Conditions: Effect of Drugs
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This is phase II study. Efficacy and safety evaluation of IBI308 in patients with relapsed/refractory extranodal NK/T cell lymphoma, nasal type: a multicenter, single arm.

Detailed description:
Extranodal NK/T cell lymphoma, nasal type(ENKTL) accounts for about 6% of all lymphomas in china. Epstein Barr virus (EBV) infection is found in all cases of ENKTL and maybe plays an important pathogenetic role.

Conventional anthrocycline-based regimens are not preferred to be used in ENKTL because of high p-glycoprotein expression. ORR of L-asparaginase based regimens is about 80% and no salvage regimens are recommended in ENKTL so far after failure of L-asparaginase based regimen.

Recently, a phase II clinical trial result demonstrated high ORR of anti-PD-1 antibody treatment in ENKTL.IBI308, a humanized monoclonal antibody (mAb) directly against PD-1, is investigated in this phase II Chinese ENKTL clinical trial.

Additionally the correlation between PD-L1 expression and the response to IBI308 treatment in Chinese ENKTL subjects will also be assessed.

Arms:
arm 1: None

Interventions: intervention 1: Sintilimab
Intervention descriptions: intervention 1: Sintilimab (IBI308) 200mg IV Q3W

Protocol document:
SAP_002.pdf: 
STATISTICAL ANLYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
 
 
STATISTICAL ANALYSIS PLAN 
A Multicenter, Single-arm, Phase II Clinical Trial Evaluating the Efficacy and Safety of 
IBI308 Monotherapy in the treatment of relapsed or Refractory Extranodal NK/T-Cell 
Lymphoma, Nasal Type (ORIENT-4) 
Protocol Number: CIBI308D201 
 
 
Version: 2.0 
Date: 28 Feb 2020 
  
Author: Xing Sun  
  
 
 


STATISTICAL ANLYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
APPROVAL PAGE 
 
 
 
Author:  
 
 
____________________________ 
 
 
 
          Date: ______________    
    <Name, Title> 
 
 Innovent Biologics (Suzhou) Ltd 
 
 
 
 
 
Approver:  
 
 
____________________________ 
 
 
 
          Date: ______________    
        <Name, Title> 
 
 Innovent Biologics (Suzhou) Ltd 
  
 
 
____________________________ 
 
 
 
          Date: ______________    
        <Name, Title> 
 
 Innovent Biologics (Suzhou) Ltd 
  
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
VERSION HISTORY 
 
SAP Version 
Approval date 
Description of changes 
1.0 
2019-06-24 
Update according to protocol amendment 2.0 and 
reorganized to new SAP template 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
ABBREVATION 
ADA 
Anti-drug antibody 
AE 
Adverse event 
BDRM 
Blinded data review meeting 
BMI 
Mody mass index 
CI  
Confidence interval 
CR  
Complete response 
CSR 
Clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DMC 
Data monitoring committee 
DoR 
Duration of response 
ECG  
Electrocardiography 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
GCP  
Good clinical practice 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
irAE  
Immune related adverse event 
MedDRA  
Medical Dictionary for Regulatory Activities 
ORR  
Objective response rate 
PD 
Disease progression 
PFS  
Progression free survival 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Partial response 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SS 
Safety set 
TEAE 
Treatment emergent adverse event 
TTR 
Time to response 
 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
TABLE OF CONTENT 
APPROVAL PAGE ............................................................................................................................................................ 2 
VERSION HISTORY ......................................................................................................................................................... 3 
ABBREVATION ................................................................................................................................................................. 4 
TABLE OF CONTENT ...................................................................................................................................................... 5 
1 
INTRODUCTION ..................................................................................................................................................... 7 
1.1 
STUDY OBJECTIVES ................................................................................................................................................. 7 
1.2 
STUDY DESIGN ........................................................................................................................................................ 8 
1.3 
SAMPLE SIZE ........................................................................................................................................................... 8 
1.4 
RANDOMIZATION AND MASKING ............................................................................................................................. 8 
1.5 
CHANGE OF STATISTICAL ANALYSIS PLAN IN PROTOCOL ......................................................................................... 8 
1.5.1 
Change in Protocol Amendment ................................................................................................................... 8 
1.5.2 
Changes in Statistical Analysis Plan ............................................................................................................. 8 
2 
ENDPOINTS ............................................................................................................................................................. 9 
2.1 
PRIMARY EFFICACY ENDPOINT ................................................................................................................................. 9 
2.2 
SECONDARY ENDPOINT ........................................................................................................................................... 9 
2.3 
SAFETY ENDPOINT ................................................................................................................................................... 9 
2.4 
IMMUNOGENICITY ENDPOINT ................................................................................................................................... 9 
2.5 
PHARMACODYNAMIC ENDPOINT .............................................................................................................................. 9 
2.6 
QUALITY OF LIFE ENDPOINT ..................................................................................................................................... 9 
2.7 
BIOMARKER ANALYSIS: ........................................................................................................................................... 9 
3 
ANALYSIS POPULATION ..................................................................................................................................... 9 
3.1 
ANALYSIS SET ......................................................................................................................................................... 9 
3.2 
MAJOR PROTOCOL DEVIATION ............................................................................................................................... 10 
4 
DATA HANDLING CONVENTION .................................................................................................................... 10 
4.1 
GENERAL RULES .................................................................................................................................................... 10 
4.2 
SPECIAL HANDLING OF EFFICACY DATA ................................................................................................................. 10 
4.3 
MISSING VALUE AND EXTREM VALUES .................................................................................................................. 10 
4.4 
TIME WINDOWS ..................................................................................................................................................... 12 
4.5 
STUDY CENTER EFFECT ......................................................................................................................................... 12 
5 
STATISTICAL METHODS ................................................................................................................................... 12 
5.1 
GENERAL RULES .................................................................................................................................................... 12 
5.2 
SUBJECT DISPOSITION ............................................................................................................................................ 12 
Subject Disposition .................................................................................................................................................... 12 
Protocol Deviations................................................................................................................................................... 13 
5.3 
DEMOGRAPHICS AND DISEASE CHRACTERISTICS ................................................................................................... 13 
5.3.1 
Demographics and Disease Characteristics ............................................................................................... 13 
5.3.2 
Medical History .......................................................................................................................................... 13 
5.4 
TREATMENT EXPOSURE AND COMPLIANCE ............................................................................................................ 14 
5.4.1 
Treatment Exposure .................................................................................................................................... 14 
5.5 
EFFICACY ANALYSIS.............................................................................................................................................. 15 
5.5.1 
Primary Analysis ......................................................................................................................................... 15 
5.5.2 
Secondary Analysis ..................................................................................................................................... 15 
5.5.3 
Subgroup Analysis ...................................................................................................................................... 16 
5.5.4 
Exploratory Analysis ................................................................................................................................... 16 
5.6 
SAFETY ANALYSIS ................................................................................................................................................. 16 
5.6.1 
Adverse Events ............................................................................................................................................ 16 
5.6.2 
Clinical Laboratory Evaluation .................................................................................................................. 19 
5.6.3 
Vital Sign ..................................................................................................................................................... 19 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
5.6.4 
ECG ............................................................................................................................................................ 19 
5.6.5 
Other safety measurements ......................................................................................................................... 20 
5.7 
IMMUNOGENECITY ANALYSIS ................................................................................................................................ 20 
5.8 
PD/BIOMARKER ANALYSIS ..................................................................................................................................... 20 
5.9 
QUALITY OF LIFE ................................................................................................................................................... 20 
5.10 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ................................................................................ 21 
6 
REFERENCES: ....................................................................................................................................................... 22 
APPENDICES ................................................................................................................................................................... 23 
APPENDIX 1 FLOWCHART ................................................................................................................................................ 23 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
1 
Introduction 
This statistical analysis plan (SAP) is based on CIBI308D201 “A Multicenter, Single-arm, 
Phase II Clinical Trial Evaluating the Efficacy and Safety of IBI308 Monotherapy in the treatment of 
relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal Type (ORIENT-4)” protocol, 
version 2.0 on July 05, 2017 and China regulator guidances. The objective of this SAP is to provide 
detailed definition of the endpoints and planned statistical analyses.  
1.1 
STUDY OBJECTIVES 
• 
Primary Objectives 
 
To evaluate the objective response rate (ORR) of IBI308 monotherapy in the treatment of relapsed 
or refractory extranodal natural killer (NK)/T-Cell lymphoma, nasal type (ENKTL-NT). 
• 
Secondary Objectives 
 To evaluate the rate of complete response (CR) and partial response (PR) of IBI308 
monotherapy in the treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the disease control rate (DCR) of IBI308 monotherapy in the treatment of relapsed 
or refractory ENKTL-NT; 
 To evaluate the time to response (TTR) of IBI308 monotherapy in the treatment of relapsed 
or refractory ENKTL-NT; 
 To evaluate the duration of response (DOR) of IBI308 monotherapy in the treatment of 
relapsed or refractory ENKTL-NT; 
 To evaluate the progression-free survival (PFS) and 6-month PFS rate of IBI308 monotherapy 
in the treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the overall survival (OS) and 12-month OS rate of IBI308 monotherapy in the 
treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the safety of IBI308 monotherapy in the treatment of relapsed or refractory 
ENKTL-NT; 
 To evaluate the quality of life of subjects with relapsed or refractory ENKTL-NT after IBI308 
monotherapy, using EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) and European 
Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 
(EORTC QLQ-C30). 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
1.2 
STUDY DESIGN 
This is a multicenter, single-arm, phase II clinical trial evaluating the efficacy and safety of IBI308 
monotherapy in the treatment of relapsed or refractory ENKTL-NT. 
This study will enroll patients with relapsed or refractory ENKTL-NT to receive IBI308 200mg IV 
Q3W until progression disease (PD), death, intolerable toxicity, withdrawal of ICF, or other reasons 
stated in the protocol with a maximum treatment duration of 24 months. For subjects who experience 
PD for the first time and are clinically stable, the investigator can continue treatment until subsequent 
PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol with a 
maximum treatment duration of 24 months. 
The primary efficacy endpoint of this study is ORR defined as percentage of subjects with radiological 
CR or PR as best overall response. The primary endpoint is analyzed after last subjects completing up 
to 24 weeks followup. Lugano 2014 criteria will be used for ORR. After 24 weeks, IWG 2007 criteria 
will used to assess responses. 
Subjects will continue safety followup upto 90 days after last dose of study treatment. 
1.3 
SAMPLE SIZE 
The hypothesis of this study is to evaluate the effectiveness of ORR based on Lugano 2014: 
H0: ORR≤30% 
H1: ORR>30% 
For the primary efficacy endpoint ORR, the point estimate and its (100-α)% confidence interval (α 
maybe different from 5 if interim analysis is added) will be provided using binomial distribution. If 
the lower limit of the confidence interval is greater than 30%, the effectiveness of IBI308 is established 
for r/r ENKTL. This is a single-arm trial, and 20-60 subjects are planned to be enrolled for the study. 
Under the assumption of an ORR=50%, with 43 subjects, there is 80% power to reject H0 under a two-
sided type I error rate of 0.05.  
After first 20 subjects enrolled, a safety evaluation will be conducted before continuing enrollment. 
1.4 
RANDOMIZATION AND MASKING 
NA 
1.5 
CHANGE OF STATISTICAL ANALYSIS PLAN IN PROTOCOL 
1.5.1 Change in Protocol Amendment 
NA 
1.5.2 
Changes in Statistical Analysis Plan 
See version history. 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
2 
Endpoints 
Assessment schedule for each endpoint collected is described in Appendix 1. 
2.1 
PRIMARY EFFICACY ENDPOINT 
 
ORR as estimated by binomial distribution.  
2.2 
SECONDARY ENDPOINT 
TTR、DOR、PFS、OS and 6 months PFS rate and OS rate. 
2.3 
SAFETY ENDPOINT 
Incidence rates of all adverse events (AE), treatment emergent adverse event (TEAE), adverse event 
of special interest(AESI) and serious adverse event (SAE), relationship to study treatment and severity. 
Changes in vital signs, physical exam and clinical laboratory evaluation before and after study 
treatment. 
2.4 
IMMUNOGENICITY ENDPOINT 
Anti drug antibody (ADA) and neutralizing antibody (NAb) will be tested. 
2.5 
PHARMACODYNAMIC ENDPOINT 
NA 
2.6 
QUALITY OF LIFE ENDPOINT 
Qualifty of life will be evaluated by EQ 5D-5L and EORTC QLQ-C30 changen over time. 
2.7 
BIOMARKER ANALYSIS: 
Biomarker samples will be collected to analyze PD-L1 expression in tumor tissues and RNA sequence 
and TILs. 
Blood samples will be analyzed for peripheral blood EBV-DNA changes over time, immune cell 
changes, immune-related cytokine changes and correlation with efficacy.  
3 
Analysis Population 
3.1 
ANALYSIS SET 
Analysis sets include Safety set (SS), full analysis set (FAS), per protocol set (PPS): 
1) SS: Subjects receiving at least one dose of study treatment 


STATISTICAL ANALYSIS PLAN 
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Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
2) FAS: Subjects receiving at least one dose of study treatment and with measurable disease at baseline. 
Subjects may be excluded if not satisfying ENKTL criteria by central pathological review.  
3) PPS: Subset of FAS and without major protocol deviation nor use of prohibited medication nor poor 
compliance. 
3.2 
MAJOR PROTOCOL DEVIATION 
Major protocol deviation is defined as deviation will have important impact on efficacy. In this study, 
deviations listed below are considered as major and subjects with major deviation will not be included 
in PPS: 
• 
Do not meet major inclusion/exclusion criteria; 
• 
Use of prohibited medication; 
• 
Poor compliance (<80% or >120%, less than 2 cycles of treatment); 
• 
Actual received treatment is different from being assigned. 
Major protocol deviations will be reviewed at Blind Data Review Meeting (BDRM) and listed before 
database lock.  
Major protocol deviation will be listed with detailed descriptions. 
4 
Data Handling Convention 
4.1 
GENERAL RULES 
• 
Observation Period Definition 
Observation period is defined as:  
Screening period: from inform consent to first dose of study treatment. 
On-treatment period: from first dose to last dose. 
Treatment residual period: last dose +1 to last dose + 90 days. 
Treatment emergent period include both on-treatment period and treatment residual period. 
Post-treatment period: from last dose+91 days to end of study. 
4.2 
SPECIAL HANDLING OF EFFICACY DATA 
NA 
4.3 
MISSING VALUE AND EXTREM VALUES 
 
Missing of date variables: if the date is partial or incomplete, the imputation will be done based on the 
following rules following appropriate logic:  
- 
if year, month and date are all missing, then do not impute; 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
- 
if month and date are missing, it will be assumed as July 1st with no conflict with other date 
variables; 
- 
if dates are missing, it will be assumed as 15th with no conflict with other date variables; 
- 
Original date collected from CRF will be shown in the listings. 
• 
   Missing data handling of other variables 
Efficacy variables:  All missing in the primary efficacy endpoints due to early withdrawal or lost 
follow up will be treated as "unable to evaluate ". In the calculation of time to event variables (e.g. 
PFS, DOR), subjects who have tumor evaluation missing after treatment will be reviewed to determine 
the time of censoring during data review meeting prior to database lock.  
There will be no missing value imputation for baseline and safety data. 
The extreme value of laboratory data identified as being caused by improper handling of specimens 
and blood samples will be replaced by unplanned visit data in the visit window (if available) as defined 
by the protocol. If these values cannot be replaced, they will be set as missing and be excluded from 
the analyses. 
• 
Definition of baseline 
The last non-missing data before first study drug administration will be defined as the baseline. 
• 
Data derivation rules 
Age (year) = (Informed Consent Date of Signature – Birth Date +1)/365.25, round to 1 decimal digits; 
Course of first diagnosis (Day) = Informed Consent Date of Signature – Birth Date +1; 
For efficacy related data derivation, see the sections which define efficacy endpoints. 
 
• 
Missing Relationship of AE to Study Treatment 
If relationship is missing, no imputation is made but will be considered as related. 
• 
Missing CTCAE grade 
Missing grade will not be imputed but will be counted in summary as grade ≥3 and will be listed 
separately. 
• 
Handling of Outliners 
NA 


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4.4 
TIME WINDOWS 
First dose date of the study treatment is defined as Day 1. Visit day definition: measurement date – 
first dose date +1; if measurement date is before first dose date, then visit day is defined as 
measurement date-first dose date. 
All data will be analyzed according to flowchart and nominal visit name on eCR. No visit window will 
be applied. 
Unscheduled visit will be used for baseline calculation. There will be no analysis over time for clinical 
laboratory evaluation, vital sign, ECG. Therefore no time window will be applied. Summary by all 
post-baseline results and worst post-baseline results will be analyzed. 
4.5 
STUDY CENTER EFFECT 
NA 
5 
Statistical Methods 
5.1 
GENERAL RULES 
All the statistical analyses will be performed with SAS 9.2 (or higher). 
Unless otherwise stated, all TFLs will follow the rules below: 
• 
Baseline value: last available data before first dose. 
• 
Significant level and multiplicity adjustment: 5% two-sided level, no adjustment will be made. 
• 
Summary statistics for continuous variables: N, mean, standard deviation, median, Q1, Q3, min 
and max. 
• 
Categorical variables: number of subjects and percentage. 
• 
Denominator in percentage calculation: unless otherwise specified, subjects with missing values 
will not be included. Number of subjects with missing value will be provided.  
5.2 
SUBJECT DISPOSITION 
Subject Disposition 
Number and percentage of subjects enrolled, treated, treatment continued after PD, early 
discontinuation of treatment will be summarized. The above information will also be summarized by 
study centers. 
Listing will be provided for subject discontinued early. 


STATISTICAL ANALYSIS PLAN 
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Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
In percentage calculation described above (except for screen failure and enrollment rate), denominators 
will be number of subjects receiving study treatment. In by center summary, number of subjects in 
each major category (screened, treated, discontinued, end of study, treated beyond PD, analysi 
population) will be provided.  
Protocol Deviations 
Summary will be provided for number and percentage of subjects with major protocol deviation. 
Listing will be provided for subjects with major protocol deviation and inclusion/exclusion criteria 
deviation. 
5.3 
DEMOGRAPHICS AND DISEASE CHRACTERISTICS 
5.3.1 Demographics and Disease Characteristics 
Demographics and disease Characteristics will be summarized in SS, FAS and PPS for the following 
variables: 
• 
Age, Sex, Ethnicity 
• 
Smoking history: smoking status, daily smoking quantity, duration of smoking, time since ceasing 
smoking 
• 
Allergy history: percentage of subjects with allergy history and allergy type 
• 
Baseline height, weight, BMI, BSA 
• 
Baseline vital signs SBP,DBP,pulse, temperature, respiratory 
• 
Baseline ECOGS PS  
• 
Baseline physical exam: N and percentage for each exam item 
• 
Baseline virology exam and HBV, HBV DNA, HCV RNA 
• 
Baseline anti-auto antibody 
5.3.2 Medical History 
• 
Disease Diagnosis  
• 
Cancer related disease history: including time since first diagnose, disease stage, pathological 
stage, disease range, histological subtype. 
• 
Anti-cancer therapy history: History of anti-cancer systemic therapy (number of chemotherapy 
regimens, treatment cycles, treatment type, best response), history of anti-cancer radiotherapy (site of 
radiotherapy, total dosage, treatment type and best response) and other therapies (treatment, best 
response) 


STATISTICAL ANALYSIS PLAN 
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• 
Baseline target lesion number and non-target lesion numbers, locations, sum of diameters 
Following variables will be summarized by descriptive statistics: Disease duration=date of inform 
consent-earlier time between initial diagnosis and start of prior therapy+1 
• 
Other Medical History 
The disease will be coded according to the MedDRA term, and the proportion of subjects with each 
disease will be summarized according to the preferred term (PT), including: prior disease recovered: 
A disease that has been cured in a medical history, onging disease: a disease no cured, a disease 
undergoing treatment: a disease undergoing medical treatment. 
• 
Prior and Concomitant Medication (other than anti-cancer) 
Prior and concomitant medications will be coded using The World Health Organization Drug 
Dictionary (WHODD) and will be summarized by Anatomical Therapeutic Chemical (ATC) class 1, 
2, 4 and preferred name (PN). One subject is only counted once for each corresponding category/PN. 
Prior medications: medications which started and stopped prior to the first dose of study medication, 
stop date – date of first dose of study medication < 0; 
Concomitant medications: start date – date of first dose of study medication < 0, and (start date-date 
of last dose+90)>=0 and stop date – date of first dose of study medication >= 0; 
New concomitant medications: medications newly added or changed during the study period, start date 
– end date of first dose of study medication >= 0 and (start date-date of last dose+90)>=0. 
Post study medications: medications started after last dose of study treatment+90 days. 
If the start date is missing, the medication will be considered as “concomitant medication”, unless the 
stop date is non-missing and the stop date is prior to date of first dose of study medication 
 
5.4 
TREATMENT EXPOSURE AND COMPLIANCE 
In SS, summarize exposure of study treatment. 
5.4.1 Treatment Exposure 
Summary of treatment exposure includes duration of exposure, number of cycles completed and total 
dose.  
• 
Duration of Exposure 


STATISTICAL ANALYSIS PLAN 
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Version Date: 2020-02-28 
 
Duration of exposure (days)=last dose date-first dosedate+21. 
• 
Dosage 
Following variables are summarized descriptively: 
• 
Total dose(mg)=total dose received during the study 
• 
Average dose per cycle(mg) = actual total dose received/(duration of exposure in days /21) 
5.5 
EFFICACY ANALYSIS 
 
Efficacy analyses will be based on FAS and PP. A sensitivity analysis based on all enrolled subjects 
may also be conducted. The efficacy analysis will be based on Lugano 2014. 
5.5.1 Primary Analysis 
The ORR is defined as the proportion of subjects with CR or PR as Best Overall Response (BOR).  
*100%
Total Number of Subjects
CR
PR
ORR
+
=
 
For ORR, the point estimate and 95% confidence interval will be provided using exact binomial 
distribution. 
5.5.2 Secondary Analysis 
 
DCR 
*100%
Total Number of Subjects
CR
PR
SD
DCR
+
+
=
, and 95% CI will be calculated using binomial distribution. 
PFS 
PFS: the time from the date of the first dose to the date of first disease progression (imaging), if subjects 
died due to any reason prior to disease progression, PFS is defined as the time from the date of the first 
dose to the date of death. Subjects who did not die or had disease progressed will be censored on the 
date of the last imaging assessment date. Subjects with no post-baseline imaging assessment will be 
censored on the date of the first dose of study medication. Subjects treated with other anti-cancer 
therapy before PD will be censored at last non-missing tumor assessment date before starting of the 
new anti-cancer therapy. 


STATISTICAL ANALYSIS PLAN 
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Kaplan-Meier method will be used for the analysis of PFS to evaluate the median PFS (mPFS), PFS 
rate at 6 month and at 1 year, and its 95% CI and the survival curves will be provided accordingly.  
DOR 
For subjects with complete response or partial response, the duration of response is defined as the time 
from the date of first response to the date of disease progression or death whichever is earlier, and 
subjects with no disease progression or death will be censored on the date of the last imaging 
assessment. 
Kaplan-Meier method will be used for the analysis of DOR to evaluate the median DOR and its 95% 
CI and the survival curves will be provided accordingly.  
TTR 
For subjects with complete response or partial response, the time to response is defined as time from 
the date of first dose to the date of the first objective response. 
Kaplan-Meier method will be used for the analysis of TTR to evaluate the median TTR and its 95% 
CI and the survival curves will be provided accordingly.  
 
5.5.3 Subgroup Analysis 
 
Subgroup analysis will be conducted for subgroups including PD-L1 expression, EBV, LDH, B 
symptom. 
5.5.4 Exploratory Analysis 
Correlation between gene related cancer immunity and effiacay will be explored. 
5.6 
SAFETY ANALYSIS 
Safety analysis will be conducted in safety set. 
5.6.1 Adverse Events  
All adverse events will be coded using MedDRA dictionary for lower level term (LLT), preferred term 
(PT), high level term (HLT), high level group term(HLGT) and system organ class(SOC). AE 


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reporting period will be further defined based on onset date/becoming serious/becoming more severe 
as: 
• 
Pre-treatment AE: AE occurs/becomes serious/becomes more severe before first dose of treatment 
and after inform consent.  
• 
Treatment-emergent AE: AE occurs/becomes serious/becomes more severe on or after date of first 
dose of treatment up to last dose of study treatment+90 days 
• 
Post treatment AE: AE occurs/becomes serious/becomes more severe on or after date of last dose 
of study treatment+91 days 
If onset date of AE is missing or partial missing, determination of AE reporting period will be based 
on rules in Section 4.3.  
• 
Overview of adverse event 
Listing will be provided for pre-treatment and post-treatment AE. 
Number and percentage of subjects who experience AE and event frequency will be summarized for: 
• 
Treatment emergent period 
- 
TEAE 
- 
Treatment related AE(TRAE) 
- 
Serious AE (TESAE) 
- 
AE leading to death 
- 
TRSAE 
- 
TRAE leading to death 
- 
TEAE leading to treatment discontinuation 
- 
TRAE leading to treatment discontinuation 
- 
Important AE (Chinese regulator specific requirement only) 
- 
Immune-related AE(irAE) 
Unless otherwise stated, SOC/PT summary will be sorted according to descending order of frequency. 
• 
TEAE analysis 
Number and percentage of sunjects with AE will be summarized by: 
- 
SOC and PT and by highest CTCAE grade for TEAE 


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- 
SOC and PT and by highest CTCAE grade for TRAE 
- 
SOC and PT and by highest CTCAE grade for TEAE leading to treatment discontinuation 
- 
SOC and PT and by highest CTCAE grade for TRAE leading to treatment discontinuation 
- 
SOC and PT and by highest CTCAE grade for important AE (Chinese regulator specific 
requirement only) 
- 
PT for TESAE 
- 
PT for infusion-related reactions(IRR)  
• 
Immune-related treatment emergent AE and AE of special interest 
Immune-related treatment emergent AE: 
IBI308 mechanism of action includes T-cell activitaion and proliferation. It may cause overactivation 
of immune system, which leads to systemic immune disorders. In Other immune checkpoint inhibitors 
(ipilimumab, nivolumab, pembrolizumab and atezolizumab) clinical data, AEs such as immune-
mediated pneumonitis, diarrhea/colitis adrenal insufficiency, rash, hepatitis, endocrines disorders and 
peripheral neuropathy have been observed. In this study, once a subject has above AE occurring, 
investigators should monitor subjects’s status and take proper diagnosis actions. If no alternaive causes 
(such as disease progression, concomitant medication, other infection) and corticosteroid/other 
immune suppressant treatments are needed to treat the condition (except for related endocrine disorders 
such hypo/hyperthyroidism, hypophysitis, type 1 diabetes, adrenal insufficiency, which may not be 
given this treatment), the corresponding AE should be considered as potentially immune related. 
AE of special interest: 
AE of special interest (AESI) is defined as AE requiring special attention to understand the safety 
profile of the investigational product. A non-serious AE can also be considered as AESI. 
AESI of this study include: 
- 
IRR of grade 3 and above 
- 
Diarrhea, colitis, uveitis, intestinal pneumonitis of grade 2 and above 
- 
Suspected irAE of grade 3 and above 
Number and percentage of subjects experiencing treatment emergent irAE and AESI will be 
summarized.  
In above summaries, a subject will only be counted once accoding to the highest CTCAE grade and/or 
seriousness for each SOC or PT.  
An AE with causilty reported as related, possibly related or missing/undetermined will be counted as 
treatment related. Handling of missing seriousness and CTCAE grade can be found in Section 4.3.  


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
• 
Death 
Death during the study will be listed.  
Listing of AE will include all AE, SAE, TRAE, TEAE leading to treatment discontinuation, irAE and 
AESI. Treatment emergent flag will be provided.  
5.6.2 Clinical Laboratory Evaluation 
Clinical laboratory evaluation includes hematological exam, blood chemistry, urine test. Local lab is 
used in this study and results will be analyzed and reported using international standard unit. Invalid 
resultsif marked will not be included in the analysis. Non-protocol specified laboratory test or test out 
of study center will not be included in the summary analysis. If abnormal is observed, AE will be 
reported.  
Laboratory results will be summarized as normal, abnormal low, abnormal high according to normal 
range of each center. Abnormal values will also be reported by investigators as clinically significant 
or not. If “<”, “<=”, “>” or “>=” limit of quantitation, limit of quantitation will be used for summary 
statistics. Original results will be displayed in listing. 
In SS, by visit descriptive summary will be provided for quantitative clinical laboratory evaluation. 
For qualitative evaluations, shift summary of change from baseline will be provided based on 
normal/abnormal status and clinically significant/not clinically significant status.  
Listing will be provided for clinical laboratory evaluation results. Virology and (or) pregnancy exam 
will be listed separately.  
 
5.6.3 Vital Sign 
Vital signs will be summarized by visit for absolute values and changes from baseline usingdescriptive 
statistics. 
Shift table of normal/abnormal status from baseline to post-baseline will also be provided. 
Listing will be provided for vital sign results. 
5.6.4 ECG  
Worst post baseline QTc will be summaried according to ≤450ms, >450-480ms, >480-500ms, >500ms 
categories and increase from baseline by≤30ms, >30-60ms, >60ms. On-treatment period is defined as 
the period from first dose of study treatment until the last dose of study treatment +90 days including 
both scheduled and unscheduled visits and repeated visits.  
Listing will also be provided ECG results. 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
5.6.5 Other safety measurements 
Listing will be provided for physical exam and ECOG. 
5.7 
IMMUNOGENECITY ANALYSIS 
Immunogenicity is evaluated by ADA and NAb positive rates. Analyses of immunogenicity in SS 
include: 
Baseline ADA/Nab positive rate and number of positive subjects  
Post-baseline ADA/Nab positive rate and number of positive subjects at each timepoint 
Further summary of post-baseline data by baseline status 
Number and percentage of subjects with persistent/transient post-baseline positive ADA/NAb 
Listing will also be provided for ADA titre values. Only subjects with at least one non-missing post-
baseline ADA result will be included in post-baseline positive rate calculation.  
5.8 
PD/BIOMARKER ANALYSIS  
A separate analysis plan will be provided. 
5.9 
QUALITY OF LIFE 
The EORTC QLQ-C30 is a core questionnaire for patients with cancer consisting of 30 items which 
are divided into 15 scales: 5 functional scales (physical, role, cognitive, emotional, and social function), 
3 symptom scales (fatigue, pain, and nausea/vomiting), 1 global health status/quality of life scale, and 
6 single item scales. The value of EORTC QLQ-C30 score is between 0 and 100. 
Definition of EORTC QLQ-C30 dimensions:  
 
Numbers of Items 
Item Range 
Item numbers 
Overall health and 
Quality of Life 
2 
6 
29, 30 
Function dimension 
Physical function 
5 
3 
1~5 
Role function 
2 
3 
6, 7 
Emotional function 
4 
3 
21~24 
Cognitive function 
2 
3 
20, 25 
Social function 
2 
3 
26, 27 
Symptom dimension 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
Weak 
3 
3 
10, 12, 18 
Nauseated and 
vomited 
2 
3 
14, 15 
Pain 
2 
3 
9, 19 
Short of breath 
1 
3 
8 
Poor sleep 
1 
3 
11 
Lacked appetite 
1 
3 
13 
Constipated 
1 
3 
16 
Diarrhea 
1 
3 
17 
Financial difficulties 
1 
3 
28 
Raw Score (RS) is the mean of each term, RS = (I1+I2+ ……+In) /n. Missing items are excluded from 
the calculation of the mean.  
Function dimension: Score=
100
range
1
-
RS
-
1
×






. 
For change from baseline, descriptive summary will be used. 
5.10 INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
No interim analysis planned. 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
6 
References: 
1 
NMPA guidance on good clinical practice 2013 
2 
NMPA guidance on structure and content of clinical study report for chemical medical 
product([H] GCL 3-1), Mar 2005 
3 
NMPA guidance on statistical principles in clinical tirals, Mar 2016 . 
4 
ICH. ICH E9 Guideline: Statistical Principles for Clinical Trials, 1998. Available at 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Ste
p4/E9_Guideline.pdf 
5 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports Questions & 
Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_
QAs_R1_Step4.pdf 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
APPENDICES 
APPENDIX 1 FLOWCHART 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
TABLE 1. Schedule of Visits 
Phase 
Screening 
Treatment 
End-of-Treatment 
Visit 22 
Safety Follow-
Up 
Survival Follow-
up 23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7 ~ N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28~-1 
Day 1 
Day 22 
(±3 days)  
Day 43 
(±3 days)  
Day 64 
(±3 days)  
Day 85 
(±3 days)  
Q3W 
(±3 days)  
 
since the last dose 
90 days (± 7 days) 
after safety 
follow-up 
Q60D (±7 days) 
General Study Procedures 
 
 
Written ICF 1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics /History / 
Previous Medication 2 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/Height 4 
X 
 
 
 
 
 
 
X 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS Score 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECG 5 
X 
 
 
X 
 
X 
X 
X 
 
 
Count of Whole Blood 
X 
 
X 
X 
X 
X 
X 
X 
X 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
Phase 
Screening 
Treatment 
End-of-Treatment 
Visit 22 
Safety Follow-
Up 
Survival Follow-
up 23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7 ~ N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28~-1 
Day 1 
Day 22 
(±3 days)  
Day 43 
(±3 days)  
Day 64 
(±3 days)  
Day 85 
(±3 days)  
Q3W 
(±3 days)  
 
since the last dose 
90 days (± 7 days) 
after safety 
follow-up 
Q60D (±7 days) 
Cells / Blood  
Biochemistry / Routine 
Urinalysis 6 
Pregnancy Test 7 
X 
 
 
 
 
 
 
X 
 
 
Thyroid Function 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity 9 
 
X 
X 
 
X 
 
 
 
X 
 
EBV-DNA10 
 
X 
X 
X 
X 
X 
X 
X 
 
 
HIV, HBV and HCV11 
X 
 
 
 
 
 
 
 
 
 
AE Evaluation 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant  
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Evaluation 
 
 
Bone Marrow Biopsy 13 
X 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
Phase 
Screening 
Treatment 
End-of-Treatment 
Visit 22 
Safety Follow-
Up 
Survival Follow-
up 23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7 ~ N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28~-1 
Day 1 
Day 22 
(±3 days)  
Day 43 
(±3 days)  
Day 64 
(±3 days)  
Day 85 
(±3 days)  
Q3W 
(±3 days)  
 
since the last dose 
90 days (± 7 days) 
after safety 
follow-up 
Q60D (±7 days) 
Tumor Biopsy 14 
 
 
 
 
 
 
 
 
 
 
CT/MRI Evaluation 15 
X 
 
 
 
 
 
X 
 
 
 
PET-CT16 
X 
 
 
X 
 
 
X 
X 
 
 
Disease-Related  
Symptom Evaluation 17 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Investigational Drug Infusion 
 
 
IBI30818 
 
X 
X 
X 
X 
X 
X 
 
 
 
Quality of Life Evaluation 
 
 
EQ-5D-5L/ 
EORTC QLQ-C30 19 
 
X 
 
X 
 
 
X 
X 
 
 
Biomarker Study 
 
 
Archival/Fresh 
Tumor Tissue Sample 20 
X 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
Phase 
Screening 
Treatment 
End-of-Treatment 
Visit 22 
Safety Follow-
Up 
Survival Follow-
up 23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7 ~ N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28~-1 
Day 1 
Day 22 
(±3 days)  
Day 43 
(±3 days)  
Day 64 
(±3 days)  
Day 85 
(±3 days)  
Q3W 
(±3 days)  
 
since the last dose 
90 days (± 7 days) 
after safety 
follow-up 
Q60D (±7 days) 
Peripheral Blood Sample 21 
X 
 
 
X 
 
 
X 
 
 
 
Note: 
1. 
ICFs shall be signed by subjects prior to any procedures outlined in the protocol. 
2. 
Previous medications: treatment for the initial diagnosis, including chemotherapy, radiotherapy, and surgery. 
3. 
Vital signs: body temperature, pulse, respiratory rate, and blood pressure. 
4. 
Screening: weight and height; end-of-treatment visit: weight. 
5. 
12-lead ECG schedule: during screening, prior to administration every other cycle, and during the end-of-treatment visit. 
6. 
Count of whole blood cells: RBC, HGB, white blood cell (WBC), PLT, WBC differentials [lymphocyte (LYM), ANC]. Blood biochemistry include: hepatic function [TBIL, ALT, AST, 
γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactic dehydrogenase (LDH)], renal function [(blood urea nitrogen (BUN) and Cr)], 
electrolytes (Na, K, Cl, Mg, Ca, and P), lipase, amylase, and fasting blood glucose (FBG). Routine urinalysis: pH, urinary albumin (UALB), urine protein (UPRO), urine red blood cell 
(URBC), and urine glucose (UGLU). The tests will be conducted within 7 days prior to the first dose of the investigational drug, within 3 days prior to the administration of the 
investigational drug from Cycle 2 onwards, and during safety follow-up. Tests shall be performed at the study sites. 
7. 
Women of childbearing potential shall undergo urine or blood pregnancy test within 3 days prior to the first dose and during the end-of-treatment visit. If the urine pregnancy test is not 
conclusive, then blood pregnancy test shall be performed. The conclusion shall be based on the blood pregnancy test. Tests shall be performed at the study sites. 
8. 
T3, T4, free thiiodothronine (FT3), free thiiodothronine (FT4), and TSH shall be tested during screening, prior to the administration of the investigational drug from Cycle 2 onwards, and 
during safety follow-up. Tests shall be performed at the study sites. 
9. 
Immunogenicity assays will be carried out within 1 hour prior to IBI308 administration in Cycles 1, 2, 4 and then every 4 cycles thereafter (Cycle 8, 12, 16, and so on), and during safety 
follow-up. Tests shall be conducted at the central laboratory. 
10. EBV DNA shall be tested on the day of IBI308 administration in each cycle, with 4 mL of blood collected each time, until the end of study treatment. Tests shall be conducted at the 
central laboratory. The investigator may add EBV-DNA testing at the study sites according to the efficacy assessment result. 
11. Hepatitis B panel (HBsAg, HBsAB, HBcAB, HBeAg, and HBeAb), HCV antibody, and HIV antibody will be tested during screening. If the result shows HBsAg positive, then HBV 
DNA test shall be further conducted; if the result shows HCV antibody positive, then HCV RNA test shall be further conducted. For HBV DNA-positive subjects or HBV carriers, HBV 


STATISTICAL ANALYSIS PLAN 
Innovent Biologics (Suzhou) Ltd 
Version: 2.0 
Protocol number: CIBI308D201 
Version Date: 2020-02-28 
 
activity shall be monitored regularly, and prophylactic antiviral therapy is suggested to be performed according to the treatment guidelines for chronic hepatitis B during the trial. Tests 
shall be performed at the study sites. 
12. AE and laboratory safety evaluation are performed according to NCI CTCAE v4.03. Refer to Section 7 for AE and SAE definitions, recording, determination of causal relationship, 
severity, reporting deadlines, and processing. 
13. Subjects with positive bone marrow biopsy at baseline shall repeat the biopsy if a CR by imaging is achieved during the treatment (shall be completed within 2 weeks after imaging 
evaluation). 
14. Tumor biopsy: The investigator may decide whether a biopsy is needed to confirm the results of an imaging evaluation during the study. 
15. CT/MRI evaluation: contrast-enhanced CT will be used (MRI will be performed for subjects allergic to CT contrast media). Contrast-enhanced CT shall be performed at baseline, week 
24 (± 7 days), every 12 weeks (± 14 days) after 24 weeks, and every 24 weeks (± 14 days) after 48 weeks or when it is needed during the study until initiation of new anti-tumor therapy, 
PD, withdrawal of ICF, or death. 
16. PET-CT evaluation: PET-CT shall be performed at baseline, week 6 (± 7 days), week 15 (± 7 days), and week 24 (± 7 days) or when it is needed during the study. PET-CT evaluation 
shall be performed at the end of treatment for subjects who discontinue the treatment prematurely prior to week 24. 
17. Disease-related symptom (including fever, night sweats, weight loss) evaluation shall be performed prior to administration in each cycle. 
18. IBI308 200mg IV Q3W until PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol up to 24 month. For subjects who develop PD for the first time and 
are clinically stable, the investigator can continue treatment until further PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol up to 24 month. 
19. Quality of life evaluation will be performed on the day of the first dose, during each imaging evaluation, and during the end-of-treatment visit as per EQ 5D-5L and EORTC QLQ-C30. 
20. All the eligible subjects must provide archival tumor tissue at baseline or 8–10 unstained sections (4–5 μm) of fresh samples during screening for evaluations of PD-L1 expression and 
TIL. Tests shall be conducted at the central laboratory. 
21. Ten mL whole blood samples are required to be provided by subjects for molecular tumor testing at the following time points: prior to the first dose, during efficacy evaluation but before 
the next treatment, and when PD is confirmed. 
22. Treatment discontinuation: treatment discontinuation includes premature discontinuation (treatment discontinuation for reasons other than PD) and end of treatment (treatment 
discontinuation due to PD). The end-of-treatment visit shall be conducted when treatment is discontinued. 
23. Survival follow-up: once Q60D (± 7 days) after the safety follow-up. Telephone visits is allowed. 

Prot_001.pdf: 
Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    1 
Clinical Protocol 
Study Title: 
A Multicenter, Single Arm, Phase II Clinical Trial Evaluating the 
Efficacy and Safety of IBI308 Monotherapy for the Treatment of 
Relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal 
Type (ORIENT-4) 
Protocol Number: 
CIBI308D201 
Version and Date: 
July 8, 2019, Version 2.0 
Product Name: 
IBI308 
Study Phase: 
II 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
Room 201, Building C14, BioBay, No. 218 Xinghu Street, 
Suzhou Industrial Park, Suzhou, China 
Sponsor 
Contact 
Information: 
Zhou Hui, Vice President, Medical Sciences and Strategic 
Oncology + 86 021-31652896 
hui.zhou@innoventbio.com 
 
 
Confidentiality Statement 
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd.. 
The content of this document shall not be disclosed to any person other than the investigators, research 
consultants or related personnel, and Institutional Review Board/Independent Ethics Committee. 
The information contained in this document must not be used for any purpose, except for the evaluation or 
conduction of this study, without the written consent of the sponsor. 
 
 


Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    2 
Protocol Synopsis 
Protocol Number 
CIBI308D201 
Sponsor 
Innovent Biologics (Suzhou) Co., Ltd. 
Investigational Drug 
IBI308 
Active Ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study 
Title 
 
A Multicenter, Single Arm, Phase II Clinical Trial Evaluating the Efficacy and 
Safety of IBI308 Monotherapy for the Treatment of Relapsed or Refractory 
Extranodal NK/T-Cell Lymphoma, Nasal Type (ORIENT-4) 
Trial Phase 
II 
Study Duration  
Approximately 30 months 
Study Objectives 
Primary Objective: 
 To evaluate the objective response rate (ORR) of IBI308 monotherapy 
for the treatment of relapsed or refractory extranodal natural killer 
(NK)/T-cell lymphoma, nasal type (ENKTL-NT). 
Secondary Objectives: 
 To evaluate the complete response (CR) and partial response (PR) of 
IBI308 monotherapy for the treatment of relapsed or refractory 
ENKTL-NT; 
 To evaluate the disease control rate (DCR) of IBI308 monotherapy for 
the treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the time to response (TTR) of IBI308 monotherapy for the 
treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the duration of response (DoR) of IBI308 monotherapy for 
the treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the progression-free survival (PFS) and 6-month PFS of 
IBI308 monotherapy for the treatment of relapsed or refractory 
ENKTL-NT; 


Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    3 
 To evaluate the overall survival (OS) and 6-month overall survival rate 
(OSR) of IBI308 monotherapy for the treatment of relapsed or 
refractory ENKTL-NT; 
 To evaluate the safety of IBI308 monotherapy for the treatment of 
relapsed or refractory ENKTL-NT; 
 To evaluate the quality of life of subjects with relapsed or refractory 
ENKTL-NT after IBI308 monotherapy, using EuroQoL 5 Dimensions 
5 Levels (EQ-5D-5L) and European Organization for Research and 
Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC 
QLQ-C30). 
Exploratory Objectives: 
 
To evaluate the PD-L1 expression, number of tumor-infiltrating 
lymphocytes (TIL) in tissue samples of subjects with relapsed or 
refractory ENKTL-NT, RNA expression, dynamic changes in 
Epstein-Barr virus (EBV), DNA copy number in plasma and 
peripheral blood lymphocytes, immune cell phenotyping, and 
association between immune-related cytokines and efficacy of anti-
PD-1 treatment. 
Study Design 
This is a multicenter, single-arm, phase II clinical trial evaluating the 
efficacy and safety of IBI308 monotherapy for the treatment of relapsed or 
refractory ENKTL-NT. 
Patients with relapsed or refractory ENKTL-NT will be enrolled to 
receive IBI308 200mg IV Q3W up to 24 months until progressive disease 
(PD), death, intolerable toxicity, withdrawal of ICF, or other reasons stated in 
the protocol. For subjects who develop PD for the first time and are clinically 
stable, the investigator can continue treatment up to 24 months until further 
PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the 
protocol. 


Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    4 
The primary endpoint is ORR, defined as the proportion of subjects who 
either experience CR or PR as the best overall response based on imaging 
evaluation. The primary endpoint will be analyzed after the last statistical and 
radiological evaluable subject completes a maximum of 24 weeks of follow-up. 
The tumor assessment is according to the Recommendations for Initial 
Evaluating, Staging, and Response Assessment of Hodgkin and non-Hodgkin 
Lymphoma: the Lugano Classification (Lugano 2014 Criteria) (see Appendix 
3) as the evaluation criteria and then International Working Group (IWG) 2007 
Criteria (see Appendix 4) after 24 weeks. 
The safety follow-up will be performed  until 90 days after the last dose. 
Inclusion Criteria 
1. 
Histologically confirmed ENKL-NT. 
2. 
Relapsed or refractory ENKTL-NT. Being relapsed is defined as presence 
of new lesions at the primary location or other sites after achieving CR; 
being refractory is defined as any one of the followings: PD after 2 
treatment cycles, PR not achieved after 4 treatment cycles, or CR not 
achieved after 6 treatment cycles. Patients who do not response or patients 
with relapsed disease or PD after autologous stem cell transplantation can 
enroll. 
3. 
Must have been treated with asparaginase-based regimen (radiotherapy 
must be performed for stage I/II disease). 
4. 
Long axis of a lesion > 15 mm or 18FDG-PET uptake by lesion. 
5. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
scores of 0–2. 
6. 
Signed the inform consent form (ICF) and able to comply with the 
scheduled follow-up visits and related procedures required in the protocol. 
7. 
Between the ages of ≥18 to ≤70 years. 
8. 
Life expectancy≥ 12 weeks. 


Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    5 
9. 
Patients (female patients at childbearing age or male patients whose 
partners are at childbearing age) must take effective contraceptive measures 
during the entire course of the trial and within 90 days since the last dose 
of treatment (see Section 4.3). 
10. Adequate organs and bone marrow functions, as defined below: 
 
Count of whole blood cells: absolute neutrophil count (ANC) ≥ 
1.0 × 10 9/L, platelets (PLTs) count ≥ 50 × 10 9/L, hemoglobin 
(HGB) ≥ 8.0 g/L; granulocyte colony-stimulating factor, PLT, or 
red blood cell (RBC) transfusion has not been performed within 7 
days prior to the test. 
 
Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of 
normal (ULN), alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 2.5 × ULN.  
 
Renal function:serum creatinine (Cr) ≤ 1.5 × ULN.  
 
Thyroid function: normal thyroid stimulating hormone (TSH) at 
baseline, or abnormal TSH at baseline with normal thiiodothronine 
(T3)/thiiodothronine (T4) and no symptoms. 
Exclusion Criteria 
1. 
Patients with aggressive NK cell leukemia. 
2. 
Patients with primary or secondary central nervous system (CNS) 
lymphoma. 
3. 
Patients with severe hemophagocytic syndrome at initial diagnosis of 
ENKTL-NT. 
4. 
Patients with pulmonary great vessel invasion. 
5. 
Previous exposure to any anti-PD-1, anti-PD-L1, or anti-CTLA-4 
antibodies. 
6. 
Enrolled in another interventional clinical study, unless only involved in an 
observational study (non-interventional) or in the follow-up phase of an 
interventional study. 


Investigational Drug: IBI308                Innovent Biologics (Suzhou) Co., Ltd.                          CIBI308D201 
July 8, 2019 Version2.0                          Confidential                                    6 
7. 
Received any investigational drug within 4 weeks prior to the first dose of 
study treatment. 
8. 
The last dose of radiation or anti-tumor therapy (chemotherapy, targeted 
therapy or tumor embolization) was within 3 weeks prior to receiving the 
first dose of study treatment; the last dose of nitrosourea or mitomycin C 
treatment was within 6 weeks prior to receiving the first dose of study 
treatment. 
9. 
Received immunosuppressants within 4 weeks prior to the first dose of 
study treatment, excluding local glucocorticoids administered by nasal, 
inhaled, or other topical routes, or systemic glucocorticoids of physiological 
doses (no more than 10 mg/day of prednisone or equivalents). 
10. Received any live attenuated vaccine within 4 weeks prior to the first dose 
of study treatment, or is scheduled to receive live attenuated vaccine during 
the study period. 
11. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 
weeks prior to the first dose of study treatment, or has unhealed wounds, 
ulcers, or fractures. 
12. Active, known, or suspected autoimmune disease (see Appendix 6) or 
previous medical history of these diseases within 2 years (patients with 
vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic 
treatment, hypothyroidism only requiring thyroid replacement, or type I 
diabetes only requiring insulin can enroll). 
13. Known history of primary immunodeficiency diseases. 
14. Known active pulmonary tuberculosis. 
15. Known history of allogeneic organ transplantation or allogeneic hem
atopoietic stem cell transplantation. 
16. Known to be allergic to any ingredients of monoclonal antibodies. 
17. Uncontrolled concurrent diseases including but not limited to: 


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 
HIV-infected patients (positive anti-HIV antibody). 
 
Active or poorly controlled severe infections. 
 
Symptomatic congestive heart failure (NYHA Class III-IV) or 
symptomatic or poorly controlled arrhythmia. 
 
Uncontrolled hypertension (systolic blood pressure ≥ 160 
mmHg or diastolic blood pressure ≥ 100 mmHg) despite of 
standard treatment. 
 
Any arterial thromboembolic events occurred within 6 months 
prior to enrollment, including myocardial infarction, unstable 
angina, cerebrovascular accident, or transient cerebral ischemic 
attack. 
 
Life-threatening hemorrhagic events or grade 3–4 gastrointestinal 
/variceal hemorrhage requiring blood transfusion, endoscopy, or 
surgical treatment within 3 months prior to enrollment. 
 
History of deep venous thrombosis, pulmonary embolism, or 
other serious thromboembolic events within 3 months prior to 
enrollment (implantable port or catheter-related thrombosis, or 
superficial venous thrombosis are not considered as serious 
thromboembolisms). 
 
Uncontrolled metabolic disorders, non-malignant organ or 
systemic diseases, or cancer-related secondary diseases that may 
lead to higher medical risks and/or survival evaluation 
uncertainties. 
 
Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with 
Child-Pugh grade B or C. 
 
Bowel obstruction or history of the following diseases: 
inflammatory bowel disease or extensive bowel resection (partial 


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colectomy or extensive small bowel resection accompanied with 
chronic diarrhea), Crohn's disease, and ulcerative colitis. 
 
Acute or chronic diseases, psychiatric disorders, or laboratory 
abnormalities that may lead to the following consequences: 
increased investigational drug-related risks, or interference with 
interpreting trial results, and considered ineligible for participating 
in the trial by the investigators. 
18. Known acute or chronic active hepatitis B (chronic HBV carriers or inactive 
HBsAg-positive patients can enroll if the HBV DNA < 1 × 10 3 copies/mL), 
or acute or chronic active hepatitis C (patients with negative HCV antibody 
can enroll; HCV RNA test is required for patients with positive HCV 
antibody, those test negative can enroll). 
19. History of GI perforation and/or fistula without radical treatment within 6 
months prior to the enrollment. 
20. Known interstitial lung disease. 
21. Clinically uncontrollable third spacing, such as pleural effusion and ascites 
that cannot be controlled by drainage or other methods prior to enrollment. 
22. History of other primary malignant tumors, excluding: 
 
History of radical treatment for malignant tumors with no evidence of tumor 
recurrence for more than 5 years prior to enrollment and with a very low 
risk of recurrence. 
 
Adequately treated nonmelanoma skin cancer or lentigo maligna with no 
signs of disease recurrence. 
 
Adequately treated carcinoma in situ with no signs of disease recurrence. 
23. Pregnant or breastfeeding female patients. 
Investigational Drug, 
Strengths, and 
Administration 
IBI308 100mg/10mL/vial 
200 mg IV Q3W 


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Evaluation Criteria 
Efficacy evaluation: 
 
Imaging evaluations will be performed based on Lugano 2014 Criteria 
(see Appendix 3) and IWG 2007 Criteria (see Appendix 4), evaluating 
the ORR, CR, PR, DCR, TTR, DoR, PFS, OS, 6-month PFS, and 6-
month OS after treatment. 
Safety evaluation: 
 
Incidence, relationship with investigational drug, and severity of all 
adverse events (AEs), treatment-emergent adverse events (TEAEs), 
adverse events of special interest (AESIs), and serious adverse events 
(SAEs) will be evaluated. 
 
Changes in vital signs, physical examination, and laboratory tests 
results before, during, and after treatment will be evaluated. 
Immunogenicity evaluation： 
 
Detection of anti-drug antibodies (ADAs) and neutralizing antibodies 
(NAbs) will be performed. 
Biomarker evaluation: 
 
Tumor tissue samples will be collected for cancer biomarker analysis, 
including PD-L1 expression, RNA expression and number of TIL in 
tissue samples of subjects with ENKTL-NT. 
 
Blood samples will be collected for biomarker analysis, including 
dynamic changes in EBV DNA copy number in peripheral blood, 
immune cell phenotyping, and association between immune-related 
cytokines and efficacy of anti-PD-1 treatment. 
Quality of life evaluation: 
 
The quality of life and health status during IBI308 treatment will be 
evaluated based on EQ 5D-5L and EORTC QLQ-C30. 
Statistics 
Sample size estimation: 
This is a single-arm trial. The primary objective is to evaluate the efficacy 


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of IBI308 monotherapy for the treatment of relapsed or refractory extranodal 
NK/T-Cell Lymphoma. 20-60 subjects will be enrolled. Assuming a null 
hypothesis of 30% ORR,  of 0.05 (two-sided), power of 80%, a 50% ORR after 
IBI308 treatment will be achieved and the minimum sample size will thus be 43. 
 
The sponsor will evaluate the safety data from the first 20 subjects to 
determine whether the study shall be discontinued prematurely due to safety 
concerns. 
Hypothesis for superiority: 
   H0: ORR ≤ 30% 
H1: ORR > 30% 
   The total  is set at 0.05 (two-sided), and the superiority is determined using 
confidence intervals (CIs). 
Interim analysis: 
   One interim analysis is planned for this study. It will be conducted after the 
first 20 subjects have completed the protocol-specified treatment to evaluate the 
safety. 
Primary efficacy endpoint: 
   ORR and the corresponding 1-% CI is estimated using binomial 
distribution to test for superiority. 
Secondary efficacy endpoints: 
   TTR, DoR, PFS, and OS will be estimated through the median values and 
the corresponding 95% CIs using the Kaplan-Meier method. PFS and 6-month 
PFS curves will be plotted. 
   CR, PR, and DCR and the corresponding 95% CIs will be estimated using 
binomial distribution. 
Safety analysis: 


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The incidence and severity of AEs will be summarized for each treatment 
arm, and the abnormal changes in laboratory measurements will be presented. 
Immunogenicity analysis: 
The positive rates of ADAs and NAbs will be summarized. 
Quality of life analysis: 
Data based on EQ-5D-5L and EORTC QLQ-C30 will be analyzed using 
descriptive statistics. 
Biomarker analysis: 
PD-L1 expression and number of TIL in tissue samples of subjects with 
relapsed or refractory ENKTL-NT, dynamic changes in EBV DNA copy number 
in plasma and peripheral blood lymphocytes, immune cell phenotyping, and 
association between immune-related cytokines and efficacy of anti-PD-1 
treatment will be analyzed using descriptive statistics. 


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Table 1. Schedule of visits 
Phase 
Screening 
Treatment 
End-of-Treatment 
Visit22 
Safety Follow-Up 
Survival Follow-
up23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7–N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28 to -1 
Day 1 
Day 22 
(± 3 days)  
Day 43 
(± 3 days) 
Day 64 
(± 3 days)  
Day 85 
(± 3 days)  
Q3W 
(± 3 days)  
 
90 days (± 7 days)  
since the last dose 
Q60D (±7 days) 
after safety 
follow-up 
General Study Procedures 
 
 
SignedICF1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics/Medical  
History/Previous  
Medication2 
X 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/Height4 
X 
 
 
 
 
 
 
X 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS Score 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECG5 
X 
 
 
X 
 
X 
X 
X 
 
 
Count of Whole Blood  
Cells/Blood  
Biochemistry/Routine  
Urinalysis6 
X 
 
X 
X 
X 
X 
X 
X 
X 
 


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Phase 
Screening 
Treatment 
End-of-Treatment 
Visit22 
Safety Follow-Up 
Survival Follow-
up23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7–N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28 to -1 
Day 1 
Day 22 
(± 3 days)  
Day 43 
(± 3 days) 
Day 64 
(± 3 days)  
Day 85 
(± 3 days)  
Q3W 
(± 3 days)  
 
90 days (± 7 days)  
since the last dose 
Q60D (±7 days) 
after safety 
follow-up 
Pregnancy Test7 
X 
 
 
 
 
 
 
X 
 
 
Thyroid Function8 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity9 
 
X 
X 
 
X 
 
 
 
X 
 
EBV DNA10 
 
X 
X 
X 
X 
X 
X 
X 
 
 
HIV, HBV, and HCV11 
X 
 
 
 
 
 
 
 
 
 
AE Evaluation12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant  
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Evaluation 
 
 
Bone Marrow Biopsy13 
X 
 
 
 
 
 
 
 
 
 
Tumor Biopsy14 
 
 
 
 
 
 
 
 
 
 
CT/MRI Evaluation15 
X 
 
 
 
 
 
X 
 
 
 
PET-CT16 
X 
 
 
X 
 
 
X 
X 
 
 
Disease-Related  
Symptom Evaluation17 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Investigational Drug Infusion 
 
 
IBI30818 
 
X 
X 
X 
X 
X 
X 
 
 
 
Quality of Life Evaluation 
 
 


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Phase 
Screening 
Treatment 
End-of-Treatment 
Visit22 
Safety Follow-Up 
Survival Follow-
up23 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6–N 
Visit 
1 
2 
3 
4 
5 
6 
7–N 
Premature 
discontinuation/end-
of-treatment visit 
 
 
Day 
-28 to -1 
Day 1 
Day 22 
(± 3 days)  
Day 43 
(± 3 days) 
Day 64 
(± 3 days)  
Day 85 
(± 3 days)  
Q3W 
(± 3 days)  
 
90 days (± 7 days)  
since the last dose 
Q60D (±7 days) 
after safety 
follow-up 
EQ-5D-5L/ 
EORTC QLQ-C3019 
 
X 
 
X 
 
 
X 
X 
 
 
Biomarker Study 
 
 
Archival/Fresh 
Tumor Tissue Sample20 
X 
 
 
 
 
 
 
 
 
 
Peripheral Blood  
Sample21 
X 
 
 
X 
 
 
X 
 
 
 
Note: 
1. 
ICFs shall be signed by subjects prior to any procedures outlined in the protocol. 
2. 
Previous medications: treatment for the initial diagnosis, including chemotherapy, radiotherapy, and surgery. 
3. 
Vital signs: body temperature, pulse, respiratory rate, and blood pressure. 
4. 
Screening: weight and height; end-of-treatment visit: weight. 
5. 
12-lead ECG schedule: during screening, prior to administration every other cycle, and during the end-of-treatment visit. 
6. 
Count of whole blood cells: RBC, HGB, white blood cell (WBC), PLT, WBC differentials [lymphocyte (LYM), ANC]. Blood biochemistry include: hepatic function [TBIL, ALT, AST, 
γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactic dehydrogenase (LDH)], renal function [(blood urea nitrogen (BUN) and Cr)], 
electrolytes (Na, K, Cl, Mg, Ca, and P), lipase, amylase, and fasting blood glucose (FBG). Routine urinalysis:pH, urinary albumin (UALB), urine protein (UPRO), urine red blood cell 


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(URBC), and urine glucose (UGLU). The tests will be conducted within 7 days prior to the first dose of the investigational drug, within 3 days prior to the administration of the 
investigational drug from Cycle 2 onwards, and during safety follow-up. Tests shall be performed at the study sites. 
7. 
Women of childbearing potential shall undergo urine or blood pregnancy test within 3 days prior to the first dose and during the end-of-treatment visit. If the urine pregnancy test is not 
conclusive, then blood pregnancy test shall be performed. The conclusion shall be based on the blood pregnancy test. Tests shall be performed at the study sites. 
8. 
T3, T4, free thiiodothronine (FT3), free thiiodothronine (FT4), and TSH shall be tested during screening, prior to the administration of the investigational drug from Cycle 2 onwards, 
and during safety follow-up. Tests shall be performed at the study sites. 
9. 
Immunogenicity assays will be carried out within 1 hour prior to IBI308 administration in Cycles 1, 2, 4 and then every 4 cycles thereafter (Cycle 8, 12, 16, and so on), and during safety 
follow-up. Tests shall be conducted at the central laboratory. 
10. EBV DNA shall be tested on the day of IBI308 administration in each cycle, with 4 mL of blood collected each time, until the end of study treatment. Tests shall be conducted at the 
central laboratory. According to the changes of patients’ condition and the needs of efficacy evaluation, EBV DNA test may be added by investigators at the centre. 
11. Hepatitis B panel (HBsAg, HBsAB, HBcAB, HBeAg, and HBeAb), HCV antibody, and HIV antibody will be tested during screening. If the result shows HBsAg positive, then HBV 
DNA test shall be further conducted; if the result shows HCV antibody positive, then HCV RNA test shall be further conducted. For HBV DNA-positive subjects or HBV carriers, HBV 
activity shall be monitored regularly, and prophylactic antiviral therapy is suggested to be performed according to the treatment guidelines for chronic hepatitis B during the trial. Tests 
shall be performed at the study sites. 
12. AE and laboratory safety evaluation are performed according to NCI CTCAE v4.03. Refer to Section 7 for AE and SAE definitions, recording, determination of causal relationship, 
severity, reporting deadlines, and processing. 
13. Subjects with positive bone marrow biopsy at baseline shall repeat the biopsy if a CR by imaging is achieved during the treatment (shall be completed within 2 weeks after imaging 
evaluation). 
14. Tumor biopsy: The investigator may decide whether a biopsy is needed to confirm the results of an imaging evaluation during the study. 
15. CT/MRI evaluation: contrast-enhanced CT will be used (MRI will be performed for subjects allergic to CT contrast media). Contrast-enhanced CT shall be performed at baseline, week 
24 (± 7 days), every 12 weeks (± 14 days) after 24 weeks,  every 24 weeks (± 14 days) after 48 weeks  and when clinical need arises until initiation of new anti-tumor therapy, PD, 
withdrawal of ICF, or death. 


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16. PET-CT evaluation: PET-CT shall be performed at baseline, week 6 (± 7 days), week 15 (± 7 days),  week 24 (± 7 days)  , and when clinical need arises. PET-CT evaluation shall be 
performed at the end of treatment for subjects who discontinue the treatment prematurely prior to week 24. 
17. Disease-related symptom (including fever, night sweats, weight loss) evaluation shall be performed prior to administration in each cycle. 
18. IBI308 200mg IV Q3W until PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol. For subjects who develop PD for the first time and are clinically 
stable, the investigator can continue treatment up to 24 months until further PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol. 
19. Quality of life evaluation will be performed on the day of the first dose, during each imaging evaluation, and during the end-of-treatment visit as per EQ 5D-5L and EORTC QLQ-C30. 
20. All the eligible subjects must provide archival tumor tissue at baseline or 8–10 unstained sections (4–5 μm) of fresh samples during screening for evaluations of biomarkers. Tests shall 
be conducted at the central laboratory. 
21. Ten mL whole blood samples are required to be provided by subjects for molecular tumor testing at the following time points: prior to the first dose, during efficacy evaluation but before 
the next treatment, and when PD is confirmed. 
22. Treatment discontinuation: treatment discontinuation includes premature discontinuation (treatment discontinuation for reasons other than PD) and end of treatment (treatment 
discontinuation due to PD). The end-of-treatment visit shall be conducted when treatment is discontinued. 
23. Survival follow-up: once Q60D (± 7 days) after the safety follow -up. Telephone visits is allowed. 


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Table of Contents 
Protocol Synopsis .............................................................................................................................................. 2 
Table of Contents ............................................................................................................................................... 17 
List of Abbreviations and Definitions ................................................................................................................ 20 
1 Background ..................................................................................................................................................... 24 
 Disease Background ............................................................................................................................ 24 
 Investigational Drug (IBI308) .............................................................................................................. 26 
 Risk/Benefit Assessment ...................................................................................................................... 28 
2 Study Objectives ............................................................................................................................................. 28 
 Primary Objective ................................................................................................................................ 28 
 Secondary Objectives .......................................................................................................................... 29 
 Exploratory Objectives: ....................................................................................................................... 29 
3 Study Design ................................................................................................................................................... 29 
 Overall Design ..................................................................................................................................... 29 
 Design Principles ................................................................................................................................. 30 
4 Study Population ............................................................................................................................................. 32 
 Inclusion Criteria ................................................................................................................................. 32 
 Exclusion Criteria ................................................................................................................................ 33 
 Restrictions During the Study .............................................................................................................. 36 
 Treatment Discontinuation/Withdrawal from the study ....................................................................... 37 
5 Investigational Drug and Other Treatments .................................................................................................... 38 
 Treatment Regimen .............................................................................................................................. 38 
 Investigational Drug (IBI308) .............................................................................................................. 39 
 Administration Adjustments of Investigational Drug .......................................................................... 40 
 Principles of Managing Immune Checkpoint Inhibitor Toxicities ....................................................... 42 
 Concomitant Treatments ...................................................................................................................... 43 
 Treatment Compliance ......................................................................................................................... 43 
 Medication Return and Destruction ..................................................................................................... 44 
 Investigational Drug Records .............................................................................................................. 44 
 Complaint Handling ............................................................................................................................. 44 
6 Study Evaluations and Relevant Procedures ................................................................................................... 44 
 Subject Enrollment .............................................................................................................................. 44 
 Study Plan and Schedule ...................................................................................................................... 45 


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 Imaging Evaluation .............................................................................................................................. 48 
 Safety Evaluation ................................................................................................................................. 49 
 Immunogenicity ................................................................................................................................... 51 
 Quality of Life Evaluation ................................................................................................................... 51 
 Biomarker analysis .............................................................................................................................. 51 
 Storage and Destruction of Biological Samples .................................................................................. 52 
7 Safety Reports and AE Management .............................................................................................................. 52 
 Definition of AEs ................................................................................................................................. 52 
 Definition of SAEs ............................................................................................................................... 52 
 AE Severity Grading Scale .................................................................................................................. 53 
 Correlation Between AEs and Investigational Drug ............................................................................ 54 
 Recording of AEs ................................................................................................................................. 55 
 Expedited Reporting of SAEs and Pregnancy ..................................................................................... 58 
 Abnormal Hepatic Function ................................................................................................................. 60 
 Managing of Drug-Related Toxicities .................................................................................................. 60 
8 Statistics .......................................................................................................................................................... 61 
 Statistical Analysis Plan ....................................................................................................................... 61 
 Hypothesis Test .................................................................................................................................... 61 
 Analysis Population ............................................................................................................................. 61 
 Statistical Methods ............................................................................................................................... 62 
 Sample size estimation ......................................................................................................................... 66 
 Methods for Controlling Bias .............................................................................................................. 66 
9 Quality assurance and quality control ............................................................................................................. 66 
 Clinical monitoring .............................................................................................................................. 67 
 Data Management/Coding ................................................................................................................... 67 
 Quality Assurance Audits ..................................................................................................................... 69 
10 Ethics ............................................................................................................................................................ 69 
 EC ...................................................................................................................................................... 69 
 Ethics ................................................................................................................................................. 70 
 Subject Information and Informed Consent ....................................................................................... 70 
 Data Protection of Subjects ................................................................................................................ 70 
11 Study Management ....................................................................................................................................... 71 
 Data Processing and Record Keeping ................................................................................................ 71 


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 Source Data/File Access ..................................................................................................................... 71 
 Protocol Amendments ........................................................................................................................ 71 
 Responsibilities of the Investigator .................................................................................................... 72 
 Publishing Policy ............................................................................................................................... 72 
 Financing and Insurance .................................................................................................................... 72 
12 Reference ...................................................................................................................................................... 73 
13 Appendixes ................................................................................................................................................... 76 
Appendix 1: Signature Page for Investigator ..................................................................................................... 77 
APPENDIX 2: ECOG PERFORMANCE STATUS ......................................................................................... 78 
APPENDIX 3: Lugano 2014 Recommendations ............................................................................................... 79 
APPENDIX 4 IWG 2007 Recommendations .................................................................................................... 80 
Appendix 5: Abnormal Hepatic Function Monitoring and Follow-Up Report .................................................. 81 
Appendix 6: List of Pre-Existed Autoimmune Diseases Prior to Enrollment .................................................... 84 
Appendix 7: IBI308 Administration Adjustments and Toxicity Management .................................................. 87 
Appendix 8: EQ-5D-5L Scale ........................................................................................................................ 109 
Appendix 9: EORTC-QLQ-C30 (v3) Quality of Life Scale .......................................................................... 112 
List of Tables 
Table 1. Schedule of visits 
12 
Table 2. Effective methods of contraception (one of the followings must be used) 
36 
Table 3. Administration adjustments of IBI308 
40 
Table 4. Routine laboratory safety evaluations 
49 
Table 5. Correlation determination between AEs and investigational drug 54 
Table 6. SAE report contacts 58 
Table 7. Liver injuries required to be reported as SAEs 60 
 
 
 


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List of Abbreviations and Definitions 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALB 
Albumin 
ALP  
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST  
Aspartate aminotransferase 
AUC 
Area under the curve 
BASO 
Basophil count 
BUN 
Blood urea nitrogen 
CCr 
Creatinine clearance 
ENKTL 
Extranodal natural killer/T-cell Lymphoma, nasal type 
CHO 
Chinese hamster ovary cell 
CI  
Confidence interval 
Cmax  
Maximum observed concentration 
Cr 
Serum creatinine 
CR  
Complete response 
CRO 
CRA 
Contract research organization 
Clinical Research Associate 
CSR 
Clinical study report 
CT  
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTLA-4  
Cytotoxic T-lymphocyte antigen 4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
EBV 
EBER 
EBNA1 
EC 
Duration of response 
Epstein-Barr virus; human herpesvirus 4 
Epstein-Barr virus Encoded RNA 
Epstein-Barr virus nucleus antigen 1 
Ethics committee 
ECG  
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 


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eCRF 
Electronic case report form 
EOS 
EDC 
ENKTL 
Eosinophil count 
Electronic data capture 
Extranodal NK/T-celllymphoma 
FAS 
Full analysis set 
FBG 
Fasting blood glucose 
FFPE  
Formalin fixed paraffin-embedded 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP  
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HIV 
HDACi 
HDC 
Human immunodeficiency virus 
Histone deacetylase inhibitor 
High dosage chemotherapy 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 
irAE  
Immune-related adverse event 
IRR 
Infusion-related reaction 
IV  
Intravenous infusion 
LDH 
Lactate dehydrogenase 
LYM 
LMP1 
Lymphocyte count 
Latent membrane protein1 
MedDRA  
Medical Dictionary for Regulatory Activities 
MONO 
Monocyte count 
mOS 
Median overall survival 
mPFS 
Median progression-free survival 
MTD 
Maximum tolerated dose 
NAb 
Neutralizing antibody 
NCI  
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 


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NSCLC 
NOAEL 
Non-Small cell lung carcinoma 
No-observed-adverse-effect level 
NOEL 
No-observed-effect level 
ORR  
Objective response rate 
OS 
PTCL 
Overall survival 
Peripheral T-cell lymphoma 
PD 
Progressive disease 
PD-1  
Programmed cell death-1 
PD-L1  
Programmed cell death ligand 1 
PFS  
Progression-free survival 
pH 
Potential of hydrogen 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PLT 
PPS 
Platelet 
Per protocol set 
PR 
PT 
Partial response 
Preferred ter 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
SCT 
Statistical analysis plan 
Sterm cell transplantation 
SD 
SOC 
Stable disease 
System organ classification 
SS 
Safety set 
t½ 
Half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBIL 
Total bilirubin 
TEAE 
TGF 
TIL 
TNFR 
Treatment-emergent adverse event 
Tumor growth factor 
Tumor infiltrating lymphocyte 
Tumor necrosis factor receptor 
TP 
Total protein 
TSH 
Thyroid stimulating hormone 


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TT 
Thrombin time 
TTR 
Time to response 
UALB 
Urinary albumin 
UGLU 
Urine glucose 
ULN 
Upper Limit of Normal 
UPRO 
Urine protein 
URBC 
VAS 
Urine red blood cell 
Visual analogue scale 
WBC 
White blood cell 
γ-GT 
γ-glutamyltransferase 
 
 


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1 Background 
Disease Background 
Extranodal natural killer (NK)/T-cell lymphomas, nasal type (ENKTL-NT) is a subtype of 
peripheral T-cell lymphoma (PTCL) with a distinctive geographical distribution. The incidence is 
higher in Asia than in Europe and America (22% vs. 5% of all the PTCLs) [1]. In 2012, a multi-
center analysis of pathological classification of 10002 lymphoma subjects in China showed that 
ENKTL-NT accounted for 6.6% of all the non-Hodgkin lymphomas (NHLs) and 28.1% of all the 
PTCLs [2]. The 5-year overall survival rate (OSR) is approximately 32%, and the median overall 
survival (OS) is around 8 months [3, 4]. 
The Epstein-Barr virus (EBV) is a known cause and contributing factor to ENKTL-NT. EBV 
infection is always present in ENKTL-NT cases. Epstein–Barr encoding region (EBER) in situ 
hybridization (EBV encoded RNA) has become a routine test for pathological diagnosis of 
ENKTL-NT [1]. Data indicate that positive-EBER and high EBV DNA copy numbers in peripheral 
blood (> 6.1 × 10 7copies/mL) are associated with poor PTCL prognosis [5, 6] and high EBV DNA 
copy number (> 105copies/mL) indicates poor treatment efficacy [7]. EBV promotes the 
development of tumors by activating the STAT1 signaling pathway, inhibiting the TGFβ-1 
signaling pathway, and up-regulating survivin with EBV nuclear antigen 1 (EBNA1), and the 
proliferation of tumors by activating NF-κB and MAPK signaling pathways with latent membrane 
protein 1 (LMP1) and tumor necrosis factor receptor (TNFR) [8, 9]. Immunotherapy is more 
suitable for lymphomas associated with EBV, possibly because these tumor cells express more 
EBV antigens that are recognized by CD8+ T-cells [9]. 
PD-L1 positive expression is detected in approximately 70–75% and PD-1 in approximately 
10–30% of all the ENKTL-NT patients. High PD-L1 expression suggests relative good prognosis 
of PTCL [10–13]. EBV can up-regulate PD-L1 expression on tumor cells, which results in immune 
tolerance. The main mechanisms are: 1. innate immunity: up-regulation of PD-1 by activating the 
NF-κB signaling pathway with LMP1 and continuously activating oncogenic pathways. This 
mechanism does not rely on inflammatory signals in the tumor microenvironment; 2. adaptive 
immunity: up-regulation of PD-L1 induced by tumor microenvironment or anti-inflammatory 
cytokines associated with viral infections such as IFN-γ. In vitro experiments have confirmed that 
PD-1 monoclonal antibody can restore the activity of T-cells inhibited by diffuse large B-cell 
lymphoma [14, 15]. In clinical practice, nivolumab has been approved by the US Food and Drug 
Administration (FDA) for the treatment of Hodgkin lymphoma (HL). High expression of PD-L1 
is observed in HL due to the copy number amplification of 9p24.1(loci for PD-L1, PD-L2, and 
JAK2 genes) [16, 17]. The above studies provide theoretical bases for the inhibition of the PD-
1/PD-L1 axis for the treatment of EBV-associated PTCL. 


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Anthracycline-based chemotherapies are not used in patients with ENKTL-NT due to the high 
expression of multidrug-resistant (MDR) P-glycoproteins. The objective response rate (ORR) and 
complete response (CR) of L‑ asparaginase‑ based regimen, SMILE or AspaMetDex, as first-line 
treatment for ENKTL-NT was 79–80% and 45–66%, respectively [18–20]. However, 
internationally there is currently no treatment recommendation for ENKTL-NT refractory to L-
asparaginase-based regimens. Prognosis is extremely poor in these patients. 
High-dose chemotherapy (HDC)/autologous or allogeneic hematopoietic stem cell 
transplantation (ASCT or HSCT) are currently used as first-line consolidation therapy or second-
line salvage therapy. However, there is limited data. Some small sample size reports showed that 
the subjects with relapsed or refractory ENKTL-NT have a better long-term outcome after 
HDC/SCT, and sustained response can be achieved for 3–5 years [21, 22]. A retrospective study 
conducted by the NK-Cell Tumor Study Group showed that 7 of 15 subjects with ENKTL survived 
and achieved CR after HDT/ASCT [duration of response (DoR): 25+ to 87+ months]. However, 6 
of these subjects died within 5 months after the transplantation [23]. Due to the low acceptance of 
transplant therapy and limited medical resources in China, few patients receive hematopoietic stem 
cell transplantation. Patients with relapsed or refractory ENKTL in China usually choose to 
continue with drug treatment. 
There is currently no valid prospective clinical data in subjects with ENKTL-NT refractory 
to L-asparaginase. Guidelines have suggested combination chemotherapy replacing L-
asparaginase with pegaspargase for refractory ENKTL-NT may be beneficial [1]. The DeVIC 
regimen, which is comprised of non-MDR agents, is also recommended in literature[24]. However, 
this regimen is currently used sequentially after radiation for early ENKTL-NT, and there is no 
data in advanced, relapsed/refractory ENKTL-NT. The efficacy of gemcitabine for the treatment 
of PTCL has received attention. Data from a Korean study with small sample size showed that 
regimens containing gemcitabine achieved an ORR of approximately 40% in subjects with 
ENKTL-NT, with 20% achieving CR and 20% partial response (PR) [25]. Other drugs such as 
histone deacetylase inhibitors (HDACi) and anti-CD30 monoclonal antibody have demonstrated 
efficacy in PTCL but have not been studied in ENKTL-NT treatment. Therefore, there is a 
significant clinical need to find an effective drug for patients with relapsed or refractory ENKTL-
NT. 
In Feb. 2017, Yok-Lam Kwong et al. published a small-sample-size study of pembrolizumab 
for the treatment of 7 subjects with NK/T-cell lymphoma refractory to L-asparaginase regimens in 
Blood. The ORR was 100%, with 5 cases of CR (71%, among which 2 had undetectable EBV) 
and 2 cases of PR (29%). The 5 subjects who achieved CR remained in response during a follow-
up of 6 months. The treatment was well-tolerated, with only 1 subject developing a grade 2 skin 
reaction during the study [26]. Compared to other medications, the treatment of relapsed/refractory 


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NK/T-cell lymphoma with pembrolizumab was characterized by excellent efficacy and mild 
adverse reactions. On this basis, the investigator will continue to increase the number of subjects 
and other PTCL subtypes. 
In summary, immunotherapy that inhibits the PD-1/PD-L1 axis is very likely to achieve good 
results in patients with relapsed or refractory ENKTL-NT. This study is thus conducted to evaluate 
the efficacy and safety of IBI308 in relapsed/refractory ENKTL-NT. 
Investigational Drug (IBI308) 
Mechanism of action 
Immune checkpoints are a type of immune inhibitory molecules, whose physiological 
function is to regulate the the immune response, avoiding the damage and destruction of normal 
tissues. Cancer cells often use these immune checkpoints to avoid being attacked by immune 
cells. Currently, immune checkpoints CTLA-4 and PD-1/PD-L1 have been validated clinically. 
Immune checkpoint inhibitors that target PD-1/PD-L1 have better prospects for clinical 
applications due to better safety and a broader range of indications. 
PD-1 is primarily expressed on activated T-cells and has two ligands, PD-L1 and PD-L2. 
PD-L1 is the main ligand that is expressed on activate T-cells, antigen-presenting cells, and 
tumor cells[19]. The binding of PD-1 with PD-L1 plays an important role in regulating the 
activation of T cells and maintaining peripheral immune tolerance. When T cells do not express 
PD-1, they interact with antigen-presenting cells to enable the activation and proliferation of T 
cells as well as the activation of cytokine secretion, which can kill the tumor cells. The activated 
T cells begin to express PD-1. After PD-1 binds to the ligand PD-L1 expressed on the surface of 
antigen-presenting cells or tumor cells, the inhibitory signal transmitted by PD-1 inhibits the 
proliferation of T cells and activates the secretion of cytokines, thus weakens the function of T 
cells. Most tumor cells evade the attack of immune cells through this mechanism. The activity 
and ability to kill cancer cells of T cells can be restored by blocking the PD-1/PD-L1 interaction 
with drugs [20]. 
The US FDA has currently approved 3 PD-1/PD-L1 products, namely, anti-PD-1 antibodies 
by BMS——nivolumab (brand name: OPDIVO), by Merck——pembrolizumab (brand name: 
KEYTRUDA), and by Genetech——atezolizumab (brand name: Tecentriq), indicated for 
advanced melanoma, advanced non-small-cell lung cancer, advanced ENKTL-NT, advanced 
renal cell carcinoma, urothelial carcinoma, and advanced head and neck cancer. In addition, 


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many indications have been in phase III clinical studies or have been submitted for approval. 
The approval of these drugs confirms the important role of PD-1/PD-L1 immune checkpoint 
inhibitors in cancer immunotherapy. There is no available PD-1/PD-L1 immune checkpoint 
inhibitors approved for marketing in China. It is of great significance to actively develop such 
inhibitors to provide better treatment options for domestic patients with advanced cancer. 
Recombinant fully human anti-PD-1 monoclonal antibody (R&D code: IBI308) injection 
is a recombinant fully human IgG4 monoclonal antibody. Multiple preclinical in vitro trials have 
shown the blockade function of IBI308 of the PD-1 pathway, and the anti-tumor activity of 
murine analogs of IBI308 has also been indicated in various murine tumor models (refer to the 
Investigator's Brochure for details regarding study results). The preclinical study results 
demonstrate the promising use of IBI308 for PD-1 blockade. 
Clinical study results 
A phase Ia dose-escalation trial was initiated in Sep. 2016. Around 12–24 patients with 
advanced solid tumors who had failed standard treatment were enrolled. This dose escalation study 
used the standard "3 + 3" design to evaluate 4 dose levels (1 mg/kg, 3 mg/kg, 200 mg, and 10 
mg/kg) of IBI308. After the completion of 1 mg/kg dose administration, subjects were randomized 
in a 1:1 ratio to either 3 mg/kg or 200 mg arm for independent evaluations. Dose-limiting toxicity 
(DLT) was observed for 28 days after the first dose for each dose arm. After completion of DLT 
observation, subjects were treated with IBI308 once Q2W (1 mg/kg, 3 mg/kg, or 10 mg/kg) or 
Q3W (200 mg) up to 24 months until progressive disease (PD), intolerable toxicity, withdrawal of 
ICF, or other reasons requiring treatment discontinuation (whichever occurs first). 
Pharmacokinetic (PK) evaluation of IBI308 1 mg/kg was conducted in subjects with multiple 
tumors (n = 3). Preliminary results after a single-dose administration showed that IBI308 1 mg/kg 
reached the maximum drug exposure right after the completion of the single-dose infusion. The 
drug distribution was rapid after reaching the peak concentration, followed by a slow elimination 
(t1/2 ≈ 17.3 d), which is the typical two-compartment PK characteristics of a monoclonal 
antibody. The elimination half-life is similar to the physiological half-life of IgG4. 
The pharmacodynamic (PD) results showed that: a dosed of IBI308 1 mg/kg rapidly (24 h) 
saturated the peripheral PD-1 (95.8 ± 2.3%) and m aintained the receptor occupancy with 
decreasing concentrations throughout the study (28 d, C28d: 3.70 ± 0.15 μg/mL). It is estimated 
that the steady state can be reached after 84 days with 6 continuous doses of IBI308 1 mg/kg 


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administered Q2W. If there are no significant changes in drug clearance, the steady-state trough 
concentration will be around 13 μg/mL and the peripheral PD-1 receptor occupancy will be 
maintained. 
Up to Apr. 16, 2017, the phase Ia study has enrolled 12 patients (3 for each cohort ) in 4 
treatment cohorts (1 mg/kg, 3 mg/kg, 200 mg, and 10mg), and evaluated the DLTs for each arm. 
No DLTs were observed. A total of 4 serious adverse events (SAEs) ≥ grade 3 were observed in 
the phase Ia study, among which 3 cases of immune-related pneumonitis and lung infections are 
possibly related to the investigational drug. 
Risk/Benefit Assessment 
Considering the mechanism of action of IBI308 and the clinical safety information of 
products with similar mechanisms, the main adverse events (AEs) during this clinical trial will 
possibly be the immune-mediated inflammatory resulted from the activation of immune system, 
e.g. pneumonitis, colitis, hepatitis, renal insufficiency, and endocrine events. According to the 
available clinical data, anti-PD-1 monoclonal antibodies are well-tolerated despite of high 
incidence of adverse reactions. Treatment discontinuation due to adverse reactions only occur in a 
small number of subjects, and most events resolve after appropriate interventions. Early symptoms 
of immune-related adverse events (irAEs) vary. Therefore, investigators must closely monitor 
early signs and symptoms of irAEs during the trial, make correct judgments timely, adjust the dose 
according to Section 5.4 in the protocol, and provide effective treatment measures to reduce the 
subject risks. Besides, subjects with autoimmune diseases shall be excluded from the trial to avoid 
exacerbation of the original disease due to the activation of immune system. 
Pharmacological and safety data from the phase Ia clinical trial showed that IBI308 is of clear 
pharmacological activity and good safety in subjects with advanced cancers. 
The preliminary data of the above study show that IBI308 has good pharmacological activity 
and safety. Since other anti-PD-1 monoclonal antibodies have demonstrated significant efficacy in 
ENKTL-NT, it is reasonable to conduct a clinical study of IBI308 in Chinese patients with relapsed 
or refractory ENKTL-NT.  
2 Study Objectives 
Primary Objective 
 To evaluate the ORR of IBI308 monotherapy for the treatment of relapsed or refractory 
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Secondary Objectives 
 To evaluate the CR and PR of IBI308 monotherapy for the treatment of relapsed or 
refractory ENKTL-NT; 
 To evaluate the disease control rate (DCR) of IBI308 monotherapy for the treatment of 
relapsed or refractory ENKTL-NT; 
 To evaluate the time to response (TTR) of IBI308 monotherapy for the treatment of 
relapsed or refractory ENKTL-NT; 
 To evaluate the DoR of IBI308 monotherapy for the treatment of relapsed or refractory 
ENKTL-NT; 
 To evaluate the progression-free survival (PFS) and 6-month PFS of IBI308 monotherapy 
for the treatment of relapsed or refractory ENKTL-NT; 
 To evaluate the OS and 6-month OSR of IBI308 monotherapy for the treatment of 
relapsed or refractory ENKTL-NT; 
 To evaluate the safety of IBI308 monotherapy for the treatment of relapsed or refractory 
ENKTL-NT; 
 To evaluate the quality of life of subjects with relapsed or refractory ENKTL-NT after 
IBI308 monotherapy, using EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) and European 
Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 
30 (EORTC QLQ-C30). 
Exploratory Objectives: 
 To evaluate the PD-L1 expression and number of tumor-infiltrating lymphocytes (TIL) in 
tissue samples of subjects with relapsed or refractory ENKTL-NT, RNA expression,  
dynamic changes in Epstein-Barr virus (EBV) DNA copy number in plasma and 
peripheral blood lymphocytes, immune cell phenotyping, and association between 
immune-related cytokines and efficacy of anti-PD-1 treatment. 
3 Study Design 
Overall Design 
This is a multicenter, single-arm, phase II clinical trial evaluating the efficacy and safety of 
IBI308 monotherapy for the treatment of relapsed or refractory ENKTL-NT.  Patients with 
relapsed or refractory ENKTL-NT will be enrolled to receive IBI308 200mg IV Q3W up to 24 
months until PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the 


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protocol. For subjects who develop PD for the first time and are clinically stable, the investigator 
can continue treatment up to 24 months until further PD, death, intolerable toxicity, withdrawal of 
ICF, or other reasons stated in the protocol. 
The primary endpoint is ORR, defined as the proportion of subjects who either experience 
CR or PR as the best overall response based on imaging evaluation. The primary endpoint will be 
analyzed after the last statistical and radiological evaluable subject completes a maximum of 24 
weeks of follow-up. The tumor assessment is according to Lugano 2014 Criteria (see Appendix 3) 
and IWG 2007 Criteria after week 24 (see Appendix 4). 
The safety follow-up will be performed until 90 days after the last dose. 
Design Principles 
Rationale for a single-arm design 
It is recommended the DeVIC regimen, which is comprised of non-MDR agents [24], and 
sequential radiotherapy for the treatment of early ENKTL-NT. There is no data in advanced, 
relapsed/refractory ENKTL-NT. Data from a Korean study with small sample size showed that 
regimens containing gemcitabine achieved an ORR of approximately 40% in subjects with 
ENKTL-NT, with 20% achieving CR and 20% PR [25]. Other drugs such as HDACi and anti-
CD30 monoclonal antibody have demonstrated efficacy in PTCL, but have not been used in 
ENKTL-NT treatment. Therefore, there is a significant clinical need to find an effective drug for 
patients with relapsed or refractory ENKTL-NT. 
In Feb. 2017, Yok-Lam Kwong et al. published a small-sample-size study of pembrolizumab 
for the treatment of 7 subjects with NK/T-cell lymphoma refractory to L-asparaginase regimens in 
Blood. The ORR was 100%, with 5 cases of CR (71%, among which 2 had undetectable EBV) 
and 2 cases of PR (29%). The 5 subjects who achieved CR remained in response during a follow-
up of 6 months. The treatment was well-tolerated, with only 1 subject developing a grade 2 skin 
reaction during the study [34]. Compared to other medications, the treatment of relapsed/refractory 
NK/T-cell lymphoma with pembrolizumab was characterized by excellent efficacy and mild 
adverse reactions. The data of the above studies indicate that anti-PD-1 monoclonal antibodies 
may have significant efficacy in patients with relapsed or refractory ENKTL-NT who have failed 
multiple lines of treatment and are better tolerated compared to other drugs. A single-arm design 
will be used because there is no standard treatment for relapsed/refractory ENKTL-NT in China. 


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Rationale for a treatment regimen of 200 mgQ3W 
In this study，IBI308 will be administrated as 200 mg Q3W. This method of administration 
is used primarily due to the safety and exposure (concentration)-response (PD-1 receptor 
occupancy) correlation data from the ongoing phase I study (CII308A101) as well as the 
preclinical in vitro/in vivo PD comparisons with drugs of the same class. 
In vivo PD studies involving SCID-Winn mice model and MC38 mice colon cancer model 
showed that the anti-tumor effect of IBI308 increased with dose, and IBI308 10 mg/kg 
significantly inhibited cancer growth. The human equivalent dose is 0.8 mg/kg. IBI308 1 mg/kg 
rapidly (24 h) saturated the peripheral PD-1 (95.8 ± 2.3%) and maintained the receptor occupancy 
with decreasing concentrations throughout the study (28d, C28d: 3.70 ± 0.15 μg/mL). Tissue 
distribution of IBI308 in cynomolgus monkeys showed that IBI308 exposure in lungs, liver, colon, 
small intestine, lymph nodes were 3.5–1/10 of its serum concentration. Given there are no 
significant changes in drug clearance, it is estimated that steady state can be reached after 84 days 
with 6 continuous doses of IBI308 200 mg Q3W. The steady-state trough concentration would be 
around 26 μg/mL and peripheral PD-1 receptor occupancy would still be maintained. The above 
data support the use of IBI308 200 mg Q3W as the treatment regimen of this study. 
Rationale for a primary endpoint analysis after the maximum of 24 weeks 
There are currently no large-scale and long-term follow-up clinical trials evaluating PD-1/PD-
L1 monoclonal antibodies for the treatment of ENKTL-NT. In the latest small-sample-size study 
of pembrolizumab for the treatment of 7 subjects with NK/T-cell lymphoma refractory to L-
asparaginase regimens, the ORR was 100%, with 5 cases of CR remained in response during a 
follow-up of 6 months [26]. Therefore, it is expected that most ORR events will be observed if the 
primary endpoint analysis is conducted after the last subject has completed up to 24 weeks of 
treatment. 
Rationale for choosing ORR as the primary endpoint 
There are currently no similar large-scale clinical trials available for reference in China or 
abroad. The ORR is 40%, CR is approximately 20% [25], and 5-year OSR is around 32% in 
subjects with relapsed/refractory ENKTL-NT with monotherapy [3, 4]. Therefore, there is a 
significant clinical need to find an effective drug for patients with ENKTL-NT. There is only one 
small-sample-size study of pembrolizumab for the treatment of 7 subjects with NK/T-cell 
lymphoma refractory to L-asparaginase regimens. The ORR was 100%, with 5 cases of CR (71%, 


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among which 2 had undetectable EBV) and 2 cases of PR (29%). The 5 subjects who achieved CR 
remained in response during a follow-up of 6 months [26]. Since it is likely that IBI308 will yield 
similar results in the relapsed/refractory ENKTL subtype, ORR is chosen as the primary endpoint 
for this study. 
Rationale for treatment after PD 
Clinical data from approved products showed that a small number of subjects receiving 
immunotherapy may benefit clinically despite of preliminary evidence of PD (based on routine 
response criteria) prior to achieving objective response and/or stable disease [27, 28]. This 
phenomenon can be explained by two possibilities. First, increased inflammation in tumors may 
lead to increase of tumor volume, manifested as elevated measurable lesions and emergence of 
new, visible, non-measurable lesions. Over time, the malignant and inflammatory parts of the mass 
may shrink, resulting in significant imaging response and improvement in clinical signs. Second, 
in some patients, the initiation of anti-tumor immune response is slow, and tumor inhibition in the 
early stages is less than the tumor growth. Over time, anti-tumor activity will dominate, giving rise 
to imaging response and improvement in clinical signs. In Checkmate 205, a reduction in tumor 
burden after continuing treatment was observed in 6 of 9 cHL subjects with PD [27]. Response 
after pseudo-progression has also been seen in subjects with renal carcinoma during treatment with 
immune checkpoint inhibitors [28]. A small--sample-size study conducted at the University of 
Hong Kong involving pembrolizumab for the treatment of ENKTL-NT also had 1 subject who 
achieved CR after pseudo-progression [26]. Thus, subjects treated with IBI308 treatment may 
continue to receive the study treatment after being initially assessed to have PD by the investigator 
according to the Lugano 2014 Criteria, provided the subject is will benefit clinically and can 
tolerate the drug (see Section 5.1.2). Subjects must discontinue the study treatment if there are 
further evidence of PD. 
4 Study Population 
Inclusion Criteria 
1. Histologically confirmed ENKL-NT. 
2. Relapsed or refractory ENKTL-NT. Being relapsed is defined as presence of new lesions at 
the primary location or other sites after achieving CR; being refractory is defined as any one 
of the followings: PD after 2 treatment cycles, PR not achieved after 4 treatment cycles, or 


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CR not achieved after 6 treatment cycles. Patients who do not response or patients with 
relapsed disease or PD after autologous stem cell transplantation can enroll. 
3. Must have been treated with asparaginase-based regimen (radiotherapy must be performed for 
stage I/II disease). 
4. Long axis of a lesion > 15 mm or 18FDG-PET uptake by lesion. 
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores of 0–2. 
6. Signed the ICFs and able to comply with the scheduled follow-up visits and related procedures 
required in the protocol. 
7. Between the ages of  ≥18 to ≤70 years. 
8. Life expectancy ≥ 12 weeks. 
9. Patients (female patients at childbearing age or male patients whose partners are at 
childbearing age) must take effective contraceptive measures during the entire course of the 
trial and within 90 days since the last dose of treatment (see Section 4.3). 
10. Adequate organs and bone marrow functions, as defined below: 
 
Count of whole blood cells: absolute neutrophil count (ANC) ≥ 1.0 × 10 9/L, platelets 
(PLTs) count ≥ 50 × 109/L, hemoglobin (HGB) ≥ 8.0 g/L; granulocyte colony-
stimulating factor, PLT, or red blood cell (RBC) transfusion has not been performed 
within 7 days prior to the test. 
 
Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.  
 
Renal function:serum creatinine (Cr) ≤ 1.5 × ULN.  
 
Thyroid function: normal thyroid stimulating hormone (TSH) at baseline, or abnormal 
TSH at baseline with normal T3/T4 and no symptoms. 
Exclusion Criteria 
1. Patients with aggressive NK cell leukemia. 
2. Patients with primary or secondary central nervous system (CNS) lymphoma. 
3. Patients with severe hemophagocytic syndrome at initial diagnosis of ENKTL-NT. 
4. Patients with pulmonary great vessel invasion. 
5. Previous exposure to any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies. 


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6. Enrolled in another interventional clinical study, unless only involved in an observational 
study (non-interventional) or in the follow-up phase of an interventional study. 
7. Received any investigational drug within 4 weeks prior to the first dose of study treatment. 
8. The last dose of radiation or anti-tumor therapy (chemotherapy, targeted therapy, or tumor 
embolization) was within 3 weeks prior to receiving the first dose of study treatment; the last 
dose of nitrosourea or mitomycin C treatment was within 6 weeks prior to receiving the first 
dose of study treatment. 
9. Received immunosuppressants within 4 weeks prior to the first dose of study treatment, 
excluding local glucocorticoids administered by nasal, inhaled, or other topical routes, or 
systemic glucocorticoids of physiological doses (no more than 10 mg/day of prednisone or 
equivalents). 
10. Received any live attenuated vaccine within 4 weeks prior to the first dose of study treatment, 
or is scheduled to receive live attenuated vaccine during the study period. 
11. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the 
first dose of study treatment, or has unhealed wounds, ulcers, or fractures. 
12. Active, known, or suspected autoimmune disease (see Appendix 6) or previous medical 
history of these diseases within 2 years (patients with vitiligo, psoriasis, alopecia, or Graves' 
disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, 
or type I diabetes only requiring insulin can enroll). 
13. Known history of primary immunodeficiency diseases. 
14. Known active pulmonary tuberculosis. 
15. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell 
transplantation. 
16. Known to be allergic to any ingredients of monoclonal antibodies. 
17. Uncontrolled concurrent diseases including but not limited to: 
 
HIV-infected patients (positive anti-HIV antibody). 
 
Active or poorly controlled severe infections. 
 
Symptomatic congestive heart failure (NYHA Class III-IV) or symptomatic or poorly 
controlled arrhythmia. 
 
Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) despite of standard treatment. 


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 
Any arterial thromboembolic events occurred within 6 months prior to enrollment, 
including myocardial infarction, unstable angina, cerebrovascular accident, or transient 
cerebral ischemic attack. 
 
Life-threatening hemorrhagic events or grade 3–4 gastrointestinal /variceal hem
orrhage requiring blood transfusion, endoscopy, or surgical treatment within 3 
months prior to enrollment. 
 
History of deep venous thrombosis, pulmonary embolism, or other serious 
thromboembolic events within 3 months prior to enrollment (implantable port or 
catheter-related thrombosis, or superficial venous thrombosis are not considered as 
serious thromboembolisms). 
 
Uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or 
cancer-related secondary diseases that may lead to higher medical risks and/or survival 
evaluation uncertainties. 
 
Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh grade B 
or C. 
 
Bowel obstruction or history of the following diseases: inflammatory bowel disease or 
extensive bowel resection (partial colectomy or extensive small bowel resection 
accompanied with chronic diarrhea), Crohn's disease, and ulcerative colitis. 
 
Acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that may 
lead to the following consequences: increased investigational drug-related risks, or 
interference with interpreting trial results, and considered ineligible for participating in 
the trial by the investigators. 
18. Known cute or chronic active hepatitis B (chronic HBV carriers or inactive HBsAg-positive 
patients can enroll if the HBV DNA < 1 × 10 3 copies/mL), or acute or chronic active hepatitis 
C (patients with negative HCV antibody can enroll; HCV RNA test is required for patients 
with positive HCV antibody, those test negative can enroll). 
19. History of GI perforation and/or fistula without radical treatment within 6 months prior to the 
enrollment. 
20. Known interstitial lung disease. 
21. Clinically uncontrollable third spacing, such as pleural effusion and ascites that cannot be 
controlled by drainage or other methods prior to enrollment. 


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22. History of other primary malignant tumors, excluding: 
 
History of radical treatment for malignant tumors with no evidence of tumor recurrence 
for more than 5 years prior to enrollment and with a very low risk of recurrence; 
 
Adequately treated nonmelanoma skin cancer or lentigo maligna with no signs of 
disease recurrence; 
 
Adequately treated carcinoma in situ with no signs of disease recurrence. 
23. Pregnant or breastfeeding female patients. 
Restrictions During the Study 
For women of childbearing potential who are sexually active with male partners who have 
not undergone surgical sterilization, the subjects must use 1 acceptable and effective methods of 
contraception (see Table 2) starting from the screening, and agree to continue these measures 
during the 90 days since the last dose of study treatment. Besides, the subjects shall discuss with 
a responsible physician about the discontinuation of contraception after this time point. Periodic 
abstinence, calendar-based method, and withdrawal method are not the acceptable forms of 
contraception. 
Women of childbearing potential is defined as any female who has not undergone surgical 
sterilization (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or is not 
postmenopausal (defined as 12 months of amenorrhea without alternative medical causes).  
Menopause is defined as 12 months of amenorrhea of a woman without any other medical 
reasons. Age requirement are as follows: 
 
Females ≥50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, and luteinizing hormone and follicle stimulating hormone 
levels within the postmenopausal range, are considered menopausal; 
 
Females < 50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, radiation-induced ovariectomy and the time from the last 
menorrhea > 1 year, chemotherapy-induced amenorrhea and the time from the last 
menorrhea > 1 year, or surgical sterilization (bilateral ovariectomy or hysterectomy), are 
considered menopausal. 
Table 2. Effective methods of contraception (one of the followings must be used) 
Barrier Method 
Intrauterine Devices (IUDs) 
Hormonal Methods 
Male condom with spermicide 
Copper-T IUD 
Implant 


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Barrier Method 
Intrauterine Devices (IUDs) 
Hormonal Methods 
Cervical cap with spermicide 
Progesterone-T IUDa 
Hormonal injection 
Diaphragm with spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g. Mirena®)a 
Combined oral contraceptive pill 
Low-dose oral contraceptive pill 
Contraceptive patch 
aAlso considered as a hormonal method. 
Treatment Discontinuation/Withdrawal from the study  
Subjects should discontinue treatment/withdrawal from the study in any of the following 
circumstances: 
1. Subjects do not meet the inclusion/exclusion criteria, and are deemed unsuitable to 
continue in this study by the sponsor and investigator. 
2. Subjects seriously violate the study protocol, and deemed unsuitable to continue in this 
study by the sponsor and investigator. 
3. Subjects are enrolled in another clinical trial that is considered scientifically or 
medically incompatible with this study. 
4. Subjects are lost to follow-up (study site personnel shall regain contact with the 
subjects to determine the cause of loss to follow-up and reschedule study visits if 
possible. The date and method of contact shall be documented in the study documents). 
5. Decided by the investigator 
 
Subjects should discontinue the treatment or withdraw from the study based on the 
safety and benefits of the subjects. 
 
If the subjects require treatment with another drug for any reason, and the drug has 
been demonstrated to be effective for the indication of this study, then the subject 
shall withdraw from this study prior to starting the new drug. 
 
PD is developed or the investigator believes that continuing with study treatment is 
not appropriate. 
 
A life-threatening event that is treatment-related occurred, regardless of the severity of 
the event. 
 
The investigational drug shall be discontinued due to toxicities (see Section 5.4). 
6. Subjects or their representatives (such as parents or legal guardians) requests to 
withdrawal from the study or discontinue the investigational drug (subjects may be 


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eligible for long-term follow-up if he/she withdraws ICF for treatment but not for 
follow-up). 
7. The sponsor may terminate the study or discontinue a subject from participating in the 
study due to medical, safety, regulatory, or other reasons related to the applicable laws, 
regulations, and Good Clinical Practice (GCP). 
8. Subjects who delay the treatment for 6 weeks due to adverse reactions shall withdraw 
from the study. 
9. Subjects may withdraw from the study if the investigator believes that the local lesions 
should also be treated with radiation or other therapies after the subject reaches the 
primary endpoint. 
The reasons and dates of discontinuation for all the subjects shall be documented. Subjects 
who discontinue the treatment shall undergo other study procedures as specified in the schedule of 
visits. 
5 Investigational Drug and Other Treatments 
Treatment Regimen 
Treatment Regimen 
The investigational drug is IBI308, given at the dose of 200mg IV Q3W up to 24 months until 
PD, death, intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol. Other 
drugs used in this study are non- investigational drugs. 
Continuing Treatment After PD 
During the treatment with IBI308, if subjects must meet all of the following criteria, he/she 
couldcontinueto receive IBI308 after initial PD (first PD): 
1. 
The investigator believes that continuing treatment may yield clinical benefits, and 
the disease is not progressing rapidly; 
2. 
Subjects are able to the tolerate investigational drug; 
3. 
Stable ECOG PS score; 
4. 
The treatment of serious complications requiring urgent interventions (such as CNS 
metastasis)could be managed on time; 
5. 
Before continuing treatment with IBI308, subjects must be fully informed and the 
investigator must elucidate the foreseeable risks or discomforts and alternative 
treatments. 


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If the above criteria are met, the investigator and sponsor's medical manager will decided 
whether the subjects shall continue the treatment after PD, and document in the study records. 
Data from subjects who continue IBI308 treatment after initial PD shall be collected. Refer 
to Table 1 for collection of data variables. 
If the subjects continue to receive the investigational drug, imaging evaluation shall also be 
continued at the specified interval. Treatment is continued up to 24 months until further PD, death, 
intolerable toxicity, withdrawal of ICF, or other reasons stated in the protocol. 
For subjects who continue IBI308 treatment after initial PD, treatment shall be discontinued 
if clinical symptoms worsen, even if there are no imaging evidence of further PD. It should be 
documented as "exacerbation of clinical symptoms". 
Investigational Drug (IBI308) 
Description 
The investigational drug is a recombinant fully human anti-PD-1 monoclonal antibody 
injection, IBI308. 
The main active ingredient of IBI308 is the recombinant fully human anti-PD-1 monoclonal 
antibody. The strength of IBI308 is 10 ml: 100 mg. IBI308 does not contain any preservatives. 
The concentration is 10 mg/mL, with excipients including 140 mmol/L mannitol, 25 mmol/L 
histidine, 20 mmol/L sdihydrate sodium citrate, 50 mmol/L sodium chloride, 0.02 mmol/L 
disodium edetate (ethylenediaminetetraacetic acid disodium salt), and 0.2 mg/mL polysorbate 80, 
pH 6.0. 
This product is a clear, colorless liquid, no foreign matter, flocs, and precipitation. 
Manufactured by: Innovent Biologics (Suzhou) Co., Ltd.. 
Labels 
The smallest packaging unit is a box. Each box contains two vials of IBI308 injection. The 
package label shoude contains the drug name, medication number, dosage form, strengths, drug 
code, batch number, expiration date, storage conditions, dosage and administration, precautions, 
and sponsor's information. The label on the vial contains the same information as the outer package 
except for dosage form and precautions. The package and vial shall be both labeled "use for clinical 
study only".  


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Storage 
Store at 2–8℃away from light. The shelf life is 24 months. If quality issues such as turbidity 
and precipitation are observed in the injection, seal the vial immediately and notify the sponsor. 
Preparation and administration 
The preparation and administration of IBI308 is as follows: 
1. Completely draw the contents of two vials of IBI308 injection and transfer them into a 100-
mL IV infusion bag containing 0.9% (w/v) sterile sodium chloride solution, then document the 
start time of the preparation. 
2. Gently invert the infusion bag to mix the solution, ensuring the uniformity of the contents. 
Do not violent shake t to avoid foam. 
3. Administer with a 0.2–1.2 μm in-line filter (suggested infusion time is around 30~60 min). 
Document the start and stop time of infusion. 
Note: For each dose infusions, do not mix the drugs of different batches; make sure that the 
IBI308 injection is clear without any quality issues such as turbidity or precipitation. Make sure 
that the time from drawing IBI308 from the first vial to the end of infusion is no more than 24 
hours (storage conditions for the prepared solution is at 2–8 ℃ in the fridge or at the room 
temperature/under the light). Avoid mixing with other drugs. Do not administer as an IV bolus. 
Administration Adjustments of Investigational Drug 
General principles 
 
The subject's hematologic, hepatic, and renal function must meet the requirements for 
administration of study treatment prior to each dose. All the toxicities must resolve to 
NCI CTCAE v4.03 grade 0–1 or baseline levels (excluding alopecia, fatigue, etc.). 
 
Reasons for administration adjustments and actual changes shall be documented in the 
original medical records and electronic case report forms (Electronic case report form ，
eCRFs). 
Administration adjustments of IBI308 
Dose adjustments of IBI308 are not permitted throughout the trial. Refer to the following 
table for administration adjustments of IBI308 (only for AEs related to IBI308 as determined by 
the investigator). 
Table 3. Administration adjustments of IBI308 


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AEs 
Severity 
Administration 
Adjustments 
Pneumonitis 
Grade 2 pneumonitis 
Interrupta 
Grade 3 or 4 pneumonitis 
Permanently 
discontinue 
Diarrhea or 
Enterocolitis 
Grade 2 or 3 diarrhea or enterocolitis 
Interrupta 
Grade 4 diarrhea or enterocolitis 
Permanently 
discontinue 
Dermatitis 
Grade 3 dermatitis 
Interrupta 
Grade 4 dermatitis 
Permanently 
discontinue 
Hepatitis 
Grade 2 AST, ALT, or TBIL elevation for subjects with normal AST, 
ALT or TBIL at baseline; AST, ALT, or TBIL elevation of ≥ 50% 
for < 7 days for subjects with AST, ALT, or TBIL > ULN at baseline 
Interrupta 
Grade 3 or 4 AST, ALT, or TBIL elevation for subjects with normal 
AST, ALT or TBIL at baseline; AST, ALT, or TBIL elevation of ≥ 
50% for ≥ 7 days for subjects with AST, ALT, or TBIL > ULN at 
baseline 
Permanently 
discontinue 
Hypophysitis 
Grade 2 hypophysitis 
Interruptb 
Grade 3 or 4 hypophysitis 
Permanently 
discontinue 
Adrenocortical 
insufficiency 
Grade 2 adrenocortical insufficiency 
Interruptb 
Grade 3 or 4 adrenocortical insufficiency 
Permanently 
discontinue 
Hyperthyroidism 
Grade 3 or 4 hyperthyroidism 
Permanently 
discontinue 
Type I Diabetes 
Grade 3 hyperglycemia 
Interruptb 
Grade 4 hyperglycemia 
Permanently 
discontinue 
Renal 
insufficiency 
Grade 2 or 3 Cr elevation 
Interrupta 
Grade 4 Cr elevation 
Permanently 
discontinue 
Neurotoxicity 
Grade 2 neurotoxicity 
Interrupta 


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AEs 
Severity 
Administration 
Adjustments 
Grade 3 or 4 neurotoxicity 
Permanently 
discontinue 
Infusion 
Reactions 
Grade 3 or 4 infusion reaction 
Permanently 
discontinue 
Other AEs 
First occurrence of other grade 3 AEs 
Interrupta 
Second occurrence of other grade 3 AEs 
Permanently 
discontinue 
Grade 3 AE that cannot resolve to grade 0–2/baseline levels within 7 
days or grade 0–1/baseline levels within 14 days 
Permanently 
discontinue 
Grade 4 AE 
Permanently 
discontinuec 
a: Resume the investigational drug after symptoms resolve to grade 0–1 or baseline levels. 
b: Resume the investigational drug if hypophysitis, adrenocortical insufficiency, or type I diabetes is 
adequately controlled and require only physiological hormone replacement. 
c: For grade 4 laboratory abnormalities, the event shall be determined based on clinical signs/symptoms and 
the clinical judgment of the investigator. 
Investigational drug is allowed to be interrupted for up to 6 weeks. If the symptoms do not 
resolve within 6 weeks and treatment cannot be resumed, the subject must permanently discontinue 
IBI308 treatment and enter the follow-up phase of the study. Except for the following two cases: 
 
IBI308 interruption > 6 weeks due to glucocorticoid reduction for irAEs: Consult the 
sponsor's medical manager prior to resuming IBI308. Tumor imaging evaluation for 
efficacy shall not be affected by treatment interruption and will be performed as scheduled. 
 
IBI308 interruption > 6 weeks due to AEs possibly related or unrelated to IBI308: Consult 
the sponsor's medical manager prior to resuming IBI308. Tumor imaging evaluation for 
efficacy shall not be affected by treatment interruption and will be performed as scheduled. 
Principles of Managing Immune Checkpoint Inhibitor Toxicities 
The mechanism of action of IBI308 is to stimulate T-cell activation and proliferation. The 
result is an immune hyperfunction leading to autoimmune disease involving multiple systems. 
Autoimmune AEs such as immune-related pneumonitis, diarrhea/enterocolitis, renal insufficiency, 
rash, hepatitis, endocrine disorders, and peripheral or central neuritis have been observed with the 
clinical application of other immune checkpoint inhibitors including ipilimumab, nivolumab, 


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pembrolizumab, and atezolizumab. If subjects experience the AEs described above, the signs and 
symptoms shall be monitored, relevant examinations shall be performed, and the cause shall be 
identified. If an alternative cause is not found (such as PD, concomitant medications, or infections) 
and glucocorticoids and/or other immunosuppressants are required, then any AE described above 
is considered related to IBI308-induced immune hyperfunction, and should be diagnosed as an 
irAE (except for endocrine events such as hyperthyroidism/hypothyroidism, hypophysitis, type I 
diabetes, and adrenal insufficiency which may not require immunosuppressants but are still 
considered as immune hyperfunction related to IBI308). 
See Appendix 7 for dose adjustments and toxicity management of major potential irAEs, 
other potential irAEs, and infusion reactions. 
Concomitant Treatments 
Prohibited treatments 
 Other anti-tumor therapy (except for palliative radiotherapy), chemotherapy, 
immunotherapy, targeted therapy, or hormone therapy. 
 Immunosuppressants and high-dose glucocorticoids (except for treatments of AEs at a 
dose of no more than 10 mg daily prednisone or equivalents). 
 Immunoglobulins. 
 Live attenuated vaccine. 
 Autologous hematopoietic stem cell transplantation. 
Permitted treatments 
 Medications that meet the protocol requirements, as determined by the investigator (e.g. 
concomitant medication used for disease-related symptoms and treatment-related AEs). 
 
Long-term medication for underlying diseases such as high blood pressure and diabetes.. 
 Supportive care for relieving tumor-related symptoms. 
 Use of topical, such as dermal, ocular, nasal, and inhaled, corticosteroids. 
Drug-drug interactions 
 IBI308: No interaction information is currently available. 
Treatment Compliance  
Study treatment is given at the study sites. Treatment compliance is monitored by medication 
dispensing and return records, medical records, and eCRFs. 


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Medication Return and Destruction 
The packages and vials of used or partially used investigational drugs for this study shall be 
verified by the Clinical Research Associate (CRA) and returned to the sponsor for destruction. 
Arrangements for the return of investigational drug will be made by the designated CRA. 
Upon the completion or discontinuation of the study, all unused or expired investigational 
drugs must be returned to the sponsor for destruction. Arrangements for the return of 
investigational drug will be made by the designated CRA. 
Investigational Drug Records 
The designee of the study sites shall make timely records of receiving, dispensing, using, 
storing, returning, and destroying the study drugs in accordance with the relevant regulations and 
guidelines and the operation requirements of this study. 
Complaint Handling  
To ensure the safety and proper monitoring of the subjects and facilitate the improvement of 
trial process and drug product, the sponsor will collect complaints related to the investigational 
drug. 
Complaints regarding concomitant medications will be directed to the manufacturer 
according to the prescribing information of the drugs. 
The investigator or designee must complete the following procedures for product complaints 
in accordance with applicable requirements of the study: 
 
A drug complaint form specific for clinical trials will be used to document product 
complaints and relevant description completely. 
 
The completed product complaint form shall be submitted to the sponsor or designee by 
fax within 24 hours. 
If the investigator is asked to return the product for further investigation, the investigator shall 
return the product along with a copy of the complaint form. 
6 Study Evaluations and Relevant Procedures 
Subject Enrollment 
Subject enrollment 
The investigator will enroll subjects by the following steps: 
1. Obtain the ICF signed by the subjects prior to any study-related procedures. 


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2. Confirm the subjects' eligibility by the principal investigator or trained designee after 
reviewing the inclusion/exclusion criteria. 
3. Prior to enrollment, the trained designee must mail the subjects' medical information 
including those regarding the inclusion/exclusion to the sponsor's medical manager for 
review. The subject can only be enrolled after confirmation by the sponsor's medical 
manager. 
Subjects who do not meet the criteria (screen failures) may be re-screened. If re-screening is 
considered, the investigator must contact the sponsor's medical manager. Each subject can be re-
screened once. The subject must sign the ICF again and receive a new identification number when 
re-screening. 
Enrollment error handling 
The inclusion/exclusion criteria must be followed strictly. If an ineligible subject is enrolled, 
the sponsor's medical manager and investigator must discuss whether to allow the subject to 
continue participating in the study and whether to use the investigational drug. If the subject is 
appropriate medically to continue with the study judged by the investigator, which is also agreed 
with by the sponsor's medical manager, then the subject will continue participating in the study 
and receive the investigational drug; if the subject is appropriate medically to continue with the 
study judged by the investigator,, which is not agreed with by the sponsor's medical manager, then 
the subject shall not continue participating in the study (regardless of receiving the investigational 
drug or not). The investigator must not allow the improperly enrolled subject to continue with the 
study until receive the written approval from the sponsor. 
Study Plan and Schedule 
Screening 
The following procedures must be completed during the screening (Day -28 to -1) to ensure 
subject eligibility: 
 
Signing of the ICF 
 
Confirming the inclusion/exclusion criteria 
 
Recording the demographics, medical history, and prior medications 
 
Recording the vital signs, height and weight.  
 
Physical examination 
 
ECOG PS score 


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 
12-lead ECG 
 
Count of whole blood cells/blood biochemistry/routine urinalysis (within 7 days prior to 
the first dose) 
 
Pregnancy test (within 3 days prior to the first dose) 
 
Thyroid function 
 
HIV antibody, hepatitis B panel, HCV antibody (patients testing positive for HCV 
antibody shall also be tested for HCV RNA) 
 
EBV DNA copy number in peripheral blood 
 
AE evaluation 
 
Concomitant medication 
 
Bone marrow biopsy 
 
Tumor imaging evaluation (PET-CT and contrast-enhanced CT) 
 
Archival or fresh tumor tissue sample 
Refer to Table 1 for schedule of visits during screening. 
Refer to Sections 6.3 and 6.4 for details regarding tumor evaluation and safety evaluation. 
Baseline (prior to Day 1 of Cycle 1) 
 
Recording the vital signs□ 
 
ECOG PS score□ 
 
Immunogenicity 
 
AE evaluation 
 
Concomitant medication 
 
Disease-related symptom evaluation 
 
EQ-5D-5L and EORTC QLQ-C30 
 
Blood sampling for biomarkers 
Treatment period 
 
Recording the vital signs 
 
Physical examination 
 
ECOG PS score 
 
12-lead ECG 
 
Count of whole blood cells/blood biochemistry/routine urinalysis 
 
Thyroid function 


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 
EBV DNA copy number in peripheral blood 
 
Immunogenicity 
 
AE evaluation 
 
Concomitant medication 
 
Tumor imaging evaluation 
 
Bone marrow biopsy: repeat the bone marrow biopsy if the imaging shows CR 
 
Tumor biopsy: perform a tumor biopsy if clinically indicated 
 
Disease-related symptom evaluation 
 
Investigational drug administration 
 
Blood sampling for biomarkers 
 
EQ-5D-5L and EORTC QLQ-C30 
Refer to Table 1 for schedule of visits during treatment. 
Refer to Sections 6.3, 6.4, and 6.5 for details regarding tumor evaluation, safety evaluation, 
blood sampling for immunogenicity. 
End-of-treatment visit 
If the treatment ends or the investigational drug is discontinued prematurely for any reasons, 
an end-of-treatment visit shall be carried out as soon as possible after the investigational drug is 
discontinued and before the subject receives new anti-tumor therapy. The visit shall include the 
followings: 
 
Recording the vital signs and weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead ECG 
 
Count of whole blood cells/blood biochemistry/routine urinalysis 
 
EBV DNA copy number in peripheral blood 
 
Thyroid function 
 
Pregnancy test 
 
AE evaluation 
 
Concomitant medication 
 
PET-CT (if applicable) 
 
EQ-5D-5L and EORTC QLQ-C30 


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Safety follow-up 
The safety follow-up should be performed on 90 ± 7 days after the last dose or before 
initiation of a new anti-tumor therapy (whichever comes first). Subjects with drug-related AEs that 
result in treatment discontinuation will be followed up until the AE resolves to grade 0 or 1, 
symptoms are stable, subject withdraws ICF, or a new anti-tumor therapy is started (whichever 
comes first). 
 
Vital signs 
 
Count of whole blood cells/blood biochemistry/routine urinalysis 
 
Thyroid function 
 
AE evaluation 
 
Immunogenicity 
 
Concomitant medication 
Survival Follow-Up 
After completing the safety follow-up, the subject shall be contacted with (telephone visits is 
allowed) once 60 days (± 7 days) to obtain the survival information, any subsequent systemic anti -
tumor therapy, and PD information (for subjects with no imaging PD). Long-term follow-up shall 
be continued until death or end of study. 
Imaging Evaluation 
Baseline evaluation is conducted within 28 days prior to the first dose of the study treatment. 
The investigator can evaluate the imaging results within 28 days prior to the enrollment. 
PET-CT and contrast-enhanced CT will be used (MRI will be performed for subjects allergic 
to CT contrast media). PET-CT shall be performed at baseline, week 6 (± 7 days), week 15 (± 7 
days), and week 24 (± 7 days). PET -CT evaluation shall be performed at the end of treatment for 
subjects who discontinue the treatment prematurely prior to week 24 (unless the previous PET-CT 
scan is done within the past month). Contrast-enhanced CT shall be performed at baseline, week 
24 (± 7 days), every 12 weeks (± 14 days) after 24 weeks, and every 24 weeks (± 14 days) after 
48 weeks initiation of new anti-tumor therapy, PD, withdrawal of ICF, or death.  Unplanned PET-
CT and contrast-enhanced CT shall be added to evaluate the efficacy when investigators deem 
appropriate, if the subjects agree. The examinations will be taken at sponsor’s expense. First PD 
shall be confirmed after 4–6 weeks. For subject who discontinue the treatment for reasons other 


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than PD, tumor imaging evaluation shall be continued according to the study protocol until 
initiation of new anti-tumor therapy, PD, withdrawal of ICF, or death. 
Imaging data shall be copied or saved according to the requirements of the sponsor. 
Safety Evaluation 
Routine laboratory safety evaluations 
Table 4. Routine laboratory safety evaluations 
Count of Whole Blood Cells 
RBC, HGB, WBC, PLT, LYM, and ANC 
Blood Biochemistry 
TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, BUN, Cr, Na, K, Cl, Mg, 
Ca, P, lipase, amylase, and FBG 
Routine Urinalysis 
PH, UALB, UPRO, URBC, and UGLU 
Physical examination 
A comprehensive physical exam includes general conditions, respiratory tract, cardiovascular 
system, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, 
thyroid, musculoskeletal system (including spine and limbs), genitalia/anus, and nervous system. 
Refer to the schedule of visits in Table 1 for examination time. Refer to Appendix 2 for ECOG 
PS criteria. 
12-lead ECG 
A resting 12-lead ECG is performed at the local laboratory in accordance with the schedule 
of visits in Table 1.  
 A 12-lead ECG examination will be performed after the subject rested for at least 5 minutes 
in the supine position. All 12-lead ECGs should be recorded while the subject is resting in a supine 
position. Further ECG shall be performed if clinically indicated, such as a cardiac AE. The 
investigator shall review the ECG on the day it is performed, and document the results on the ECG. 
The same method of evaluation shall be used throughout the trial. 
The investigator shall evaluate all the ECG as either a clinically significant/insignificant 
abnormality. If it is a clinically significant abnormality, the investigator shall document the results 
as an AE in the eCRF. 
Vital signs 
Vital signs are examined in accordance with the schedule of visits in Table 1, including body 
temperature, pulse, respiratory rate, and blood pressure. 


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Additional monitoring of vital signs is allowed based on standard clinical practice or clinical 
need,and shall be documented in the eCRF when an AE/SAE occurs (if applicable).  
The time and date of measurement shall be documented in the appropriate section of the eCRF. 
6.4.4.1 Pulse and blood pressure 
The subject's blood pressure and pulse in the supine position is measured after rest for at least 
5 minutes. Two or more readings shall be done with 2-minute intervals and the readings shall be 
averaged. If the first two systolic blood pressure readings differ by more than 5 mmHg, measure 
again and average the readings. The time and date of measurement shall be documented in the 
appropriate section of the eCRF. 
Pulse and blood pressure shall be measured prior to the administration of investigational drug. 
6.4.4.2 Body temperature and respiratory rate 
Collect the body temperature and respiratory rate prior to the infusion on the scheduled 
administration day. 
Weight and height 
Height is only measured during screening. Weight is measured during screening and at the 
end of treatment. 
Pregnancy test 
Urine or serum β human chorionic gonadotropin (β-HCG) pregnancy test must be performed 
in women of childbearing potential (refer to Section 4.3 for definition) within 3 days prior to the 
first dose of study treatment. If the result of urine β-HCG is positive or inconclusive, then serum 
β-hCG pregnancy test shall be performed. The conclusion shall be based on the serum pregnancy 
test. If the β-hCG result is positive, the subject is not eligible or must discontinue participating in 
the study. A repeated test shall be performed if pregnancy is suspected during the study. 
Other safety examinations include the followings: 
 
Hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb). 
 
HIV antibody, HCV antibody (if the result shows HCV antibody positive, then HCV RNA 
test shall be further conducted). 
 
Thyroid function: T3, T4, TSH, FT3, and FT4. T3, T4, FT3, FT4, and TSH shall be 
tested during screening and prior to the administration of IBI308 from Cycle 2 
onwards. 


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Immunogenicity 
Immunogenicity assays will be carried out within 1 hour prior to IBI308 administration in 
Cycles 1, 2, 4 and then every 4 cycles thereafter (Cycle 8, 12, 16, and so on), and during safety 
follow-up. Tests shall be conducted at the central laboratory. 
Anti-drug antibody (ADA) titer shall be tested for each subject. ADA-positive specimens 
shall be further tested for neutralizing antibodies (NAbs). 
For ADA and NAb assays, 4 mL of whole blood is collected using vacutainers with clot 
activator. Serum is then separated, dispensed in aliquots, and frozen. 
Refer to the Laboratory Manual provided by the sponsor-designated central laboratory for 
sampling methods, sample storage, transport, and analysis. 
Quality of Life Evaluation 
Quality of life evaluation will be performed on the day of the first dose, during each imaging 
evaluation, and during the end-of-treatment visit as per EQ 5D-5L and EORTC QLQ-C30. 
EQ-5D-5L is a standardized tool used for patients to self-report their health status. Subjects 
will fill out a questionnaire that consists of 5 levels (no problems, slight problems, moderate 
problems, severe problems, and extreme problems) and 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression). A single EQ-5D health status is defined after 
combining the different levels of all 5 dimensions. In addition, subjects will mark on a visual 
analog scale (VAS) for their health status, which ranges from 0 (the imaginable worse state) to 100 
(the best imaginable state). 
The EORTC QLQ-C30 is a core questionnaire for patients with cancer consisting of 30 items 
which are divided into 15 scales: 5 functional scales (physical, role, cognitive, emotional, and 
social function), 3 symptom scales (fatigue, pain, and nausea/vomiting), 1 global health 
status/quality of life scale, and 6 single item scales. 
Biomarker analysis  
If permitted by the EC, all the eligible subjects must provide tumor tissue during screening. 
Acceptable tumor tissue include 8–10 unstained sections (4–5 μm) of archival specimen or fresh 
specimens for evaluations of PD-L1 expression, RNA expression and number of TIL. 
EBV DNA copy number in plasma and peripheral blood lymphocytes shall be tested on the 
day of IBI308 administration in each cycle, with 4 mL of blood collected each time, until the end 
of study treatment. Tests shall be conducted at the central laboratory. According to the changes of 


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patients’ condition and the needs of efficacy evaluation, EBV DNA test may be added by 
investigators at the centre.Ten mL whole blood samples are required to be provided by subjects for 
molecular tumor testing at the following time points: during screening, during efficacy evaluation 
but before the next treatment, and when PD is confirmed. The followings may be tested to predict 
anti-PD-1 treatment efficacy and prognosis of subjects: lymphocyte (T cell and NK cell) 
phenotyping and immune-related cytokines (TNF-α, IL-6, IL-15, soluble PD-L1 et al.) in different 
subtypes. 
Refer to Laboratory Manual for details regarding sample processing, handling, and transport. 
Storage and Destruction of Biological Samples 
Samples will be disposed or destroyed, pooled and anonymized. Additional analyses of 
pooled and anonymized samples may be performed to further evaluate and validate the analytical 
method. Results of these analyses may be published separately from the Clinical Study Report 
(CSR). 
Reproducibility (if performed) will be assessed simultaneously with the biological analysis 
of the samples. The results of these evaluations will not be published in the clinical study report, 
but will be presented separately in a biological analysis report. 
7 Safety Reports and AE Management 
Definition of AEs 
An AE is defined as any adverse medical event that occurs after the signing of the informed 
consent form within 90 days since the last dose of the study treatment, regardless of whether or 
not considered as related to the study drugs. AEs include but are not limited to the followings: 
 
Worsening of pre-existing (prior to enrollment) medical conditions/diseases (including 
symptoms, signs, and laboratory abnormalities); 
 
Any new adverse medical conditions (including symptoms, signs, and newly diagnosed 
diseases); 
 
Clinically significant laboratory abnormalities.  
Definition of SAEs 
An SAE refers to an AE meeting at least one of the followings: 
 
Results in death, except for death caused by PD. 


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 
Life-threatening (a life-threatening event is defined as an AE when the subject is at 
immediate risk of death at the time, but does not include the one that may lead to death 
only when the event worsens). 
 
Requires hospitalization or prolonged hospitalization, excluding the followings: 
 Hospitalization at a rehabilitation institution 
 Hospitalization at a sanatorium 
 General emergency admission 
 Day surgery (e.g. outpatient/same-day/ambulatory surgery) 
 Hospitalizations or prolonged hospitalizations unrelated to worsening of an AE are 
not considered as an SAE. For example: hospitalization due to pre-existing disease, 
without new AEs and exacerbation of pre-existing disease (e.g. hospitalization to 
examine laboratory abnormalities that have been persistent before the study starts); 
hospitalization for administrative reasons (e.g. annual routine physical examinations); 
hospitalizations during the study as specified in the protocol (e.g. hospitalization 
performed in accordance study protocol); elective hospitalization unrelated to 
worsening of AEs (e.g. elective surgery); scheduled treatment or surgical procedures, 
which shall be documented in the entire study protocol and/or individual subject's 
baseline information; and hospitalization merely due to the use of blood products. 
 
Results in permanent or serious disability/incapacity. 
 
Results in congenital anomalies/birth defects 
 
Other important medical events: defined as events that may jeopardize the subjects and 
require medical or surgical interventions to prevent one of the other outcomes listed in 
the definition above. 
AE Severity Grading Scale 
The severity of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03. 
For adverse event terms not included in NCI CTCAE version 4.03, graded according to the 
following CTCAE classification principles: 
 
Grade 1 Mild; asymptomatic or mild sings; clinical or diagnostic observations only; 
medical intervention not indicated. 


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 
Grade 2 Moderate; minimal, local or non-invasive intervention required; limiting age-
appropriate instrumental activities of daily living (e.g., cooking, shopping, using the 
telephone and managing money, etc.). 
 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolonged hospitalization indicated; disabling; limiting self-care 
activities of daily life (e.g. bathing, dressing and undressing, feeding self, using the 
toilet, and taking medications), but not bedridden. 
 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
 
Grade 5 Death related to AE. 
Correlation Between AEs and Investigational Drug 
The relationship between the investigational drug and AEs can be determined using the 
followings: 
Table 5. Correlation determination between AEs and investigational drug 
Correlation 
Criteria 
Definitely 
Related 
 
The AE occurrence has a reasonable time relationship with administration time; 
 
The investigational drug can more reasonably explain the AE than the other causes 
(such as concurrent disease, environment, toxicity, or other treatment received); 
 
The AE resolves or is alleviated after treatment interruption or dose reduction; 
 
The event meets the recognized pharmacological AE type; 
 
The AE does not occur after re-administration. 
Probably 
Related 
 
The AE occurrence has a reasonable time relationship with administration time; 
 
The investigational drug provide more reasonable explanations on the AE than the other 
causes (such as concurrent disease, environment, toxicity, or other treatment received); 
 
The AE resolves or is alleviated after treatment interruption or dose reduction (if 
applicable); 
Probably 
Unrelated 
 
Other causes provide more reasonable explanations on the AE than the investigational 
drug (such as concurrent disease, environment, toxicity, or other treatment received); 
 
The AE does not resolve or be alleviated after treatment interruption or dose reduction 
(if applicable), or the situation is unclear; 
 
The AE does not occur after re-administration or the situation is unclear. 
Definitely 
Unrelated 
 
The AE occurrence has no reasonable time relationship with administration time, or 
 
Other causes provide evident explanations (such as concurrent disease, environmental, 
toxicity, or other treatment received by the subject). 


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Correlation 
Criteria 
Unable to 
Determine 
 
The above information is unclear and the AE cannot be determined based on the 
available information. Further follow-up information is not accessible to the 
investigator. 
Recording of AEs 
The investigator shall document AEs and SAEs using medical terms and concepts. Avoid 
colloquialisms/abbreviations. All the AEs (including SAEs) shall be documented on the AE forms 
in the eCRFs. 
Collection and time of AEs 
The investigator shall use non-leading questions when asking the subjects about AEs. 
All the AEs, including SAE, that occur after the signing of the ICF within 90 days since the 
last dose shall be collected, regardless of whether it is observed by the investigator or self-reported 
by the subject. 
Within 90 days since the last dose, if the subjects receive other anti-tumor therapy, any AEs 
related to the study drugs shall be collected, and be followed-up until the adverse reactions return 
to grade 0-1 or baseline.  
After 90 days since the last dose, the investigator should report any SAEs that are considered 
related to the study drugs. 
AE Follow-Up 
The AE shall be followed until the events return to the baseline values or grade 0–1, or until 
the investigator believes that no further follow-up is required for reasonable reasons (if the event 
cannot be resolved or has already been improved). If the event cannot be resolved, a reasonable 
explanation shall be documented in the eCRF. The outcome of an AE/SAE and date shall be 
documented in the eCRF and medical record, regardless of whether the event is related to the study 
drugs. 
Contents of AE documentation 
The investigator must document all the AEs, including the diagnosis (document signs and 
symptoms including the laboratory abnormalities if there is no diagnosis), time and date of 
occurrence (if applicable), CTCAE grade of severity and changes in severity (events ≥ grade 3), 
whether it is an SAE, whether it is an AE of special interest (AESI), measures taken for the study 


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drugs, treatment for the AE and outcome of the event, and relationship between the event and study 
drugs. 
For an SAE, the investigator shall also provide the date when the AE meets the criteria for an 
SAE, the date when the investigator is informed of the SAE, the reason of being an SAE, date of 
hospitalization, date of hospital discharge, possible cause of death, date of death, whether an 
autopsy has been performed, causality assessment of the study procedures, causality assessment 
of other drugs, and other possible causes of the SAE. The investigator shall provide the rationales 
of the causality and a description of the SAE. In the SAE description, the followings shall also be 
included: the subject number, age, gender, height, and weight; indication for receiving the 
investigational drug, cancer staging, and overall condition; SAE occurrence, development, 
outcome, and result; laboratory results related to the SAE (the time of the examination, units, and 
normal ranges must be provided); medical history, onset and duration of concurrent diseases 
related to the SAE; medication history and initiation, duration, and dosage of concomitant 
medications related to the SAE; initiation, duration, and dosage of the investigational drug. 
Descriptions of the AE are as follows: 
Diagnosis, signs, and symptoms 
Document the definite diagnosis, if there is one, rather than just listing the independent signs 
and symptoms (e.g. hepatic failure rather than jaundice, elevated transaminase, and asterixis). 
Signs and symptoms shall be reported as separate AEs/SAEs if cannot be attributed to the diagnosis. 
If it is determined that the signs and symptoms are caused by the diagnosis, then only the diagnosis 
shall be reported, included the signs and symptoms. The record of signs and symptoms shall then 
be deleted. A follow-up SAE report shall be submitted. 
AEs secondary to other events 
Generally, AEs secondary to other events (such as result of another event or clinical sequelae) 
shall be documented as the primary event, unless the event is severe or an SAE. However, clinically 
significant secondary events shall be recorded as independent adverse events in the eCRFs if they 
occur at different time than the primary event. If the relationship between events is unclear, 
document them as separate events in the eCRFs. 
Ongoing or recurrent AEs 


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An ongoing AE refers to an event that does not resolve and is ongoing between two 
assessment time points. These AEs shall only be documented once in the eCRFs. The initial 
severity shall be documented, and the information shall be updated if the event exacerbates. 
Recurring AEs refer to AEs that have resolved between the two time points of assessment but 
subsequently occur again. These events shall be independently documented in the eCRFs. 
Laboratory abnormalities 
Any clinically significant laboratory abnormalities shall be reported as AEs. The 
investigator is responsible for reviewing all the laboratory abnormalities, and determine whether 
the findings shall be reported as AEs. 
Death 
During the entire course of the study, all the deaths that occur within 90 days after the last 
dose shall be documented in the eCRFs and Mortality Report Form and reported to the sponsor 
timely, regardless of the causality with the study drugs. 
If the cause of death is known, record the cause of death as an AE and the outcome of the 
event as a death and submit an SAE report; if the cause of death is unclear, the AE shall be 
recorded as Death of Unknown Cause in the AE form, and submit the SAE report as Death of 
Unknown Cause. The exact cause of the death shall be further investigated. 
If the cause of death is confirmed to be PD, then the event shall not be documented and 
reported as an AE/SAE. However, the event shall be documented in the Mortality Report Form 
of the eCRF and reported to the sponsor timely. 
Pre-existing medical conditions 
Symptoms/signs present during the screening period will be recorded and reported as AEs 
only if their severity, frequency, or property becomes aggravated (except for worsening of the 
studied disease). The relative changes shall be documented, such as increased frequency of 
headaches. 
Hospitalization and prolonged hospitalization, or surgery 
Any AEs leading to hospitalization or prolonged hospitalization shall be recorded and 
reported as SAEs, with the following exceptions: 
 
Hospitalization or prolonged hospitalization as required by study protocol (such as for 
dose administration or efficacy evaluation). 
 
Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective 


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surgery/therapy scheduled prior to the study. 
However, elective surgery/therapy required because of the exacerbated condition during the 
study (e.g. surgery/therapy required earlier than scheduled) shall be considered as an AE. 
PD 
PD is defined as the worsening of subject condition caused by the primary tumor that the 
study drug is targeting, the appearance of new lesions, or the progression of the primary lesion. 
PD will not be reported as an AE. Any deaths, life-threatening events, hospitalization or 
prolonged hospitalization, permanent or significant disability/incapacity, congenital 
anomaly/birth defects, or other important medical events caused by PD will not be reported as an 
SAE. 
Overdose 
An overdose is the administration of a drug at more than the dose specified in the study 
protocol. All the occurrences of overdose must be documented in the eCRF. 
Expedited Reporting of SAEs and Pregnancy 
SAE reporting: 
SAEs should be reported  from the signing of informed consent  to 90 days (inclusive)after 
the last doseof investigational drug administration. The investigator must fill out the "CFDA SAE 
Report Form", regardless of whether it is the initial report or a follow-up report, and sign and date 
the form. The investigator must report the SAE to the sponsor, CFDA, and ethics committee within 
24 hours of noticing the event. Refer to the table below for contact details. 
For SAEs occurring outside of the above-mentioned period, those considered related to the 
investigational drug shall also be reported to the sponsor. 
The investigator must submit the completed SAE report form to the sponsor within 24 hours 
of noticing the event. The investigator shall urgently perform visit on missing information and 
provide a complete SAE report for events that result in death or are life-threatening. 
The investigator shall also report the event to the CFDA, health administration departments, 
and EC in accordance with the regulations. 
Table 6. SAE report contacts 
Organization 
Contact Person 
Fax/Telephone/Address 
Hospital Name 
EC 
Hospital Fax/Telephone 


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Innovent Biologics (Suzhou) Co., 
Ltd. 
Clinical Study Department 
PV 
Fax: 021-31652800 
Email: drugsafety@innoventbio.com 
Office of Drug Research and 
Supervision, Department of Drug 
and Cosmetics Registration, China 
Food and Drug Administration 
 
Address: 
Building 
2, 
No. 
26, 
Xuanwumen West Street, Xicheng 
District, Beijing 
Postal Code: 100053 
Telephone: 010-88330732 
Fax: 010-88363228 
Medical 
Administrative 
Department, Health Administration 
 
Address: No. 38, Lishi Road, Xicheng 
District, Beijing 
Telephone: 010-68792001 
Fax: 010-68792734 
Province, 
Autonomous 
Region, 
Municipality 
Food 
and 
Drug 
Administration 
Based on the requirements of the Food and Drug Administration 
Department of each province, autonomous region or municipality  
Pregnancy 
The risk of embryotoxicity exists for the similar kind of drugs. All the subjects with 
childbearing potential must take effective contraceptive measures. 
During the study, if a female subject becomes pregnant, she must be withdrawal from the 
study. The investigator must report to the sponsor within 24 hours of noticing the event and submit 
the Innovent Clinical Study Pregnancy Report/Follow-Up Form. 
During the study, if a female partner of a male subject exposed to the study drugs becomes 
pregnant, the subject will continue in the study. The investigator must report to the sponsor within 
24 hours of noticing the event and submit the Innovent Clinical Study Pregnancy Report/Follow-
Up Form. 
The investigator must continuously monitor and follow-upthe outcome of the pregnancy until 
8 weeks after the subject gives birth. The outcome shall be reported to the sponsor. 
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any 
congenital anomaly/birth defects), or medical abortion, it shall be considered a SAE and the event 
requires to be reported in accordance with SAE procedures and time limits. 
If the subject also experiences a SAE during the pregnancy, the CFDA SAE Report Form 
shall also be filled out and reported according to SAE's procedures. 


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Abnormal Hepatic Function 
It is considered as drug-induced liver injury if abnormal AST and/or ALT levels are 
accompanied with abnormal elevation of TBIL, and the following conditions are met without other 
possible causes. Such cases shall always be considered as important medical events and be 
expeditiously reported as per the procedures and time limits. 
Table 7. Liver injuries required to be reported as SAEs 
Baseline 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment 
ALT or AST ≥ 3 × ULN  
with TBIL ≥ 2 × ULN  
and ALP ≤ 2 × ULN  
and no hemolysis 
ALT or AST ≥ 8 × ULN  
and TBIL increase ≥ 1× ULN or value 
≥ 3× ULN 
Once being notified with the abnormalities, the subject must return to the study site promptly 
(ideally within 48 hours) and receive an assessment. The assessment must include the laboratory 
tests, detailed medical history, and physical assessment, and the possibility of hepatic tumor 
(primary or secondary) shall be considered. 
Other than repeated AST and ALT tests, albumin, creatine kinase, TBIL, direct and indirect 
bilirubin, γ-GT, PT/INR, and ALP shall also be tested. Detailed medical history include history of 
alcohol, acetaminophen, soft drugs, various supplements, traditional Chinese medicine, chemical 
drug exposure, family diseases, occupational exposure, sexual behavior, travel, contact with 
patients with jaundice, surgery, blood transfusion, hepatic diseases or allergies, cardiac diseases, 
and immune diseases. Further tests may include the detection of acute hepatitis A, B, C and E, 
hepatic imaging (such as biliary tract), autoantibodies, and echocardiography. If a retest showed 
consistency with the criteria outlined in Table 10 and there are no other possible causes, the 
possibility of drug-induced liver injury could be considered before all the results of etiological 
tests are accessible. These potentially drug-induced liver injury shall be reported as SAEs, and the 
Appendix 5: Abnormal Hepatic Function Monitoring and Follow-Up Report shall be submitted to 
the sponsor. 
Managing of Drug-Related Toxicities 
During the course of the trial, the sponsor will conduct regularly monitoring of safety. 
Detailed information regarding the frequency of review and type of data to be reviewed will be 
presented in a separate safety review plan. 


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irAEs 
Since the mechanism of action of IBI308 involves T-cell activation and proliferation, irAEs 
are likely to be observed during this study. Refer to Section 5.4 for the definition of an irAE. Signs 
and symptoms of irAEs shall be monitored. 
Refer to Sections 5.3 and 5.4 for administration adjustments and management of AEs of 
IBI308. Refer to Appendix 7 (Tables 1 and 2) for a detailed guide on irAE management. 
AESIs 
AESIs refer to events that require close monitoring in order to enhance the understanding of 
the safety of the investigational drug. AESIs can be non-serious events. 
AESIs for this trial include the followings: 
 
Infusion reactions ≥ grade 3 
 
Diarrhea/colitis, uveitis, interstitial pneumonia ≥ grade 2 
 
Suspected immune-related AEs ≥ grade 3 
8 Statistics 
Statistical Analysis Plan 
A detailed statistical analysis plan (SAP) will begin to be written after the first enrollment and 
will be finalized prior to database locking. The SAP will contain details of all analyses and the 
presentation of results. 
Hypothesis Test 
The primary efficacy endpoint is ORR evaluated using the 2014 Lugano Criteria. The 
hypotheses for the superiority test are as follows: 
 H0: ORR ≤ 30% 
H1: ORR > 30% 
The superiority is determined using confidence intervals (CIs). Superiority of IBI3088 
monotherapy for the treatment of relapsed or refractory ENKTL-NT is established if the lower 
limit of the (1-α)% CI for ORR is greater than 30% (α may be adjusted according to interim 
analysis). 
Analysis Population 
Analysis population include the safety set (SS), full analysis set (FAS), and per-protocol set 
(PPS): 


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1) SS: subjects who received at least one dose of the investigational drug. 
2) FAS: subjects with measurable lesion at baseline and received at least one dose of the 
investigational drug. Subjects who do not meet the criteria for ENKTL-NT by central 
pathological review are excluded in the FAS. 
3) PPS: a subset of the FAS, includes subjects with good compliance and no serious 
protocol violations or prohibited medications. 
Statistical Methods 
General statistical analysis 
Variable data will be summarized using the mean, standard deviation, median, maximum, and 
minimum. Attributes data will be described using frequency and percentage. 
All the statistical analyses will be performed with SAS 9.2 (or higher). 
Analysis of primary efficacy endpoint 
ORR is evaluated using the 2014 Lugano Criteria: 
, superiority is tested using (1-α)% CI 
based on the binomial distribution. 
Analysis of secondary efficacy endpoints 
 
TTR 
TTR (CR or PR): time from the first dose to the first tumor response. 
The median TTR and corresponding 95% CI will be estimated via the Kaplan-Meier method, 
and survival curves will be plotted. 
 
DoR 
DoR (CR or PR): time from first date of response to PD or death. Subjects who neither 
progress nor die will be censored at the date of their last tumor imaging evaluation. 
The median DoR and corresponding 95% CI will be estimated via the Kaplan-Meier method, 
and survival curves will be plotted. 
 
PFS 
PFS: time from first dose to first PD (by imaging), or to death due to any causes. Subjects 
who neither progress nor die will be censored at the date of their last tumor imaging evaluation. 
Subjects who did not have any tumor imaging evaluation after baseline will be censored on the 
date of enrollment. 


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The median PFS (mPFS) and corresponding 95% CI will be estimated via the Kaplan-Meier 
method, and survival plots will be plotted. 
 
OS (investigator-evaluated) 
OS: time from first dose to death. 
The median OS and corresponding 95% CI will be estimated via the Kaplan-Meier method, 
and survival curves will be plotted. 
 
DCR 
, superiority is tested using 95% CI based 
on the binomial distribution. 
Biomarker evaluations 
Descriptive summary statistics of PD-L1 expression levels and distribution will be presented, 
and the association with efficacy will be explored. 
The potential association between number of TIL and treatment efficacy will be summarized 
using descriptive statistics. 
Dynamic changes in EBV DNA copy number in peripheral blood will be summarized using 
descriptive statistics, and the potential association with efficacy will be explored. 
Dynamic changes in immune cell phenotypes in peripheral blood will be summarized using 
descriptive statistics, and the potential association with efficacy will be explored. 
The correlation between immune-related cytokines IL-6, IL-15, TNF-α and soluble PD-L1 
and efficacy of anti-PD-1 treatment will be presented using descriptive statistics. 
Post-hoc analyses may possibly be carried out. The analyses described in this section will 
be carried out based on the data collected. 
Quality of life analysis 
The EQ-5D-5L and EROTC QLQ-C30 scores at each evaluation time point will be calculated. 
The overall score and each dimension score at each time point, as well as relative changes from 
baseline, will be summarized using descriptive statistics. 
Safety analysis 
The safety analysis will use the SS. Safety parameters include AEs, laboratory examinations, 
vital signs, ECG, immunogenicity, etc. 


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8.4.6.1 Drug exposure 
The amount of drug exposure and duration of treatment (number of treatment cycles) will be 
summarized. 
8.4.6.2 AEs 
All the AEs will be coded according to MedDRA. 
The incidence (frequency) of AEs, TEAEs, ADRs, irAEs, AESIs, SAEs, and AEs resulting in 
study treatment discontinuation will be summarized. The severity distribution of TEAEs, ADRs, 
irAEs, AESIs, and AEs resulting in study treatment discontinuation will be summarized using 
NCI CTCAE v4.03 presented via SOC/PT. 
Subjects who discontinue the treatment due to AEs, develop SAE, or die will be listed 
(include at least the followings: start and end date of the AEs, severity grades, relationship with 
study drugs, measures taken, and outcomes). 
8.4.6.3 Laboratory tests 
Measurements and changes after treatment in count of whole blood cells and blood 
biochemistry parameters will be described using mean ± SD, maximum, minimum, and median. 
Normal and abnormal changes after treatment will be described using the cross-classification 
table. 
Routine urinalysis: A cross-classification table is used to describe changes between 
normalities and abnormalities before and after the treatment. 
The proportion of subjects with "clinically significant abnormalities" will be presented. The 
clinical significance will be determined by the investigator. 
Subjects with abnormal changes after treatment (whether clinically significant or not) will be 
listed. 
8.4.6.4 ECG 
Descriptive statistics are used for ECG and changes from baseline. A cross-classification 
table is used to describe ECG and changes from baseline before and after the treatment and data 
lists will be provided. 
8.4.6.5 Vital signs, physical examination and other safety-related examinations 
Descriptive statistics of vital signs and relative changes from baseline will be shown. 
Abnormal changes from baseline in physical examination will be listed. 


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Immunogenicity 
The rates of ADA and NAB development will be calculated. Subjects' antibody titer will be 
listed. 
Compliance 
The frequency and proportion of subjects who violate the treatment regimen will be presented. 
The proportion of subjects administered study drug doses between 80–120% of the dose 
specified in the protocol, 
who complete the study, and who complete different number of treatment cycles will also be 
summarized. 
Subjects' baseline characteristics 
Subjects' demographics (sex and age), tumor diagnosis information (pathological diagnosis, 
tumor staging, prior treatment), baseline tumor evaluation (target lesion, number of non-target 
lesions, sites, total diameter, etc.), and other baseline information (height and weight (BMI, BSA), 
vital signs, laboratory tests, past/concomitant medications) will be analyzed using descriptive 
statistics. 
Interim analysis 
One interim analysis is planned for this study: 
Time point for the analysis: after the first 20 subjects have completed the treatment as per the 
study protocol for the safty evaluation. 
Multiple comparisons and adjustments 
One interim analysis is planned for this study. The interim analysis will analyze safety data 
of the first 20 subjects, and the  will not be adjusted. 
Subgroup analysis 
Treatment efficacy in PD-L1-positive subjects is analyzed. 
Subgroup efficacy analyses will be performed based on age and previous treatment. 
Eligible subject data lists 
In addition to subjects' data list, tumor evaluation (date of evaluation, lesion status, evaluation 
results) and efficacy endpoints of subjects who have achieved CR and PR will be listed separately. 
PFS data of all the subjects at the end of the study will be also be presented. 


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Exploratory analysis 
The association between PD-L1 expression levels and treatment efficacy will be examined 
using descriptive statistics. 
The association between number of TIL and treatment efficacy will be summarized using 
descriptive statistics. 
The association between dynamic changes in EBV DNA copy number and treatment efficacy 
will be presented using descriptive statistics. 
Dynamic changes in immune cell phenotypes in peripheral blood will be summarized using 
descriptive statistics, and the potential association with efficacy will be explored. 
The correlation between immune-related cytokines IL-6, IL-15, TNF-α and soluble PD-L1 
and efficacy of anti-PD-1 treatment will be presented using descriptive statistics. 
Sample size estimation 
This is a single-arm trial. The primary objective is to evaluate the efficacy of IBI308 monotherapy for 
the treatment of relapsed or refractory extranodal NK/T-Cell Lymphoma. 20-60 subjects will be enrolled. 
Assuming a null hypothesis of 30% ORR,  of 0.05 (two-sided), power of 80%, a 50% ORR after 
IBI308 treatment will be achieved and the minimum sample size will thus be 43.  
The sponsor will evaluate the safety data from the first 20 subjects to determine whether the 
study shall be discontinued prematurely due to safety concerns. 
Methods for Controlling Bias 
Randomization and blinding 
This is a single-arm, open-label study. There is no randomization or blinding. 
Blinding maintenance evaluation 
Not applicable. 
Emergency unblinding 
Not applicable. 
9 Quality assurance and quality control 
In accordance with GCP guidelines, the sponsor is responsible for the implementation and 
maintenance of quality assurance and quality control systems as per appropriate standard 
operating procedures to ensure the study is implemented and authentic data is collected, 
documented, and reported in accordance with the requirements of the protocol, GCP, and 
applicable regulations. 


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Clinical monitoring 
The sponsor or its authorized contract research organization (CRO) will conduct clinical 
monitoring of this study. The clinical research associate (CRA) shall perform the monitoring in 
accordance with the standard operating procedures provided by the sponsor or CRO, and has the 
same rights and responsibilities as the sponsor's CRA. The CRA must maintain regular 
communication with the investigator, authorized research personnel, and sponsor. 
Before the study begins, the CRA will assess the competency of each study site, and report 
issues related to facilities, technical equipment, and medical personnel to the sponsor. During the 
course of the study, the CRA is responsible for the monitoring of whether the written ICF from 
all subjects has been obtained and whether the data records are correct and complete. The CRA 
shall compare the data inputted in the eCRFs with the raw data, and inform the investigator of 
any errors or omissions. Besides, the CRA will also control the compliance of the protocol and 
study procedures for each study sites, arrange for the supply of investigational drug, and ensure 
that the drug is kept under proper conditions. 
The monitoring visits shall be conducted in accordance with the requirements of relevant 
laws and regulations. From the time the subjects are enrolled, each center shall receive regular 
visits for the purpose of monitoring. After each visit to the investigator, the CRA shall submit a 
written report to the sponsor. 
Data Management/Coding 
This study will use an electronic data collection (EDC) system, and the research data will be 
recorded in the eCRFs by the investigators or its authorized personnel. Before the initial of the 
study site or data entry, the investigators and authorized personnel shall be properly trained and 
appropriate security measures shall be taken for the computer and other equipment. 
Data entry into the eCRFs shall be completed as soon as possible during or after visiting. 
The eCRFs shall be updated at any time to ensure that they reflect the latest data of the subjects. 
To avoid the differences in outcome evaluations by different evaluators, it is recommended that 
the baseline and all the subsequent efficacy and safety evaluations of a given subject shall be 
performed by the same individual. The investigators are required to review the data to ensure the 
accuracy and correctness of all the data entered into the eCRFs. If no evaluations are conducted 
during the study, or some obtained information are not evaluable, not applicable, or unknown, 


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the investigators shall record the above information in the eCRFs. The investigator shall sign the 
verified data electronically. 
The CRA will review the eCRFs, and evaluate the completeness and consistency by 
comparing with the source document to ensure consistency of key data. Data entry, corrections, 
and modifications shall be performed by the investigator or designee. The data in the eCRFs is 
submitted to the data server and any modifications in the data shall be recorded in the audit trail, 
including reasons, operator names, time, and dates of modification. The roles and permission levels 
of the personnel responsible for data entry in the study site will be determined in advance. The 
CRA or data management personnel may raise an inquiry in the EDC in the event of suspicious 
data. The study site personnel are responsible for dealing with such inquiry. The EDC system will 
record the audit trail of the inquiry, including the investigator name, time, and date. 
Unless otherwise stated, the eCRFs shall only be used as forms to collect data, instead of 
source. The source documents are used by the investigators or hospital, including all records 
related to the subjects, which are able to demonstrate the presence, inclusion criteria, and 
participation of subjects (laboratory records, ECGs, pharmaceutical records, subject folders, etc.). 
The investigator is responsible for the maintenance of all source documents and shall offer 
the documents to the CRA for review during each visit. In addition, the investigator must submit 
a complete eCRF for each enrolled subject, regardless of the duration of participation. The protocol 
number and subject numbers of all supporting documents (such as laboratory records or hospital 
records) submitted with the eCRFs shall be carefully verified. All the personal privacy information 
(including the subjects' names) shall be deleted or made illegible to protect the privacy of the 
subjects. The investigator verifies that the record has been reviewed using an electronic signature 
and ensures the accuracy of the recorded data. The electronic signature shall be completed using 
the investigator's user ID and password. The system will automatically attach the date and time of 
signing to the signature. The investigator must not share his/her user ID and password with others. 
If the data in the eCRFs are required to be changed, the change shall be performed according to 
the procedure outlined by the EDC system. All the changes and corresponding reasons shall be 
recorded in the audit trail. 
AEs and concomitant diseases/history shall be coded. The dictionary for coding will be 
described in the Clinical Study Report (CSR). 


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Quality Assurance Audits 
During the course of the study, the sponsor or designee may conduct quality assurance audits 
on the study sites, database and related research documents. At the same time, the corresponding 
regulatory authorities may also inspect the study sites, database and related research documents at 
their own discretion. The investigator shall notify the sponsor immediately after being notified of 
inspection from regulatory authorities. 
The sponsor's quality assurance department will audit the clinical trial sites. The audits 
include the supply of drugs, required trial documents, records of informed consent process, as well 
as the consistency of medical report forms with the source documents. The content and scope of 
the audits can also be increased as the circumstance requires. After reasonable notice, the 
investigator shall allow auditors commissioned by the sponsor to conduct audits related to the trials 
and inspections conducted by the regulatory authorities. The primary purpose of an audit or an 
inspection is to verify that the rights or health of the trial subjects are protected, the signing of the 
informed consent form and the correct implementation of the trial process, and all data related to 
the evaluation of the investigational drug is processed, reported and pre-planned. In addition, the 
protocol, facility, ethical standard operating procedures, GCP and applicable regulatory 
requirements are consistent. The investigators shall have direct access to all trial files, source 
records, and source data. 
10 Ethics 
EC 
The sponsor or designee will prepare the relevant documents including the trial protocol, 
ICF, Investigator’s Brochure, subject recruitment materials or advertising, and other documents 
required by regulations, which are to be submitted to the corresponding EC in of the study site 
for approval. Prior to the start of the trial, written approval from the EC must be obtained and 
submitted to the sponsor. The written approval from the EC shall specify the name, number, 
version number and version number of other documents (such as ICF) and date of approval. The 
investigator is required to notify the sponsor of the EC's written comments regarding delay, 
interruption, and re-approval of the study. 
The study site must follow the requirements of the EC in the study site. Protocol modifications, 
ICF or recruitment materials shall be submitted to the EC for approval. Local safety reports shall 
be made and updated regularly in accordance with the regulations from the EC, and the final report 


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shall be submitted. All the above documents and EC approvals must be provided to the sponsor or 
designee. 
Ethics 
The process of study and informed consent are subject to the Declaration of Helsinki, 
relevant GCP requirements, as well as laws and regulations related to the protection of drug and 
data in China. 
GCP provides ethical and scientific, global quality standards for the design, implementation, 
documentation, and reporting of clinical studies involving human subjects. This study will be 
conducted in accordance with the GCP and relevant national regulations and in accordance with 
the relevant ethical principles of the Declaration of Helsinki to protect the rights, safety, and 
health of the subjects. 
The investigator is required to follow the procedures specified in this protocol and must not 
change the procedures without the permission from the sponsor. Any protocol violations must be 
reported to the EC, sponsor, or regulatory authorities. 
Subject Information and Informed Consent 
Before the start of any study process, the ICF is used to explain the risks and benefits of this 
study to potential participants, and the expression used in the ICF shall be straightforward. The 
ICF statement shall clarify that this ICF is voluntarily signed, and the risks and benefits of 
participating in this study shall be clearly outlined. The subject can withdraw from the study at 
any time. Subjects can only be enrolled if he/she fully understands the study in detail, has 
received satisfactory answers to his/her inquiries, and has sufficient time for consideration. 
Written consent must also be obtained from the subject or his/her legal representative. All the 
signed ICFs must be kept in the investigator's files or in the subject's folder. 
The investigator is responsible for the interpretation of the ICF to the subject, obtaining 
informed and dated ICF from the subject or his/her legal representative prior to the start of the 
study. After signing, the investigator shall send the subject a copy of the signed ICF. The 
investigator is required to document the process of informed consent in the source study document. 
Data Protection of Subjects 
An ICF shall include (or in some cases, use separate files together) information on data and 
privacy protection. 


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Take precautions to ensure the confidentiality of the documents and prevent the disclosure of 
information that can determine the identity of the subject. However, under special circumstances, 
some personnel may be permitted to see the genetic data and personal identification number of a 
subject. For example, in the event of a medical emergency, the sponsor, designated physician, or 
investigator will have access to the subject identification code and the subject's genetic data. In 
addition, relevant regulatory authorities require access to relevant documents. 
11 Study Management 
Data Processing and Record Keeping 
Records from the clinical trial (such as protocol and protocol revision, completed eCRFs, 
and signed ICFs) are to be kept and managed in accordance with the GCP. The study sites shall 
keep these documents for 5 years after the end of the study. 
The study documents shall be reasonably kept for future interviews or data traceability. 
Security and environmental risks shall be considered when storing documents. 
No study documents shall be destroyed without the written consent from the sponsor and 
investigator. The investigator/study site may transfer the study documents to other parties that 
comply with the record-keeping requirements or to another location that meet record-keeping 
requirements only after notifying the sponsor and obtaining the written consent. 
Source Data/File Access 
The investigator agrees that the sponsor, CRO, and relevant authorized regulatory agencies 
shall have direct access to all the study-related documents, including medical records of the 
subjects. 
Protocol Amendments 
Any possible amendments to the protocol during the course of the study will be 
communicated between and agreed by the sponsor and the investigator. The sponsor shall ensure 
that the protocol amendment is submitted to the regulatory authority in a timely manner. 
All revisions to the protocol shall be kept as supplements to the protocol. Any changes to the 
protocol must be submitted to the EC for approval or filing in accordance with the ECs regulations. 
If necessary, it shall also be submitted to regulatory authorities for approval and only implemented 
after being approved by the EC and regulatory authorities (if applicable) (with the exception of 
changes to the protocol that eliminate direct hazards to the trial subjects). 


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Responsibilities of the Investigator 
The investigator shall adhere to the protocol, ethical principles of the Declaration of Helsinki, 
Chinese GCP and requirements of the corresponding regulations for this study. 
The detailed responsibilities of the relevant investigators are listed in Chapter 5 (Investigator's 
Responsibilities) of the Chinese GCP (Order No. 3). 
Publishing Policy 
All the data generated in this study is the confidential information owned by the sponsor. 
The sponsor has the right to publish study results. Information on the publishing policies of the 
sponsor and investigator will be described in the clinical trial agreement. 
All the information on this trial (not limited to the protocol and Investigators Brochure) 
must be kept strictly confidential. The investigator must recognize that the scientific or medical 
information derived from this trial may be of commercial value to the sponsor. The investigator 
shall keep the information and data related to this study confidential. The sponsor must be 
consulted in advance and written consent must be obtained prior to publishing of any study-
related information or conclusions. In order to protect the rights and interests, the sponsor may 
request the investigator not to publish information on this trial before the investigational product 
is approved for marketing. 
The sponsor has the right to announce or publish information or data related to the trial or to 
report it to the drug administration. The sponsor must obtain the consent of the investigator if the 
name of the investigator is included in the content of the announcement, publication or 
advertising. 
Financing and Insurance 
The sponsor shall purchase insurance for participants in the study in accordance with local 
regulations and minimum requirements. Insurance related terms shall be saved in the study 
folder. 
 


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12 Reference 
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Version 2.2017. Feburary. 
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10002 cases analysis from many domestic centricity. J Diagn Concepts Pract 2012; 111-115. 
3. Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I, et al. 
Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 
cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113(17):3931-7.  
4. Vose J, Armitage J, Weisenburger D, International TCLP. International peripheral T-cell 
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2008;26(25):4124-30. 
5. Au WY, Pang A, Choy C, Chim CS, Kwong YL. Quantification of circulating Epstein-
Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive 
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6. Kim HS, Kim KH, Kim KH, Chang MH, Ji SH, Lim DH, et al. Whole blood Epstein-Barr 
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lymphoma. Leukemia & lymphoma. 2009;50(5):757-63. 
7. Ito Y, Kimura H, Maeda Y, Hashimoto C, Ishida F, Izutsu K, et al. Pretreatment EBV-
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8. Bi XW, Wang H, Zhang WW, Wang JH, Liu WJ, Xia ZJ, et al. PD-L1 is upregulated by 
EBV-driven LMP1 through NF-kappaB pathway and correlates with poor prognosis in natural 
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clinical practice. Blood. 2006;107(3):862-9. 
10. Jo JC, Kim M, Choi Y, Kim HJ, Kim JE, Chae SW, et al. Expression of programmed cell 
death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Annals 
of hematology. 2017;96(1):25-31. 
11. Kim WY, Jung HY, Nam SJ, Kim TM, Heo DS, Kim CW, et al. Expression of 
programmed cell death ligand 1 (PD-L1) in advanced stage EBV-associated extranodal NK/T cell 
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pathology. 2016;469(5):581-90.  
12. Kim YJ, Won CH, Chang SE, Lee MW, Choi JH, Lee WJ. Expression of programmed 
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JEADV. 2017. 
13. 赵越, 卜庆. PD-L1 和PD-1 在外周T 细胞淋巴瘤中的表达及临床意义. 天津医药. 
2016;44(3):349-52. 
14. Quan L, Chen X, Liu A, Zhang Y, Guo X, Yan S, et al. PD-1 Blockade Can Restore 
Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro. 
PloS one. 2015;10(9):e0136476. 
15. Fang W, Zhang J, Hong S, Zhan J, Chen N, Qin T, et al. EBV-driven LMP1 and IFN-
gamma up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. 
Oncotarget. 2014;5(23):12189-202. 
16. Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and 
PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. Journal of 
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17. Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: 
microsatellite instability vs. PD-L1. Journal of gastrointestinal oncology. 2016;7(5):771-88. 
18. Yamaguchi M, Suzuki R, Kwong YL, Kim WS, Hasegawa Y, Izutsu K, et al. Phase I study 
of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) 
chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell 
lymphoma and leukemia. Cancer science. 2008;99(5):1016-20. 
19. Yamaguchi M, Kwong YL, Kim WS, Maeda Y, Hashimoto C, Suh C, et al. Phase II study 
of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural 
killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2011;29(33):4410-6. 
20. Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, et al. Efficacy of L-
asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with 
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2011;117(6):1834-9. 
21. Yokoyama H, Yamamoto J, Tohmiya Y, Yamada MF, Ohguchi H, Ohnishi Y, et al. 
Allogeneic hematopoietic stem cell transplant following chemotherapy containing l-asparaginase 


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as a promising treatment for patients with relapsed or refractory extranodal natural killer/T cell 
lymphoma, nasal type. Leukemia & lymphoma. 2010;51(8):1509-12. 
22. Li M, Gao C, Li H, Wang Z, Cao Y, Huang W, et al. Allogeneic haematopoietic stem cell 
transplantation as a salvage strategy for relapsed or refractory nasal NK/T-cell lymphoma. Medical 
oncology. 2011;28(3):840-5. 
23. Suzuki R, Suzumiya J, Nakamura S, Kagami Y, Kameoka JI, Sakai C, et al. Hematopoietic 
stem cell transplantation for natural killer-cell lineage neoplasms. Bone marrow transplantation. 
2006;37(4):425-31. 
24. Makita S, Tobinai K. Clinical Features and Current Optimal Management of Natural 
Killer/T-Cell Lymphoma. Hematology/oncology clinics of North America. 2017;31(2):239-53.  
25. Wang JJ, Dong M, He XH, Li YX, Wang WH, Liu P, et al. GDP (Gemcitabine, 
Dexamethasone, and Cisplatin) Is Highly Effective and Well-Tolerated for Newly Diagnosed Stage 
IV and Relapsed/Refractory Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type. Medicine. 
2016;95(6):e2787. 
26. Kwong YL, Chan TS, Tan D, Kim SJ, Poon LM, Mow B, et al. PD1 blockade with 
pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing L-
asparaginase. Blood. 2017. 
27. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab 
for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and 
brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. The Lancet Oncology. 
2016;17(9):1283-94. 
28. Ghatalia P, Zibelman M, Geynisman DM, Plimack ER. Checkpoint Inhibitors for the 
Treatment of Renal Cell Carcinoma. Current treatment options in oncology. 2017;18(1):7. 
 
 


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13 Appendixes 


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Appendix 1: Signature Page for Investigator 
Protocol Title: A Multicenter, Single Arm, Phase II Clinical Trial Evaluating the Efficacy and 
Safety of IBI308 Monotherapy for the Treatment of Relapsed or Refractory Extranodal NK/T-
Cell Lymphoma, Nasal Type (ORIENT-4) 
Protocol Number:  CIBI308D201 
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd.. I have read 
and fully understood this protocol, and agree to conduct this study in accordance with the 
requirements found in this protocol and the Good Clinical Practice, and in compliance with 
relevant laws and regulations and the Declaration of Helsinki. Also, I promise not to reveal any 
confidential information to a third-party without the written consent from Innovent Biologics 
(Suzhou) Co., Ltd.. 
Instructions for investigators: please sign and date this page, print the name of the 
investigator, position, and study site, and return the signed form to Innovent Biologics 
(Suzhou) Co., Ltd.. 
 
I have read the entire contents of this study protocol and shall perform the study as required: 
Signature of Investigator:       ____________  Date:  ________ 
Name (Print):              ___________________________ 
Title of Investigator:         ___________________________ 
Study Site/Address:         ___________________________ 
 
   ___________________________ 
 
   ___________________________ 


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APPENDIX 2: ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair. 
5 
Dead. 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 
 
 


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APPENDIX 3: Lugano 2014 Recommendations  
Lugano 2014 will be used in this study for assessment of non-Hodgkin lymphoma. As published in the journal 
of clinical oncology.  
Cheson, B. D., et al. (2014). "Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification." J Clin Oncol 32(27): 3059-3068. 


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APPENDIX 4 IWG 2007 Recommendations 
IWG 2007 will be used in this study for assessment of non-Hodgkin lymphoma. As published in the journal of 
clinical oncology.  
Cheson, B. D., et al. (2007). "Revised response criteria for malignant lymphoma." J Clin Oncol 25(5): 579-
586. 


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Appendix 5: Abnormal Hepatic Function Monitoring and Follow-Up Report 
Please submit the report to Innovent PV: 
Fax: 021-31652800                      Email: drugsafety@innoventbio.com 
 
Contact information of reporter (please provide the followings in order to receive a timely response): 
Reporter's Email:                            Reporter's Telephone:                                    
Reporter's Signature:                            Date of Report:                                          
 
Abnormal Hepatic Function Follow-Up Information: 
Trial Number:                                Subject Number:             
1. Symptoms of abnormal hepatic function (check the followings if present): 
Decreased appetit e□, tired of grease □, indigestion □, nausea □, emesis □, bloating 
□, abdominal pain □, diarrhea □, constipation □, clay stool □, fatigue □, weakness □, 
lethargy □, weight loss □, asterixis □, mental state changes □, hemorrhagic tendency □, 
fever □, others □ 
 
2. Signs of abnormal hepatic function (check the followings if present): 
Facial appearance of liver disease □, spider nevus □, liver palm □, ascites □, abdominal 
wall varicose veins □, jaundice □, yellow body fluid □, hepatomegaly □, splenomegaly □, 
liver area tenderness □, hepatic encephalopathy □, dyspnea □, crackles □, peripheral edema 
□, jugular varicose veins □, abnormal heart sounds □, others □ 
 
3. Disease history (check the followings if present): 
Viral hepatitis (HBV-A □; HBV-B □; HBV-C □; HBV-D □; HBV-E □), alcoholic 
hepatitis □, fatty liver □, hepatic cancer □, hepatic metastasis □, hepatic cirrhosis □, liver 
transplantation □, blood transfusion □, elevated liver enzymes prior to  investigational drug 
administration □, autoimmune disease □, biliary tract disease □, cardiovascular disease □, 
hypotension □, diabetes □, surgery □, bone metastasis or bone damage □, HIV infection □, 
EB virus infection □, drug toxicity □, obesity □, others □ 
 
4. Family history (check the followings if present): 
 
5. Concomitant medication and diet (check the followings if present): 


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Chemotherapy □, Chinese herbal medicine □, OTC □, dietary supplement □, alcohol 
consumption □, drug abuse □, history of chemical exposure □, anti-infectives □, 
paracetamol □, NSAIDS □, metronidazole □, others □ 
 
6. All the relevant laboratory test results (include those at the baseline, during treatment period, and 
after the treatment. If tested, please check and provide the test results, units and reference 
ranges): 
Count of whole blood cells □, 
Eosinophil count □, 
AST □, ALT □, ALP □, GGT □,  
Total bilirubin □/Direct bilirubin □, 
Total serum protein □/Albumin □/Immunoglobulin □, 
Total cholesterol □/cholesterol ester □, 
Coagulation function □, such as: 
Other □, such as: 
 
7. Serologic tests (if performed, please check and provide the test results):  
Epstein-Barr virus (EBV) □, 
Cytomegalovirus (CMV) □, 
Herpes simplex virus (HSV) □, 
Toxoplasmosis □, 
Hepatitis (A □, B □, C □, D □, E □), 
HIV □, 
Anti-nuclear antibodies □, 
Other antibodies □, such as: 
Others □, such as: 
  
8. Auxiliary tests or procedures (if performed, please check and provide the test results): 
Liver ultrasound □, 
Abdominal CT □, 
Liver biopsy □, 
Liver transplantation (planned or completed) □, 


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Others □, such as: 
  


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Appendix 6: List of Pre-Existed Autoimmune Diseases Prior to Enrollment 
Ask whether the subject has acquired or congenital immunodeficiency or autoimmune diseases. These 
subjects are excluded from the study. Unless the subject has a history of allergic reactions and juvenile arthritis, 
the likelihood of suspected autoimmune disease is very low. In addition, subjects with transient autoimmune 
manifestations due to acute infections (such as Lyme arthritis) can enroll if have been treated with antibiotics. If 
an autoimmune disease cannot be confirmed, please contact the sponsor's medical manager. 
Autoimmune diseases include but are not limited to: 
Acute sporadic encephalomyelitis 
IgA nephropathy 
Addison's disease 
Inflammatory bowel disease 
Alopecia 
Interstitial cystitis 
Ankylosing spondylitis 
Myasthenia gravis 
Antiphospholipid antibody syndrome 
Lupus 
Aplastic anemia 
Lyme disease (chronic) 
Asthma 
Meniere's syndrome 
Autoimmune hemolytic anemia 
Corneal ulcer 
Autoimmune hepatitis 
Localized autoimmune hypophysitis 
Multiple sclerosis 
Autoimmune hypoparathyroidism 
Myasthenia gravis 
Autoimmune myocarditis 
Neuromuscular ankylosis 
Autoimmune ovaritis 
Myoclonus syndrome 
Autoimmune orchitis 
Optic neuritis 
Autoimmune 
thrombocytopenia 
purpura 
Ord's thyroiditis 
Bechet disease 
Pemphigus 
Bullous pemphigoid 
Pernicious anemia 
Celiac disease 
Multiple arteritis 
Chronic fatigue syndrome 
Polyarthritis 
Chronic inflammation 
demyelinating 
Polyneuropathy 
Autoimmune syndrome 
Churg-Strauss syndrome 
Primary biliary cirrhosis 
Crohn's disease 
Psoriasis 
dermatomyositis 
Rett syndrome 
Type I diabetes 
Rheumatoid arthritis 
Autonomic dysfunction 
Sarcoidosis 
Eczema 
Scleroderma 
Sjogren syndrome 
Bullous dermolysis 
Stiff-person syndrome 
Pemphigus during 
pregnancy 
Takayasu arteritis 
Giant cell arteritis 
Ulcerative colitis 
Pulmonary 
hemorrhage-
glomerulonephritis 
syndrome 
Vitiligo 
Graves’ disease 
Vogt-Kovanagi-Harada 
disease 
Guillain-Barre 
syndrome 
Vulvodynia 
Hashimoto's disease 


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Wegener's 
granulomatosis 
Kawasaki disease 


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Appendix 7: IBI308 Administration Adjustments and Toxicity Management 
Table 1. IBI308 administration adjustments and toxicity management of major potential irAEs 
 
AE Grade/Administration 
Adjustments 
Toxicity Management 
General Principles 
AEs are graded according to NCI 
CTCAE v4.03. Refer to this guideline 
if the event is an irAE 
It is recommended to manage irAEs according to the guideline in this 
table. 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
(e.g. PD, concomitant medication, infection, etc.) 
- 
The event is an irAE if there are no clear alternative causes and 
treatment with corticosteroids is required 
- 
Consider symptomatic and local treatment for low grade events 
(grade 1 or 2, unless otherwise stated) 
- 
Consider systemic glucocorticoid therapy for persistent low grade 
events (grades 1–2) or severe events (grade ≥ 3) 
- 
If the event re-occurs or worsens during tapering of glucocorticoids, 
the glucocorticoid dose shall be increased until symptoms resolve 
Grade 
1 
No dose adjustments  
required 
Grade 
2 
Interrupt 
• If worsens, treat as a 
grade 3/4 event 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
Grade 
3 
Interrupt or permanently  
discontinue 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
4 
Permanently discontinue 
or improve, then taper with a lower rate 
- 
Once persistent clinical improvement is observed, subjects 
receiving glucocorticoids IV can start tapering the dose or switch to 
an equivalent dose of glucocorticoid PO at an earlier time (a lower 
bioavailability of oral administration should be considered) 
- 
For events that unresponsive to glucocorticoid treatment, consider 
a stronger immunosuppressants, e.g. TNF blockers (e.g. infliximab) 
or mycophenolate mofetil, after discussing with the physicians 
- 
For grade 3/4 local inflammation of lesions (such as local pain, 
irritation, and rash), IBI308 may be continued as determined by the 
investigator 
Pneumonitis 
Any 
grade 
 
- 
Monitor signs and symptoms of pneumonitis or interstitial lung 
disease (e.g. new shortness of breath, cough, chest pain or 
exacerbation of existing symptoms and signs), evaluate subjects by 
imaging, pulmonary function, and other examinations 
- 
Initial examination may include clinical evaluation, arterial oxygen 
saturation, laboratory tests, and high-resolution CT scans  
Grade 
1 
No 
dose 
adjustments 
required However, consider 
interrupting the treatment 
based on clinical needs and 
during diagnostic tests for 
other causes 
For grade 1 events: 
- 
Monitor signs and symptoms and arterial oxygen saturation for 2–
4 days 
- 
Perform other laboratory tests if clinically indicated 
- 
Consider consulting a respirologist and infectious diseases 
specialist 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 
Interrupt 
• If worsens, treat as a 
grade 3/4 event 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
For grade 2 events: 
- 
Monitor signs and symptoms daily, consider hospitalization 
- 
Discuss with sponsor's medical manager, consider systemic 
glucocorticoid treatment 
- 
Repeat imaging if clinically indicated 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
If no improvement is seen within 3–5 days, consider a stronger 
immunosuppressant (e.g. infliximab) 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
- 
Consider consulting a respirologist and infectious diseases 
specialist 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
3 or 
grade 
4 
Permanently discontinue 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Consider consulting a respirologist and infectious diseases 
specialist 
- 
Hospitalization 
- 
Supportive care (oxygen) 
- 
Begin systemic glucocorticoid treatment based on experience  
- 
If no improvement is seen within 3–5 days, consider other tests and 
stronger immunosuppressants (e.g. infliximab) 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
Diarrhea or Enterocolitis 
Any 
grade 
 
- 
Monitor 
possible 
signs 
and 
symptoms 
related 
to 
diarrhea/enterocolitis (abdominal pain, enterospasm, changes in 
bowel habits, melena, mucous stool, bloody stool, or muscle 
guarding) 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
(e.g. PD, infection, etc.) 
- 
If alternative causes cannot be determined, consider glucocorticoid 
treatment for low grade events to prevent from escalating to high 
grade 
- 
Use analgesics with caution (may mask the symptoms of 
perforation and peritonitis) 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
1 
No dose adjustments  
required 
For grade 1 events: 
- 
Closely monitor symptom exacerbation 
- 
Consider symptomatic treatment, including fluid replacement, 
electrolyte replacement, diet modifications, and loperamide 
administration 
Grade 
2 or 
Grade 
3 
Interrupt 
• If worsens, treat as a 
grade 3/4 event 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
 
For grade 2–3 events: 
- 
Consider symptomatic treatment, including fluid replacement, 
electrolyte replacement, diet modifications, and loperamide and/or 
budesonide administration  
- 
If the event persists for > 3–5 days or worsens, consider systemic 
corticosteroid treatment 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
If no improvement is seen or exacerbation occurs within 3–5 days, 
consider other tests and stronger immunosuppressants (e.g. 
infliximab)  
- 
If not reduces to grade 0–1 within 3–4 days, discuss with sponsor's 
medical manager 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
4 
Permanently discontinue 
For grade 4 events: 
- 
Monitor frequency and volume of bowel movement, maintain 
hydration 
- 
If applicable, perform emergency GI consultation and lower GI 
endoscopy and imaging to confirm the presence of intestinal 
perforation 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If no improvement is seen within 3–5 days, consider increasing the 
glucocorticoid dose 
- 
If no improvement is seen within 3–5 days, consider other 
immunosuppressants (e.g. infliximab, but not in subjects with 
perforations or sepsis) 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Hepatitis (ALT, AST, or TBIL 
increased) 
Any 
grade 
 
 
Monitor hepatitis-related signs and symptoms (e.g. jaundice, tea-
colored urine, nausea, emesis, loss of appetite, hepatalgia, 
hemorrhagic tendency, etc.) 
 
Monitor and evaluate hepatic function 
 
Evaluate alternative causes (e.g. viral hepatitis, PD, concomitant 
medication) 
 
The dose adjustments and toxicity management in this table is 
applicable only to subjects with normal ALT, AST, and TB at 
baseline; for subjects with ALT, AST, or TB > ULN at baseline, 
interrupt the drug if ALT, AST, or TB elevation of ≥ 50% for < 
7 days and discontinue permanently if ALT, AST, or TB elevation 
of ≥ 50% for ≥ 7 days. Toxicities should be managed based 
on the investigator's clinical judgment. 
Grade 
1 
No dose adjustments  
required 
For grade 1 events: 
- 
Continue monitoring hepatic function according to protocol 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 
Interrupt 
• If worsens, treat as a 
grade 3/4 event 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
For grade 2 events: 
- 
If not reduces to grade 0–1 within 3–4 days, discuss with sponsor's 
medical manager 
- 
For ALT, AST, or TBIL elevations, retest hepatic function within 
3–4 days and increase monitoring frequency 
- 
If the event persists for > 3–5 days or worsens, consider systemic 
corticosteroid treatment 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
If no improvement is seen within 3–5 days, consider stronger 
immunosuppressants (e.g. mycophenolate mofetil)  
- 
Once improved, taper steroids within 4 weeks, and consider 
prophylactic antibiotic 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
3 or 
grade 
4 
Permanently discontinue 
 
 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If no improvement is seen within 3–5 days, consider stronger 
immunosuppressants (e.g. mycophenolate mofetil) 
- 
If no improvement is seen within 3–5 days, consider other 
immunosuppressants based on local guidelines 
- 
If applicable, consult a gastroenterologist, perform abdominal 
examination and imaging 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
Dermatitis 
Any 
grade 
 
- 
Monitor signs and symptoms or dermatitis, e.g. rash, exudation, 
hypopigmentation, photaesthesia, and pruritus 
- 
If there is formation of bullae, contact the sponsor's medical 
manager 
- 
Consult a dermatologist 
- 
Perform skin biopsy when necessary 
Grade 
1 
No dose adjustments  
required 
For grade 1 events: 
- 
Consider symptomatic treatment, including oral antipruritic agents 
(e.g. diphenhydramine or hydroxyzine) and local treatment (e.g. 
urea cream or topical glucocorticoids) 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 
No 
dose 
adjustments 
required 
• 
For a refractory (> 1–2 
weeks) grade 2 event, 
interrupt until reduces  
to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2 events: 
- 
Consider symptomatic treatment including oral antipruritic agents 
and local treatment 
- 
Consider a medium-potency topical glucocorticoid 
- 
If no improvement is seen with 3–5 days, discuss with sponsor's 
medical manager and consider systemic glucocorticoid treatment 
- 
Consult a dermatologist 
- 
Consider skin biopsy if persists for > 1–2 weeks or relapses 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
Grade 
3 
Interrupt 
• 
If worsens, treat as a 
grade 4 event 
• 
Permanently discontinue 
if a grade 3 rash does not 
reduce to grades 0–1 or 
baseline within 30 days 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Consider hospitalization 
- 
Monitor affected area (rule of nine) 
- 
Consult a dermatologist  
- 
If clinically feasible, consider skin biopsy (preferably more than 
once) 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
Grade 
4 
Permanently discontinue 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Hypopituitarism 
All 
grades 
 
- 
Monitor signs and symptoms of endocrine disorders, including 
weakness, fatigue, drowsiness, nausea, emesis, chills, changes in 
bowel habits, behavioral changes, mental state changes, 
hypotension, hypoglycemia, dizziness, headache, impaired vision, 
low libido in males, irregular menstruation in females, etc. 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
(e.g. PD, brain metastasis, infection, etc.) 
- 
Monitor and evaluate pituitary function: TSH, FT3, FT4, 
adrenocorticotropic hormone, cortisol, luteinizing hormone, follicle 
stimulating hormone, growth hormone, prolactin, Na+, blood 
glucose, estradiol, testosterone, and other laboratory parameters 
related to endocrine disorders. Perform functional tests when 
necessary (including adrenocorticotropic hormone (ACTH) 
stimulation test and insulin-induced hypoglycemia test) 
- 
Consider pituitary MRI 
- 
Consider consulting an endocrinologist 
- 
Consider testing for autoantibodies 
Grade 1 
No dose adjustments  
required 
For grade 1 events: 
- 
Monitor pituitary function 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Consider consulting an endocrinologist if clinically indicated 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 
 
Interrupt 
• If worsens to grades 3–4, 
permanently 
discontinue 
• If reduces to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2–4 events: 
 
Discuss with sponsor's medical manager 
 
Consult an endocrinologist 
 
Hospitalization when necessary 
 
Evaluate endocrine function, consider pituitary MRI if clinically 
indicated 
 
Begin hormone replacement therapy when necessary (cortisone 
replacement therapy shall begin one week prior to levothyroxine 
treatment) 
 
Begin immunosuppressive therapy based on experience, consider 
systemic glucocorticoid treatment 
 
Once improved, taper glucocorticoids within 4 weeks (the dose of 
cortisone used for hormone replacement may be adjusted 
accordingly, but subjects whose endocrine function do not recover 
require long-term treatment); consider prophylactic antibiotic during 
taper to prevent infections 
Grade 
3 or 
grade 
4 
Permanently discontinue 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Adrenocortical Insufficiency 
Any 
grade 
 
- 
Monitor signs and symptoms of endocrine disorders, including 
fatigue, pigmentation, loss of appetite, hypotension, and weakness 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Monitor 
and 
evaluate 
adrenal 
function: 
cortisol, 
adrenocorticotropic hormone, blood sodium, blood potassium, 
blood glucose, and other endocrine laboratory parameters suspected 
to be related to adrenal function. The ACTH stimulation test shall 
be performed when necessary 
- 
Immunosuppressive therapy when necessary 
- 
Hormone replacement therapy (cortisone) when necessary 
- 
Consider consulting an endocrinologist 
- 
Consider testing for autoantibodies 
Grade 
1 
No 
dose 
adjustments 
required 
For grade 1 events: 
 
Monitor adrenal function 
 
Consider consulting an endocrinologist if clinically indicated 
Grade 
2 
Interrupt 
• If worsens to grades 3–4, 
permanently 
discontinue 
• If reduces to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2 events: 
 
Discuss with sponsor's medical manager 
 
Evaluate adrenal function, begin hormone replacement therapy 
when necessary 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
3 or 
Permanently discontinue 
 
For grade 3–4 events: 
 
Discuss with sponsor's medical manager 
 
Consult an endocrinologist 
 
Consider systemic corticosteroid treatment 
 
Begin corticosteroids with mineralocorticoid activity 
immediately for adrenal crisis, severe dehydration, hypotension, 
or shock 
 
Once improved, taper glucocorticoids within 4 weeks (the dose of 
cortisone used for hormone replacement may be adjusted 
accordingly, but subjects whose endocrine function do not recover 
require long-term treatment); consider prophylactic antibiotic 
during taper to prevent infections 
grade 
4 
Hyperthyroidism/Hypothyroidism 
Any 
grade 
 
- 
Monitor signs and symptoms of thyroid dysfunction, e.g. 
hyperthyroidism (palpitations, sweating, increased appetite and 
bowel movement, and weight loss) and hypothyroidism (general 
weakness, fatigue, cold, memory loss, and constipation) 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Monitor and evaluate thyroid function 
- 
Consider consulting an endocrinologist 
- 
Consider testing for thyroid autoantibodies (antithyroglobulin 
antibodies, anti-thyroid peroxidase antibodies, and thyroid-
stimulating hormone receptor antibodies) 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
1 or 
grade 
2 
No dose adjustments  
required 
For grade 1–2 events: 
- 
Monitor thyroid function and thyroid autoantibodies regularly 
- 
L-thyroxine replacement therapy or anti-thyroid medications when 
necessary 
Grade 
3 or 
grade 
4 
Hyperthyroidism 
• Permanently discontinue 
Hypothyroidism 
• No dose adjustments  
• required 
For grade 3–4 events: 
 
Discuss with sponsor's medical manager 
- 
Monitor thyroid function and thyroid autoantibodies 
- 
Consult an endocrinologist 
Hyperthyroidism 
- 
Anti-thyroid medications 
- 
Consider β-blockers for tachycardia 
Hypothyroidism 
- 
L-thyroxine replacement therapy 
Type I Diabetes 
Any 
grade 
 
- 
Monitor signs and symptoms closely, e.g. polyuria, polydipsia, 
polyphagia, fatigue, weakness, and weight loss 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Monitor and assess pancreas islet function: blood glucose, insulin, 
c-peptide, β-cell autoantibodies, blood ketones, and other endocrine 
laboratory parameters related to type I diabetes 
Grade 
1 or 
grade 
2 
No dose adjustments  
required 
For grade 1–2 events: 
 
Monitor and assess pancreas islet function 
 
Start insulin therapy when necessary 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
3 
Interrupt 
 Resume treatment after 
blood glucose is under 
control 
For grade 3–4 events: 
 
Consult with sponsor's medical manager 
 
Monitor and assess pancreas islet function 
 
Consider consulting an endocrinologist 
 
Blood glucose control with insulin, adjust insulin dose accordingly 
 
If ketoacidosis occurs, subjects shall be hospitalized to receive 
insulin, fluid replacement, and alkali therapy 
Grade 
4 
Permanently discontinue 
Renal Insufficiency (Creatinine 
Elevated) 
Any 
grade 
 
 
Monitor signs and symptoms closely (e.g. oliguria, dark urine, 
anemia, fatigue, and weight loss) 
 
Subjects shall be fully evaluated to rule out any alternative causes 
 
Monitor and evaluate renal function 
 
Consider consulting a nephrologist 
 
Consider kidney biopsy when necessary to distinguish between 
inflammatory and non-inflammatory causes 
Grade 
1 
No dose adjustments  
required 
 
For grade 1 events: 
- 
Monitor creatinine levels Q1W 
- 
If creatinine level returns to baseline level, resume routine 
creatinine monitoring according to the study protocol 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 or 
grade 
3 
Interrupt 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
• If persists for > 7 days or 
worsens, treat as a grade 
4 event 
For grade 2–3 events: 
- 
Discuss with sponsor's medical manager 
- 
Monitor creatinine levels every 2–3 days 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If reduces to grade 1, taper glucocorticoid for at least 1 month, 
consider prophylactic antibiotic to prevent infections 
- 
Consider kidney punch biopsy 
- 
Consult a nephrologist 
Grade 
4 
Permanently discontinue 
For grade 4 events: 
- 
Discuss with sponsor's medical manager 
- 
Monitor creatinine levels once daily 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If reduces to grade 1, taper glucocorticoid for at least 1 month, 
consider prophylactic antibiotic to prevent infections 
- 
Consult a nephrologist 
- 
Consider kidney punch biopsy 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Immune-related neurotoxicities 
(except for myasthenia gravis and 
Guillain-Barré syndrome)  
 
Any 
grade 
 
- 
Monitor the subject's systemic symptoms (headache, nausea, 
dizziness, behavioral changes, or weakness) 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
(e.g. PD, infection, metabolic syndrome, medications, etc.) 
- 
Consider appropriate diagnostic tests (e.g. electromyography and 
nerve conduction study) 
- 
If applicable, begin symptomatic treatment and consult a 
neurologist 
Grade 
1 
No dose adjustments  
required 
- 
Closely monitor signs and symptoms 
Grade 
2 
Interrupt 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
• If worsens, treat as a 
grade 3 event 
For grade 2–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Consider consulting a nephrologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain with appropriate 
medications (e.g. gabapentin, duloxetine, etc) 
- 
Consider systemic corticosteroid treatment 
- 
If no improvement is seen within 3–5 days, consider other tests and 
immunosuppressants (e.g. intravenous immunoglobulin G, IVIgG) 
- 
Once stabilized, taper glucocorticoids within ≥ 4 weeks 
Grade 
3 
Permanently discontinue 
Grade 
4 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Immune-related peripheral 
neuropathy, e.g. Guillain-Barré 
syndrome and myasthenia gravis 
Any 
grade 
 
- 
Monitor signs and symptoms closely (myasthenia gravis: eye or 
limb soreness and discomfort, blurred vision, fatigue, which 
worsens as the day goes on; Guillain-Barré syndrome: sudden and 
severe nerve pain, paralysis of the limbs, and prickling or burning 
sensation in the limbs) 
- 
Timely diagnosis of immune-related peripheral neuropathy is very 
important, as subjects may suffer from unpredictable acute 
compensation, which may lead to severe disease or death.Pay 
special attention to signs and symptoms that may indicate serious 
consequences, e.g. significant dysphagia, rapidly progressive 
weakness, respiratory insufficiency, or autonomic dysfunction 
- 
Neuroelectrophysiological tests shall be performed to rule out any 
alternative causes (e.g. PD, infection, metabolic syndrome, 
medications, etc.) It is worth noting that cancer itself and cancer 
treatment can affect neural function. The diagnosis of immune-
related peripheral neuropathies is thus difficult. Neurological 
consultation shall be actively carried out. 
- 
Plasmapheresis or IVIgG should be considered for subjects with 
Guillain-Barré syndrome (glucocorticoids ar e generally ineffective) 
Grade 
1 
No dose adjustments 
required 
For grade 1 events: 
- 
Discuss with a physician 
- 
Monitor signs and symptoms 
- 
Consider consulting a nephrologist 


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AE Grade/Administration 
Adjustments 
Toxicity Management 
Grade 
2 
Interrupt 
• If reduces to grades 0–1 
or baseline, continue 
the treatment at the 
next scheduled date 
• If worsens, treat as a 
grade 3–4 event 
For grade 2–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Monitor signs and symptoms 
- 
Consider consulting a nephrologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain with appropriate 
medications (e.g. gabapentin, duloxetine, etc.) 
      Myasthenia Gravis 
- 
Glucocorticoids may be used to treat myasthenia gravis (shall be 
used under the supervision of a neurologist since corticosteroids, 
especially high-dose, may result in initial exacerbation of 
symptoms) 
- 
Subjects intolerant to glucocorticoids may be treated with 
plasmapheresis or IVIgG 
- 
For 
myasthenia 
gravis-like 
neurotoxicities, 
consider 
acetylcholinesterase inhibitors in addition to glucocorticoids 
     Guillain-Barre Syndrome 
- 
Plasmapheresis or IVIgG should be considered for subjects with 
Guillain-Barré syndrome (glucocorticoids are generally ineffective)  
Grade 
3 or 
grade 
4 
Permanently discontinue 
 
 


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Table 2. IBI308 administration adjustments and toxicity management of other potential irAEs 
 
CTD Grade/Administration Adjustments 
Toxicity Management 
Any grade 
Dose adjustments are not required for AEs unrelated to 
study treatment or laboratory abnormalities that are not 
clinically significant (events caused by underlying 
disease) 
Manage based on local clinical practice 
Grade 1 
No dose adjustments required 
Grade 2 
Consider interruption until reduces to grade 0–1 or 
baseline 
Grade 3 
• 
First occurrence: interrupt until reduces to grade 0–
1 or baseline 
• 
Second occurrence: permanently discontinue 
• 
For an AE that reduces to grades 0–2 within 7 days, 
or grades 0–1 or baseline within 14 days, interrupt 
and then resume the treatment at the next scheduled 
date Otherwise, permanently discontinue 
Grade 4 
Permanently discontinue (Note: for grade 4 laboratory 
abnormalities, the event shall be determined based on 
clinical signsasymptoms and the clinical judgment of the 
investigator) 
 
 


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Table 3. Dose adjustments and toxicity management for infusion reactions 
CTD 
Grade 
Administration Adjustments 
Toxicity Management 
Any 
grade 
 
- 
Manage based on local clinical practice 
- 
Monitor infusion-related reactions (e.g. fever or chills, flushing and/or pruritus, 
changes in heart rate and blood pressure, dyspnea, chest discomfort, rash, etc.) 
and allergic reactions (e.g. systemic urticaria, angioedema, asthma, hypotension, 
tachycardia, etc.) 
Grade 
1 
Reduce to 50% of the original infusion rate or 
interrupt the infusion until the infusion reaction 
resolves 
For grade 1–2 events: 
- 
Administer acetaminophen and/or antihistamine according to local clinical 
practice based on the investigator' judgment 
- 
Consider prophylactic premedications for subsequent infusion according to local 
clinical practice 
Grade 
2 
Reduce to 50% of the original infusion rate or 
interrupt the infusion until the infusion reaction 
resolves, then resume at 50% of the original infusion 
rate 
Grade 
3/4 
Permanently discontinue 
For grade 3–4 events: 
- 
Manage severe infusion-related reactions according to local clinical practice (e.g. 
administration of epinephrine, diphenhydramine, ranitidine, and glucocorticoids) 
 
 
 
 
 
 
 


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Appendix 8: EQ-5D-5L Scale 
By placing a tick (√) in one box in each group below, please indicate which statements best 
describe your own health state today. 
 
Mobility 
I have no problems in walking about.   
 
 
 
 
 
 
 
 
 
 
 
□ 
I have slight problems in walking about.   
 
 
 
 
 
 
 
 
 
 
□ 
I have moderate problems in walking about.  
 
 
 
 
 
 
 
 
 
 
□ 
I have severe problems in walking about.   
 
 
 
 
 
 
 
 
 
 
□ 
I am unable to walk about.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
□ 
 
Self-Care 
I have no problems caring for myself.   
 
 
 
 
 
 
 
 
 
 
 
□ 
I have slight problems washing or dressing myself.   
 
 
 
 
 
 
  
 
□ 
I have moderate problems washing or dressing myself.   
 
 
 
 
 
 
 
□ 
I have severe problems washing or dressing myself.  
 
 
 
 
 
 
 
 
□ 
I am unable to wash or dress myself.   
 
 
 
 
 
 
 
 
 
 
 
□ 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
I have no problems with performing my usual activities.  
 
 
 
 
 
 
 
□ 
I have slight problems performing my usual activities.   
 
 
 
 
 
 
 
□ 
I have moderate problems performing my usual activities.   
 
 
 
 
 
 
□ 
I have severe problems performing my usual activities.   
 
 
 
 
 
 
 
□ 
I am unable to perform my usual activities.  
 
 
 
 
 
 
 
 
 
 
□ 
 
Pain/Discomfort 


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I have no pain or discomfort.   
 
 
 
 
 
 
 
 
 
 
 
 
 
□ 
I have slight pain or discomfort.   
 
 
 
 
 
 
 
 
 
 
 
   □ 
I have moderate pain or discomfort.   
 
 
 
 
 
 
 
 
 
 
   □ 
I have severe pain or discomfort.   
 
 
 
 
 
 
 
 
 
 
 
   □ 
I have extreme pain or discomfort.  
 
 
 
 
 
 
 
 
 
 
 
   □ 
 
Anxiety/Depression 
I am not anxious or depressed.  
 
 
 
 
 
 
 
 
 
 
 
 
   □ 
I am slightly anxious or depressed.  
 
 
 
 
 
 
 
 
 
 
 
   □ 
I am moderately anxious or depressed  
 
 
 
 
 
 
 
 
 
   □ 
I am severely anxious or depressed  
 
 
 
 
 
 
 
 
 
 
 
   □ 
I am extremely anxious or depressed   
 
 
 
 
 
 
 
 
 
 
   □ 
 
 


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Appendix 9: EORTC-QLQ-C30 (v3) Quality of Life Scale 
We would like to know about you and your health status. Please answer all the questions yourself by circling 
the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide 
will be kept confidential. 
    Please fill in your initials:                              
     Date of Birth:            YYYY       MM       DD 
     Today's date:           YYYY       MM       DD 
__________________________________________________________________________________                     
 
Not 
at 
All 
A Little 
Quite 
a Bit 
Very 
Muc
h 
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 shortwalk outside of the house? 
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, washing yourself or using the 
1 
2 
3 
4 
 
During the past week: 
Not 
at 
All 
A Little 
Quite 
a Bit 
Very 
Muc
h 
 6. Were you limited in doing either your work or other daily activities?    
1 
2 
3 
4 
 7. Were you limited in pursing 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 


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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 
 
During the past week: 
Not 
at 
All 
A Little 
Quite 
a Bit 
Very 
Muc
h 
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 
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 
1 
2 
3 
4 
27. Has your physical condition or medical treatment interfered with your 
1 
2 
3 
4 
28. Has your physical condition or medical treatment caused you financial 
1 
2 
3 
4 
 
 
 
 
 
 
  For the following questions, please circle the number between 1 and 7 that 
best applies to you 
29. How would you rate your overall health during the past week?        
     1          2          3         4         5         6        7 
    Very poor                                                   Excellent 
30. How would you rate your overall quality of life during the past week?         


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     1          2          3         4         5         6        7 
    Very poor                                                   Excellent 
 
 
 


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Summary of Amendment 
Alternative Version 2 to Version 1 (Version Date:May.11, 2017) 
Main change 
Description 
1. Sample 
sizes 
changed 
from 
minimum of 60 patients to 20-60 patients 
When 28 patients were enrolled, several early PD 
were observed, and the Lugano 2014 criteria made 
response evaluation difficult due to the lack of a 
definition 
for 
pseudo-progression. 
Therefore, 
enrollment was paused, but treatment was continued 
to confirm the true nature of the pseudo-progression 
according to investigator’s discretion. After 3 
months of observation and in-depth analysis of the 
28 patients, sintilimab demonstrated 67.9% ORR 
when taking pseudo-progression into consideration. 
Planned total enrollment was not reached. When 
hypothesizing that the 15 yet-to-be-enrolled patients 
would be non-responders, there would be 19 
responders out of 43 (28 actually enrolled + 15 
fictive), providing a 95% CI by Wilson’s method of 
30.4%-58.9%, where the lower boundary is still 
greater than the pre-planned 30% threshold. There’s 
no need to enroll a total of 60 patients.  
2. Add RNA expression as a biomarker Detection of RNA expression could help to capture 
potential biomarker for predicting response. 
3. Modify the tratement duration up to 
24 months 
No clinical benefit evidence to support a long 
treatment duration for more than 2 years. 
4. Modify the final injection volume 
(after preparation) from 250 ml to 100 ml 
Based on the updated stability test of sintilimab, the 
recommended final concentration is 1.5~2 mg/ml. 
5. Remove the second interim analysis There no need to perform a second interim analysis.