-CT for efficacy follow-up. 
• 
Collection of adverse events: Collect adverse events starting from the signing of ICF. 
• 
Concomitant medications/treatments: Concomitant medications/treatments within 28 days 
prior to the first dose of the study drug should be documented. 
• 
ECOG PS. 
• 
Vital signs: pulse, respiratory rate, temperature, and blood pressure. 
• 
Comprehensive physical examination: height, weight, general condition, head and face, 
neck, chest, abdomen, perineum, extremities, etc. 


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• 
Hematology: Red blood cell count (RBC), hemoglobin (Hb), blood platelet count (PLT), 
white blood cell count (WBC), absolute neutrophil count (ANC), and lymphocyte count 
(LYM). 
• 
Urinalysis: WBC, RBC, and urine protein. If urine protein is ≥ 2+, then a quantitative 
24-h urine protein test should be added. 
• 
Fecal occult blood (OB): within 7 days before the first dose. 
• 
Blood biochemistry: Alanine transaminase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), 
alkaline phosphatase (AKP), blood urea nitrogen (BUN) or urea, total protein (TP), 
albumin (ALB), creatinine (Cr), blood glucose (GLU), serum potassium (K+), serum 
natrium (Na+), serum calcium (Ca2+), serum magnesium (Mg2+), and blood chloride 
(Cl-). 
• 
Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time 
(PT), thrombin time (TT), fibrinogen (FIB), and international normalized ratio (INR). 
• 
Thyroid function: Including serum thyroid stimulating hormone (TSH), free 
triiodothyronine (FT3), and free thyroxine (FT4). If FT3 and FT4 cannot be obtained, T3 
and T4 are allowed for substitution; 
• 
12-Lead ECG: Attentions should be paid to heart rate, QT, QTcF, and P-R intervals. The 
investigator may decide to add other investigations if the results are abnormal. 
• 
Echocardiography 
• 
Pregnancy test (serum pregnancy test will be performed for women of childbearing 
potential). 
• 
Quality of life score. 
11.4.2 Treatment period 
The content of the visit is the same as 11.2.1 Treatment period for the investigational treatment 
group. 
11.4.3 Follow-up period 
The content of the visit is the same as 11.3.1 Safety follow-up for the investigational treatment 
group. 


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11.5 Unscheduled Visit 
The following shall be documented during unscheduled visits when subjects develop AEs during 
the study: 
• 
Concomitant medications/treatments; 
• 
Adverse events; 
• 
All examinations performed related to adverse events (including radiographic 
examinations, if any). 
12 EVALUATIONS 
12.1 Efficacy Evaluation 
In addition to the investigator's assessments of the tumor imaging results in this study, the sponsor 
will also collect all imaging results (except for the imaging results of the control group after 
crossover treatment), and use them for blinded independent review (all per RECIST v1.1). The 
specific procedures for independent review are described in the "Third-Party Independent Review 
Charter" for this study, written by the central imaging. 
PFS: the time between the date of enrollment and the date of the first documented tumor 
progression (as per RECIST v1.1, regardless of whether treatment is continued), or death from any 
cause, whichever occurs first. 
In addition, subjects in the investigational treatment group will continue the study treatment after 
progressive disease. The investigator will perform subsequent imaging assessments as per 
iRECIST (see Appendix 11; independent imaging evaluation is still carried out as per RECIST 
v1.1) for exploratory evaluation of PFS in the investigational treatment group as per iRECIST. 
PFS is defined as the period of time from the date of the subject's enrollment to the first iUPD that 
can be subsequently confirmed or the date of death due to any cause, whichever occurs first. The 
imaging evaluation criteria of the control group after crossover treatment are the same as those of 
the investigational treatment group, but no independent review of central imaging will be 
performed. The subjects after crossover will be analyzed based on the PFS data as per RECIST 
v1.1 and iRECIST. 
OS: the time from the date of enrollment to the date of death from any cause. Subjects whose final 
status is "survived" are censored, and the date of censoring is the date of the last follow-up. 
ORR: the proportion of treated subjects whose best overall response (BoR) is complete response 
(CR) or partial response (PR) as per RECIST1.1. 


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DCR: the proportion of treated subjects whose best overall response is complete response (CR), 
partial response (PR), or stable disease (SD) as per RECIST v1.1. 
DoR: the period of time from the first documented tumor response (as per RECIST v1.1) to the 
first documented objective progression (as per RECIST v1.1) or death of any cause. 
iORR: the proportion of treated subjects whose best overall response (BoR) is complete response 
(CR) or partial response (BOR) as per iRECIST v1.1. 
iDCR: the proportion of treated subjects whose best overall response is complete response (CR), 
partial response (PR), or stable disease (SD) as per iRECIST v1.1. 
iDoR: the period of time from the first documented tumor response (as per iRECIST v1.1) to the 
date of the first iUPD that can be subsequently confirmed or the date of death from any cause. 
12.2 Safety Evaluation 
12.2.1 Pregnancy test 
Female subjects of childbearing potential will receive a sub-serum pregnancy test before the start 
of administration. When the pregnancy test shows negative during the screening period, 
appropriate contraceptive measures shall be taken. 
Pregnancy test will also be performed routinely once every two cycles during the treatment period 
and at the end of study treatment, or additionally when a menstrual cycle is missed or when signs 
of pregnancy are suspected. If the HCG test is positive, the subject discontinues the dose but will 
continue to be observed for follow-up of the pregnancy event. 
12.2.2 Adverse event 
The evaluation of an adverse event (AE) includes the type, incidence, severity (according to 
NCI-CTCAE v4.03), and start and end time of the AE, as well as whether the AE is a SAE, the 
correlation of the AE to the study drug, and the outcome of the AE. 
AEs that occur during the study, including signs and symptoms at screening, will be recorded on 
the AE page of the CRF. 
12.2.3 
Laboratory safety assessment 
The blood samples for hematology and blood biochemistry tests will be collected according to the 
Schedule of Activities, and will be analyzed at the local laboratory. 


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Table 9. Laboratory tests 
Hematology 
Blood biochemistry 
Serum natrium 
FT4 (or T4) 
Red blood cell 
ALT 
Serum calcium 
Myocardial zymogram 
Hemoglobin 
AST 
Serum magnesium 
Lactate dehydrogenase 
Blood platelet 
Glutamyl transpeptidase 
Blood chlorine 
Creatine kinase 
White blood cell 
Total bilirubin 
Coagulation 
function 
Hybrid creatine kinase 
Absolute neutrophil count 
Direct bilirubin 
APTT 
Pregnancy Test 
Lymphocyte count 
Alkaline phosphatase 
PT 
Serum pregnancy test 
Urinalysis 
Blood urea nitrogen (or urea) TT 
 
White blood cell 
Total protein 
FIB 
 
Red blood cell 
Albumin 
INR 
 
Urine protein 
Creatinine 
Thyroid function 
 
Fecal occult blood 
Glucose 
TSH 
 
Occult blood 
Serum potassium 
FT3 (or T3) 
 
12.2.4 Vital signs and physical examination 
Physical examinations and vital sign examinations are completed by the research physician. 
Vital signs include temperature, blood pressure, pulse, and respiratory rate. 
Physical examination: height, weight, general condition, head and neck, chest, abdomen, 
perineum, and extremities. Height will be measured during screening only. 
12.2.5 12-Lead electrocardiography (ECG) 
12-Lead ECG shall be performed at the time points specified in the "Schedule of Activities". 
Subjects are required to rest quietly for at least 10 minutes in a supine position prior to undergoing 
the ECG. The ECG includes at least: heart rate, QT, and P-R intervals. QTcF can be calculated as: 
QTcF = QT/(60/heart rate)0.33. 
12.2.6 Echocardiography 
Echocardiography will be performed by qualified physicians. LVEF is also measured. 
12.3 Collection and Processing of Immunogenicity and Drug Trough Concentration Blood 
Samples 
Peripheral blood of subjects receiving SHR-1210 combined with apatinib will be used for 
immunogenicity and PK concentration testing. Refer to the "Laboratory Manual" for details. 


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12.4 Independent Data Monitoring Committee 
In this study, an Independent Data Monitoring Committee (IDMC) will be established to evaluate 
the safety and efficacy of the study drug at the data review meetings on a regular basis. An interim 
analysis will be performed when about 143 (67%) OS events will be collected. The IDMC will 
make recommendations on whether to continue or terminate the study based on the safety and 
efficacy data and results. The IDMC review meeting will be held at the time specified in the 
charter of the IDMC. The study enrollment will continue during IDMC meetings. 
After the data review, the IDMC will provide suggestions on whether to continue the study, 
whether to modify the protocol, or whether to discontinue the study. Finally, Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. will decide whether to adopt the IDMC suggestions. 
See details in IDMC charter. 
13 ADVERSE EVENTS REPORTING 
13.1 Adverse Events (AEs) 
13.1.1 Definition of adverse event 
An AE refers to any untoward medical condition in a clinical study subject who receives a 
pharmaceutical product, and the condition does not necessarily have a causality with the treatment. 
AEs can include any unfavorable and unintended symptoms, signs, abnormal laboratory finding, 
or diseases, including the following: 
1)  Worsening of pre-existing (prior to entering clinical study) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2)  Any new AE: Any new adverse medical conditions (including symptoms, signs, and 
newly diagnosed diseases); 
3)  Clinically significant abnormal laboratory findings. 
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, causality assessment, duration, 
measures taken, as well as final results and outcomes. 
13.1.2 AE severity grading criteria 
The severity of AEs will be graded as per NCI-CTCAE v4.03. Refer to the following criteria for 
AEs not listed in the table of NCI CTCAE v4.03: 


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Table 10. 
CTC-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 noninvasive intervention indicated; limiting age-appropriate instrumental 
activities of daily life, e.g., cooking, shopping, using the telephone, counting money, etc. 
3 
Severe or medically significant but not immediately life-threatening; leading to hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ADL). 
Self-care ADL: refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Resulting in death 
13.1.3 Determination of the relationship between AEs and the study drug 
AEs include all unexpected clinical manifestations. All AEs that occur after the signing of the ICF 
must be reported regardless of whether the AEs are related to the study drug, whether the subject is 
allocated to the treatment group, and whether the subject receives the drug. Any discomforts 
complained by the subject or changes in objective laboratory measurements during the treatment 
period should be truthfully recorded. The severity, duration, measures taken, and the outcome of 
AEs should also be documented. The study physician shall assess the relationship between the AE 
and the study drugs by considering the time sequence between the administration of study drug and 
the occurrence of AE, characteristics and toxicology of the study drug, concomitant medications, 
underlying diseases, medical history, family history, as well as dechallenge and rechallenge. The 
causality assessment will be provided using the following five categories "definitely related, 
possibly related, unlikely related, definitely unrelated, and indeterminable". "Indeterminable" to 
be adverse drug reaction. 
13.2 Serious Adverse Event (SAE) 
13.2.1 Definition of SAE 
A 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 resulting in death; 
• 
Life-threatening events (defined as when the subject is at immediate risk of death at the 
time of the event); 
• 
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• 
Events resulting in permanent or serious disability/incapacity/impairment of work ability; 
• 
Congenital anomalies or birth defects; 
• 
Other important medical events (defined as events that may jeopardize the subject or 
require interventions to prevent any of the above). 
13.2.2 Hospitalization 
AEs resulting in hospitalization (even if for less than 24 hours) 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.) 
Hospitalization or prolonged hospitalization unrelated to the worsening of an AE is not a SAE. For 
example: 
 
Hospitalization due to the pre-existing disease without new AEs and aggravation of the 
pre-existing disease (e.g., hospitalization to examine laboratory abnormalities that have 
persisted from before the study until now); 
 
Hospitalization for management reasons (e.g., annual physical examination); 
 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to worsening of AEs (e.g., elective surgery); 
 
Scheduled treatment or surgery that should be documented throughout the entire study 
protocol and/or in the subjects' individual baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) and non-invasive procedures should not be 
reported as AEs. However, when a condition resulting in such procedures meets the definition of 
AE, it should be reported as such. For example, acute appendicitis during the AE reporting period 
should be reported as an AE, and the resulting appendicectomy shall be recorded as the treatment 
of the AE. 


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13.2.3 Progressive disease 
Progressive disease is defined as the worsening of the subject's conditions caused by the 
indications of the study, including radiological progressions and progressions in clinical symptoms 
and signs. New metastases relative to the primary tumor or progressions of the previous metastases 
are recognized as PD. Life-threatening events, hospitalization or prolonged hospitalization, or 
events resulting in permanent or severe disability/incapacity/impairment of work ability, 
congenital anomalies or birth defects arising from the symptoms and signs of PD are not reported 
as SAEs. Death caused by the symptoms and signs of PD will be reported as a SAE. 
13.2.4 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 total bilirubin, the following criteria are met, and when there are no 
other causes of liver injury. These cases should always be considered as important medical events. 
Potential drug-induced liver injury is defined as follows: 
Baseline Period 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment period 
• 
ALT or AST ≥ 3 × ULN 
• 
with TBIL ≥ 2 × ULN 
• 
and ALP ≤ 2 × ULN 
• 
and no hemolysis 
• 
AST or ALT ≥ 2 × baseline level, and ≥ 3 × 
ULN; or AST or ALT ≥ 8 × ULN 
• 
with TBIL increase ≥ 1 × ULN or ≥ 3 × ULN 
After being notified of the abnormal results, the subjects should return to the study center for an 
assessment as soon as possible (preferably within 48 h). Assessments include the laboratory tests, 
detailed medical history, and physical assessment, and the possibility of hepatic tumor (primary or 
secondary) should be considered. 
Except for reexaminations of AST and ALT, other laboratory tests include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, γ-glutamyltransferase, PT/INR, and alkaline 
phosphatase. 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 a SAE. 


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13.2.5 SAE reporting 
In the event of a SAE, whether it is the first report or a follow-up report, the investigator must 
complete the "Serious Adverse Event Report Form" immediately, with a signature and date, and 
notify the sponsor within 24 h of knowing of the event. Relevant authorities must be informed of 
such SAE in a timely manner according to regulatory requirements. 
SAEs that occur after the safety follow-up period which are suspected to be related to the study 
drugs should be collected. 
The symptoms, severity, causality with the study drug, time of onset, time of treatment, measures 
taken, time and method of follow-up, and outcome should be documented in detail in the SAE 
report. If the investigator believes that a 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 study drug changes, a 
follow-up report should be submitted immediately. If an error is found in a previously reported 
SAE, such SAE may be revised, revoked, or downgraded in follow-up reports and reported in 
accordance with the SAE reporting procedure. 
The sponsor's email address for safety data of this study is: hengrui_drug_safety@hrglobe.cn 
13.2.6 
Time limit for collection and follow-up of AEs/SAEs 
All AEs/SAEs will be collected from the signing of the informed consent form. The time limit and 
follow-up periods for new events are described in the table below. 
Table 11. 
Principles of AE/SAE collection and follow-up 
Classification 
Onset Time 
Follow-up Time 
Unrelated AEs 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related AEs 
Until the end of safety follow-up 
period 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 
Unrelated SAEs 
(including SIEs) 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related SAEs 
(including SIEs) 
No time limit 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 


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13.3 Pregnancy 
If a female subject becomes pregnant during the clinical study (until the end of the safety 
follow-up period or start of a new anti-tumor treatment), the subject must withdraw; if the partner 
of a male subject becomes pregnant during the clinical study, the subject may continue the study. 
The investigators must fill out the "Pregnancy Report/Follow-up Form for Hengrui's Clinical 
Studies" and report to the sponsor within 24 hours after becoming aware of the pregnancy, and 
report to the ethics committee promptly. 
The investigator should follow up the outcome of the pregnancy until 1 month after delivery, and 
report the outcome to the sponsor. 
Pregnancy outcomes such as stillbirth, spontaneous abortion, and fetal malformation are 
considered SAEs and need to be reported according to the time requirements for SAEs. 
If the subject also experiences a SAE during the pregnancy, the CFDA (now NMPA) Serious 
Adverse Event Report Form should also be filled out and reported according to the SAE reporting 
procedure. 
13.4 Adverse Events of Special Interest 
When an AE of special interest specified in the study protocol occurs, the investigator must fill out 
the "Report of Adverse Event of Special Interest for Hengrui's Clinical Studies" and report to the 
sponsor within 24 h of being notified. If the AE of special interest is also a SAE, the "NMPA 
Serious Adverse Event Report Form" should also be completed and submitted to the relevant 
authorities according to SAE reporting procedure. 
• 
Grade ≥ 3 infusion reactions; 
• 
Grade ≥ 3 irAEs; 
14 DATA ANALYSIS/STATISTICAL METHODS 
14.1 Sample Size 
In this study, IRC-assessed PFS will be used as the primary endpoint for superiority test with the 
control group. An interim analysis will be performed to determine the efficacy of the drugs and to 
determine whether to terminate or continue the study. The parameters for sample size calculation 
are as follows: 
• 
Enrollment rate = 3 subjects/month (150 subjects/year), enrollment time = 20 months (the 
overall time will be 26 months) 
• 
Randomization in a 1:1 ratio; one-sided α = 0.025; the power of the test is 90%; 


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• 
Hazard ratio (investigational treatment group/control group [HR]) = 0.64 (estimated median 
PFS is 4.5 months in the control group and 7.0 months in the investigational treatment group) 
• 
An interim analysis will be performed when 67% of PFS events (143) are collected to 
determine whether the drug is effective or ineffective, and to decide whether to terminate or 
continue the study. 
Based on the above parameters, at least 214 PFS events shall be collected according to the log-rank 
test for PFS comparison in the two groups and the O'Brien & Fleming spending function 
(EAST6.4.1) in the α spending function method proposed by Lan-DeMets, i.e., approximately 
262 subjects are needed. Considering a 10% dropout rate, 292 subjects are finally required for 
enrollment. 
14.2 Statistical Analysis Plan 
The primary objective is to evaluate whether SHR-1210 combined with apatinib is superior to 
doxorubicin combined with ifosfamide in improving the PFS (assessed by the IRC as per RECIST 
v1.1) of subjects with soft tissue sarcoma. In this study, SAS 9.4 or above will be used for data 
processing and analysis. 
Detailed summaries and methods of statistical analyses for the data collected from the study shall 
be included in the statistical analysis plan (SAP), which shall be finalized and filed by the sponsor. 
The SAP should be revised accordingly if there are any changes to the study protocol that may 
have a major impact on the SAP, as determined by the sponsor or principal investigator. Relevant 
content in statistical analysis plan that is relevant to this protocol may be revised. However, if 
revised content involves the main and/or key factors of the protocol (such as the definition of 
endpoints or their analysis), such content in the protocol will be revised. 
14.3 Analysis Population 
This study will involve the following analysis sets: 
▪ 
Full analysis set (FAS): All enrolled subjects who have received at least one dose of the 
study drug. This analysis set will be used for the efficacy analysis. 
▪ 
Per-protocol Set (PPS): A subset of the FAS. Subjects with major protocol deviations 
judged to have a significant impact on treatment efficacy will be excluded from this 
analysis set. The list of subjects included into or excluded from the PPS should be 
reviewed and determined by the sponsor and the investigator before the database is 
locked. 
▪ 
Safety Set (SS): All enrolled subjects who have received at least one dose of the study 
drug and had post-administration safety data. 


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▪ 
PK concentration analysis set: All subjects who have undergone blood sampling for 
trough concentration testing of SHR-1210. 
Other analysis populations: In this study, some analysis populations depend on the study endpoint. 
For example, the analysis population of DoR is the subjects with response, and the analysis 
population of PFS after crossover is the subjects who have received the crossover treatment. 
14.4 Statistical Methods 
14.4.1 Basic methods 
In this study, unless otherwise stated, all data will be summarized using descriptive statistics in 
accordance with the following general principles. 
The quantitative variables will be summarized using mean, standard deviation, median, maximum, 
and minimum. The categorical variables will be summarized using frequency and percentage. For 
time-event data, the survival rate will be estimated using the Kaplan-Meier method and the 
survival curve will be plotted. 
14.4.2 Primary efficacy endpoint analysis 
The primary endpoint of the study is the IRC-assessed PFS (as per RECIST v1.1). The primary 
analysis will be based on the FAS set. The survival functions of PFS of the two groups will be 
compared using stratified log-rank tests with and without random stratification factors. The 
Kaplan-Meier method will be used to estimate the PFS rate, plot the survival curve, and estimate 
the median PFS, and its 95% CI will be calculated (Brookmeyer-Crowley method). The analysis 
with stratification factors will be used as the primary analysis. 
In addition, as a supporting analysis and under the assumption of proportional hazards, the Cox 
models with and without stratification factors will be used to estimate the hazard ratio (HR) and 
calculate the corresponding 95% CI (Wald method). 
The analysis methods for PPS will be the same as those for FAS. 
Refer to section 14.4.6 for the interim analysis of PFS. The final analysis will be performed when 
214 PFS events are collected, with a one-sided testing level of 0.023 to maintain the planned 0.025 
(see Table 12). When the P-value (one-sided) based on the log-rank test of PFS is < 0.023, the 
comparison of anti-PD-1 antibody SHR-1210 combined with apatinib mesylate (investigational 
treatment group) vs. doxorubicin combined with ifosfamide (control group) is statistically 
significant. When the actual number of observed events does not reach or exceed 214 in the final 
analysis, automatic adjustments may be performed using EAST (e.g., "last look" item in the EAST 
IM tool) to control the overall type I errors. 


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14.4.3 Secondary efficacy endpoint analysis 
The analysis of secondary efficacy endpoints will be based on the FAS. 
For the secondary endpoint PFS assessed by the investigator (as per RECIST v1.1), the analytical 
method will be the same as that of the primary endpoint mentioned above. 
The secondary endpoint OS will be statistically described using the similar method for the primary 
endpoint. For DoR, the Kaplan-Meier method will be used to plot the survival curve and estimate 
the median DoR and its 95% confidence interval will be calculated (Brookmeyer-Crowley 
method). 
For the objective response rate (ORR) and disease control rate (DCR), the rates in the two groups 
and their two-sided 95% CI (Clopper-Pearson method) will be estimated, and the inter-group 
difference of rates and its two-sided 95% CI will be calculated (CMH method). 
Other endpoints will be statistically summarized in accordance with general principles. 
14.4.4 Handling of missing data 
In this study, the missing data of the efficacy endpoints will not be treated specially, and the 
missing values will not be estimated in the safety evaluation. 
14.4.5 Safety analysis 
AEs that occur during the study will be coded according to MedDRA. The frequency and 
incidence of AEs will be summarized by system organ class and preferred term. The relevance and 
severity of AEs will be further tabulated for description. Descriptive statistics will be used to 
summarize other safety endpoints. Summarize the incidence of AEs, adverse drug reactions, AEs 
resulting in withdrawal from the study, AEs resulting in death, and SAEs. Severity of adverse 
events and adverse drug reactions: For the same AE with multiple occurrences in the same subject, 
the highest severity will be included in the analysis; for different AEs occurring in the same 
subject, the most severe AE will be included in the analysis. 
Laboratory tests: Abnormal laboratory values will be summarized using descriptive statistics. 
Vital signs: Measured values and changes will be summarized using mean, maximum, minimum, 
median, and SD. 
Physical examination and 12-Lead ECG will be summarized descriptively. 
Baseline is defined as the most recent test data before the first dose. 


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14.4.6 Interim analysis 
In this study, one interim analysis will be carried out for the primary efficacy endpoint PFS. To 
control the overall type I errors, the O'Brien-Fleming spending function of the alpha spending 
function method will be used. The boundary of superiority determined using this method is as 
follows: 
Table 12. 
Termination criteria and α spending in the interim analysis and final analysis of 
PFS 
Time Point 
PFS 
Number of events 
Termination boundary value of HR 
(Investigational treatment 
group/control group) 
One-sided nominal 
significance level 
Nominal α (one-sided) 
Effective (≤ lower limit) 
Interim (1st) 
143 (67%) 
-2.506 (HR = 0.658) 
0.006 
Final 
214 (100%) 
-1.993 (HR = 0.761) 
0.023 
Note: HR = Hazard ratio (investigational treatment group/control group); α = Alpha; PFS = Progression free survival; 
NA = Not applicable; 
The results will be based on the z-scores calculated by EAST 6.4.1, and the O'Brien & Fleming spending function 
method of the α spending function method proposed by Lan-DeMets will be used for boundary testing and analysis. 
The interim analysis will be performed when 67% of PFS events (166) will be collected to evaluate 
the efficacy of the drugs and to determine whether to terminate the study. When the z-score of PFS 
based on the log-rank test result exceeding the unbound effective boundary is -2.506 (P-value 
[one-sided] < 0.006), the study will end early because it is effective. If the efficacy is not 
established, the study will continue. If, in the interim analysis, the actual number of observed 
events does not reach or exceed 143, the boundary should be timely monitored and adjusted using 
EAST (e.g., using IM tool for monitoring). The final analysis will not be performed until 214 PFS 
events are collected (see 14.4.2). 
The results of interim analysis will be reviewed by the IDMC, which will recommend whether to 
continue the study. 
14.4.7 Subgroup analysis 
Subgroup analyses will be performed for primary endpoint PFS according to (including but not 
limited to) the following factors, and the forest plot on HR will be produced: 
Stratification factors: 
• 
Age (< 65 years old vs. ≥ 65 years old) 
• 
Gender 


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• 
ECOG PS (0 vs. 1 vs. 2) 
• 
Site of primary lesion 
• 
Pathological type 
• 
Histological Classification 
• 
Presence of lung metastases 
• 
Presence of liver metastases 
• 
Previous chemotherapy 
14.4.8 Multiple comparison/multiplicity 
The primary endpoint of the study is the IRC-assessed PFS (as per RECIST v1.1). The primary 
analysis of this endpoint will be based on the FAS, and a stratified log-rank method will be used to 
test the difference in survival function between the two groups. The overall alpha levels will be 
strictly controlled using the O'Brien-Fleming method for alpha spending during the interim and 
final analyses, as described in Section 14.4.6. 
14.4.9 Exploratory analysis 
Statistical description will be given for the production of anti-SHR-1210 antibodies (ADA) at  
time points of measurement, as well as the drug concentrations of SHR-1210 and apatinib. 
For the investigator-assessed PFS and DoR (as per iRECIST) in the investigational treatment 
group, the PFS and DoR (as per RECIST v1.1 and iRECIST) after crossover treatment in the 
control group, and the OS, the Kaplan-Meier method will be used to plot the survival curves and 
estimate the medians and their 95% confidence intervals will be calculated (Brookmeyer-Crowley 
method). 
For the investigator-assessed ORR and DCR (as per iRECIST) in the investigational treatment 
group and the ORR and DCR (as per RECIST v1.1 and iRECIST) after crossover treatment in the 
control group, the rates and their 95% confidence intervals will be estimated (Clopper-Pearson 
method). 
The safety and quality of life scores of the control group after crossover treatment will be 
summarized using descriptive statistics in accordance with general principles. 


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15 DATA MANAGEMENT 
15.1 Data Recording 
Data will be collected and managed using the electronic case report form (eCRF). 
15.1.1 Source documents and records 
Source documents of the clinical study should be retained in their entirety. The investigator is 
responsible for filling out and keeping the source documents. Medical records should be neat and 
legible such that the sponsor's monitor can verify data with the eCRF during each inspection. 
15.1.2 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 trial 
should be entered in the eCRF in a timely, accurate, complete, clear, normative and verifiable 
manner. Data should not be changed arbitrarily. All items in the CRF should be filled out, with no 
blank or omissions. 
Modifications: The system instructions must be followed when correcting the eCRF data as 
needed, and the reason for data correction must be recorded. The logic verification program in the 
system will verify the integrity and logic of the clinical study data entered into the EDC system and 
generate an error message prompt for questionable data. The PI or CRC will be permitted to 
modify or explain the problematic data. If necessary, multiple inquiries can be raised until the 
event of problematic data is resolved. 
15.1.3 eCRF review 
The investigator must complete, review, and submit the eCRF after the end of each subject's 
treatment course. The investigator or the data input staff (CRC) should promptly respond to 
queries raised by the monitor, data manager, and medical reviewer. After data cleaning is 
completed, the investigator will sign the completed eCRF for verification. 
15.2 Data Monitoring 
The monitor shall ensure that the data in the eCRF is consistent with the source data. This process 
is also known as source data verification (SDV), including the following contents: verify whether 
the study protocol is adhered to; whether the records on CRF is correct and complete, and 
consistent with the original medical records and laboratory test results, and whether there are 
errors or omissions in the data. According to the monitoring plan, the CRA will verify the 
completeness, consistency, and accuracy of study data in the database. The CRA will discuss any 
queries with study personnel and direct them to add or correct the data whenever necessary. 


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15.3 Data Management 
15.3.1 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. (Access to EDC system will only be granted to the study center staff who have completed 
the training.) 
15.3.2 Data entry and verification 
The investigator or CRC should input data into the EDC system in accordance with the 
requirements of the visit procedures and the eCRF completion guide. After submitting the eCRF, 
the CRA, data manager, and medical personnel should review the data. Questions during the 
review will be submitted to the investigator or CRC in the form of queries. After data cleaning is 
completed, the investigator should sign the completed eCRF for verification. 
15.3.3 Database lock 
After SDV is completed by the CRA, the data manager and medical reviewer will conduct a final 
quality control of all data in the database, summarize all protocol deviations and violations during 
the study, and hold the data review meeting. The database will be locked after quality requirements 
are met. The data manager will export the data to the statistics department for data analysis. 
15.3.4 Data archiving 
After the study is completed, the eCRFs of the subjects must be generated from the EDC system in 
the PDF format and kept on non-rewritable CD-ROMs, which will be archived by the sponsor and 
various institutions for auditing and/or inspection. 
All materials shall be preserved and managed in accordance with GCP requirements, and 
necessary documents of clinical studies shall be preserved until 2 years after the investigational 
drug is approved for marketing or 5 years after the termination of the clinical study. 
16 SOURCE DATA AND DOCUMENTS 
According to ICH E6, relevant regulations, and requirements for subjects' personal information 
protection of the study centers, each study center must properly keep all the treatment and 
scientific research records related to this study. As a part of the study that Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. sponsors or participates in, each study center must allow the authorized 
representative of Jiangsu Hengrui Pharmaceuticals Co., Ltd. and regulatory authorities to inspect 
the clinical records (which may be copied if permissible by law) for quality review, audit, and 
evaluations of safety, study progress, and data validity. 


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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. 
17 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure study quality, the sponsor and the investigator will jointly discuss and formulate a 
clinical study plan before the formal study initiation. All study personnel participating in the study 
will receive GCP training. 
All the study centers must comply with the SOPs for the management of the study drug, including 
receipt, storage, dispensing, return, and destruction (if applicable). 
According to the GCP guidelines, necessary measures must be taken at the design and 
implementation phases of the study to ensure that all collected data are accurate, consistent, intact, 
and reliable. All observed results and abnormal findings in the clinical study must be verified and 
recorded in a timely manner to ensure data reliability. All devices, equipment, reagents, and 
standards used in various tests in the study must have stringent specifications and be operated 
under normal conditions. 
The investigator will input data required by the protocol into the eCRF. The CRA will check 
whether the eCRF is completely and accurately filled and guide the study center personnel for 
necessary revision and addition. 
The drug regulatory authorities, independent ethics committee/institutional review board 
(IEC/IRB), sponsor's monitor and/or auditor may carry out systemic inspection of study-related 
activities or documents to assess whether the study is implemented based on the study protocol, 
SOPs, and relevant regulations (such as Good Laboratory Practices [GLP] and Good 
Manufacturing Practices [GMP]) and whether the study data is recorded in a prompt, truthful, 
accurate, and complete manner. The audit should be performed by personnel not directly involved 
in this clinical study. 


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18 REGULATORY ETHICS, INFORMED CONSENT, AND SUBJECT 
PROTECTION 
18.1 Regulatory Considerations 
According to the corresponding regulatory requirements in China, an application should be 
submitted to the CFDA (now NMPA) before starting a new drug study and the study can only be 
carried out after approval is obtained. The clinical approval number of SHR-1210 is 2016L01455. 
The clinical approval numbers of apatinib mesylate tablets are 2014L00876 and 2014L00877. 
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 
18.2 Ethical Standards 
This study protocol must first be reviewed and approved in writing by the IEC/IRB of the Hospital 
before being implemented. The study protocol, protocol revisions, ICF, and other relevant 
documents such as recruitment advertisements should be submitted to the ethics committee. This 
clinical study must comply with the "Declaration of Helsinki", NMPA's (former CFDA) "Good 
Clinical Practice" (GCP), and other relevant regulations. Before the study is initiated, approval 
must be obtained from the IEC/IRB of the hospital. 
The study protocol must not be unilaterally modified without approvals from both the sponsor and 
investigator. The investigator can modify or deviate from the study protocol before obtaining an 
approval from the IEC/IRB only when in purpose of eliminating direct and immediate harm to the 
subject. Besides, the deviation or change and the corresponding reason, and the recommended 
protocol modification should be submitted to the IEC/IRB for review. The investigator must 
provide explanations and document any protocol deviation. 
During the study, any changes to this study protocol must be submitted to the IEC/IRB. If 
necessary, corresponding changes should be simultaneously made to other study documents and 
submitted and/or be approved according to the pertinent requirements of the IEC/IRB. The 


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investigator is responsible for submitting the interim reports regularly according to the pertinent 
requirements of the IEC/IRB. After the end of the study, the completion should be informed to the 
IEC/IRB. 
18.3 Independent Ethics Committee 
The protocol, ICF, recruitment material, and all subject materials must be reviewed and approved 
by the IEC/IRB. Subjects may be enrolled only after the protocol and ICF have been approved. 
Any revisions to the protocol must be reviewed and approved by the EC prior to being 
implemented. All revisions to the ICF must be approved by the IEC/IRB, who will decide whether 
the subjects who have signed the previous version of the ICF are required to sign the new one. 
18.4 Informed Consent 
All subjects participating in the study sponsored by Hengrui shall provide the informed consent. 
The investigator shall follow applicable regulatory requirements and conduct the study in full 
compliance with ICH E6. Before the start of the study, the investigator shall obtain written 
approval of the study protocol from the IRB, ICF signed in writing, and other written information 
required to be provided to the subjects. 
18.4.1 
ICF and other written information for subjects 
The ICF describes the study drugs and study process in detail and fully explains the risks of the 
study to the subjects. Written documentation of informed consent must be obtained before starting 
any study-related procedures. 
18.4.2 Informed consent process and records 
Informed consent will begin before an individual decides to participate in the clinical study and 
continues during the entire clinical study. The risks and potential benefits of participating in the 
study should be discussed fully and in detail with the subjects or their legal representatives. 
Subjects will be asked to read and review the ICF that has been approved by the IEC/IRB. The 
investigator will explain the clinical study to the subjects and answer any questions posed by the 
subjects. Subjects can only participate in the study after they have signed the ICFs. During the 
clinical study, subjects can withdraw the informed consents at any time. One copy of the signed 
ICF will be kept by the subjects. Even if a patient refuses to participate in this study, his or her 
rights will be fully protected, and the nursing quality will not be affected. 
18.5 Confidentiality of Subject Information 
The confidentiality of subject information will be strictly enforced by the investigator, participated 
study personnel, and sponsor and its representative. In addition to the clinical information, 
confidentiality also simultaneously covers biological samples and genetic tests of the subjects. 


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Therefore, the study protocol, documents, data, and other information generated from these 
materials will be kept strictly confidential. All relevant study or data information should not to be 
disclosed to any unauthorized third-party without prior written approval from the sponsor. 
Other authorized representatives of the sponsor, IRB or regulatory authorities, and the 
representatives of the pharmaceutical company that provides the study drugs can examine all the 
documents and records that are maintained by the investigator, including but are not limited to the 
medical records and subject's administration records. The study center should allow access to these 
records. 
The contact information of the subjects will be safely kept in each study center and only used 
internally during the study. When the study is ended, all the records will be kept in a secure place 
based on the time limit specified by local IRB and regulations. 
The study data of the subjects collected for statistical analysis and scientific reports will be 
uploaded and stored at the sponsor or a third-party company entrusted by the sponsor. This should 
not include the contact information or identification information of subjects. Instead, individual 
subjects and their study data will be given a unique study identification number. The study data 
entry and study management system used by the study personnel at the study centers will be 
confidential and password-protected. 
18.5.1 Use of samples, specimens, or data 
• 
Planned use: The samples and data collected in accordance with the protocol will be used 
for the content specified in the protocol and will not be used for any unrelated purposes. 
• 
Storage: Samples and data are numbered for storage. The data in the computer will also 
be password-protected. Only the study personnel can have access to these samples and 
data. 
19 PUBLICATION OF STUDY RESULTS 
The study results belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd.   If the investigator plans 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. 


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20 CLINICAL STUDY PROGRESS 
Anticipated enrollment of the first subject: Sep. 2018 
Anticipated enrollment of the last subject: Dec. 2020 
Anticipated study completion: Sep. 2022 
21 REFERENCES 
1) 
The Society of Sarcoma of China anti-tumor Association. Chinese Expert Consensus on the 
Diagnosis and Treatment of Soft Tissue Sarcoma. Fudan University Press, 2015. 
2) 
Chinese Expert Consensus on the Diagnosis and Treatment of Soft Tissue Sarcoma (2015 
Edition). Chinese Journal of Oncology. 2016:38(4), 310-320 
3) 
Cormier JN, Pollock RE. Soft tissue sarcomas. CA Cancer J Clin, 2004, 54(2):94-109. 
4) 
Hui JY. Epidemiology and etiology of sarcomas. Surg Clin North Am, 2016, 96(5): 901-914 
5) 
Crago AM, Brennan MF. Principles in Management of Soft Tissue Sarcoma. Adv Surg. 
2015; 49:107-22. 
6) 
NCCN Guideline. Soft tissue sarcoma. 2018, V1 
7) 
Chinese Society of Clinical Oncology. Guidelines for the Prevention and Treatment of 
Cardiotoxicity of Anthracyclines (2013 Edition). Journal of Clinical Oncology, 2013, 
18(10):925-934. 
8) 
Feijen EAM, Leisenring WM, Stratton KL, et al. Equivalence Ratio for Daunorubicin to 
Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer. Journal of 
Clinical Oncology Official Journal of the American Society of Clinical Oncology, 2015, 
33(32):3774-80. 
9) 
Seymour PL, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use 
in trials testing immunotherapeutics [J]. Lancet Oncology, 2017, 18(3):e143. 
10) Seymouretal: Supplementary Appendix to: iRECIST: guidelines for response criteria for use 
in trials testing immunotherapeutics. Lancet Oncology, 2017, 18(3):e143-e152.


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Appendix 1. The WHO Soft Tissue Tumor Classification (2013 Edition) 
Adipocytic Tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
Lipoma 
Atypical lipomatous 
tumor 
Dedifferentiated liposarcoma 
 
Lipomatosis 
Well-differentiated 
liposarcoma 
Myxoid liposarcoma 
 
Lipomatosis of nerve 
 
Pleomorphic liposarcoma 
 
Lipoblastoma/lipoblasto
matosis 
 
Mixed-type liposarcoma 
 
Angiolipoma 
 
Liposarcoma, not otherwise 
specified 
 
Mylipoma 
 
 
 
Chondroid lipoma 
 
 
 
Extrarenal 
angiomyolipoma 
 
 
 
Extra-adrenal medullary 
lipoma 
 
 
 
Spindle/pleomorphic 
lipoma 
 
 
 
Hibernoma 
 
 
Fibroblast/myofibroblast 
tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
Nodular fasciitis 
Palmar/plantar 
fibromatoses 
Adult fibrosarcoma 
 
Proliferative fasciitis 
Desmoid-type 
fibromatoses 
Myxofibrosarcoma 
 
Proliferative myositis 
Lipofibromatosis 
Low-grade fibromyxoid 
sarcoma 
 
Myositis ossificans 
Giant cell fibroblastoma Hyalinizing spindle cell tumor 
 
Fibro-osseous 
pseudotumor of digits 
Intermediate 
(occasionally 
metastatic) 
Sclerosing epithelioid 
fibrosarcoma 
 
Ischaemic fasciitis 
Dermatofibrosarcoma 
protuberans 
 
 
Elastofibroma 
Fibrosarcomatoid 
dermatofibrosarcoma 
protuberans 
 
 
Fibrous hamartoma of 
infancy 
Pigmented 
dermatofibrosarcoma 
protuberans 
 
 
Fibromatosis colli 
Solitary fibrous tumor 
 
 
Juvenile hyaline 
fibromatosis 
Solitary fibrous tumor, 
malignant 
 


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Adipocytic Tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
Inclusion body 
fibromatosis 
Inflammatory 
myofibroblastic tumor 
 
 
Fibroma of tendon sheath 
Low grade 
myofibroblastic 
sarcoma 
 
 
Desmoplastic 
fibroblastoma 
Myxoinflammatory 
fibroblastic sarcoma 
 
 
Mammary-type 
myofibroblastoma 
Atipical 
myxoinflammatory 
fibroblastic tumor 
 
 
Calcifying aponeurotic 
fibroma 
Infantile fibrosarcoma 
 
 
Angiomyofibroblastoma 
 
 
 
Cellular angiofibroma 
 
 
 
Nuchal-type fibroma 
 
 
 
Gardner fibroma 
 
 
 
Calcifying fibrous tumor 
 
 
So-called fibrohistio cytic 
tumors 
 
 
 
Tenosynovial giant cell tumor, 
localized-type, and 
diffuse-type, malignant 
 
 
 
Plexiform fibrohistiocytic 
tumor 
 
 
 
Giant cell tumor of soft tissues  
 
 
Deep benign fibrous 
histiocytoma 
 
 
 
Smooth muscle tumors 
Benign 
 
Malignant 
 
Deep leiomyoma 
 
Leiomyosarcoma (not 
including skin) 
Pericytic (perivascular) 
tumors 
 
 
 
Glomus tumor and variants 
 
 
 
Glomangiomatosis 
 
 
 
Malignant glomus tumor 
 
 
 
Myopericytoma 
 
 
 
Myofibroma 
 
 
 
Myofibromatosis 
 
 
 
Angioleiomyoma 
 
 
 


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Adipocytic Tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
Skeletal muscle tumors 
Benign 
 
Malignant 
 
Rhabdomyoma 
 
Embryonic 
rhabdomyosarcoma 
(including grape clusters, 
anaplastic) 
 
Adult-type 
 
Alveolar rhabdomyosarcoma 
(including solid, anaplastic) 
 
Fetal-type 
 
Pleomorphic 
rhabdomyosarcoma 
 
Genital-type 
 
Spindle cell/sclerosing 
rhabdomyosarcoma 
Vascular tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
Haemangiomas 
Kaposiform 
haemangioendothelioma 
Epithelioid 
haemangioendothelioma 
 
Synovial 
Intermediate 
(occasionally 
metastatic) 
Angiosarcoma of soft tissue 
 
Venous 
Retiform 
haemangioendothelioma  
 
Arteriovenous 
Papillary intralymphatic 
angioendothelioma 
 
 
Intramuscular 
Composite 
haemangioendothelioma  
 
Epithelioid haemangioma 
Pseudomyogenic 
(epithelioid 
sarcoma-like) 
haemangioendothelioma 
 
 
Angiomatosis 
Kaposi sarcoma 
 
 
Lymphangioma 
 
 
Chondro-osseous tumors 
 
 
 
Soft tissue chondroma 
 
 
 
Extraskeletal mesenchymal 
chondrosarcoma 
 
 
 
Extraskeletal osteosarcoma 
 
 
 
Gastrointestinal stromal 
tumors 
 
 
 
Gastrointestinal stromal tumor  
 
 
Gastrointestinal stromal tumor, 
uncertain malignant potential 
 
 
 
Gastrointestinal stromal tumor, 
malignant 
 
 
 


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Adipocytic Tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
Nerve sheath tumors 
Benign 
 
Malignant 
 
Schwannoma (including 
variants) 
 
Malignant peripheral nerve 
sheath tumor 
 
Melanotic Schwannoma 
 
Epithelioid malignant 
peripheral nerve sheath tumor 
 
Neurofibroma (including 
variants) 
 
Malignant triton tumor 
 
Plexiform neurofibroma 
 
Malignant granular cell tumor 
 
Perineurioma 
 
Ectomesenchymoma 
 
Malignant perineurioma 
 
 
 
Granular cell tumor 
 
 
 
Dermal nerve sheath 
myxoma 
 
 
 
Solitary circumscribed 
neuroma 
 
 
 
Ectopicmeningioma 
 
 
 
Nasal glial heterotopia 
 
 
 
Benign triton tumor 
 
 
 
Hybrid nerve sheath 
tumors 
 
 
Tumors of uncertain 
differentiation 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
Acral fibromyxoma 
Hemosiderotic 
fibrohistiocytic 
lipomatous tumor 
Synovial sarcoma, NOS 
 
Intramuscular myxoma, 
including cellular variant 
Intermediate 
(occasionally 
metastatic) 
Synovial sarcoma, spindle cell 
 
Juxta-articular myxoma 
Atypical fibroxanthoma Synovial sarcoma, biphasic 
 
Deep ("aggressive") 
angiomyxoma 
Angiomatoid fibrous 
histocytoma 
Epithelioid sarcoma 
 
Pleomorphichyalinizing 
angiectatic tumor 
Ossifying fibromyxoid 
tumor 
Alveolar soft-part sarcoma 
 
Ectopic haemartomatous 
thymoma 
Ossifying fibromyxoid 
tumor, malignant 
Clear cell sarcoma of soft 
tissue 
 
 
Mixed tumor, NOS 
Extraskeletal myxoid 
chondrosarcoma 
 
 
Mixed tumor, NOS, 
malignant 
Extraskeletal Ewing sarcoma 
 
 
Myoepithelioma 
Desmoplastic small round cell 
tumor 


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Adipocytic Tumors 
Benign 
Intermediate (locally 
aggressive) 
Malignant 
 
 
Phosphaturic 
mesenchymal tumor, 
benign 
Extra-renal rhabdoid tumor 
 
 
Phosphaturic 
mesenchymal tumor, 
malignant 
Malignant mesenchymoma 
Neoplasms with perivascular 
epithelioid cell 
differentiation, PEComa 
 
 
 
PECOma, NOS, benign 
 
 
 
PECOma, NOS, malignant 
 
 
 
Intimal sarcoma 
 
 
 
Undifferentiated/Unclassified 
Sarcomas 
 
 
 
Undifferentiated spindle cell 
sarcoma 
 
 
 
Undifferentiated pleomorphic 
sarcoma 
 
 
 
Undifferentiated round cell 
sarcoma 
 
 
 
Undifferentiated epithelioid 
cell sarcoma 
 
 
 
Undifferentiated sarcoma, NOS  
 
 
 


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Appendix 2. Common Soft Tissue Sarcomas with Poor Chemotherapy Sensitivity 
 
Alveolar soft-part sarcoma 
 
Clear cell sarcoma of soft tissue 
 
Dedifferentiated liposarcoma 
 
Atypical lipomatous tumor 
 
Well differentiated liposarcoma 


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Appendix 3. Dose Conversion of Anthracyclines[7-8] 
 
Conversion Ratio 
Doxorubicin 
1 
Epirubicin 
0.5 
Pirarubicin 
1 
Liposomal Doxorubicin 
0.625 
 
 


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Appendix 4. ECOG PS 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair 50% or more of waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair. 
 
 


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Appendix 5. Cockroft-Gault Formula (for Calculating Creatinine Clearance) 
Serum creatinine: mg/dL 
Creatinine Clearance in Males ( ml
min) = (140 −Age) × Weight
72 × Serum creatinine 
Creatinine Clearance in Females ( ml
min) = 0.85 × (140 −Age) × Weight
72 × Serum creatinine
 
 
Serum creatinine: μmol/L 
Creatinine Clearance in Males ( ml
min) =
(140 −Age) × Weight
0.818 × Serum creatinine 
Creatinine Clearance in Females ( ml
min) = 0.85 × (140 −Age) × Weight
0.818 × Serum creatinine  
 
Age in years, weight in kilogram (kg). 
 
 
 


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Appendix 6. Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
1  BACKGROUND 
Omitted 
2  PURPOSE 
Omitted 
3  MEASURABILITY OF TUMOR AT BASELINE 
3.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1  
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter is to be 
recorded) with a minimum size of: 
▪ 
CT scan 10 mm (the thickness of CT scan layer shall not be more than 5 mm) 
▪ 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
▪ 
20 mm by chest X-ray; 
▪ 
Malignant lymph nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15 mm in short axis by CT scan (CT scan slice thickness no greater than 
5 mm). At baseline and during follow-up, only the short axis will be measured and 
followed. 
3.1.2  
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodule 
with a short axis ≥ 10 mm and < 15 mm) as well as truly non-measurable lesions. Non-measurable 
lesions include: meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses unable to be diagnosed 
or followed by imaging techniques, and cystic lesions. 


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3.1.3  
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
▪ 
Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
▪ 
Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by tomography techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above; 
▪ 
Blastic lesions are non-measurable. 
Cystic lesions: 
▪ 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts; 
▪ 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
▪ 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
3.2  Specifications by Methods of Measurements 
3.2.1  
Measurement of lesions 
All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
28 days (4 weeks) before the beginning of the treatment. 


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3.2.2  
Method of assessment 
The same method and technique should be used to assess lesions at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of cutaneous lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both imaging and clinical examination, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end of 
the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT and MRI: CT is currently the best available and reproducible method for response evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm CR when biopsies are obtained, or to 
determine relapse in trials where recurrence following CR or surgical excision is an endpoint. 
Tumor biomarkers: Tumor biomarkers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper normal limit at baseline, they must return to the 
normal levels for evaluation of complete response. Because tumor biomarkers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line studies in ovarian cancer. 


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Cytology/histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual benign tumor tissue is commonly observed in 
lesions of germ cell neoplasm). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met the criteria for response or stable disease in order to 
differentiate between response (or stable disease) and PD. 
4  TUMOR RESPONSE EVALUATION 
4.1  Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable lesions at baseline should be included in protocols where objective response is the 
primary endpoint. Measurable lesion is defined by the presence of at least one measurable lesion. 
In trials where the primary endpoint is tumor progression (either time to progression or proportion 
with progression at a fixed date), the protocol must specify if enrollment is restricted to those with 
measurable lesions or whether patients with non-measurable lesions are also eligible. 
4.2  Baseline Documentation of 'Target' and 'Non-Target' Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ), representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where subjects have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal tissues which may be visible by imaging 
even if not involved by tumor metastasis. Pathological nodes which are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. 
Only the short axis of these nodes needs to be measured at baseline. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by tumor metastasis. 
Nodule size is normally reported as two dimensions in the plane in which the image is obtained 
(for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, 


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sagittal or coronal). The smallest of these measures is the short axis. For example, an abdominal 
node which is reported as being 20 mm × 30 mm with a short axis of 20 mm qualifies as a 
malignant and measurable node. In this example, 20 mm should be recorded as the node 
measurement. Nodes with a short axis ≥ 10 mm but < 15 mm should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and are thus not to 
be recorded or followed up. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions 
should be recorded as "present", "absent", or in rare cases "unequivocal progression". It is possible 
to record multiple target lesions involving the same organ as a single item on the case record form 
(e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
4.3  Response Criteria 
4.3.1  
Evaluation of target lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodules 
(whether target or non-target) must have reduction in short axis to < 10mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, compared 
with baseline. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm (the 
appearance of one or more new lesions is also considered PD). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
4.3.2  
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, since a normal lymph 
node is defined as having a short axis < 10 mm. CRFs or other data collection methods may 


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therefore be designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must have a short axis < 10 mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being "too small to 
measure". When this occurs it is important that a value be recorded on the CRF. If it is the opinion 
of the radiologist that the lesion has likely disappeared, the measurement shall be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm can be assigned. (Note: It is less likely that this rule will be used for lymph nodules since 
they usually have a definable size when normal and are frequently surrounded by adipose tissues 
as in the retroperitoneum; however, if a lymph nodule is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm can be assigned in this circumstance as well). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false evaluation based upon measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce: When non-nodal lesions fragmented, the longest diameters of the 
fragmented portions should be added together to calculate the target lesion sum. Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion. 
4.3.3  
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
biomarker level. All lymph nodules must be non-pathological in size (short axis < 10 mm). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
biomarker level above the normal limits. 


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Progressive disease (PD): Unequivocal progression of existing non-target lesions. Note: the 
appearance of one or more new lesions is also considered PD. 
4.3.4  
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: When 
the patient also has measurable disease, to achieve unequivocal progression on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target disease 
such that the overall tumor load has increased sufficiently to the point where treatment must be 
discontinued. A modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment. Because worsening in non-target disease cannot be easily quantified (by definition: if 
all lesions are truly non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease load based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. For example, an increase in tumor burden representing an 
additional 73% increase in volume (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from "trace" to "large", an 
increase in lymphangitic disease from "localized" to "widespread", or may be described in 
protocols as "sufficient to require a change in treatment". Examples include an increase in a pleural 
effusion from trace to large, an increase in lymphangitic disease from localized to widespread, or 
may be described in protocols as "sufficient to require a change in therapy". If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so, therefore the increase must be substantial. 
4.3.5  
New lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important. There are no specific criteria for the identification of radiographically 
detected lesions; however, the finding of a new lesion should be unequivocal. For example, it 
should not be attributable to differences in scanning technique, change in imaging modality, or 
findings thought to represent something other than tumor (for example, some new bone lesions 
that may be simply healing, or re-occurrence of pre-existing lesions). This is particularly important 


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when the patient's baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a new cystic lesion, which it is not. 
A lesion identified on a follow-up study that is not scanned at baseline will be considered a new 
lesion and will indicate PD. An example of this is the patient who has visceral disease at baseline 
and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain 
metastases are considered to be evidence of PD even if he/she did not have brain imaging at 
baseline. 
If a new lesion is equivocal, for example, because of its small size, continued treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial identification. 
While FDG-PET response evaluations generally need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible new disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following process: 
▪ 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
▪ 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
▪ 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, PD is confirmed. 
▪ 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
▪ 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the imaging examination, this is not PD. 
4.4  Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement for confirmation. On occasion a response may 
not be documented until after the end of treatment, so protocols should be clear if post-treatment 
assessments are to be considered in the evaluation of best overall response. Protocols must specify 
how any new treatment introduced before progression will affect best response evaluation. The 
patient's best overall response evaluation will depend on the findings of both target and non-target 


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diseases and will also take into consideration the characteristics of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomized studies where response is the primary 
endpoint, confirmation of PR or CR is needed to determine either one is the BOR. 
4.4.1  
Time point response 
It is assumed that at each time point specified in protocol, an efficacy response occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 1. Time point response: subjects with target (+/- non-target) disease 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 
PR 
Non-PD or not all evaluable 
Non 
PR 
SD 
Non-PD or not all evaluable 
Non 
SD 
Not all evaluable 
Non-PD 
Non 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 
Table 2. Time point response: subjects with non-target lesion only 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
Non 
CR 
Non-CR/Non-PD 
Non 
Non-CR/Non-PDa 
Not all evaluable 
Non 
Not evaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a: "Non-CR/non-PD" is preferred over SD for non-target disease. Since SD is increasingly used as an endpoint for 
response evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
at that time point. If only a subset of lesion measurements is made at an evaluation, usually the case 
is also considered not evaluable at that time point, unless a convincing argument can be made that 


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the contribution of the individual missing lesion(s) has/have no effect on the assigned time point 
response. This would be most likely to happen in the case of PD. For example, if a patient had three 
measured lesions with a baseline sum of 50 mm and only two lesions with a sum of 80 mm were 
assessed at a subsequent follow-up, the patient has achieved PD status, regardless of the 
contribution of the missing lesion. 
4.4.3  
Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
BOR determination in studies where confirmation of complete or partial response is not required: 
BOR in these studies is defined as the best response across all time points (for example, a patient 
who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at the last cycle has a BOR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
calculated from baseline. If the minimum time is not met when SD is otherwise the BOR, the 
patient's BOR depends on the subsequent assessments. For example, a patient who has SD at Cycle 
1, PD at Cycle 2 and does not meet minimum duration for SD, will have a BOR of PD. The same 
patient lost to follow-up after the first SD assessment would be considered not evaluable. 
BOR determination in studies where confirmation of complete or partial response is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). In this circumstance, the BOR can 
be interpreted as in Table 3. 
Table 3. Best overall response when confirmation of CR and PR required 
Overall Response at First 
Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, 
otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, 
otherwise, PD) 


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Overall Response at First 
Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
PR 
NE 
SD (provided minimum criteria for SD duration met, 
otherwise, NE) 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable. 
a: If a CR is truly met at first time point, then efficacy of any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, will still be evaluated as PD at that point (since disease will reappear after 
CR). Best response will depend on whether minimum duration for SD is met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions are likely still present and in fact the subject has PR, not CR at 
the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
4.4.4  
Special notes on response evaluation 
When nodal disease is included in the sum of target lesions and the nodules decrease to a normal 
size < 10 mm, they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodules are normal in order not to overstate progression should it be 
based on increase in size of the nodules. As noted earlier, this means that subjects with CR may not 
have a total sum of zero on the CRF. 
In trials where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response evaluation. The analysis plan for the trial must address how missing 
data/evaluations will be addressed in determination of response and progression. For example, in 
most studies it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
Subjects with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as symptomatic deterioration. 
Efforts should be made to evaluate objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a description of an objective response: it is a reason for 
discontinuation of treatment. The objective response status of such subjects is to be determined by 
evaluation of target and non-target lesion as shown in Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study specific 
and shall be clearly described in each protocol (depending on treatment duration and treatment 
cycle). 
In some circumstances it may be difficult to distinguish residual lesions from normal tissues. 
When the evaluation of complete response depends upon this definition, it is recommended to 
perform a biopsy before evaluating the efficacy of complete remission of local lesions. FDG-PET 
may be used to confirm a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 


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circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled evaluation. If at 
the next scheduled evaluation, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
4.5  Frequency of Tumor Re-Evaluation 
Frequency of tumor re-evaluation during treatment should be protocol-specific and consistent with 
the type and schedule of treatment. However, in the phase II studies where the beneficial effect of 
treatment is not known, follow-ups for every 6-8 weeks (timed to coincide with the end of a cycle) 
is reasonable. Interval adjustments can be justified in specific regimens or circumstances. The 
protocol should specify which organ sites are to be evaluated at baseline (usually those most likely 
to be involved with metastatic disease for the tumor type under study) and how often evaluations 
are repeated. Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when CR is identified in target disease or when progression in 
bone is suspected. 
After the treatment, the need for tumor re-evaluations depends on whether the trial has made the 
response rate or the time to an event (progression/death) an endpoint. If time to an event (e.g. 
TTP/DFS/PFS) is the main endpoint of the study, then routine scheduled re-evaluation of protocol 
specified sites of disease is warranted. In randomized comparative studies in particular, the 
scheduled assessments should be performed as identified on a calendar schedule (for example: 
every 6-8 weeks on treatment or every 3-4 months after treatment) and should not be affected by 
delays in therapy, drug holidays or any other events that might lead to imbalance in a treatment 
group in the timing of disease assessment. 
4.6  Confirmatory Evaluation/Duration of Response 
4.6.1 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (phase II or III) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the interpretation 


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of trial results. However, elimination of the requirement for response confirmation may increase 
the importance of central review to protect against bias, in particular in studies which are not 
blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6-8 weeks) that is defined in the study protocol. 
4.6.2  
Duration of overall response 
The duration of overall response will be measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response will be measured from the time 
criteria are first met for CR until the first date that recurrent or progressive disease is truly 
documented. 
4.6.3  
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of stable disease varies in different studies and diseases. If the proportion 
of patients achieving SD for a minimum period of time is an endpoint in a particular study, the 
protocol should specify the minimal time interval required between two measurements for 
determination of SD. 
Note: The duration of response and stable disease as well as the progression free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account many 
parameters including disease types and stages, treatment periodicity and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into account 
if comparisons between trials are to be made. 
4.7  PFS/TTP 
4.7.1  
Phase II studies 
This guideline is focused primarily on the use of objective response endpoints for phase II clinical 
studies. In some circumstances, response rate may not be the optimal method to assess the 
potential anti-cancer activity of new agents/regimens. In such cases PFS/PPF at landmark time 
points, might be considered appropriate alternatives to provide an initial signal of biologic effect of 
new agents. It is clear, however, that in an uncontrolled trial, these measures are subject to 


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criticism since an apparently promising observation may be related to biological factors such as 
patient selection and not the impact of the intervention. Thus, phase II screening studies utilizing 
these endpoints are best designed with a randomized control. Exceptions may exist where the 
behavior patterns of certain cancers are so consistent (and usually consistently poor) that a 
non-randomized trial is justifiable. However, in these cases it will be essential to document with 
care the basis for estimating the expected PFS or PPF in the absence of a treatment effect. 


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Appendix 7. Management Principles for Immune Related Adverse Events 
The principles specified in this section can be used as reference for the investigator when 
managing immune-related AEs. Investigators can select their own dosing regimens according to 
clinical reality. 
The general principle is that AEs should be carefully evaluated and the differential diagnosis be 
made in accordance with the standard medical practice. Non-inflammatory causes should be 
considered and properly handled. 
Corticosteroids are preferable drug for immuno-oncology treatment-related AEs. An oral dose 
equivalent to the recommended IV dose can be considered for ambulatory patients with low grade 
toxicity. The low bioavailability of oral administration should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Consultation with an internist or surgeon is recommended, especially before an invasive 
diagnostic or therapeutic procedure. 
The frequency and severity of related adverse events included in these protocols will depend on the 
cancer immunotherapy or regimen being used. 


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Appendix 7.1. Management Principles for Gastrointestinal Adverse Events 
Inflammatory causes of disease should be excluded. Opioids/anesthetics may mask the symptoms 
of perforation. Do not use infliximab in the case of perforation/sepsis. 
Diarrhea/Colorectitis Grade 
(NCICTCAEv4) 
Handling 
Follow-Up 
Grade 1 
Diarrhea: Defecation frequency 
exceeds baseline by < 4 
times/day; 
Colitis: no symptom. 
 
Continue the 
immunotherapy 
according to the study 
protocol; 
 
Symptomatic treatment. 
 
Closely monitor aggravated symptoms. 
 
Educate subjects to report aggravated 
symptoms immediately. 
If it is aggravated: 
 
Provide treatment according to the method 
for grade 2 or grade  
3/4 situations. 
Grade 2-3 
Diarrhea (Grade 2): Defecation 
frequency exceeds baseline for  
4-6 times/day; intravenous 
infusion of  
< 24 h is required; daily living is 
not affected; 
Colitis (Grade 2): abdominal pain; 
hematochezia. 
Diarrhea (Grade 3): Defecation 
frequency exceeds baseline for  
≥ 7 times/day; fecal incontinence; 
intravenous infusion of ≥ 24 h is 
required; daily living is affected; 
Colitis (Grade 3): severe 
abdominal pain; indications for 
medical intervention; peritoneal 
signs; 
 
Delay the immunotherapy 
according to the study 
protocol; 
 
Symptomatic treatment. 
If it is improved to Grade 1: 
 
Resume the immunotherapy according to 
the study protocol. 
If it lasts for > 5-7 days or relapses: 
 
Intravenous administration of  
0.5-1.0 mg/kg/d methylprednisolone or an 
equivalent orally administrated dose; 
 
When the symptoms improve to grade 1, 
reduce the dose of steroids for at least 1 
month and consider prophylactic antibiotics 
to prevent opportunistic infections, then 
resume the immunotherapy as per study 
protocol. 
If the symptoms aggravated or persisted after > 
3-5 days of oral administration of steroids: 
 
Provide treatment according to the method 
for grade 3/4 situations. 
Grade 4 
Grade 4: life-threatening; 
perforation. 
 
Terminate the 
immunotherapy 
according to the study 
protocol; 
 
Intravenous 
administration of 1.0-2.0 
mg/kg/d 
methylprednisolone or an 
equivalent IV dose; 
 
Add prophylactic 
antibiotics to prevent 
opportunistic infections; 
 
Consider lower GI 
endoscopy. 
If symptoms improve: 
 
Continue steroid treatment until the 
symptoms return to grade 1, then gradually 
reduce the dose of steroids for at least 1 
month. 
If it lasts for > 3-5 days or relapses after 
improvement: 
 
Add 5 mg/kg infliximab (if there are no 
contraindications). Note: Do not use 
infliximab in the case of perforation/sepsis. 
Once a subject given intravenous injections of steroids shows a sustained clinical improvement, the subject can 
switch to an equivalent dose of oral corticosteroids (e.g., prednisone) by the time or before the dose of steroid 
injections starts to be gradually reduced. When switching to oral corticosteroids with an equivalent dose, it 
should be considered that the bioavailability of oral corticosteroids is relatively low. 


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Appendix 7.2 Management Principles for Pulmonary Adverse Events 
Inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a 
symptomatic treatment should be given while the immunotherapy should be continued. Imaging 
evaluation and consultations with the respiratory department should be performed. 
Grade of Pulmonitis 
(NCICTCAEv4) 
Handling 
Follow-Up 
Grade 1 
Only radiographic changes 
 
 
Consider delaying the 
immunotherapy; 
 
Monitor symptoms every 
2-3 days; 
 
Consider consulting with 
respirologist and infectious 
diseases specialist. 
 
Repeat imaging examinations at least 
every 3 weeks. 
If it is aggravated: 
 
Provide treatment according to the method 
for grade 2 or grade 3/4 situations. 
Grade 2 
Mild to moderate new symptoms 
 
Delay the immunotherapy 
according to the study 
protocol; 
 
Consult with respirologist 
and infectious diseases 
specialist; 
 
Intravenous administration 
of 1.0 mg/kg/d 
methylprednisolone or an 
equivalent orally 
administrated dose; 
 
Consider bronchoscopy and 
lung biopsy. 
 
Repeat imaging examinations every  
1-3 days. 
If symptoms improve: 
 
When symptoms return to near baseline 
levels, reduce the dose of steroids for at 
least 1 month and then resume the 
immunotherapy as per study protocol 
while considering prophylactic antibiotics. 
 
If the symptoms are not improved or aggravated 
after 2 weeks: 
 
Provide treatment according to the method 
for grade 3/4 situations. 
Grade 3-4 
Severe new symptoms; new 
onset/aggravation of hypoxia; 
life-threatening. 
 
Terminate the 
immunotherapy according 
to the study protocol; 
 
Consult with respirologist 
and infectious diseases 
specialist; 
 
Intravenous administration 
of 2-4 mg/kg/d 
methylprednisolone or an 
equivalent IV dose; 
 
Add prophylactic 
antibiotics to prevent 
opportunistic infections; 
 
Consider bronchoscopy and 
lung biopsy. 
If symptoms improve to the baseline level: 
 
Gradually reduce the dose of steroids for at 
least 6 weeks. 
If the symptoms are not improved or aggravated 
after 48 h: 
 
Add other immunosuppressants (e.g., 
infliximab, cyclophosphamide, 
intravenous immunoglobulin or 
mycophenolate mofetil). 
Once a subject given intravenous injections of steroids shows a sustained clinical improvement, the subject can 
switch to an equivalent dose of oral corticosteroids (e.g., prednisone) by the time or before the dose of steroid 
injections starts to be gradually reduced. When switching to oral corticosteroids with an equivalent dose, it 
should be considered that the bioavailability of oral corticosteroids is relatively low. 


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Appendix 7.3. Management Principles for Hepatic Adverse Events 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, 
a symptomatic treatment should be given while the immunotherapy should be continued. Consider 
imaging examinations to rule out obstruction/tumor progression. 
Elevation Grade in the 
Hepatic Function Test 
(NCICTCAEv4) 
Handling 
Follow-Up 
Grade 1 
AST/ALT > 3 × ULN 
and/or TBIL > 1 × ULN 
but ≤ 1.5 × ULN 
 
Continue the immunotherapy 
according to the study protocol. 
 
Continue hepatic function monitoring as per 
study protocol. 
If it is aggravated: 
 
Provide treatment according to the method 
for grade 2 or grade 3/4 situations. 
Grade 2 
AST/ALT > 3 × ULN, but 
≤ 5 × ULN 
and/or TBIL> 1.5 × ULN 
but ≤ 3 × ULNN 
 
Delay the immunotherapy 
according to the study protocol; 
 
Increase the monitoring 
frequency to once every 3 days. 
If symptoms recover to the baseline level: 
 
Resume routine monitoring and resume the 
immunotherapy according to the study 
protocol. 
If elevation persists for > 5-7 days or aggravates: 
 
Intravenous administration of 0.5-1 mg/kg/d 
methylprednisolone or an equivalent orally 
administrated dose. If LFT recovers to Grade 
1 or to the baseline level, reduce the dose of 
steroids for at least 1 month, and consider 
prophylactic antibiotics to prevent 
opportunistic infection and then resume the 
immunotherapy according to study protocol. 
Grade 3-4 
ALT/AST > 5 × ULN 
and/or TBIL > 3 × ULN 
 
Terminate the immunotherapy 
according to the study protocol*; 
 
Increase the monitoring 
frequency to once every 1-2 days; 
 
Intravenous administration of 
1.0-2.0 mg/kg/d 
methylprednisolone or an 
equivalent dose via intravenous 
injection**; 
 
Add prophylactic antibiotics to 
prevent opportunistic infections; 
 
Consultation with the 
gastroenterology department. 
If it recovers to Grade 2: 
 
Reduce the dose of steroids for at least  
1 month. 
If not improving, or even aggravating or recurring 
after > 3-5 days: 
 
Add 1 g of mycophenolate mofetil, bid; 
 
If the symptoms are not relieved within  
3-5 days, other immunosuppressants are 
considered based on local guidelines. 
Once a subject given intravenous injections of steroids shows a sustained clinical improvement, the subject can 
switch to an equivalent dose of oral corticosteroids (e.g., prednisone) by the time or before the dose of steroid 
injections starts to be gradually reduced. When switching to oral corticosteroids with an equivalent dose, it 
should be considered that the bioavailability of oral corticosteroids is relatively low. 
* If AST/ALT ≤ 8 × ULN and TBIL ≤ 5 × ULN, the immunotherapy can be delayed rather than discontinued. 
**For grade 4 hepatitis, the recommended starting dose of methylprednisolone via intravenous injection is 
2 mg/kg/d. 
 


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Appendix 7.4. Management Principles for Endocrine Adverse Events 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, 
a symptomatic treatment should be given while the immunotherapy should be continued. Visual 
field tests, endocrinology consultation and imaging examinations are considered. 
TSH Increased/Thyroxine Decreased 
 
Continue the immunotherapy according to the 
study protocol; 
 
Treatment may be continued through initiation of 
thyroid hormone replacement therapy if 
thyroxine is reduced. 
Immune-Related Hypophysitis 
 
Assess endocrine functions; 
 
Consider pituitary scans; 
 
Continue the medication for Grade 1; 
 
Delay the immunotherapy according to the study 
protocol for Grade 2-3; 
 
Treatment discontinuation for Grade 4 
Suspected Adrenal Crisis (e.g., severe dehydration, 
hypotension, and shock that does not match the severity 
of the disease) 
 
Terminate the immunotherapy according to the 
study protocol; 
 
Exclude sepsis; 
 
Intravenous administration of a stress dose of 
steroids containing mineralocorticoids; 
 
Intravenous infusion; 
 
Consult an endocrinologist; 
 
If adrenal crisis is ruled out, treat the 
symptomatic endocrinopathy using the methods 
described above. 
Once a subject given intravenous injections of steroids shows a sustained clinical improvement, the subject can 
switch to an equivalent dose of oral corticosteroids (e.g., prednisone) by the time or before the dose of steroid 
injections starts to be gradually reduced. When switching to oral corticosteroids with an equivalent dose in the 
lungs and liver, it should be considered that the bioavailability of oral corticosteroids is relatively low. 
 
 
 


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Appendix 8. Percent Bone Marrow Content in Human Skeleton 
 
 
 


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Appendix 9. Prohibited Traditional Chinese Medicines During the Study Period  
Traditional Chinese medicines prohibited during the study include but are not limited to the 
following: 
✓ Huatan Huisheng tablet 
✓ Brucea Javanica oil soft capsule 
✓ Mandarin melon berry syrup 
✓ Cantharidin 
✓ Cinobufotalin 
✓ Bufotoxin 
✓ Kang'ai injection 
✓ Kanglaite injection 
✓ Zhongjiefeng injection 
✓ Aidi injection 
✓ Awei Huapi ointment 
✓ Kangaiping pill 
✓ Fukang capsule 
✓ Xiaoaiping 
✓ Pingxiao capsule 
✓ Pingxiao tablet 
✓ Shendan Sanjie capsule 
✓ Ankangxin capsule 
✓ Boshengaining 
✓ Zedoary turmeric oil and glucose injection 
✓ Kanglixin capsule 
✓ Cidan capsule 
 


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Appendix 10. EORTC QLQ-C30 Scale 
EORTC Quality of Life Measurement Scale QLQ-C30 (V3.0) (Chinese Version) 
(When there is inconsistency with the official scale, the official scale prevails) 
We would like to know about you and your health status. Please answer all the questions yourself. 
Please circle the number that best applies to you. There are no "right" or "wrong" answers. The 
information you provide will be kept strictly confidential. 
Please fill in your code (no.): __________ 
Date of birth (DD/MM/YYYY): _________ 
Today's date (DD/MM/YYYY): _________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
None 
A little 
bit 
Quite a 
bit 
Very 
much 
1. Do you have any trouble doing strenuous activities, like carrying a heavy 
shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, bathing or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
None 
A little 
bit 
Quite a 
bit 
Very 
much 
6. Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
Continued on next page 
 
 


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During the past week: 
None 
A little 
bit 
Quite a 
bit 
Very 
much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, like reading a newspaper 
or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment interfered with your 
family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment interfered with your social 
activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment caused you financial 
difficulties? 
 
 
 
 
 
For the following questions, please circle the number from 1 to 7 that best applies to you 
 
29. How would you rate your overall health condition during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very bad 
 
 
 
 
 
Very good 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very bad 
 
 
 
 
 
Very good 
 
 
 


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Appendix 11. iRECIST Response Evaluation Criteria in Solid Tumors 
iRECIST Response Evaluation Criteria in Solid Tumors (Excerpt) 
(Seymouretal: Supplementary Appendix to: iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol, 2017; 18(3): e143-e152.) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
3 
iRECIST Response Evaluation 
iRECIST can be used to assess overall efficacy. In immunotherapy, the infiltration of immune 
cells may cause temporary enlargement of the tumor tissue, and may also cause the tumor tissue 
that would otherwise be undetectable large enough to be detectable. In many respects, the 
provisions of iRECIST are the same as those of RECIST v1.1, but some of the contents have been 
adjusted to accurately reflect whether the tumor is really progressing when the tumor burden 
increases or new lesions appear. 
The main differences between iRECIST and RECIST v1.1 are detailed below. Reactions judged 
using iRECIST are marked with the prefix "i". The overall response and the BOR of iRECIST at a 
certain time point are recorded separately. 
3.1  Progression Confirmation 
Unlike RECIST v1.1, iRECIST requires further confirmation of progressive disease (PD), using 
iUPD to represent unconfirmed progression, and iCPD to represent confirmed progression. The 
confirmatory imaging evaluation will be performed 4 weeks (but no more than 8 weeks) after 
iUPD. 
Compared with the previous imaging evaluation, if the tumor burden increases further and meets at 
least one of the following criteria, iCPD is confirmed: 
➢ Among the tumor burdens (including target lesions, non-target lesions, or new lesions) 
judged to be progressive (iUPD) as per RECIST v1.1, the burden continued to increase 
compared with the burden at iUPD. 
 
The absolute value of the sum of diameters of target lesions continues to increase by 
at least 5 mm; 
 
Non-target lesions continue to progress significantly, accompanied by an increase in 
tumor burden; 


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 
Enlargement of new lesions which occurred recently (the absolute value of the sum 
of diameters of new target lesions must increase by at least 5 mm) or appearance of 
other new lesions 
➢ Progression in lesions not previously identified as progressive (target lesions, non-target 
lesions, or new lesions) (as per RECIST v1.1), including the appearance of new lesions. 
If iUPD is not confirmed in the next evaluation, it should be judged as other results (if it still meets 
the PD criteria and does not aggravate, it is judged as iUPD; compared with the baseline, if it meets 
the evaluation criteria of SD, PR, or CR, then it is judged as iSD , iPR, or iSD, respectively). As 
shown in Table 2, if a previous iUPD is not confirmed as iCPD in the next evaluation, then the 
response evaluation (including the best overall response) at the next time point can be iCR, iPR, or 
iSD. 
3.2  New Lesions 
New lesions should be evaluated and measured as per RESIST1.1 [up to 5 lesions, no more than 
2 lesions per organ, and the long diameter of the lesion shall be at least 10 mm (for lymph node 
lesions, the short diameter shall be at least 15 mm)]. New lesions will be recorded as new target 
lesions (NLT) and new non-target lesions (NLNT) to clearly distinguish them from baseline target 
lesions and non-target lesions. 
New lesions can be judged as NLT or NLNT and used as the basis for the judgment of iUPD (or 
iCPD). However, the measurement of the new target lesions should not be included in the 
measured sum of the original target lesions at baseline. Instead, these measurements will be 
collected separately in the case record form. 
Since the appearance of new lesions is assessed as iUPD, and the next evaluation will be 
performed in at least 4 weeks (up to 8 weeks), progression can be confirmed when any of the 
following situations occurs: the sum of diameters of new target lesions has increased by at least 
5 mm; or the new non-target lesions have enlarged (no significant progression required); 
appearance of other new lesions. 
Table 3. Evaluation of immune response at various time points 
Original target 
lesion* 
Original non-target 
lesion* 
New 
Lesion 
Judgment of overall response at this time point 
Not iUPD 
last time** 
iUPD last time**; *** 
iCR 
iCR 
None 
iCR 
iCR 
iCR 
Non-iCR/Non-iUPD 
None 
iPR 
iPR 
iPR 
Non-iCR/Non-iUPD 
None 
iPR 
iPR 
iSD 
Non-iCR/Non-iUPD 
None 
iSD 
iSD 


SHR-1210, Apatinib 
SHR-1210-II-212 
Version 3.0 (Version Date: 25 Feb., 2019) 
 
Hengrui Confidential 
135 
Original target 
lesion* 
Original non-target 
lesion* 
New 
Lesion 
Judgment of overall response at this time point 
Not iUPD 
last time** 
iUPD last time**; *** 
iUPD has no 
progression or has 
decreased 
iUPD has no 
progression or has 
decreased 
Yes 
NA 
The increase in the size or number of new 
lesions (the sum of diameters of new 
target lesions increases by ≥ 5 mm or new 
non-target lesions increase) is iCPD. If 
the changes in new lesions do not reach 
the above level, they are still iUPD. 
iSD 
iUPD 
None 
iUPD 
The original non-target lesions, if further 
increasing in size (no need become 
significant PD as per RECIST v1.1), are 
iCPD; otherwise, the iUPD conclusion is 
maintained. 
iUPD 
Non-iCR/Non-iUPD 
None 
iUPD 
The original target lesions, if further 
increasing in size by ≥ 5 mm, are iCPD; 
otherwise, they are iUPD. 
iUPD 
iUPD 
None 
iUPD 
If the original target lesions increase in 
size by ≥ 5 mm, or the original non-target 
lesions increase in size (no need to 
increase significantly), they are iCPD; if 
there is no increase, they are iUPD. 
iUPD 
iUPD 
Yes 
iUPD 
If the original target lesions increase in 
size by ≥ 5 mm, or the original non-target 
lesions increase in size (no need to 
increase significantly), or the new lesions 
increase in size or number, they are 
iCPD; otherwise, they are iUPD. 
Non-iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
The new lesions, if with an increase in 
size or number, are iCPD; otherwise, they 
are iUPD. 
*As per RECIST v1.1. If there is no pseudoprogression, the criteria for CR, PR, and SD as per RECIST v1.1 and 
iRECIST are the same; ** Any lesion type; *** Judged in the evaluation prior to this time point. 
 

SAP_001.pdf: 
Title: A multicenter, randomized, open-label phase II clinical study of anti-PD-1 
antibody SHR-1210 combined with apatinib mesylate vs. doxorubicin combined with 
ifosfamide in treatment of soft tissue sarcoma 
NCT number: NCT03711279 
Date: 23 Nov., 2020 


SHR-1210-II-212  
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Statistical Analysis Plan 
1 
Translated from Original Document 
 
 
 
 
A MULTICENTER, RANDOMIZED, OPEN-LABEL PHASE II CLINICAL 
STUDY OF ANTI-PD-1 ANTIBODY SHR-1210 COMBINED WITH 
APATINIB MESYLATE VS. DOXORUBICIN COMBINED WITH 
IFOSFAMIDE IN TREATMENT OF SOFT TISSUE SARCOMA 
 
Statistical Analysis Plan 
(SAP) 
 
Written by: 
 
Company: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Version: 1.0/Initial Draft 
Date: 23 Nov., 2020 
This SAP has been reviewed by the following personnel before being approved and effective. 
Functional Role 
Reviewer 
Medical Science 
 
Statistics 
 


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Statistical Analysis Plan 
2 
ABBREVIATIONS 
Term 
Definition 
AE 
Adverse event 
BOR 
Best overall response 
CR 
Complete response 
DCR 
Disease control rate 
ECG 
Electrocardiogram 
ES 
Evaluable set 
FAS 
Full analysis set 
NE 
Not evaluable 
ORR 
Objective response rate 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PT 
Preferred term 
QD 
Quaque die 
Q3W 
Once every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SOC 
System organ classification 
SD 
Stable disease 
SAS 
Statistical analysis system 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
TRAE 
Treatment-related adverse event 
VS 
Vital signs 
 
 


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Statistical Analysis Plan 
3 
TABLE OF CONTENTS 
ABBREVIATIONS ....................................................................................................................... 2 
1 
REVISION ............................................................................................................................. 6 
2 
INTRODUCTION ................................................................................................................ 6 
2.1 
Study Design .................................................................................................................. 6 
2.2 
Study Objectives ............................................................................................................. 8 
2.2.1 
Primary objective ................................................................................................ 8 
2.2.2 
Secondary objectives ........................................................................................... 8 
2.2.3 
Exploratory objectives ........................................................................................ 8 
2.3 
Sample Size .................................................................................................................... 9 
3 
STATISTICAL HYPOTHESES ......................................................................................... 9 
4 
STUDY ENDPOINTS ........................................................................................................... 9 
4.1 
Efficacy Endpoints ......................................................................................................... 9 
4.1.1 
Primary efficacy endpoint ................................................................................... 9 
4.1.2 
Secondary efficacy endpoints ........................................................................... 10 
4.2 
Safety Endpoints ........................................................................................................... 11 
4.2.1 
Adverse event .................................................................................................... 12 
4.2.2 
Laboratory tests ................................................................................................. 12 
4.2.3 
Vital signs.......................................................................................................... 12 
4.2.4 
12-Lead ECG .................................................................................................... 12 
4.2.5 
Physical examination ........................................................................................ 12 
4.2.6 
Other safety endpoints ....................................................................................... 12 
4.3 
Immunogenicity and Drug Trough Concentration ....................................................... 12 
5 
STATISTICAL ANALYSIS .............................................................................................. 13 
5.1 
General Considerations ................................................................................................ 13 
5.1.1 
Analysis sets ...................................................................................................... 13 
5.1.2 
General rules and analysis ................................................................................. 13 
5.1.3 
Derived variables .............................................................................................. 15 
5.1.4 
Missing data ...................................................................................................... 16 
5.1.5 
Protocol deviations ............................................................................................ 16 
5.1.6 
Inclusion/exclusion violation ............................................................................ 17 


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Statistical Analysis Plan 
4 
5.2 
Study Subjects .............................................................................................................. 17 
5.2.1 
Disposition of subjects ...................................................................................... 17 
5.2.2 
Demographics ................................................................................................... 17 
5.2.3 
Tumor diagnosis ................................................................................................ 17 
5.2.4 
Medical history .................................................................................................. 18 
5.2.5 
Tumor treatment history .................................................................................... 18 
5.2.6 
Prior therapy and concomitant medication ....................................................... 18 
5.3 
Follow-up Systemic Anti-Tumor Therapy ................................................................... 18 
5.4 
Efficacy analysis ........................................................................................................... 18 
5.4.1 
Primary efficacy analysis .................................................................................. 18 
5.4.2 
Secondary efficacy analysis .............................................................................. 19 
5.5 
Safety Analysis ............................................................................................................. 19 
5.5.1 
Extent of exposure ............................................................................................. 19 
5.5.2 
Adverse event .................................................................................................... 19 
5.5.3 
Laboratory tests ................................................................................................. 20 
5.5.4 
Vital signs.......................................................................................................... 21 
5.5.5 
12-Lead ECG .................................................................................................... 21 
5.5.6 
ECOG PS ........................................................................................................... 21 
5.5.7 
Physical examination ........................................................................................ 21 
5.5.8 
Other safety measures ....................................................................................... 21 
5.6 
Pharmacokinetic Analysis ............................................................................................ 21 
5.7 
Other analyses .............................................................................................................. 21 
6 
INTERIM ANALYSIS ....................................................................................................... 22 
7 
REFERENCES .................................................................................................................... 22 
8 
APPENDICES ..................................................................................................................... 23 
Appendix 1 Response Evaluation Criteria in Solid Tumors ................................................... 23 
Appendix 2 Common Soft Tissue Sarcomas With Poor Chemotherapy Sensitivity ............ 36 
Appendix 3 Histological Coding for Common Soft Tissue Sarcomas  
With Poor Chemotherapy Sensitivity ....................................................................................... 36 
 


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Statistical Analysis Plan 
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LIST OF TABLES 
Table 1. Derived variables of SHR-1210 ...................................................................................... 15 
Table 2. Derived variables of apatinib .......................................................................................... 15 
Table 3. Derived variables of doxorubicin ................................................................................... 15 
Table 4. Derived variables of ifosfamide ...................................................................................... 16 
Table 1. Time point response: subjects with target (+/- non-target) disease ................................ 31 
Table 2. Time point response: subjects with non-target lesion only............................................. 31 
Table 3. Best overall response when confirmation of CR and PR required ................................. 32 
 
 


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Statistical Analysis Plan 
6 
1 REVISION 
This statistical analysis plan is the initial version, drafted based on the final version of the study 
protocol (version no.: 3.0, version date: 25 Feb., 2019). 
The final draft of this plan will be completed before database locking and will be signed by various 
functional departments for confirmation. 
2 INTRODUCTION 
SHR-1210 (camrelizumab) is a recombinant humanized anti-programmed cell death-1 (PD-1) 
monoclonal antibody independently developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. It is 
a new class 1 therapeutic biological product and has been marketed. Preclinical studies have 
shown that SHR-1210 has comparable in vivo pharmacological and safety profiles to those of 
drugs of the same class abroad, and may have a better clinical potential for anti-tumor treatment. 
Apatinib is a highly effective and selective inhibitor of VEGFR-2. The activity assay showed that 
its inhibitory effect against VEGFR-2 is stronger than that of drugs of same class (sorafenib, 
sunitinib, pazopanib, etc.); its selectivity for VEGFR-2 is ≥ 30 times stronger than that of other 
targets (VEGFR-1/PDGFR, SRC, etc.). Apatinib can effectively inhibit the in vitro lumen 
formation of Human Umbilical Vein Endothelial Cells (HUVEC) and the formation of arterial ring 
capillaries in rats, and has a strong inhibitory effect against neovascularization. 
Based on the past successes of VEGFR inhibitors combined with anti-PD-1/anti-PD-L1 antibodies 
in clinical studies and the current treatment status of soft tissue sarcoma, VEGFR-2 inhibitor 
apatinib combined with SHR-1210 may also exert considerable synergistic effect in the treatment 
of soft tissue sarcoma, thereby providing a novel and effective non-chemotherapy treatment for 
patients with soft tissue sarcoma. 
2.1 
Study Design 
This study is a multi-center, randomized, open-label phase II clinical study, with a total of 292 subjects 
planned to be enrolled. 
Qualified subjects with soft tissue sarcoma will be randomized in a 1:1 ratio into the SHR-1210 + 
apatinib group (investigational treatment group) and the doxorubicin + ifosfamide/ifosfamide 
monotherapy group (control group). The stratification factors include: 1) ECOG PS, 0 vs. 1-2; 2) 
Whether the pathological type of the tumor is poorly sensitive to chemotherapy (see Appendix 2. 
Common Types of Soft Tissue Sarcoma with Poor Chemotherapy Sensitivity); 3) Whether the 
subjects have previously undergone chemotherapy. The administration regimens for 
investigational treatment group and control group are as follows: 


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Statistical Analysis Plan 
7 
Investigational treatment group: SHR-1210 200 mg q3w (up to 2 years of treatment) + apatinib 
500 mg qd. 
Control group: doxorubicin 60 mg/m2 on D1 + ifosfamide 2 g/m2/d on D1-D4, in 3-week cycles 
(i.e., the total dose per cycle is 8 g/m2), and 6 cycles are recommended. If the investigator judges 
that the subject can benefit from continued doxorubicin + ifosfamide chemotherapy, additional 
chemotherapy cycles may be administered. When the subject's dose of anthracyclines has reached 
the recommended maximum cumulative dose of doxorubicin, the chemotherapy regimen should 
be adjusted to ifosfamide monotherapy, 2 g/m2/d on D1-D5, in 3-week cycles (i.e., the total dose 
per cycle is 10 g/m2). If the investigator judges that the subject can benefit from ifosfamide 
chemotherapy, additional chemotherapy cycles may be administered. 
 
In this study, the screening period should be no more than 28 days. After completing screening 
examinations and assessments, eligible subjects will enter the treatment period and receive the 
study treatment and study visits according to the protocol. Among them, tumor imaging 
assessment will be performed once in every 2 cycles during the first 16 cycles and once every 4 
cycles thereafter. The independent review committee (IRC) will review the imaging evaluation 
results of each study center. The safety follow-up period of subjects in the investigational 
treatment group starts after the last dose, and the subjects will be followed up once every 30 days 
until 90 days after the last dose. Among them, the first safety follow-up will be carried out at the 
Main Subject Characteristics 
• Metastatic or locally advanced 
unresectable soft tissue sarcoma  
(except Ewing's sarcoma, embryonic 
rhabdomyosarcoma, osteochondroma, 
and intermediate tumors without 
extensive metastasis) 
• Have not received any prior systemic 
therapy or have sensitive relapse after 
chemotherapy (sensitive relapse refers to 
recurrence more than 6 months after the 
last chemotherapy) 
Stratification factors 
• ECOG PS: 0 or 1-2 
• Receiving any prior chemotherapy:  
Yes or No 
• Chemotherapy sensitivity: Poor 
sensitivity to chemotherapy or other 
SHR-1210 200 mg q3w[1] 
+ 
Apatinib 500 mg qd 
Radiological PD+ subjects meeting 
inclusion/exclusion criteria can be 
crossed over to receive the treatment for 
investigational treatment group 
Doxorubicin 60 mg/m2 on D1 + 
Ifosfamide 2 g/m2  on D1-D4 
q3w, routinely for 6 cycles[2] 
PD/intolerability 
1. The treatment duration of SHR-1210 should be no more than 2 years; interruption of one drug does not require the 
interruption of the other; 2. If anthracycline 450 mg/m2 is used for the control group, the chemotherapy regimen will be 
adjusted to ifosfamide monotherapy, 2 g/m2 on D1-D5, q3w; more than 6 chemotherapy cycles may be administered. 


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Statistical Analysis Plan 
8 
study center; the second and the third follow-up visits will be made via phone calls. For subjects in 
the control group, if they do not receive SHR-1210 + apatinib treatment, their safety follow-up 
period will be 21 days after the last dose; otherwise, the same arrangement as that in the 
investigational treatment group will be used. The survival follow-up period will start after the end 
of the safety follow-up period. The survival follow-up period will end upon the subject's death, lost 
to follow-up, withdrawal of informed consent, or study termination by the sponsor. During this 
period, a follow-up shall be conducted every 2 months via phone calls or other effective methods 
to collect information on subject survival and subsequent anti-tumor treatment. 
2.2 
Study Objectives 
2.2.1 
Primary objective 
 
To evaluate whether SHR-1210 combined with apatinib is better than doxorubicin 
combined with ifosfamide in the treatment of soft tissue sarcoma based on the 
progression-free survival (PFS). 
2.2.2 
Secondary objectives 
 
To evaluate and compare the objective response rate (ORR) and disease control rate 
(DCR) of SHR-1210 combined with apatinib vs. doxorubicin combined with ifosfamide 
in the treatment of soft tissue sarcoma; 
 
To evaluate and compare the safety of SHR-1210 combined with apatinib vs. 
doxorubicin combined with ifosfamide in the treatment of soft tissue sarcoma;  
 
To evaluate and compare the quality of life scores in subjects with soft tissue sarcoma 
after treatment with SHR-1210 combined with apatinib vs. doxorubicin combined with 
ifosfamide. 
2.2.3 
Exploratory objectives 
 
To explore the correlation between the immunogenicity and the efficacy/safety of 
SHR-1210; 
 
To explore the correlation between the concentrations of SHR-1210 and apatinib and the 
efficacy/safety; 
 
PFS of subjects in the doxorubicin plus ifosfamide group after crossover treatment (as 
per RECIST v1.1); 
 
ORR, DCR (as per RECIST v1.1), safety, and quality of life scores of subjects in the 
doxorubicin plus ifosfamide group after crossover treatment. 


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Statistical Analysis Plan 
9 
2.3 
Sample Size 
In this study, IRC-assessed PFS will be used as the primary endpoint for superiority test with the 
control group. An interim analysis will be performed to determine the efficacy of the drugs and to 
determine whether to terminate or continue the study. The parameters for sample size calculation 
are as follows: 
 
Enrollment rate = 13 subjects/month (156 subjects/year), enrollment time = 20 months (the 
overall time will be 26 months) 
 
Randomization in a 1:1 ratio; one-sided α = 0.025; the power of the test is 90%; 
 
Hazard ratio (treatment group/control group [HR]) = 0.64 (estimated median PFS is 4.5 
months in the control group and 7.0 months in the treatment group) 
 
An interim analysis will be performed when 67% of PFS events (143) are collected to 
determine whether the drug is effective or ineffective, and to decide whether to terminate or 
continue the study. 
Based on the above parameters, at least 214 PFS events shall be collected according to the log-rank 
test for PFS comparison in the two groups and the O'Brien & Fleming spending function 
(EAST6.4.1) in the  spending function method proposed by Lan-DeMets, i.e., approximately 262 
subjects are needed. Considering a 10% dropout rate, 292 subjects are finally required for 
enrollment. 
3 STATISTICAL HYPOTHESES 
A superiority test will be conducted to compare SHR-1210 combined with apatinib (treatment 
group) vs. doxorubicin combined with ifosfamide (control group) in improving the PFS (assessed 
by the IRC as per RECIST v1.1) of patients with soft tissue sarcoma, at a significance level of 
one-sided α = 0.025. The null hypothesis (H0) and alternative hypothesis (H1) are: 
H0: PFS hazard ratio (treatment group/control group) ≥ 1; 
H1: PFS hazard ratio (treatment group/control group) < 1. 
4 STUDY ENDPOINTS 
4.1 
Efficacy Endpoints 
4.1.1 
Primary efficacy endpoint 
4.1.1.1 
PFS assessed by the independent review committee as per RECIST v1.1 
The primary endpoint of the study is the IRC-assessed PFS (as per RECIST v1.1). 


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Statistical Analysis Plan 
10 
PFS: the time between the date of randomization and the date on which the first tumor progression 
is documented (as per RECIST v1.1, regardless of whether treatment is continued), or death from 
any cause, whichever comes first. 
The censoring rules for PFS are as follows: 
− 
If there is no post-baseline objective tumor response evaluation or death, then the date of 
randomization will be censored.  
− 
If there is no progressive disease (PD) or death as per RECIST v1.1, then the date of the last 
objective tumor response evaluation will be censored.  
− 
If no imaging PD or death is recorded before the subject uses the new anti-tumor drug, the 
censoring date is the date of the last objective tumor response evaluation carried out before 
the subject uses the new anti-tumor drug. 
− 
Before PD or death, if a subject has missed ≥ 2 consecutive scheduled imaging assessments, 
then the date of the last objective tumor response evaluation prior to the missing ones will be 
censored. 
4.1.2 
Secondary efficacy endpoints 
4.1.2.1 
PFS assessed by the investigator (as per RECIST v1.1) 
PFS assessed by the investigator (as per RECIST v1.1) is one of the secondary endpoints in this 
study. 
4.1.2.2 
Objective response rate (ORR) assessed by the investigator and independent 
review committee 
ORR: the proportion of treated subjects with a best overall response (BOR) of complete response 
(CR) or partial response (PR) as per RECIST v1.1. 
4.1.2.3 
Disease control rate (DCR) assessed by the investigator and independent review 
committee 
DCR: the proportion of treated subjects with a best overall response of complete response (CR), 
partial response (PR), or stable disease (SD) as per RECIST v1.1. 
4.1.2.4 
Quality of life score (EORTC QLQ-C30) 
To evaluate the quality of life scores of SHR-1210 combined with apatinib and doxorubicin 
combined with ifosfamide in the treatment of subjects with soft tissue sarcoma 


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Statistical Analysis Plan 
11 
4.1.2.5 
Best overall response (BOR) 
The best overall response (BOR) is calculated based on the evaluation of imaging efficacy of soft 
tissue of all visits. The best response until the last response evaluation shall be used if no 
progressive disease is noted during the period between the date of first dose and the date of PD or 
initiation of other anti-tumor treatments. BOR is classified as: CR, PR, SD, PD, and NE. If the 
tumor is assessed as PD at a visit, the date of the PD should be recorded as the date of imaging 
assessment of the target lesion, the date of imaging assessment of the non-target lesion, or the date 
of discovery of the new lesion, whichever is earlier. 
 
Confirmed CR: Response evaluation of CR that has been reconfirmed as CR in a 
response evaluation 4 weeks later. 
 
Confirmed PR: 
- 
Response evaluation as CR that has been reconfirmed as PR instead of CR. 
- 
Response evaluation as PR that has been reconfirmed as CR/PR in a response 
evaluation 4 weeks later. 
 
SD: 
- 
Response evaluation as CR/PR that has been reconfirmed as SD instead of CR/PR. 
- 
The response is evaluated as SD at least once within the shortest time interval (not 
less than 6 weeks) after the start of the study. 
4.2 
Safety Endpoints 
The following safety data will be collected and summarized following the study protocol: 
• 
Adverse event 
• 
Laboratory test data 
• 
Vital signs data 
• 
12-Lead ECG 
• 
Physical examination 
• 
Other safety endpoints 


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Statistical Analysis Plan 
12 
4.2.1 
Adverse event 
An AE refers to any untoward medical condition in a clinical study subject who receives a 
pharmaceutical product, and the condition does not necessarily have a causality with the treatment. 
AEs can include any unfavorable and unintended symptoms, signs, abnormal laboratory finding, 
or diseases, including the following: 
1)  Worsening of pre-existing (prior to entering clinical study) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2)  Any new AE: Any new adverse medical conditions (including symptoms, signs, and 
newly diagnosed diseases); 
3)  Clinically significant abnormal laboratory findings. 
4.2.2 
Laboratory tests 
Hematology, urinalysis, stool occult blood, clinical chemistry, coagulation function, thyroid 
function (FT3, FT4, and TSH), myocardial zymography, and other laboratory data will be 
collected at the protocol-specified visit time points. 
4.2.3 
Vital signs 
Vital signs including body temperature, heart rate, respiration, blood pressure, and pulse will be 
collected at the protocol-preset time points. 
4.2.4 
12-Lead ECG 
Heart rate, QT, P-R interval, and other data will be collected at the protocol-preset time points. 
4.2.5 
Physical examination 
Physical examination includes height, weight, general condition, head, neck, chest, abdomen, 
perineum, and extremities. These data will be collected at protocol-specified visit/time points. 
4.2.6 
Other safety endpoints 
Electrocardiography and pregnancy test. 
4.3 
Immunogenicity and Drug Trough Concentration 
 
Anti-drug antibody and neutralizing antibody levels of SHR-1210 
 
Serum concentration of SHR-1210 and plasma concentration of apatinib 


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Statistical Analysis Plan 
13 
5 STATISTICAL ANALYSIS 
5.1 
General Considerations 
5.1.1 
Analysis sets 
Full analysis set (FAS) 
It includes all subjects who are randomized and have received study drugs at least once. This 
analysis set will be used for the efficacy analysis. 
Per-protocol set (PPS) 
It is a subset of the full analysis set, and subjects with major protocol deviations judged to have a 
significant impact on treatment efficacy will be excluded from this set. The list of subjects 
included into or excluded from the PPS should be reviewed and determined by the sponsor and the 
investigator before the database is locked. 
Safety set (SS) 
It includes all enrolled subjects who have received the study drugs at least once and have 
post-administration evaluable safety data. 
PK concentration set 
All enrolled subjects who have received at least one dose of the investigational drug and have 
post-baseline PK data. 
Immunogenicity analysis set 
All enrolled subjects who have received at least one dose of the investigational drug and have 
baseline and at least one post-baseline evaluable ADA data. 
5.1.2 
General rules and analysis 
Baseline 
Unless otherwise stated, "baseline" in this study is defined as the last non-missing measurement 
value obtained before the first use of study drugs. 
Study days 
The day of the first dose is used as the start date of the study (Day 1). 


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Statistical Analysis Plan 
14 
• 
If the evaluation date (adverse event, laboratory tests, etc.) is on or after the study 
medication, the study date shall be calculated as follows: 
Study days = evaluation/event date – start date of study + 1. 
• 
If the evaluation date (baseline characteristics, medical history, etc.) is before the study 
medication, the number of study days is a negative figure and shall be calculated as follows: 
Study days = evaluation/event date – start date of study; 
General analysis 
Unless otherwise specified, the following descriptive statistics will be summarized by the type of 
variables: 
• 
The measurement data will be summarized using mean, standard deviation, median, 
maximum, minimum, and quartile. 
• 
Count data will be summarized using frequency and percentage; 
• 
For time-to-event data, Kaplan-Meier method will be used to estimate the survival 
function and median time to event onset, and a survival curve will be plotted. 
Number of decimal places 
Unless otherwise specified, number of decimal places in the analysis report will be determined as 
per the following rules: 
• 
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 1 decimal place. If the frequency is 0, the percentage is 
not displayed. 
• 
The P value will retain 4 decimal places. If the P value is < 0.0001, it will be expressed as 
"< 0.0001"; if the P value is > 0.9999, it will be reported as "> 0.9999". 
• 
The 95% CI, if being a decimal, will retain at least 2 decimal places, up to 4 decimal 
places. Details are as follows: The 95% confidence interval will have one more decimal 
place than that of the raw data. If the raw data have no decimal place, the 95% confidence 
interval will retain 2 decimal places; if the raw data have 4 or more decimal places, the 
95% confidence interval will retain at most 4 decimal places. 
• 
Time to event (in months) will be rounded to one decimal place. 


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Statistical Analysis Plan 
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Results of Laboratory Tests 
The results of laboratory tests are generally continuous numerical variables or character variables. 
If continuous numerical variables recorded in eCRF contain special characters (such as < xx and > 
xx), the following rules will be applied: 
• 
When there is a situation of < xx or ≤ xx, half of the xx value will be used for analysis. 
• 
When there is a situation of > xx or ≥ xx, the value of xx will be used for analysis. 
Analysis software 
All statistical analyses will be conducted using SAS® 9.4 or later version. 
5.1.3 
Derived variables 
Table 1. Derived variables of SHR-1210 
Variable 
SHR-1210 
Protocol-Specified Method of 
Administration 
200 mg/dose, intravenous drip (no less than 20 min and no more than  
60 min) on Day 1 of each 3-week cycle. 
Duration of Drug Exposure (Month) 
(Actual date of last dose − actual date of first dose + 21)/30.4375 
Drug Exposure (mg) 
The total administered dose of SHR-1210 in the subject 
Actual Dose Intensity (mg/3 weeks) 
Drug exposure/[duration of drug exposure (month) × 30.4375/21] 
Relative Dose Intensity (%) 
100 × actual  dose intensity (mg/3 weeks)/200 (mg/3 weeks) 
Table 2. Derived variables of apatinib 
Variable 
Apatinib 
Protocol-Specified Method of 
Administration 
Administered orally at 500 mg/day once daily. Each cycle contains 3 weeks. 
Duration of Drug Exposure (Month) 
(Actual date of last dose − actual date of first dose + 1)/30.4375 
Drug Exposure (mg) 
The total administered dose of apatinib in the subject 
Intended Dose Intensity (mg/day) 
500 
Actual Dose Intensity (mg/day) 
Drug exposure (mg)/[duration of drug exposure (month) × 30.4375] 
Relative Dose Intensity (%) 
100 × actual dose intensity (mg/day)/500 
Table 3. Derived variables of doxorubicin 
Variable 
Doxorubicin 
Protocol-Specified Method of 
Administration 
Administered via intravenous drip infusion at 60 mg/m2 within 2 h on Day 1 
of each 3-week cycle. 
Duration of Drug Exposure (Month) 
(Actual date of last dose − actual date of first dose + 21)/30.4375 
Drug Exposure (mg/m2) 
Subject's actual cumulative dose (mg)/body surface area (1) 
Intended Dose (mg/m2) 
(Actual date of last dose − actual date of first dose + 21) × 60 mg/m2/21 
Relative Dose Intensity (%) 
100 × drug exposure (mg/m 2)/scheduled dose (mg/m2) 


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Table 4. Derived variables of ifosfamide 
Variable 
Ifosfamide 
Protocol-Specified Method of 
Administration 
Combination with doxorubicin: Ifosfamide 2 
g/m2/d on D1-D4, intravenous drip infusion 
within 4-6 h, in 3-week cycles (i.e., the total 
dose per cycle shall be 8 g/m2).  
Ifosfamide monotherapy: 2 g/m2/ d on 
D1-D5, intravenous drip infusion 
within 4-6 h, in 3-week cycles (i.e., the 
total dose per cycle shall be 10 g/m2). 
Duration of Drug Exposure 
(Month) 
(Actual date of last dose − actual date of first dose + 21)/30.4375 
Drug Exposure (g/m2) 
Actual cumulative dose/body surface area (1) 
Intended Dose (g/m2) 
[(Date of last dose of doxorubicin − date of first dose of doxorubicin + 21)/21] ×  
8 g/m2 + [CEIL × (date of last dose of ifosfamide − date of last dose of doxorubicin − 
4)/21] × 10 g/m 2 
Relative Dose Intensity (%) 
100 × drug exposure (g/m 2)/intended dose (g/m2) 
(1) The body surface area is calculated as: body surface area (m2) = 0.0061 × height (cm) + 0.0128 × weight (kg) − 
0.1529. The body weight at baseline should be used. 
*CEIL: round up 
5.1.4 
Missing data 
In this study, the missing data of the efficacy endpoints will not be treated specially, and the 
missing values will not be estimated in the safety evaluation. 
If the specific date of death is missing, it will be imputed based on the first day of month of death. 
If the specific day of the initial diagnosis is missing, it will be imputed with the first day of the 
month of initial diagnosis. If the month and day of the initial diagnosis are missing and the year of 
the initial diagnosis is before the year of the first dose, it will be imputed with 1 Jan. If the month 
and day of the initial diagnosis are missing and the year of the initial diagnosis is the same as the 
year of the first dose, it will be imputed with 1 Jan. If the date of the initial diagnosis is completely 
missing, it will not be imputed. 
5.1.5 
Protocol deviations 
Before database locking, data of all subjects on the CRF will be checked for major protocol 
deviations. All potential major protocol deviations will be reviewed and evaluated by the 
investigator and the sponsor. 
All major protocol deviations will be summarized and described separately by type and treatment 
group, and will be tabulated and analyzed. 


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Definitions of major protocol deviations:  
• 
Serious violation of the inclusion/exclusion criteria;  
• 
Incorrect treatment by study drugs (not treated using the drug or dose as per 
randomization);  
• 
Other major protocol deviations jointly recognized by the investigator and the sponsor. 
5.1.6 
Inclusion/exclusion violation 
All violations of the inclusion and exclusion criteria will be listed by subject number. 
5.2 
Study Subjects 
The study subjects will be analyzed by treatment group. 
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 (including the full analysis set, 
per-protocol set, safety set, PK concentration set, and immunogenicity analysis set), number of 
subjects who discontinue study/treatment, and number and percentage of corresponding subjects 
to the reasons for discontinuation. 
5.2.2 
Demographics 
Age, gender, ethnicity, height, weight, and other demographic data of the subjects will be 
summarized using descriptive statistics by treatment group. 
For continuous variables (such as age, height, weight, body mass index, doxorubicin dose 
corresponding to cumulative anthracycline, etc.), the number of observed subjects, mean, standard 
deviation, median, quartile, minimum, and maximum will be listed by treatment group. 
For categorical variables (such as gender, ethnicity, ECOG PS, etc.), the frequency and percentage 
will be listed by treatment group. 
Demographic and baseline characteristics will be tabulated. 
5.2.3 
Tumor diagnosis 
The following tumor parameters will be summarized using relevant descriptive statistics: the site 
of primary lesion, histological type, and clinical stage at screening will be summarized by the 
number and percentage of subjects involved in each treatment group. The course of disease (year) 
will be summarized using descriptive statistics such as mean, standard deviation, median, 
minimum, and maximum. A detailed list of subjects for tumor diagnosis will be provided. 


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The course of disease (year) is defined as the time from the date of the first diagnosis to the time of 
randomization, which should be calculated as: (date of randomization − date of first diagnosis + 1)/ 
365.25. 
5.2.4 
Medical history 
A detailed list of subjects and their medical history will be provided. 
5.2.5 
Tumor treatment history 
Tumor treatment history mainly includes the history of tumor surgery, the history of systemic 
anti-tumor treatment, the history of chemotherapy, and the history of radiotherapy. 
For tumor treatment history, the following descriptive statistics will be provided: 
• 
Number and percentage of subjects who have received tumor surgery; 
• 
The number and percentage of subjects who have received chemotherapy; 
• 
The number and percentage of subjects who have received radiotherapy; 
• 
The number and percentage of subjects who have received systemic anti-tumor therapy. 
In addition, a detailed list of subjects will be provided. 
5.2.6 
Prior therapy and concomitant medication 
All previous medication, concomitant medication, and concomitant non-drug therapy will be listed. 
5.3 
Follow-up Systemic Anti-Tumor Therapy 
Follow-up systemic anti-tumor treatments will be listed by treatment group. 
5.4 
Efficacy analysis 
5.4.1 
Primary efficacy analysis 
The primary endpoint of the study is the IRC-assessed PFS (as per RECIST v1.1). The primary 
analysis will be based on the FAS. The survival functions of PFS of the two groups will be 
compared using stratified log-rank tests with and without random stratification factors. The 
Kaplan-Meier method will be used to estimate the PFS rate, plot the survival curve, and estimate 
the median PFS, and its 95% CI will be calculated (Brookmeyer-Crowley method). The analysis 
with stratification factors will be used as the primary analysis. 
In addition, as a supporting analysis and under the assumption of proportional hazards, the Cox 
models with and without stratification factors will be used to estimate the hazard ratio (HR) and 
calculate the corresponding 95% CI (Wald method). 


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5.4.2 
Secondary efficacy analysis 
The analysis of secondary efficacy endpoints will be based on the FAS. 
For the secondary endpoint PFS assessed by the investigator (as per RECIST v1.1), the analytical 
method will be the same as that for the primary endpoint mentioned above. 
For the objective response rate (ORR) and disease control rate (DCR), the rates in the two groups 
and their two-sided 95% CI (Clopper-Pearson method) will be estimated, and the inter-group 
difference of rates and its two-sided 95% CI will be calculated (CMH method). A swimmer plot of 
ORR will also be produced. 
Other endpoints (best overall response, quality of life score, etc.) will be statistically summarized 
in accordance with general principles. 
5.5 
Safety Analysis 
All safety analyses will be conducted based on SS. All safety analyses will be presented by 
treatment group. 
5.5.1 
Extent of exposure 
See Section 5.1.3 for the specific defining rules of the derived variables of study drugs SHR-1210, 
apatinib, doxorubicin, and ifosfamide. 
The drug exposure, duration of drug exposure, actual dose intensity, and relative dose intensity of 
apatinib and SHR-1210, as well as the duration of drug exposure and drug exposure of doxorubicin 
and ifosfamide are described using the mean, standard deviation, maximum, minimum, and median. 
5.5.2 
Adverse event 
AEs will be classified by treatment stage (before and after study treatment). 
All AEs will be coded with MedDRA (version, 23.1). and graded using NCI-CTCAE v4.03. For 
the same SOC and/or PT, multiple cases of the same events that occur in one subject will be 
counted only once. For the same AE reported in one subject multiple times but varying in CTCAE 
grade, the AE of the greatest grade will be enumerated. 
AEs will be sorted by incidence from high to low based on SOC, and PT under each SOC. If the 
incidence of ≥ 2 PT is equal, the AEs will be sorted alphabetically. If there is no AE under a SOC 
or PT, then analysis will not be conducted. 
A treatment-emergent adverse event (TEAE) is defined as any adverse event that occurs after the 
start of study treatment. Only TEAEs will be summarized. All AEs will be listed. AEs with 
completely missing onset time will be treated as TEAEs. 


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For AEs occurring after the start of study treatment, treatment-related AEs include those whose 
causality with the study drug is definitely related, possibly related, or indeterminable; if the 
causality assessment is missing, then the AE will be deemed treatment-related for analysis. 
In a listing of AEs, TEAEs will be analyzed by group, and frequencies and proportions will be 
statistically described. AEs will be summarized using descriptive statistics according to Hengrui's 
Statistical Analysis Reporting Standards, including but not limited to the following contents: 
 
Any TEAE 
 
Treatment-related AEs (TRAEs) 
 
Any TESAE 
 
Treatment-related SAEs (TRSAEs) 
 
Any SAE 
 
Any drug-related SAE 
 
TEAEs resulting in dose reduction, dose interruption followed by reduction, interruption, 
or treatment discontinuation 
 
TRAEs resulting in dose reduction, dose interruption followed by reduction, interruption, 
or treatment discontinuation 
 
TEAEs resulting in death 
 
Immune-related adverse events ("reactive capillary endothelial proliferation" will all be 
considered immune-related events)? 
 
Was hormone therapy used? 
The incidence of AE is calculated based on the number of subjects having an AE, instead of the 
number of AE episodes. 
All AEs will be listed. Drug-related AEs, AEs resulting in treatment discontinuation, AEs 
resulting in dose reduction or dose interruption followed by reduction or treatment interruption, 
and death will be listed. 
5.5.3 
Laboratory tests 
Baseline laboratory measurement is defined as the latest non-missing test result prior to the first 
dose of study drugs. 
Laboratory results will be listed. 


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5.5.4 
Vital signs 
All vital signs will be listed. 
5.5.5 
12-Lead ECG 
Mean values of 12-Lead ECG results will be taken at each visit. ECG data include: HR 
(beats/min), PR interval (ms), QT interval (ms), and QTcF (ms). 
ECG parameters measured at the study site will be summarized as follows: 
- 
Maximum PR interval ≥ 300 ms 
- 
Maximum QT interval ≥ 500 ms 
- 
Maximum QTcF interval (ms) (450–<480, 480–<500, or ≥500) 
- 
Maximum QTcF interval ≥ 480 ms or increase > 60 ms from baseline 
Related data will also be listed. 
5.5.6 
ECOG PS 
All ECOG PS will be listed. 
5.5.7 
Physical examination 
Data of physical examination will be listed. 
5.5.8 
Other safety measures 
Echocardiography will be listed by treatment group and time. 
Pregnancy test results will be listed by treatment group and time. 
Observation results of reactive capillary endothelial proliferation will be listed. 
The subjects' virological examinations will be listed. 
5.6 
Pharmacokinetic Analysis 
The drug concentrations of SHR-1210 and apatinib will be statistically described by time point. 
5.7 
Other analyses 
A statistical analysis will be performed according to the confirmatory results of immunogenicity. 
The number and percentage of subjects who are ADA positive at baseline, ADA negative at 
baseline and positive post baseline, and ADA positive for at least once at baseline or post baseline 
will be summarized using descriptive statistics. 


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For the population who are ADA negative at baseline and positive post baseline, the following 
items will be analyzed: the time to the first positive ADA result, the number and percentage of 
subjects with transient positive post-baseline results (transient ADA positive is defined as the 
subjects who are negative at baseline and have only one ADA-positive sample post baseline before 
the last sample and are not persistent ADA positive), the number and percentage of subjects with 
persistent positive post-baseline results (persistent ADA positive can be divided to two categories: 
1) negative at baseline, there are at least two positive samples post baseline, where the first and last 
ADA-positive samples are separated by a period >16 weeks, or 2) negative at baseline, the last 
post-baseline sample is positive, or the last post-baseline sample is negative and the second last 
post-baseline sample is positive), and the number and percentage of subjects with other positive 
post-baseline results (other ADA positive is defined as the subjects who are negative at baseline, 
have at least two ADA positive samples post baseline, but not persistent ADA positive, and the last 
sample is negative). 
The number of ADA positive and negative subjects will be summarized and analyzed, and the 
efficacy and safety of ADA positive and negative subjects will be analyzed to investigate the 
impact of ADA on efficacy and safety. ADA-positive subjects are subjects with post-baseline 
ADA-positive samples, mainly including: a. the subjects who have the baseline negative and 
post-baseline positive samples, or b. the subjects who have both baseline and post-baseline 
positive samples, and the titer of the post-baseline samples is ≥ 4-fold of the baseline titer. 
ADA-negative subjects are those who are not ADA positive. 
In addition, the positive ADA results of the subjects producing neutralizing antibodies (Nab) will 
be summarized and analyzed. Nab-positive subjects are defined as the subjects who have 
post-baseline Nab positive samples (but those who have baseline and post-baseline Nab positive 
samples will be classified as Nab inconclusive subjects), and Nab-negative subjects are those who 
do not have post-baseline Nab positive samples. 
Immunogenicity raw data will be reported in the form of listing. 
6 INTERIM ANALYSIS 
No interim analysis will be conducted for this study. 
7 REFERENCES 
None. 


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8 
APPENDICES 
Appendix 1 Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) 
Note: This appendix is translated internally and is for reference only. Please refer to the 
English version during practice. 
1 
BACKGROUND 
Omitted 
2 
PURPOSE 
Omitted 
3 
MEASURABILITY OF TUMOR AT BASELINE 
3.1 Definition 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1 
Measurable lesions 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter is to be 
recorded) with a minimum size of: 
▪ 
CT scan 10 mm (the thickness of CT scan layer shall not be more than 5 mm) 
▪ 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
▪ 
20 mm by chest X-ray; 
▪ 
Malignant lymph nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15 mm in short axis by CT scan (CT scan slice thickness no greater than 5 mm). 
At baseline and during follow-up, only the short axis will be measured and followed. 
3.1.2 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodule 
with a short axis ≥ 10 mm and < 15 mm) as well as truly non-measurable lesions. Non-measurable 
lesions include: meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses unable to be diagnosed 
or followed by imaging techniques, and cystic lesions. 


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3.1.3 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
▪ 
Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
▪ 
Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by tomography techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above; 
▪ 
Blastic lesions are non-measurable. 
Cystic lesions: 
▪ 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts; 
▪ 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
▪ 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
3.2 Specifications by Methods of Measurements 
3.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 28 
days (4 weeks) before the beginning of the treatment. 


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3.2.2 
Method of assessment 
The same method and technique should be used to assess lesions at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of cutaneous lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both imaging and clinical examination, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end of 
the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT and MRI: CT is currently the best available and reproducible method for response evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm CR when biopsies are obtained, or to 
determine relapse in trials where recurrence following CR or surgical excision is an endpoint. 
Tumor biomarkers: Tumor biomarkers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper normal limit at baseline, they must return to the 
normal levels for evaluation of complete response. Because tumor biomarkers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line studies in ovarian cancer. 


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Cytology/histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual benign tumor tissue is commonly observed in 
lesions of germ cell neoplasm). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met the criteria for response or stable disease in order to 
differentiate between response (or stable disease) and PD. 
4 
TUMOR RESPONSE EVALUATION 
4.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable lesions at baseline should be included in protocols where objective response is the 
primary endpoint. Measurable lesion is defined by the presence of at least one measurable lesion. 
In trials where the primary endpoint is tumor progression (either time to progression or proportion 
with progression at a fixed date), the protocol must specify if enrollment is restricted to those with 
measurable lesions or whether patients with non-measurable lesions are also eligible. 
4.2 Baseline Documentation of 'Target' and 'Non-Target' Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ), representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where subjects have only one or two organ sites involved, a maximum of two and four 
lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal tissues which may be visible by imaging 
even if not involved by tumor metastasis. Pathological nodes which are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. 
Only the short axis of these nodes needs to be measured at baseline. The short axis of a node is the 
diameter normally used by radiologists to judge if the node is involved by tumor metastasis. 
Nodule size is normally reported as two dimensions in the plane in which the image is obtained 
(for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, 


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sagittal or coronal). The smallest of these measures is the short axis. For example, an abdominal 
node which is reported as being 20 mm × 30 mm with a short axis of 20 mm qualifies as a 
malignant and measurable node. In this example, 20 mm should be recorded as the node 
measurement. Nodes with a short axis ≥ 10 mm but < 15 mm should be considered non-target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and are thus not to 
be recorded or followed up. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions 
should be recorded as "present", "absent", or in rare cases "unequivocal progression". It is possible 
to record multiple target lesions involving the same organ as a single item on the case record form 
(e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
4.3 Response Criteria 
4.3.1 
Evaluation of target lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodules 
(whether target or non-target) must have reduction in short axis to < 10mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, compared 
with baseline. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm (the 
appearance of one or more new lesions is also considered PD). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
4.3.2 
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the sum of lesions may not be zero even if CR criteria are met, since a normal lymph 
node is defined as having a short axis < 10 mm. CRFs or other data collection methods may 


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therefore be designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must have a short axis < 10 mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being "too small to 
measure". When this occurs it is important that a value be recorded on the CRF. If it is the opinion 
of the radiologist that the lesion has likely disappeared, the measurement shall be recorded as 0 
mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm can be assigned. (Note: It is less likely that this rule will be used for lymph nodules 
since they usually have a definable size when normal and are frequently surrounded by adipose 
tissues as in the retroperitoneum; however, if a lymph nodule is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm can be assigned in this circumstance 
as well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, and therefore providing this default value will prevent false evaluation based 
upon measurement error. To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce: When non-nodal lesions fragment, the longest diameters of the 
fragmented portions should be added together to calculate the target lesion sum. Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion. 
4.3.3 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
biomarker level. All lymph nodules must be non-pathological in size (short axis < 10 mm). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
biomarker level above the normal limits. 


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Progressive disease (PD): Unequivocal progression of existing non-target lesions. Note: the 
appearance of one or more new lesions is also considered PD. 
4.3.4 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: When 
the patient also has measurable disease, to achieve unequivocal progression on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target disease 
such that the overall tumor load has increased sufficiently to the point where treatment must be 
discontinued. A modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment. Because worsening in non-target disease cannot be easily quantified (by definition: if 
all lesions are truly non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease load based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. For example, an increase in tumor burden representing an 
additional 73% increase in volume (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from "trace" to "large", an 
increase in lymphangitic disease from "localized" to "widespread", or may be described in 
protocols as "sufficient to require a change in treatment". Examples include an increase in a pleural 
effusion from trace to large, an increase in lymphangitic disease from localized to widespread, or 
may be described in protocols as "sufficient to require a change in therapy". If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so, and therefore the increase must be substantial. 
4.3.5 
New lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important. There are no specific criteria for the identification of radiographically 
detected lesions; however, the finding of a new lesion should be unequivocal. For example, it 
should not be attributable to differences in scanning technique, change in imaging modality, or 
findings thought to represent something other than tumor (for example, some new bone lesions 
that may be simply healing, or re-occurrence of pre-existing lesions). This is particularly important 
when the patient's baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a new cystic lesion, which it is not. 


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A lesion identified on a follow-up study that is not scanned at baseline will be considered a new 
lesion and will indicate PD. An example of this is the patient who has visceral disease at baseline 
and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain 
metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example, because of its small size, continued treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial identification. 
While FDG-PET response evaluations generally need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible new disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following process: 
▪ 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
▪ 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
▪ 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, PD is confirmed. 
▪ 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
▪ 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the imaging examination, this is not PD. 
4.4  Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement for confirmation. On occasion a response may 
not be documented until after the end of treatment, so protocols should be clear if post-treatment 
assessments are to be considered in the evaluation of best overall response. Protocols must specify 
how any new treatment introduced before progression will affect best response evaluation. The 
patient's best overall response evaluation will depend on the findings of both target and non-target 
diseases and will also take into consideration the characteristics of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomized studies where response is the primary 
endpoint, confirmation of PR or CR is needed to determine either one is the best overall response. 


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4.4.1  
Time point response 
It is assumed that at each time point specified in protocol, an efficacy response occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 1. Time point response: subjects with target (+/- non-target) disease 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 
PR 
Non-PD or not all evaluable 
Non 
PR 
SD 
Non-PD or not all evaluable 
Non 
SD 
Not all evaluable 
Non-PD 
Non 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable 
 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 
Table 2. Time point response: subjects with non-target lesion only 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
Non 
CR 
Non-CR/Non-PD 
Non 
Non-CR/Non-PDa 
Not all evaluable 
Non 
Not evaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a: "Non-CR/non-PD" is preferred over SD for non-target disease. Since SD is increasingly used as an endpoint for 
response evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
at that time point. If only a subset of lesion measurements is made at an evaluation, usually the case 
is also considered not evaluable at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) has/have no effect on the assigned time point 
response. This would be most likely to happen in the case of PD. For example, if a patient had three 
measured lesions with a baseline sum of 50 mm and only two lesions with a sum of 80 mm were 
assessed at a subsequent follow-up, the patient has achieved PD status, regardless of the 
contribution of the missing lesion. 


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4.4.3 
Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
BOR determination in studies where confirmation of complete or partial response is not required: 
BOR in these studies is defined as the best response across all time points (for example, a patient 
who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at the last cycle has a BOR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
calculated from baseline. If the minimum time is not met when SD is otherwise the BOR, the 
patient's BOR depends on the subsequent assessments. For example, a patient who has SD at Cycle 
1, PD at Cycle 2 and does not meet minimum duration for SD, will have a BOR of PD. The same 
patient lost to follow-up after the first SD assessment would be considered not evaluable. 
BOR determination in studies where confirmation of complete or partial response is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). In this circumstance, the BOR can 
be interpreted as in Table 3. 
Table 3. Best overall response when confirmation of CR and PR required 
Overall Response 
at First Time Point 
Overall Response at 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable. 
a: If a CR is truly met at first time point, then efficacy of any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, will still be evaluated as PD at that point (since disease will reappear after 
CR). Best response will depend on whether minimum duration for SD is met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions are likely still present and in fact the subject has PR, not CR at 
the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 


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


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


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


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Appendix 2 Common Soft Tissue Sarcomas With Poor Chemotherapy Sensitivity 
 
Alveolar soft-part sarcoma 
 
Clear cell sarcoma of soft tissue 
 
Dedifferentiated liposarcoma 
 
Atypical lipomatous tumor 
 
Well differentiated liposarcoma 
Appendix 3 Histological Coding for Common Soft Tissue Sarcomas With Poor 
Chemotherapy Sensitivity 
No. Histological Classification 
Other Types 
Histological Coding 
1 Alveolar soft tissue sarcoma 
 
Alveolar soft tissue sarcoma 
2 Clear cell sarcoma of soft tissue  
Clear cell sarcoma 
3 Atypical lipomatous tumor 
 
Liposarcoma 
4 Well-differentiated liposarcoma  
Liposarcoma 
5 Leiomyosarcoma  
(not including skin) 
 
Leiomyosarcoma 
6 Pleomorphic rhabdomyosarcoma  
Rhabdomyosarcoma 
7 Dedifferentiated liposarcoma 
 
Liposarcoma 
8 Myxoid liposarcoma 
 
Liposarcoma 
9 Pleomorphic liposarcoma 
 
Liposarcoma 
10 Synovial sarcoma, non-specific 
 
Synovial sarcoma 
99 Others 
Adult fibrosarcoma 
Fibrosarcoma 
99 Others 
Desmoplastic small round cell tumor 
Desmoplastic small round  
cell tumor 
99 Others 
Low-grade myofibroblastic tumor 
Fibrosarcoma 
99 Others 
Low-grade fibromyxoid sarcoma 
Fibrosarcoma 
99 Others 
Pleomorphic undifferentiated sarcoma 
Undifferentiated sarcoma 
99 Others 
Malignant solitary fibrous tumor 
Fibrosarcoma 
99 Others 
Malignant granular cell tumor 
Nerve sheath tumor 
99 Others 
Malignant neurilemmoma 
Nerve sheath tumor 
99 Others 
Malignant peripheral nerve sheath tumor 
Nerve sheath tumor 
99 Others 
Solitary fibrous tumor 
Fibrosarcoma 
99 Others 
Synovial sarcoma, non-specific 
Synovial sarcoma 
99 Others 
Synovial sarcoma, biphasic 
Synovial sarcoma 
99 Others 
Synovial sarcoma, spindle cell 
Synovial sarcoma 
99 Others 
Giant cell tumor of soft tissues 
Fibrosarcoma 


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No. Histological Classification 
Other Types 
Histological Coding 
99 Others 
Angiosarcoma of soft tissue 
Angiosarcoma 
99 Others 
Epithelioid sarcoma 
Epithelioid sarcoma 
99 Others 
Epithelioid hemangioendothelioma 
Angiosarcoma 
99 Others 
Spindle cell/sclerosing rhabdomyosarcoma 
Rhabdomyosarcoma 
99 Others 
Synovial sarcoma, spindle cell 
Synovial sarcoma 
99 Others 
Undifferentiated/unclassified sarcomas 
Undifferentiated sarcoma 
99 Others 
Undifferentiated pleomorphic sarcoma 
Undifferentiated sarcoma 
99 Others 
Undifferentiated spindle cell sarcoma 
Undifferentiated sarcoma 
99 Others 
Myxofibrosarcoma 
Fibrosarcoma