Clinical trial NCT03568539
Conditions: Advanced/Metastatic Solid Malignancies
Keywords: Advanced/metastatic solid malignancies, TMB high
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2018-06-27; Completion date: 2020-12-07
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is to evaluate preliminary anti-tumor activity (overall response rate, ORR) of IBI308 monotherapy in subjects with advanced/metastatic solid malignancies.

Patients will be recruited for 2 cohorts:

• Cohort 1: Advanced/metastatic cancers with TMB\>10 mutations per megabase (mut/Mb). This enrollment of this cohort has been stopped per sponsor's communication with the sites. For patients who have already enrolled in this cohort, treatment and monitoring will be conducted as stipulated by the protocol. The patients will remain on study until disease progression or intolerable toxicity, death, withdrawal of consent, or end of study, whichever occurs first.

Cohort 2: Advanced/metastatic endometrial cancer (N=40)

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: IBI308
Intervention descriptions: intervention 1: IBI308 200mg IV infusion, every 3 weeks.

Protocol documents:
Prot_000.pdf: 
Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
Date: 01/07/2019 
Protocol # CIBI308A102 
 
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CLINICAL STUDY PROTOCOL 
 
An open-label, phase 1b multicenter study of IBI308 in subjects with 
advanced/metastatic solid malignancies. 
 
This study will be conducted according to this protocol, including protocol amendments and in 
compliance with Good Clinical Practice, ethical principles, and other applicable regulatory 
requirements 
 
Protocol Number: 
CIBI308A102 
Clinical Phase: 
Phase 1b 
IND Number: 
136159 
Sponsor: 
Innovent Biologics(Suzhou) Co.Ltd 
Version:                                 6 
Effective Date:                      January 7, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
Date: 01/07/2019 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ......................................................................................... 1 
SPONSOR SIGNATURE ........................................................................................................ 7 
INVESTIGATOR AGREEMENT ......................................................................................... 8 
List of Abbreviations ................................................................................................................. 9 
Synopsis ................................................................................................................................... 11 
Schedule of Events ................................................................................................................. 14 
1. 
Introduction ...................................................................................................................... 18 
1.1 
Background and Rational for Tumor Selection .................................................. 18 
1.2 
IBI308 ................................................................................................................. 19 
1.3 
Rational of the study ........................................................................................... 19 
1.3.1 
Preclinical Studies ............................................................................................... 19 
1.3.2 
Clinical Studies ................................................................................................... 19 
2. 
Objectives ........................................................................................................................ 22 
2.1 
Primary Objectives.............................................................................................. 22 
2.2 
Secondary Objectives.......................................................................................... 22 
2.3 
Exploratory Objective ......................................................................................... 22 
3. 
Study Design .................................................................................................................... 22 
3.1 
Scheme of The Study design............................................................................... 22 
3.2 
Overview ............................................................................................................. 23 
3.2.1 
Rationale of Dose Selection ................................................................................ 23 
3.3 
Randomization Procedures ................................................................................. 24 
4. 
Study Population .............................................................................................................. 25 
4.1 
Patient Number/Study Sites ................................................................................ 25 
4.2 
Eligibility Criteria ............................................................................................... 25 
4.2.1 
Overview ............................................................................................................. 25 
4.2.2 
Inclusion Criteria ................................................................................................ 25 
4.2.3 
Exclusion Criteria ............................................................................................... 26 
4.3 
Subject Screening Procedures ............................................................................. 27 


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5. 
Study Intervention ............................................................................................................ 28 
5.1 
Study Drug .......................................................................................................... 28 
5.2 
Treatment Compliance and drug accountability ................................................. 28 
5.3 
Dosage and Drug Administration ....................................................................... 29 
5.4 
Dosing Procedure and Treatment cycles ............................................................. 29 
5.5 
Duration of Treatment......................................................................................... 29 
5.6 
Treatment Beyond Disease Progression ............................................................. 29 
5.7 
Dose Modification and Management of Withholding, Resuming or 
Discontinuation of the Study Drug ...................................................................................... 30 
5.7.1 
Criteria for Withholding Study Drug .................................................................. 30 
5.7.2 
Criteria to Resume Treatment ............................................................................. 31 
5.7.3 
Criteria for Drug Discontinuation ....................................................................... 31 
5.8 
Special Precautions and Clinical Interventions ................................................... 31 
5.8.1 
Infusion Reactions .............................................................................................. 32 
5.8.2 
Extravasation....................................................................................................... 33 
5.8.3 
Immune Related Adverse Events (irAE) ............................................................ 33 
5.9 
Concomitant Medication ..................................................................................... 38 
5.10 
End of Treatment (EOT) ..................................................................................... 38 
5.11 
Follow-up ............................................................................................................ 38 
5.12 
Removal from Study Treatment and off-Study Criteria ..................................... 39 
5.12.1 
Criteria for removal from study treatment ................................................... 39 
5.12.2 
Off-Study Criteria ........................................................................................ 39 
5.13 
Pregnancy/Contraception/Nursing ...................................................................... 39 
5.13.1 
Pregnancy Testing ........................................................................................ 39 
5.13.2 
Contraception ............................................................................................... 40 
5.13.3 
Use in Pregnancy ......................................................................................... 40 
5.13.4 
Use in Nursing Women ................................................................................ 41 
6. 
Study assessment and Evaluations ................................................................................... 41 
6.1 
Specimen Collection and Evaluations ................................................................ 41 
6.1.1 
Pharmacokinetics (PK) ....................................................................................... 41 
6.1.2 
Immunogenicity .................................................................................................. 41 


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6.1.3 
Biomarkers .......................................................................................................... 41 
6.1.4 
Safety Laboratory Evaluations ............................................................................ 43 
7. 
Data Collection and Management .................................................................................... 43 
7.1 
Protocol Deviations ............................................................................................. 44 
7.2 
Publication and Data Sharing.............................................................................. 44 
8. 
Human Subject Protection and Regulatory Oversight ..................................................... 44 
8.1 
Informed Consent Processes and Documentation............................................... 44 
8.2 
Institutional Review Board Approval ................................................................. 45 
8.3 
Case Report Forms (CRFs) ................................................................................. 45 
8.4 
Confidentiality and Privacy ................................................................................ 46 
8.5 
Conflict of Interest .............................................................................................. 46 
9. 
Safety Reporting .............................................................................................................. 47 
9.1 
Definitions........................................................................................................... 47 
9.2 
Causality AE ....................................................................................................... 47 
9.3 
Categorizations of AEs ....................................................................................... 48 
9.4 
Reporting of SAEs .............................................................................................. 49 
9.5 
IRB Reporting ..................................................................................................... 49 
9.6 
Reporting of Pregnancy ...................................................................................... 49 
10. 
STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS .. 50 
10.1 
General Statistical Consideration ........................................................................ 50 
10.2 
Data Analysis ...................................................................................................... 51 
10.2.1 
Pharmacokinetic Data .................................................................................. 51 
10.2.2 
Immunogenicity ........................................................................................... 51 
10.2.3 
Efficacy ........................................................................................................ 51 
10.3 
Determination of Sample Size ............................................................................ 51 
10.4 
Subject Replacement Policy ............................................................................... 51 
10.5 
Safety Evaluations .............................................................................................. 52 
10.6 
Efficacy Evaluations ........................................................................................... 52 
10.7 
Population Analysis ............................................................................................ 52 
10.7.1 
Safety Population ......................................................................................... 52 
10.7.2 
Efficacy Population ...................................................................................... 53 


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10.7.3 
PK Population .............................................................................................. 53 
10.8 
Tabulation of Individual Participation Data ....................................................... 53 
11. 
Study management .............................................................................................. 53 
11.1 
Quality Assurance and Quality Control .............................................................. 53 
11.2 
Clinical Monitoring Plan..................................................................................... 54 
11.3 
Study Closure ...................................................................................................... 54 
12. 
REFERENCES ................................................................................................... 56 
13. 
GENERAL APPENDICES ................................................................................. 57 
13.1 
Appendix 1 Eastern Cooperative Status Oncology Group Performance Status 
Score 
............................................................................................................................. 57 
13.2 
Appendix 2 Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 
............................................................................................................................. 58 
13.3 
Appendix 3 modified RECIST 1.1 for immune based therapeutics (iRECIST) . 60 
 
 
 


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LIST OF TABLES 
Table-1. Schedule of Events .................................................................................................... 14 
Table-2. Details of Sampling for Pharmacokinetics (PK) ....................................................... 17 
Table-3 Clinical Trials Conducted in China: Current status (cut-off date: Oct 30, 2017)....... 20 
Table-4. Summary of AEs in subjects receiving IBI308 treatment ......................................... 21 
Table-5. Study population, sample size and treatment dose. ................................................... 29 
Table-6 Management of Infusion-Related Reactions/Hypersensitivity Reactions (NCI 
CTCAE Grade) ........................................................................................................................ 32 
Table-7  Management of Gastrointestinal irAEs ..................................................................... 33 
Table-8  Management of Hepatic irAEs .................................................................................. 34 
Table-9 Management of Dermatological irAEs. ...................................................................... 35 
Table-10  Management of Pulmonary irAEs. .......................................................................... 36 
Table-11 Management of Renal irAEs. ................................................................................... 37 
 
 
 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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SPONSOR SIGNATURE 
 
Study Title: An open-label, phase 1b multicenter study of IBI308 in subjects with 
advanced/metastatic solid malignancies 
 
Study Number: CIBI308A102 
 
Protocol Version: Version 6, Jan 07, 2019 
 
 
Person authorized to sign the protocol and protocol amendment(s) for the Sponsor, Innovent 
Biologics (Suzhou) Co. Ltd. 
 
 
Signature______________________________________________________________ 
 
Date__________________________________________________________________ 
 
 
PRINTED NAME 
Kerry Levan Blanchard 
TITLE 
Chief Science Officer 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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INVESTIGATOR AGREEMENT 
Protocol No.: CIBI308A102 
Version Date: V 6, Jan 07, 2019 
I have read the protocol CIBI308A102 and Investigators’ Brochure for study conduct and 
regarding the risks and potential benefits of the trial. I agree to conduct the protocol in accordance 
with Good Clinical Practices (ICH-GCP), Federal regulations, and state and local laws to maintain 
the protection of the rights and welfare of study participants.   
I certify that I, and my research study staff, have received adequate training to conduct this 
research protocol.  
I agree to maintain accurate and adequate records in accordance with institutional, company, 
Federal, state and local laws and regulations. 
 
 
Principle Investigator  
 
Name (printed)______________________________________________________________ 
 
Signature___________________________________________________________________  
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
aPTT 
Partial thromboplastin time 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
Complete Response 
CRF 
case report form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
EOI 
End of Infusion 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
HGB 
hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
INR 
International normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRRC 
irAE 
Independent Radiology Review Committee 
immunotherapy-related adverse events 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
overall response rate 
PD 
disease progression 
PK 
pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PT 
Prothrombin time 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
RBC 
red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
stable disease 
SD 
standard deviation 
TMB 
Tumor Mutation Burden 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
 
 
 
 
 
 
 
 
 
 
 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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Synopsis 
 
Title: 
An Open-label, Phase 1b Multicenter Study of IBI308 in Subjects 
with Advanced/Metastatic Solid Malignancies 
Sponsor 
Innovent Biologics (Suzhou) Co. Ltd. 
Study Drug 
IBI308 
Clinical Trial Phase 
Phase 1b 
Proposed Indication 
Advanced/metastatic solid malignancies  
Objectives: 
 
Primary 
• 
To evaluate preliminary anti-tumor activity (overall 
response rate, ORR) of IBI308 monotherapy in subjects 
with advanced/metastatic solid malignancies. 
 
Secondary 
• 
To measure progression-free survival rate (PFS). 
• 
To measure duration of response (DOR). 
• 
To measure overall survival rate (OS). 
• 
To obtain safety and toxicity data. 
• 
To further evaluate pharmacokinetics (PK) of IBI308. 
• 
To further evaluate immunogenicity of IBI308. 
 
Exploratory Objectives 
• 
To explore the relationship between baseline markers 
(PD-L1, TMB etc.) and clinical response. 
• 
To explore the relationship between exposure and 
efficacy/safety. 
• 
To assess the impact of ADA on PK, efficacy/safety. 
Study Population: 
≥18 years, have a histologically or cytologically confirmed 
advanced/metastatic solid tumor and have progressed on 
available standard therapies or for which no standard therapy 
exists. 
Number of Subjects 
planned 
Up to 40 subjects with advanced/metastatic endometrial cancer 
(EC) will be enrolled in cohort 2. The original planned cohort 1 
with 60 subjects with advanced/metastatic cancer and high tumor 
mutational burden (TMB) has stopped enrolling at the time of the 
protocol amendment. 
Number of Study 
Centers Planned 
Approximately 15 study sites located in the United States. 
Additional sites may be added if necessary. 
Description of Study 
Intervention: 
This is an open-label, phase 1b multicenter study of IBI308 in 
subjects with advanced/metastatic solid malignancies. Patients 
will be recruited for 2 cohorts: 
 
Cohort 1: Advanced/metastatic cancers with TMB>10 
mutations per megabase (mut/Mb).  This enrollment of this 
cohort has been stopped per sponsor’s communication with 
the sites. For patients who have already enrolled in this 
cohort, treatment and monitoring will be conducted as 
stipulated by the protocol.  The patients will remain on study 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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until disease progression or intolerable toxicity, death, 
withdrawal of consent, or end of study, whichever occurs 
first. 
 
Cohort 2: Advanced/metastatic endometrial cancer (N=40) 
Please see Table-5 for sample sizes.  A fixed dose of 200 mg 
IBI308 will be administered as IV infusion for every three weeks 
(Q3W) to the patients until disease progression or intolerable 
toxicity, death, withdrawal of consent, or end of study, whichever 
occurs first.  
Study participation 
Duration: 
The maximum treatment duration is 2 years. 
Pharmacokinetic (PK) 
evaluations 
PK of IBI308 will be investigated extensively: PK will be 
assessed at predose, within 5 min after the end of infusion 
(EOI), at 1, 6, 24, 48, 168, 336 hours post EOI in Cycle 1, 
predose in Cycle 2 and every other cycle thereafter for the first 
12 cycles, and at 30 days follow-up visit for the first 6 subjects 
in cohort 1 and first 12 subjects in cohort 2. 
PK will be sparsely assessed at predose in Cycle 2 and every 
other cycle thereafter for the first 12 cycles, and at 30 days 
follow-up visit for other subjects.   
The results of these analyses, if performed, may be reported 
separately. 
Safety Evaluations 
Safety will be assessed by physical examinations, vitals, ECG, 
laboratory tests, AE monitoring, and concomitant medication 
usage monitoring. AEs are graded according to the CTCAE 
v4.03. Investigators will report whether an AE is potentially 
immune related (irAE). irAEs are defined as AEs of unknown 
etiology potentially associated with an immune phenomenon. 
Follow up for SAEs, which are assessed as at least possibly 
related late irAEs, will be followed up to 3 months after the last 
dose of IBI308.  
Efficacy Evaluations 
Tumor assessment will be performed at baseline, every 2 cycles, 
and at the end of treatment by the investigator per RECIST v1.1. 
Efficacy evaluations will include the following: computed 
tomography (CT), magnetic resonance imaging (MRI), physical 
examination, and other procedures as necessary. If a patient is 
classified as having disease progression at a post-baseline tumor 
assessment, then confirmation by a second scan within 4-6 weeks 
in the absence of rapid clinical deterioration is required.  
Anti-cancer activity parameters that will be assessed include 
determination of the following: 
1) 
Best overall response [complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease] 
2) 
Objective response rate (ORR) (CR + PR) 
3) 
Duration of response (DOR) or duration of SD 


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4) 
Disease control rate (DCR) (CR, PR or SD) 
5) 
Progression-free survival (PFS) and overall survival (OS) 
efficacy evaluations 
Immunogenicity 
Blood samples for anti-drug antibody (ADA) analyses will be 
collected within 24 hours before start of infusion in Cycle 1 and 
Cycle 2 and then in every other subsequent cycle, and at the 
Safety Follow-up Visit or until start of a new anti-cancer therapy, 
whichever occurs first.  
Statistical Analysis: 
Summary statistics will be presented by cohort as well as overall 
for the trial. The number of subjects presenting with adverse 
events will be summarized by cohort and overall for the trial. 
Safety and tolerability will be evaluated by AEs/irAEs, laboratory 
assessments, vital signs, 12-lead electrocardiograms, physical 
examination, ECOG PS, and concomitant medication usage, 
using the safety analysis set. For laboratory data, changes over 
time will be described using descriptive statistics, and the 
percentage of subjects with values outside the normal range will 
be presented.  
All PK, immunogenicity, and safety data will be summarized 
using descriptive statistics (number of subjects, mean, median, 
standard deviation, minimum, and maximum) for continuous 
variables and using frequencies and percentages for discrete 
variables.   
ORR and the associated 2-sided 95% exact confidence limits will 
be provided. The proportion of subjects who have experienced 
best response as CR, PR, SD or disease progression (PD) will be 
calculated. PFS and OS data will be analyzed by Kaplan-Meier 
method. 
 
 
 


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Schedule of Events 
Table-1. Schedule of Events 
Study 
Day/Visit 
Day 
Screening -
28 to 0 
(± 3 Day)  
Cycle 1 Day 1 
Each Subsequent Cycle 
Day1 (± 3 Day) 
EOT  
Within 7 days16 
 (±3 Days) 
Safety FU 30 Days after 
last dose 
(± 7) 17 
Survival FU (±7)  
Every 3 months after last 
dose18 
Informed consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Safety Assessment 
 
Vital Signs 1 
X 
X 
X 
X 
X 
 
Physical 
Examination 
X 
X 
X 
X 
X 
 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
 
Disease-Specific 
Staging Criteria2 
X 
 
 
 
 
 
AE assessment 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
 
CBC w/ Diff 3 
X 
X 
X 
X 
X 
 
Blood chemistry 4 
X 
X 
X 
X 
X 
 
Thyroid 
Function 
Tests 5 
X 
 
X 
X 
X 
 
Coagulation 6  
X 
 
 
 
 
 
Pregnancy 
test 
(HCG)7 
X 
 
 
 
X 
 
Hepatitis and HIV 
screen8 
X 
 
 
 
 
 


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ECG (12 Lead)9 
X 
X 
X 
X 
X 
 
Urine Analysis 
X 
 
X 
X 
X 
 
Efficacy Assessments 
 
Imaging 
(CT 
or 
MRI)10 
X 
every 2 cycles and at EOT 
 
 
Cardiac 
Assessment 
(ECHO, MUGA)11 
X 
 
 
 
 
 
Bone scan19 
X 
 
 
 
 
 
Administration of Investigational drug 
 
Administration of 
IBI308 
 
X 
X 
 
 
 
Biomarker Assessments 
 
Tissue12 
X 
 
 
 
 
 
Blood samples13 
 
X 
X 
 
X 
 
PK and Immunogenicity 
 
PK14 (see Table 2) 
 
 
 
 
 
 
ADA15 
 
X 
X 
 
X 
 
EOT: end of treatment 
 
1 Baseline conditions 
2 Disease-specific staging criteria (for CRF purposes, e.g.: TNM classification and etc.) 
3 Including CBC with differential and platelet count performed within 7 days prior to first dose (do not repeat Cycle 1 Day 1 CBC, if screening CBC is within 7 days of dosing) 
and 72 hours prior following doses on the schedule 
4 Including alkaline phosphatase, ALT/AST, total bilirubin, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, uric acid, LDH, fasting lipid 
panel (LDL, total cholesterol, triglycerides), amylase and lipase performed within 7 days prior to first dose (do not repeat Cycle 1 Day 1 Blood Chemistry, if screening Blood 
Chemistry is within 7 days of dosing) and 72 hours prior following doses on the schedule 
5 Thyroid function tests include Thyroid stimulation hormone (TSH), Free T3 and T4 
6 Including aPTT/INR performed within 7 days prior to first dose at day 1 on a schedule 


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7 Pregnancy test needs to be performed within 72 hours before Cycle 1 dosing and at first Safety Follow-up visit 
8 Including HBsAg, HBsAb, HBcAb, Hep C RNA, HIV screen 
9 12-lead ECG on screening, 72 hours prior each dose, EOT and at first Safety Follow-up visit  
10 Tumor imaging (either CT or MRI, with preference for CT) will be performed at screening, every 2 cycles and EOT. The same imaging technique should be used in a patient 
throughout the study. Tumor assessment should be performed according to RECIST 1.1 and to iRECIST 1.1 
11 Cardiac Assessments Echocardiogram (ECHO) and/or multiple-gated acquisition scan (MUGA) at screening phase, and as clinically indicated afterwards. 
12 May be archival or recent sample. Separate ICF is needed for collecting fresh tumor tissue biopsies. 1 formalin-fixed paraffin embedded tumor tissue block, or minimum of 
10 FFPE unstained slides are needed. Evaluations include but are not limited to PD-L1 and TIL, please refer to 6.1.3 section for details. Specific instructions for tissue collection 
and shipment are provided in the procedures manual. 
13 Collected prior to first dose and every 2 cycles at predose until the Safety Follow-up Visit. Evaluations include but are not limited to factors induced by IFNγ signaling, 
antibodies to tumor-associated antigens, and soluble PD-L1 (PD-L1), please refer to 6.1.3 section for details. Specific instructions for sample collection and shipment are 
provided in the procedures manual. 
14 Please see details in specific PK (Table-2).  
15 Blood samples for anti-drug antibody (ADA) analyses will be collected within 24 hours before start of infusion in Cycle 1 and Cycle 2 and then in every other subsequent 
cycle, and at the Safety Follow-up Visit or until start of a new anti-cancer therapy, whichever occurs first. 
16 EOT visit should be completed within 7 days (±3 Days) if investigator decides to end the treatment for subject. If the physic al exams, lab tests and other relevant events 
which should be performed on the EOT have done within 7 days of next planned visit after previous dose of study medicine, these results could be recorded as EOT visit; if the 
above scheduled events have done within 21 to 30 days after the last dose of study medicine, these results could be recorded as the safety FU visit. 
17 The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of study therapy or before the initiation of a new anti-cancer treatment, 
whichever occurs first. Patients who are discontinued from the study due to an unacceptable drug-related adverse event will be followed until the resolution of the AE to Grade 
0-1 or stabilization or until beginning of a new therapy for their cancer, whichever occurs first. 
18 After the Safety Follow-UP visits, subjects will have survival follow-ups every 3 months by clinical visits or telephone calls, until death, loss-to-follow-up, withdrawal of 
consent, or study termination by sponsor.  
19 Bone scan should be performed according to local clinical practice guideline by investigators’ decision 
 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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Table-2. Details of Sampling for Pharmacokinetics (PK)  
 
Screening 
Treatment 
Safety FU 
30 Days 
(±7) 
Cycle 1 
2Cycle 2 and 
Additional Cycles 
(21 Days ±2 Days) 
Day 
-28~-1 
1 
2 
3 
8 
15 
1 
 
 
 
Predose 
 
 
Post-
dose 
 
 
 
 
 
Predose 
 
 
 
1Time 
Points  
 
-1h 
infusion 
Immediately 
at end of 
infusion 
1h 
6h 
24h 
48h 
168h 
336h 
-1h 
infusion 
Immediately 
at EOI 
 
Window 
 
 
 
+5min 
±5min  
±15mi
n 
±1h 
±2h 
±8h 
±12h 
 
 
+5min 
 
IBI308 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
4PK 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 2 
 
 
X 3 
Please note: 
1. Sample collection must be from opposite arm to that used for study drug infusion. 
2. Cycle 2 and subsequently every other cycle for the first 12 cycles. 
3. PK assays should be performed at the mandatory end of study visit. 
4. PK will be intensively assessed at predose, within 5 min after the end of infusion (EOI), at 1, 6, 24, 48, 168, 336 hours post EOI in Cycle 1, predose in 
Cycle 2 and every other cycle thereafter for the first 12 cycles, and at 30 days follow-up visit for the first 6 subjects in cohort 1 and first 12 subjects in 
cohort 2. PK will be sparsely assessed at predose, within 5 min after the end of infusion (EOI) in cycle1, predose in Cycle 2 and every other cycle thereafter 
for the first 12 cycles, and at 30 days follow-up visit for other subjects. 


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1. INTRODUCTION 
1.1 Background and Rational for Tumor Selection  
Recently emerging data has shown, that immunotherapeutic treatment with check point 
inhibitors is efficient and well tolerated, with a favorable safety profile and less toxicity as 
compared to conventional chemotherapy. The interaction between the programmed cell death 
protein 1 (PD-1) and its ligands (programmed death-ligand 1 (PD-L1) and programmed death-
ligand 2 (PD-L2), plays an important role in maintaining the balance between immune 
activation and tolerance, potentially including tumor tolerance. Blocking the interaction 
between PD-1 and PD-L1, has been reported to have antitumor effects in many malignancies. 
A number of checkpoint inhibitors including PD-1 or its ligand (PD-L1), have been approved 
by FDA for the treatment of multiple cancers including non-small cell lung cancer (NSCLC), 
melanoma, classical Hodgkin lymphoma (cHL), urothelial carcinoma, renal cell carcinoma 
(RCC), adult and pediatric microsatellite instability-high cancer(MSI-H) or mismatch repair 
deficient (dMMR) metastatic colorectal cancer (mCRC), hepatocellular carcinoma (HCC),  
gastric cancer, and recurrent or metastatic head and neck squamous cell cancer (HNSCC) 
(OPDIVO®; KEYTRUDA®).   
Endometrial cancer (EC)  
EC is the 4th most common malignancy among women and the 6th leading cause of death in 
2017. It is the most common gynecologic malignancy in the United States, with an estimated 
61,380 new cases and 11,000 deaths in 2017 (ACS, 2016). The incidence of EC is increasing 
annually by an estimated 1-2%. Obesity is a strong risk factor for the development of EC, 
accounting for approximately 50% of cases in Europe and the United States; it also has been 
associated with a relative increased risk of death of up to 6.25. While most ECs present at an 
early stage, approximately 25 % of early stage and more than 50 % of advanced stage cancers 
will recur.  
 
Current adjuvant therapies for advanced EC patients are not very effective and there are 
limited options for patients with metastatic disease. Patients with advanced stage disease at 
the time of diagnosis have a high risk for recurrence. The median survival after recurrence is 
ten months and the five-year overall survival for patients who have recurred is less than 15%. 
Unfortunately, recurrent disease is generally not curable, and response rates for hormone 
therapy are in the 15-20 % range (Lee et al., 2014). Therefore, efforts in finding effective 
treatments for this population need to be pursued. In a Phase1 Study (NCT02054806) in 
patients with EC after failure of prior systemic treatment, the confirmed response rate to 
pembrolizumab was 13 %, demonstrating a promising activity in this heavily pretreated PD-
L1 positive EC patients.   
 
Tumor mutation burden (TMB) 
TMB was defined as the number of somatic, coding, base substitution, and indel mutations per 
megabase of genome examined. Retrospective data suggest that mutational load may 
potentially predict response more robustly than PD-L1 IHC, presence of tumor infiltrating 
lymphocytes, or clinical variables.  


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TMB-h cancer types, NSCLC, melanoma, bladder cancer patients and other indications where 
PD-1 is thought to play a role in tumor immune evasion, were allowed to be enrolled in this 
IBI308 study. The sponsor has made strategic decisions to stop enrolling into this cohort. This 
decision was not related to any safety or ethic concerns. 
1.2 IBI308 
IBI308 is a novel PD-1 antagonist that is being developed for the treatment of various tumors. 
It binds to and neutralizes PD-1 receptor mediated immune suppressive signals on T cells, and 
activates human immune response to kill tumor cells. 
 
1.3 Rational of the study 
1.3.1 Preclinical Studies  
Comprehensive nonclinical studies had been conducted to study the pharmacological 
activities, pharmacokinetic-pharmacodynamics (PK/PD) relationships and safety profiles of 
IBI308. The in vivo nonclinical toxicology (4-week and 26-week) and pharmacokinetic 
studies in cynomolgus monkeys suggest that IBI308 is safe for use in clinical studies in cancer 
patients. Additional in vitro and in vivo pharmacology and toxicology studies conducted 
using nivolumab (an approved anti-PD-1 mAb) as a comparator further support the safety 
and efficacy of IBI308. In these studies, similar profiles were observed for IBI308 and 
nivolumab in terms of binding affinity, blockade of PD-1 receptor and ligand binding, 
enhancement of T cell activation in an allogenic MLR assay, anti-tumor activity in a mouse 
xenograft model, tissue cross reactivity, and cytokine release.  
Refer to the IB for more detailed information on preclinical studies of IBI308.  
 
1.3.2 Clinical Studies 
IBI308 was first developed in China intended for treating advanced/metastatic tumors. In China, 
Innovent has completed phase 1 dose escalation trials, and currently is conducting 3 Phase 2 
trials and 1 Phase 3 trial for IBI308 (Table-3). Innovent filed a BLA for IBI308 in China for 
recurrence / refractory Hodgkin's lymphoma in early December of 2017. Refer to the IB for 
more detailed safety and efficacy information on clinical studies of IBI308.  
As of October 30, 2017, a total of 267 advanced cancer patients received ≥1 dose of study drug, 
of whom 40.45% completed 5 or more treatment cycles with a median duration of 12 weeks 
(9.0 to 17.9), and maximum of 23 cycles. Among the 267 patients who received IBI308, 258 
patients were treated at the 200 mg fixed dose as monotherapy or in combination with 
chemotherapeutic agents, 6 patients received an equivalent (3 mg/kg, n=3) or higher dose than 
200 mg (10 mg/kg, n=3). Only 3/267 patients received a dose less than 200 mg (1 mg/kg, n=3). 
Overall, the 200 mg fixed dose was well tolerated in patients with various advanced cancers. 
 


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Table-3 Clinical Trials Conducted in China: Current status (cut-off date: Oct 30, 2017) 
 
Study 
Disease 
IBI308 Dose 
Subject 
Number 
 
 
 
 
CIBI308A101 
Phase Ia 
Advanced solid tumor 
4 dosage level:  1 mg/kg, 3mg/kg, 
200mg, 10mg/kg 
12 (n=3 
per 
cohort) 
CIBI308A101 
Phase Ib 
Cohort A: Advanced melanoma 
200mg Q3W 
20 
Cohort B: Digestive or neuroendocrine 
tumors, failed in standard treatment 
200mg Q3W 
74 
Cohort C: Advanced NSCLC, failed in 
standard treatment 
200mg Q3W 
26 
Cohort D: Advanced NSCLC, Naïve 
patients 
200mg Q3W 
pemetrexed 500 mg/m2 and cisplatin 
75 mg/m2 Q3W 
7 
Cohort E: Advanced squamous cell 
NSCLC, 
never 
received 
systemic 
treatment 
200mg Q3W 
gemcitabine 1250 mg/m2 IV and 
cisplatin 75 mg/m2 IV Q3W 
1 
CIBI308B201 
Phase 
2 
(ORIENT-1) 
 
Recurrence 
/ 
refractory 
Hodgkin's 
lymphoma 
200 mg Q3W 
95 
CIBI308A201 
Phase 
2 
(ORIENT-2) 
Second-line esophageal squamous cell 
carcinoma 
200 mg Q3W 
15 
CIBI308C301 
Phase 
3 
(ORIENT-3) 
Advanced 
or 
metastatic 
squamous 
NSCLC who have failed platinum-based 
chemotherapy 
200 mg Q3W 
2 
CIBI308D201 
Phase 
2 
(ORIENT-4) 
Recurrence / refractory NK/T cell 
lymphoma 
200 mg Q3W 
15 
Total number 
 
 
267 
The safety analysis included 267 subjects treated with IBI308, among whom 220 (82.4%) had 
at least one adverse event (AE) and 80.1 % had at least one treatment-emerged AEs (TEAE) 
during treatment (Table-4). The most common AEs were fever (27.7%), anemia (13.9%) and 
increased aspartate aminotransferase (11.2%), fatigue (10.5%), decreased white blood cell 
count (9.4%), elevated alanine aminotransferase (8.2%), albuminuria (7.5%), constipation 
(7.1%), rash (6.4%), elevated serum bilirubin (6.4%), hypoalbuminemia (6.0%), reduced 
platelet count (6.0%), decreased appetite (5.6%), and upper respiratory tract infection. The 
incidence of IBI308-related TEAEs was 63.7%, of which TEAE ≥3 grade was 10.1%. The most 
common IBI308-related TEAEs (Classified by PT) were fever (20.6%), elevated aspartate 
aminotransferase (7.1%), fatigue (6.7%), elevated alanine aminotransferase (6.4%) and 
elevated bilirubin (5.2%), rash (5.2%).  
A total of 12 out of 267 patients experienced adverse events with special interest (AESI). 
Pneumonia accounts for 2.2% of all AESIs (all were immune reaction related pneumonia).  The 
incidence of Severe AEs (SAEs) during treatment was 12.7 % (34 cases), and 6.0 % of the 
SAEs were considered possibly related to IBI308 (Table-4). The most common SAEs included 
pulmonary infection (1.9%), pneumonia (1.5%), fever (0.8%), upper gastrointestinal bleeding 
(0.8%), and dysphagia (0.8%).  
The above AEs were also commonly seen from the FDA approved Nivolumab and 
Pembrolizumab. The 200mg fixed dose was well tolerated in patients with various advanced 


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cancers and the overall safety profiles of IBI308 were similar to those of the FDA approved 
anti-PD-1 products. 
Refer to the IB for more detailed safety information on clinical studies of IBI308.  
Table-4. Summary of AEs in subjects receiving IBI308 treatment  
index 
CIBI308A101  
(N = 140) 
CIBI308A201  
Total (N = 15) 
CIBI308B201  
Total (N = 95) 
CIBI308C301  
Total (N = 2) 
CIBI308D201  
Total (N = 15) 
CIBI308  
(N = 267) 
Adverse Events 
(AE) 
106 
(75.7%) 
12 (80.0%) 
86 (90.5%) 
1 (50.0%) 
15 
(100.0%) 
220 
(82.4%) 
Treatment emergent 
adverse events 
(TEAE) 
105 
(75.0%) 
10 (66.7%) 
84 (88.4%) 
1 (50.0%) 
14 (93.3%) 
214 
(80.1%) 
IBI308 treatment 
related AE (TRAE) 
79 (56.4%) 
8 (53.3%) 
70 (73.7%) 
1 (50.0%) 
12 (80.0%) 
170 
(63.7%) 
≥ Grade 3 TEAEs 
33 (23.6%) 
4 (26.7%) 
12 (12.6%) 
1 (50.0%) 
2 (13.3%) 
52 
(19.5%) 
≥ Grade 3 TRAEs 
15 (10.7%) 
2 (13.3%) 
9 (9.5%) 
0.0 
1 (6.7%) 
27 
(10.1%) 
Immune-related 
AEs 
22 (15.7%) 
3 (20.0%) 
22 (23.2%) 
0.0 
1 (6.7%) 
48 
(18.0%) 
Special interests of 
AEs (AESIs) 
6 (4.3%) 
3 (20.0%) 
3 (3.2%) 
0.0 
0.0 
12 
(4.5%) 
SAEs 
22 (15.7%) 
2 (13.3%) 
8 (8.4%) 
1 (50.0%) 
1 (6.7%) 
34 
(12.7%) 
SAEs related to 
IBI308 
9 (6.4%) 
1 (6.7%) 
6 (6.3%) 
0.0 
0.0 
16 
(6.0%) 
AEs leading to 
permanent 
treatment 
discontinuation 
10 (7.1%) 
1 (6.7%) 
1 (1.1%) 
0.0 
0.0 
12 
(4.5%) 
AEs leading to 
death 
2 (1.4%) 
1 (6.7%) 
0.0 
0.0 
1 (6.7%) 
4 
(1.5%)* 
AEs leading to 
terminate the study 
8 (5.7%) 
1 (6.7%) 
0.0 
0.0 
1 (6.7%) 
10 
(4.5%) 
Important TEAE 
78 (55.7%) 
7 (46.7%) 
57 (60.0%) 
1 (50.0%) 
9 (60.0%) 
152 
(56.9%) 
 a CTCAE version 4.03 for severity grading. Adverse events of death level 5.  
 b Serious adverse events include any death, life-threatening, hospital-related or prolonged hospital stay, 
adverse events that result in continuing or major disability / incapacity, congenital anomalies / birth defects, 
or other major medical hazards. 
 
 
 


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2. OBJECTIVES 
2.1 Primary Objectives 
To evaluate preliminary anti-tumor activity (overall response rate, ORR) of IBI308 as a single 
treatment agent in selected populations 
 
2.2 Secondary Objectives 
 To measure progression-free survival rate (PFS). 
 To measure duration of response (DOR). 
 To measure overall survival rate (OS). 
 To obtain toxicity data. 
 To further evaluate PK parameters. 
 To further evaluate immunogenicity of IBI308. 
2.3 Exploratory Objective 
 To explore the relationship between baseline markers (TMB) and clinical response 
 To explore the relationship between exposure and efficacy/safety 
 To assess the impact of ADA on PK, efficacy/safety 
 
3. STUDY DESIGN  
3.1 Scheme of The Study design 
 


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3.2 Overview 
This is an open-label, phase 1b multicenter study of IBI308 in subjects with 
advanced/metastatic solid malignancies. The trial will recruit 2 cohorts: cohort 1 consisting of  
advanced/metastatic cancer patients with TMB>10 mut/Mb, and cohort 2 consisting of 
advanced endometrial cancer patients (refer to Study Design Scheme, and Table-5 for sample 
sizes). Sponsor has made strategic decisions to stop enrollment in cohort 1 in this protocol 
amendment. In each cohort a fixed dose of 200 mg IBI308 will be administered Q3W to the 
patients. Additional cohorts may be added to this study via a new IND package or will be added 
with a protocol amendment submission during the clinical trial stage.  
3.2.1 Rationale of Dose Selection  
Innovent would like to initiate the Phase 1b expansion study with a fixed dose of 200 mg 
IBI308 Q3W, based on all nonclinical and clinical data obtained from Chinese studies, as well 
as the FDA approved clinical dose of similar anti-PD-1 products.   
 The no observed adverse effect level (NOAEL) of 200 mg/kg observed in the pivotal 4-
week toxicity study in monkeys was used to determine the maximum recommended 
starting dose (MRSD) for IBI308.  Applying a 10-fold safety margin, the corresponding 
MRSD is 20 mg/kg (1/10 of NOAEL). The proposed Phase 1b dose (200 mg) is 


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equivalent to 3 mg/kg given an average body weight of 70 kg. This dose is 6-fold lower 
than the MRSD.  
 A Phase 1 dose-escalation (3+3) study at doses of 1 mg/kg, 3 mg/kg, 200 mg (fixed dose), 
and 10 mg/kg Q3W was completed in Chinese patients with advanced malignancies 
(N=12). A Phase 1 dose expansion (200 mg as monotherapy or in combination with other 
chemotherapies in various cancer diseases) is ongoing in China. There were no DLT at 
any dose up to including 10mg/kg in the completed Phase 1a study. IBI308 was generally 
well tolerated after single and multiple dose administration in patients with advanced 
cancers.  
 Currently, there are 5 clinical studies with IBI308 in China. As of October 30, 2017 
(cutoff date), a total of 267 advanced cancer patients received ≥1 dose of study drug, of 
whom 91.76 received ≥2 cycles, 79.40% received ≥3 cycles, 57.68% received ≥4 
cycles, and 40.45% received ≥5 cycles of dosing. Among the total of 267 patients who 
received at least one dose of IBI308, 258 patients were treated at the 200 mg fixed dose 
as monotherapy or in combination with chemotherapeutic agents. Overall, the 200 mg 
fixed dose was very well tolerated in patients with various advanced cancers. Refer to the 
IB for more detailed information on clinical studies of IBI308.  
 The CIBI308B201 Phase 2 study showed robust PD-1 receptor occupancy (RO) on 
peripheral blood CD3 + T cells by IBI308 was achieved in patients with 
recurrence/refractory Hodgkin's lymphoma treated with a 200 mg fixed dose. The overall 
response rate (ORR) per independent radiology review committee (IRRC) was 65.0% 
(N=60) following treatment with IBI308 at 200mg Q3W. 
 Pharmacokinetics of IBI308 were characterized in solid cancer patients with an 
elimination half-life (geometric mean) of 14.4 days (ranged from 8.0-23.3 days) at the 1st 
cycle and 13.4 days (ranged from 10.6-14.7 days) at the 4th cycle (steady state).  
 The proposed dose and dosing intervals are also based on the approved anti-PD-1/PD-L1 
products. Based on literature reports and data obtained from other anti-PD-1 products, 
body size and race are less likely to affect PK or efficacy/safety of anti-PD-1 products at 
the therapeutic dose.  
We therefore propose a fixed dose of 200 mg IBI308 for every 3 weeks (Q3W) in the US trial. 
 
3.3 Randomization Procedures 
Randomization and blinding procedures are not applicable in this open-label study. Eligible 
subjects will be registered and assigned to the available treatment cohorts. Subjects will be 
assigned to the cohort allocation after they have given their written informed consent and have 
completed the necessary baseline assessments. The subject will be assigned an identification 
number, which will be used on all case report forms (CRFs) and other study-related 
documentation 
 


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4. STUDY POPULATION 
4.1 Patient Number/Study Sites 
Approximately 50 subjects will be recruited for this study in the United States.  
 
4.2 Eligibility Criteria 
4.2.1  Overview 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and 
all regulatory requirements for informed consent.  The written informed consent must be 
obtained from the patient prior to enrollment.   
The following criteria apply to all patients enrolled in the study unless otherwise specified. 
 
4.2.2 Inclusion Criteria 
 
1) 
Subjects able to give voluntary informed consent, understand the study and are willing 
to follow and complete all the test procedures.  
2) 
Subjects (males and females) of childbearing potential should be willing to use reliable 
contraception methods that are deemed effective by the investigator from visit 1 through 90 
days following the last dose of study drug. Postmenopausal women must have been amenorrhea 
for at least 12 months to be considered of non-childbearing potential.  
3) 
Male or female subjects ≥18 years 
a) At least one measurable lesion (per RECIST version 1.1) 
b) Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1. 
c) Subjects with life expectancy of ≥ 3 month 
4) 
If subject received anti-tumor therapy: 
a) Generalized radiation therapy must have been completed 3 weeks prior to enrollment, 
or local radiotherapy or radiation therapy for bone metastases for 2 weeks prior to 
enrollment. Treatment with radiopharmaceuticals must have been completed 8 weeks 
prior to enrollment. 
b) Previous chemotherapy, biotherapy (tumor vaccines, cytokines, or growth factors that 
control cancer), tyrosine kinase inhibitors, or approved targeting and other treatments 
should have completed at least 3 weeks prior to the first administered dose in this study; 
5) 
Subjects must have adequate organ function (liver, kidney function and hematopoietic 
function tests) prior IBI308 administration 
a) Absolute neutrophil count (ANC) ≥1.5 x109/L 
b) Platelet count ≥ 100 x 109/L 
c) Hemoglobin ≥ 9 g / dL (whole blood or component transfusion within 7 days before 1st 
dose of study drug is prohibited) 
d) Renal function tests: serum creatinine ≤1.5 ×upper limit of normal range (ULN) or an 
estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2  
e) Liver function tests alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤3 x ULN, for patients with known liver cancer or liver metastases, AST and 
ALT ≤ 5 x ULN  


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f) Total bilirubin (TBil) ≤1.5 x ULN; If Gilbert's Syndrome may have Bilirubin> 1.5 x 
ULN 
g) Coagulation tests: aPTT ≤ 1.5 x ULN and INR ≤2.0 
6) 
Cohort Specific Inclusion Criteria:  
Cohort 1: Advanced/metastatic cancers with high TMB expression 
 
i. 
Advanced/metastatic cancers with TMB level > 10 mut/Mb 
ii. 
Histologically or cytologically confirmed unresectable Stage III/IV NSCLC or other 
advanced/metastatic cancers (for example, melanoma, bladder cancer, SCLC, prostate 
cancer, colorectal cancer, gastric cancer)  
iii. 
Separate informed consent is required for subjects who provide fresh biopsies for serial 
tumor biopsies for biomarker testing.  TMB testing should be performed on the most 
recently obtained tumor sample. 
iv. 
Subjects must be tested for TMB level before entering the study, and pre-screen 
informed consent is required for TMB testing. Subjects who have existing 
FoundationOne TMB testing results from within 6 months of study entry do not need 
to have repeat testing. 
v. 
Refractory or intolerant to standard therapy or for whom no standard therapy exists.  
Subjects must have no available therapy likely to confer clinical benefit for their cancer. 
Subjects who experienced irAE grade ≥ 3, or grade 2 recurrent pneumonitis, or who 
had to discontinue prior anti-PD-1/PD-L1 treatment due to irAEs of any grade will not 
be eligible. 
vi. 
NSCLC subjects with EGFR mutation and/or ALK rearrangement and/or ROS-1 
positive, should have received appropriate targeted therapy and are refractory to 
targeted therapy prior to enrolling this trial.   
 
Cohort 2: Advanced/metastatic endometrial Cancer  
i. 
Histologically confirmed advanced/metastatic endometrial cancer.  
ii. 
Refractory or intolerant to standard therapy, and no available therapy likely to confer 
clinical benefit for their cancer. Subjects who experienced irAE grade ≥ 3, or who had to 
discontinue prior anti-PD-1/PD-L1 treatment due to irAEs of any grade will not be eligible.   
 
4.2.3 Exclusion Criteria 
1) Legal incapacity or limited legal capacity. 
2) Pregnancy, lactation, breastfeeding. 
3) Concurrent anticancer treatment (e.g., cytoreductive therapy or cytokine therapy except for 
erythropoietin) or use of other investigational product within 28 days before start of trial 
treatment; major surgery within 28 days before start of trial treatment (excluding prior 
diagnostic biopsy.  
Note: Small molecule or antibody targeted therapy < 3 weeks from start of trial treatment 
will be excluded. 
4) Received a biologic (G-CSF, GM-CSF) within 14 days prior to the first dose of study drug. 
5) Vaccination within 4 weeks of first dose of IBI308 and while on study except for 
administration of inactivated vaccines (e.g., inactivated influenza vaccines) 
6) Failure to recover from adverse events from the most recent anti-tumor treatment to 
CTCAE ≤ grade 1 or baseline with the exception of alopecia; 
7) Active autoimmune disease requiring systemic treatment within the past 1 year or a 
documented history of clinically severe autoimmune disease or a syndrome that requires 


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systemic steroids or immunosuppressive agents during the conduct of this study. 
Exceptions: - Vitiligo, eczema, psoriasis (<10% of body surface area (BSA) of skin 
eruption or systemic involvement) or resolved childhood asthma/atopy, autoimmune 
hypothyroidism stable on hormone replacement.  
8) History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan. 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.  
9) Acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection. 
10) History of primary immunodeficiency, stem cell or organ transplant, or previous clinical 
diagnosis of tuberculosis. 
11) Subject who have had severe infection within 4 weeks or signs and symptoms of any active 
infection within 2 weeks prior to the first dose administration. 
12) Known allergies, hypersensitivity, or intolerance to protein-based therapies or with a 
history of any significant drug allergy (e.g., anaphylaxis, hepatotoxicity, immune-mediated 
thrombocytopenia or anemia 
13) Subjects who experienced (irAE) grade ≥3 immunotherapy-related adverse events. 
Subjects with CNS metastasis unless they are asymptomatic or adequately treated with 
radiotherapy and/or surgery and subjects are neurologically stable with minimal residual 
symptoms/signs 14 days prior to dosing.  
14) Patients who require high dose of systemic corticosteroids (>10 mg/day prednisone or 
equivalents) for at least 2 weeks prior to treatment are not eligible. 
15) Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New 
York Heart Association) NYHA III or IV, unstable angina pectoris even if medically 
controlled, history of myocardial infarction during the last 3 months, serious arrhythmias 
requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular 
tachycardia). 
16) Any other serious underlying medical (e.g., uncontrolled hypertension,  active uncontrolled 
infection, active gastric ulcer, uncontrolled seizures, cerebrovascular incidents, 
gastrointestinal bleeding, severe signs and symptoms of coagulation and clotting disorders, 
other serious cardiac conditions not listed in exclusion criteria), psychiatric, psychological, 
familial or geographical condition that, in the judgment of the investigator, may interfere 
with the planned staging, treatment and follow-up, affect patient compliance or place the 
patient at high risk from treatment-related complications. 
 
4.3 Subject Screening Procedures 
A written ICF must be obtained prior to initiating pre-screening for TMB status with the 
FoundationOne assay. TMB testing should be performed on the most recently obtained tumor 
sample. Specimen handling is described in the Biomarker section of this protocol (6.1.3.2).  If 
the subject meets the TMB eligibility criteria for cohort 1, the subject will be asked to sign the 
main study ICF and will then undergo the complete screening.  Subjects who have existing 
FoundationOne TMB testing results from within 6 months of study entry do not need to have 
repeat testing. 
Written ICF must be obtained prior to any study-related procedures. Screening procedures will 
be conducted at qualified clinical research centers. Demographic data to be recorded in the 
eCRFs include subjects’ gender, race, and date of birth.  


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Prior to participation in the study, all volunteers will have a routine history and physical along 
with screening blood tests. The screening procedures and assessments must be completed 
within 28 days of the study treatment visit Day 1 (Schedule of Events).  Weight, height and 
vital signs will also be obtained upon screening. All female volunteers will have a urine 
pregnancy test and will be asked to participate only if the test is negative.  In addition, female 
and male subjects will be asked to practice a reliable medically accepted form of birth control 
during participation in the study.  In this proposed application, all subjects will have a baseline 
12-lead ECG to exclude cardiovascular disease before entering the study.  Subject’s current 
medication schedule will be reviewed to ensure patients safety during the treatment.  
After all the screening results are obtained eligibility criteria will be reviewed and a complete 
clinical evaluation will be performed. All screening assessments will occur within 28 days prior 
to the first dose of study drug.  
If an assessment was performed as part of the subject’s routine clinical evaluation and not 
specifically for this study, it does not need to be repeated after signed ICF has been obtained. 
However, the assessments must fulfill the study requirements and should be performed within 
the specified timeframe prior to the first dose of study drug. Retesting of abnormal screening 
values that lead to exclusion are allowed only once during the Screening Phase (to reassess 
eligibility). The last result obtained prior to the first dose of study drug will be used to determine 
eligibility.  
The prospective subject’s medical history will be assessed prior to the initial treatment for 
continued study eligibility and adherence to final inclusion/exclusion criteria. During the 
Treatment Period, a symptom-based assessment will be maintained. The recent medical history 
assessment will include recent medication changes that have occurred since the previous visit. 
5. STUDY INTERVENTION  
5.1 Study Drug 
The IBI308 drug product (DP), is a 10 mg/mL solution for IV infusion, to be stored at 2-8 ℃, 
in single-use colorless and transparent 15 ml borosilicate glass Type I vials.  Each vial of 
IBI308 DP contains 100 mg/10 mL of IBI308 drug substance in 30.06 mg/mL mannitol, 3.73 
mg/mL L-histidine, 2.92 mg/mL sodium chloride, 0.0075 mg/mL ethylenediaminetetraacetic 
acid (EDTA-2Na), 0.2 mg/mL polysorbate 80, 5.88 mg/mL sodium citrate dehydrate.   The DP 
vial is capped with polytetrafluoroethylene membrane chlorinated butyl rubber stopper and 
sealed with an aluminum cap.  IBI308 will be supplied by the sponsor.  
The storage and handling of the diluted DP should meet the following time and temperature 
limits: 
 
Storage time should be limited to 8 hours at room temperature following DP dilution into 
the infusion bag including infusion time. 
 
Storage time should be limited to 24 hours at 2-8 oC following DP dilution into the infusion 
bag including infusion time.  
5.2 Treatment Compliance and drug accountability 
The site should maintain accurate dosage preparation records and should ensure that all 
pertinent/required information on the preparation and administration of the dose is captured in 


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source documents, and appropriate dosing information is entered onto CRFs. This information 
should be readily available during the monitoring visits.  
Upon termination of the study, or at the request of the sponsor, the pharmacist must return the 
study drugs to sponsor, unless it is destroyed at the site as agreed upon by both the sponsor and 
the site. 
 
5.3 Dosage and Drug Administration 
This is an open label study without blinding or randomization. Prior to use, DP is supplied as 
a solution for IV infusion packaged in single-use glass vials. Prior to administration, IBI308 
will be diluted to the required volume to achieve a final concentration of 2mg/mL using 0.9% 
sodium chloride solution. Administer the infusion over 60 minutes through an intravenous line 
containing a sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer).   
All dose administrations will be performed in the clinical center under the supervision of 
appropriately trained staff. Blood samples will not be collected from the arm used for the IV 
infusion for at least 24 hours after administration. Subjects should not receive prophylactic pre-
medication, unless they have suffered an infusion reaction in a prior cycle of administration of 
study drug. 
 
5.4 Dosing Procedure and Treatment cycles 
This trial will include 2 cohorts, and total of approximately 50 subjects. Please see Table-5. 
Each cycle will consist of 21 days and each subject will receive IBI308 on a Day1 of each 
cycle and continue treatment with IBI308 until disease progression or intolerable toxicity, 
withdrawal of consent, or end of study, whichever occurs first. 
 
Table-5. Study population, sample size and treatment dose.  
Cohort Number 
Indication 
Patient Number 
IBI308 Dose 
Cohort 1 
Advanced/metastatic cancers with TMB 
level >10mut/Mb 
2 enrolled as of 
1/7/2019 
200 mg 
Cohort 2 
Advanced/Metastatic Endometrial Cancer 
40 
200 mg 
 
5.5 Duration of Treatment 
Patients may continue to receive IBI308 until disease progression or intolerable toxicity, death, 
withdrawal of consent, or end of study up to 2 years, whichever occurs first.  
 
5.6 Treatment Beyond Disease Progression 
Subjects treated with IBI308 will be permitted to continue treatment beyond initial RECIST 
1.1 defined disease progression as long as they meet the following criteria:  
1. Investigator-assessed clinical benefit, and do not have rapid disease progression  


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2. Continue to meet all other study protocol eligibility criteria  
3. Tolerance of study drug 
4. Stable performance status  
5. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. CNS metastases)  
6. Subject provides written informed consent prior to receiving additional IBI308 treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options. 
 
The decision to continue treatment beyond initial progression should be discussed with the 
Sponsor Medical Manager and documented in the study records.  
A radiographic assessment/scan should be performed within six (6) weeks of original disease 
progression to determine whether there has been a decrease in the tumor size, or continued 
disease progression. The assessment of clinical benefit should be assessed by clinical judgment 
as to whether the subject is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with IBI308. 
If the investigator considers that the subject on IBI308 continues to achieve clinical benefit by 
continuing treatment, the subject should remain on the trial and continue to receive monitoring 
according to the Schedule of Events. The decision to continue treatment should be discussed 
with the Sponsor Medical Manager and documented in the study records.  
 
5.7 Dose Modification and Management of Withholding, Resuming or Discontinuation of 
the Study Drug 
Dose modifications are not permitted during this study unless intolerable toxicities occur.  If 
significant toxicity occurs, dosing may be delayed or permanently discontinued as described 
below. In the event of multiple toxicities, dosing management should be based on the worst 
toxicity observed (Refer to Section 5.8). 
 
5.7.1 Criteria for Withholding Study Drug 
1) Grade ≥2 non-skin, drug-related AEs with the following exceptions: Grade 2 drug-related 
fatigue or laboratory abnormalities do not require a treatment delay 
2) Grade ≥2 immune-mediated ocular disease will result in withholding study drug. 
3) Any Grade 3 drug-related laboratory abnormalities with the following exceptions for 
lymphopenia, leukopenia, AST, ALT or total bilirubin 
a. Grade 3 lymphopenia or leukopenia does not require dose delay 
b. If a subject’s baseline AST, ALT or total bilirubin was WNL, delay dosing for drug-
related Grade ≥2 toxicity 
c. If a subject’s baseline AST, ALT or total bilirubin was in a Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity 


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4) Any AE, laboratory abnormalities, or intercurrent illness, which in the judgment of the 
Investigator warrants delaying the dose of study drug.  
 
5.7.2 Criteria to Resume Treatment 
Subjects may resume treatment with study drug(s) when the drug-related AEs resolve to Grade 
≤1 or baseline value or with the following: 
1) Patients with Grade 2 fatigue 
2) Patients with Grade 2 skin toxicity provided they have not experienced Grade 3 or 
higher skin toxicity  
3) Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline 
before treatment is resumed 
4) Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
 
5.7.3 Criteria for Drug Discontinuation  
1) Discontinue treatment for Grade 3 or higher drug-related AEs of pneumonitis, creatinine, 
neuropathy, diarrhea/colitis that may lead to bowel perforation 
2) Discontinue treatment for any other Grade 4 drug-related AEs or laboratory abnormality, 
except for the following events which do not require discontinuation. 
a. Isolated grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to < grade 4 within 1 week of 
onset 
b. Isolated grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
3) Discontinue treatment for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks (except for endocrinopathies that are 
controlled with replacement hormones)  
4) Grade 4 increases in liver function tests (subjects with liver involvement) or Grade 3 
increases in liver function tests (subjects without liver involvement) 
5) Discontinue treatment for persistent drug-related AE that does not recover to Grade 0-1 or 
baseline within 12 weeks unless otherwise agreed to by the sponsor representative and the 
investigator based on evidence of clinical benefit 
6) Discontinue treatment for any recurrent Grade 2 pneumonitis or recurrence of same Grade 
3 AEs 
7) Discontinue treatment for any AE, laboratory abnormality, or intercurrent illness which, in 
the judgment of the investigator, presents a substantial clinical risk to the subject with 
continued investigational drug dosing.  
Following treatment discontinuation, the subject should complete the EOT Visit as described 
in Schedule of Events.  
 
5.8 Special Precautions and Clinical Interventions 


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5.8.1 Infusion Reactions 
All therapeutic monoclonal antibodies (mAbs) used for cancer treatment have the potential to 
cause infusion reactions.  Symptoms vary with a wide spectrum of severity, ranging from mild 
fever and chills to life-threatening anaphylaxis with bronchospasm, and hypotension. Typically, 
infusion reactions to monoclonal antibodies develop within 30-120 minutes after the initiation 
of drug infusion, although symptoms may not show up until 24 hours. The majority of reactions 
occur after the first or second exposure to drug, although it can also rarely occur during 
subsequent treatments. Additionally, the risk of infusion reaction declines with each 
subsequent course of therapy.  
Most common symptoms or “standard infusion reactions” (SIRs) are fever/chills, nausea, 
vomiting diarrhea, itching/flushing, rash changes in blood pressure (BP) and heart rate (HR), 
dyspnea, chest discomfort, back and abdominal pain.   
Although exact mechanism of SIRs caused by mAbs is not fully clear, most likely it is a result 
of antibody-antigen interactions resulting in cytokine release.  
Although premedication can help to prevent and/or reduce the severity of infusion reactions, 
anaphylaxis generally cannot be prevented by premedication. Thus, the following supplies and 
equipment needs to be readily available in any area where chemotherapy is administered: IV 
fluids, epinephrine, antihistamines, oxygen, aerosolized bronchodilators, intubation and 
tracheostomy equipment, and a defibrillator. 
The investigator will be responsible for managing infusion related and hypersensitivity 
reactions according to local standard procedure or follow the recommendations listed Table-6. 
Table-6 Management of Infusion-Related Reactions/Hypersensitivity Reactions (NCI 
CTCAE Grade) 
Grade 1 
Mild transient reaction; 
infusion interruption NOT 
indicated; 
intervention 
NOT indicated 
 
Monitor subject closely until recovery from symptoms, Consider 
premedication with 50 mg diphenhydramine or 650 acetaminophen at least 
30 minutes before additional study drug administration 
Grade 2 
Cessation of infusion or 
therapy 
is 
indicated. 
Responds 
promptly 
to 
symptomatic treatment. 
 
Stop infusion; start IV saline infusion; IV 50 mg diphenhydramine or 650 
acetaminophen; depending on symptoms, consider corticosteroids and 
bronchodilator therapy; remain at bedside and monitor subject until 
recovery from symptoms 
 
Restart infusion at 50% of initial rate: if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate; 
monitor subject closely.  
 
Prophylactic medication indicated for less than or equal to 24 hours 
 
Symptoms recur: stop and discontinue further treatment at that visit; 
administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the eCRF. 
Grade 3-4  
Prolonged recurrence of 
symptoms, hospitalization 
indicated for other clinical 
sequelae, maybe life 
threatening and 
 
Stop infusion; start IV saline infusion; recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1: 1,000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1: 10,000 solution injected slowly for 
IV 
administration, 
and/or 
diphenhydramine 
50 
mg 
IV 
with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
 
Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Investigators should follow their institutional 


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hospitalization may 
require. 
Should discontinuation 
from treatment  
guidelines for the treatment of anaphylaxis. In the case of late-occurring 
hypersensitivity symptoms (for example, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment 
may be given (e.g., oral antihistamine, or corticosteroids). 
 
5.8.2 Extravasation 
In the event of extravasation, infusion should be stopped immediately and the investigator 
needs to be consulted immediately. Treatment of extravasation should follow local standard of 
care. 
 
5.8.3 Immune Related Adverse Events (irAE) 
Checkpoint inhibition is associated with a wide spectrum of side effects defined as immune-
related adverse events (irAE). IrAEs may include gastrointestinal, hepatic, endocrine, 
dermatologic and inflammatory events. Early recognition and management of these irAEs may 
mitigate more severe and subsequent toxicities.  
General, treatment is based upon the severity of the observed toxicity. Recommendations for 
irAE treatment:  
 Subjects should be evaluated to identify any alternative etiology. 
 In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related. 
 Symptomatic and/or topical therapy should be considered for low-grade events. 
 Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event. 
Immunosuppressive agents should be considered for events not responding to systemic 
corticosteroids.  
 
5.8.3.1 Management of Gastrointestinal irAEs 
Diarrhea/colitis is the most common GI symptom in patients treated with checkpoint inhibitors.  
Usually it presents approximately in six weeks after starting treatment. 
The investigator will be responsible for managing GI irAEs according to local standard 
procedure or follow the recommendations listed Table-7. 
 
Table-7  Management of Gastrointestinal irAEs 
Grade 1 
 
Symptomatic treatment (for example, loperamide) 
according to institutional standards; 
 
Close 
monitoring; instruct subject to report 
worsening immediately and treat as Grade 2 
Grade 2 
 
5 
days: 
Symptomatic 
treatment 
according 
to 
institutional standards 
 
>5 
days 
or 
recurrence: 
0.5–1.0 
mg/kg/d 
methylprednisolone; consider prophylactic antibiotics; 
 
Persistence or worsening despite steroids >3 days: treat 
as Grade 3/4 


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 
Improvement to Grade 1: taper steroids over at least 4 
weeks, 
consider 
prophylactic 
antibiotics 
for 
opportunistic infections, resume study therapy per 
protocol 
Grade 3-4  
permanent discontinuation from treatment  
 
Immediately: 1.0–2.0 mg/kg/d methylprednisolone IV; 
consider prophylactic antibiotics and lower colonoscopy 
 
Persistence >3 days or recurrence: add infliximab 5 
mg/kg (if no contraindication such as perforation or 
sepsis) 
 
Improvement to Grade 2 within 3 days: taper steroids 
over at least 4 weeks 
 
5.8.3.2 Management of Hepatic irAEs 
The investigator will be responsible for managing hepatic irAEs according to local standard 
procedure or follow the recommendations listed Table-8:  
Hepatic function test (transaminases and bilirubin) should be monitored prior each 
administration of the investigational drug.  
 
Table-8  Management of Hepatic irAEs 
Grade 1 
 
Continue liver function monitoring 
 
If worsens: Treat as Grade 2  
Grade 2 
 
Monitor every 3 days; 
 
Returning to baseline: resume per protocol monitoring 
 
Patients who experience grade 2 hepatitis regardless of 
duration 
should 
receive 
0.5-1.0 
mg/kg/day 
methylprednisolone IV or oral equivalent; consider 
prophylactic antibiotics 
 
LFT return to Grade 1 or baseline: taper steroids over at least 
4 weeks; resume routine monitoring and resume study 
treatment per protocol 
Grade 3-4 Should be discontinued 
 
Monitor every 2 days; 
 
Immediately: 1.0-2.0 mg/kg/d methylprednisolone IV or IV 
equivalent; 
start 
prophylactic 
antibiotics; 
consult 
gastroenterologist 
 
Persistence >3 days or recurrence: add mycophenolate 
mofetil 1g bid; if no response within 5 days, consider other 
immunosuppressants per local guidelines 
 
LFT return to Grade 2: stop immunosuppressants 
 
LFT return to Grade 1: taper steroids over at least 4 weeks 
 
5.8.3.3 Management of Dermatological irAEs. 
The investigator will be responsible for managing dermatologic irAEs according to local 
standard procedure or follow the recommendations listed Table-9. For guideline of dose 
delay/discontinuation, refer to Section 5.7.  
Anti-PD-1 antibodies can cause immune mediated rash, including Steven-Johnson Syndrome 
(SJS) and toxic epidermal necrolysis (TEN) that can also lead to fatal outcomes in some cases.  


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If SJS and TEN symptoms are suspected withhold IBI308 and refer to specialized care; if SJS 
and TEN confirmed permanently discontinue IBI308. 
 
Table-9 Management of Dermatological irAEs.  
Grade 1-2 
 
Symptomatic treatment (for example, antihistamines, topical steroids); 
 
Persistence ≤2 weeks or recurrence: consider skin biopsy; consider 0.5-1.0 
mg/kg/d methylprednisolone IV or oral equivalent; consider prophylactic 
antibiotics 
 
Improvement to ≤Grade 1: taper steroids over at least 4 weeks 
 
Worsening to >Grade 2: treat as Grade 3-4 
Grade 3-4 Should 
discontinuation 
from treatment be 
warranted 
 
Consult dermatologist; consider skin biopsy; start 1.0-2.0 mg/kg/d 
methylprednisolone IV or IV equivalent; add prophylactic antibiotics 
 
Improvement to ≤ Grade 1: taper steroids over at least 4 weeks 
 
5.8.3.4 Management of Endocrine irAEs 
Endocrinopathies associated with checkpoint inhibitors include disorders of pituitary, thyroid, 
or adrenal glands, which often represents as with nonspecific symptoms such as nausea, 
headache, fatigue, and vision change.  
Hypophysitis is often manifested by headaches and fatigue. It is diagnosed by reduced levels 
of pituitary hormones (TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 
growth hormone (GH), Adrenocorticotropic hormone (ACTH), and prolactin). In the event 
when hypohysitis is suspect investigational drug should be discontinued and high dose steroids 
need to be started to prevent the need for longer-term hormone replacement. In case of 
endocrine AEs endocrinology consults is recommended. 
Hormone replacement needs be started as clinically indicated and corticosteroids should be 
administered at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper 
for moderate (Grade 2) or greater hypophysitis. 
Permanently discontinue IBI208 if AE is ≥ Grade 3. Endocrinology consults is recommended. 
In case of suspicion of adrenal crisis (e.g. severe dehydration, hypotension, shock out of 
proportion to current illness) discontinue IBI308, rule out sepsis, and urgently initiate IV fluids, 
high dose of IV steroids with mineralocorticoid activity and consult endocrinologist.  
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a 
corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. 
In addition to endocrine consult, when hypophysitis and adrenal insufficiency AE occur 
≥Grade 2 withhold the dose until improves to grade 0 or 1 and permanently discontinue  
if≥Grade 3. 
In the event of autoimmune hyper- or hypothyroidism thyroid functions needs to be monitored 
and hormone-replacement administered in case of hypothyroidism. No recommended dose 
adjustments are indicated during thyroid AEs. 


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5.8.3.5 Management of Pulmonary irAEs 
Prior diagnosing drug-induced pneumonitis, alternative diagnoses, including infections needs 
to be excluded. Although pneumonitis is not a common complication, it is a potentially severe 
or fatal complication with checkpoint inhibitor immunotherapy treatment. 
The investigator will be responsible for managing pulmonary irAEs according to local standard 
procedure or follow the recommendations listed Table-10. 
 
Table-10  Management of Pulmonary irAEs. 
Grade 1 
Asymptomatic; clinical or diagnostic 
observations 
only; 
intervention 
not 
indicated 
 
Withhold Investigational Drug for 2-4 weeks with 
close monitoring. 
 
Monitor for symptoms every 2-3 days; consider 
pulmonary and infectious-disease consult; Re-image 
every 3 weeks.  
Grade 2 
Symptomatic; 
medical 
intervention 
indicated 
 
Withhold Investigational Drug   
 
Monitor symptoms daily; Consult to pulmonary and 
infectious-disease; consider bronchoscopy and lung 
biopsy; consider hospitalization 
 
Immediately: start IV steroids or oral equivalent; 
prophylactic antibiotics  
 
Additional immunosuppression may be used in patients 
with worsening of pneumonitis 
 
Persistence for 2 weeks or worsening: treat as Grade 3-4 
 
Improvement to ≤ Grade 1 or baseline: taper steroids 
over at least 4 weeks 
Grade 3-4 
Severe symptoms; limiting self-care ADL; 
oxygen indicated 
Discontinuation permanently 
 
Hospitalize; pulmonary and infectious-disease consult; 
consider bronchoscopy and lung biopsy 
Immediately: 2-4 mg/kg/d methylprednisolone or IV 
equivalent; add prophylactic antibiotics; 
Persistence for 2 days or worsening: add immunosuppression 
(e.g., infliximab, cyclophosphamide, IVIG, or mycophenolate 
mofetil) 
Improvement to ≤ Grade 2: taper steroids over at least 6 weeks 
 
5.8.3.6 Management of Renal irAEs 
Immune-mediated nephritis and renal dysfunction is less commonly caused by PD-1/PD-L1 
inhibitors. Patients need to be monitored periodically for elevated serum creatinine prior to and 
during treatment.  
The investigator will be responsible for managing renal irAEs according to local standard 
procedure or follow the recommendations listed Table-11. 
 


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Table-11 Management of Renal irAEs. 
Grade 1 
Monitor creatinine weekly 
 
Creatinine returns to baseline: continue monitoring per protocol  
 
Creatinine increases: treat as Grade ≥2 
Grade 2-3 
Permanently discontinue 
from treatment for 
Grade 3 nephritis 
regardless of duration 
Withhold investigational Drug 
 
Monitor creatinine every ≤3 days 
 
Immediately: 1-2 mg/kg/d prednisone or equivalent; consider prophylactic 
antibiotics and nephrology consult if no improvement to ≤Grade 1: taper 
steroids over at least 4 weeks. 
 
Grade 3 nephritis regardless of duration will be permanently discontinued. 
 
Persistence >7 days or worsening: treat as Grade 4 
Grade 4  
Permanently discontinue 
from treatment 
regardless of duration 
Monitor creatinine daily 
 
Immediately: consult nephrologist; consider renal biopsy; start 1.0-2.0 
mg/kg/d methylprednisolone IV or IV equivalent; add prophylactic 
antibiotics 
 
Improvement to ≤Grade 1: taper steroids over at least 4 weeks 
 
5.8.3.7 Management of Pancreatic irAEs 
Although elevated levels of serum amylase and lipase have been reported with check point 
inhibitors but often these laboratory findings do not fulfill the criteria for acute pancreatitis and 
most of these patients are asymptomatic. Withhold treatment if Grade 2 or 3 pancreatitis, or 
Grade 3 or 4 increases in amylase or lipase levels occurs (>2.0 times ULN). In asymptomatic 
patients close observation is recommended. PI should ensure that subjects do not exhibit 
pancreatitis associated symptoms, such as abdominal pain. Corticosteroid treatment is not 
indicated in asymptomatic patients with moderate pancreatic enzyme elevations, if no other 
signs or symptoms of pancreatic inflammation exists. In any case of recurrent pancreatitis or 
grade 3 pancreatitis discontinue treatment permanently. 
 
5.8.3.8 Management of Cardiac irAEs 
Cardiotoxicity may develop in the absence of cardiac risk factors and may be associated with 
a more general myositis and other irAEs. Treatment for cardiac toxicities is usually high dose 
steroids although in some cases symptoms might still progress despite aggressive treatment. 
In case of elevated troponin and conductions abnormalities immediate transfer to a coronary 
care unit should be considered. 
 
5.8.3.9 Management of Neurologic irAEs 
A variety of neurologic syndromes have been associated with checkpoint blockade. Commonly 
reported neurologic cases includes but not limited to Guillain-Barre syndrome, myasthenia 
gravis, transverse myelitis, autoimmune encephalitis.  


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Serious neurologic irAEs should be treated with corticosteroids and consultation with 
neurology is indicated. Additionally, plasmapheresis and intravenous immunoglobulin 
treatments might be necessary. 
 
5.8.3.10 
Other Precautions 
Uveitis, iritis, myositis, hemolytic anemia, seizures, vasculitis, polymyalgia rheumatica, facial   
and   abducens   nerve   paresis were also associated with anti-PD-1 antibodies. The investigator 
will be responsible for managing irAE according to local standard procedure or refer to 
specialists. 
 
5.9 Concomitant Medication 
Some concomitant medications are allowed during the study to treat infusion-related reactions 
and other adverse events for symptomatic relief or management irAEs as specified in Section 
5.8 above. Hormonal replacement therapy anticoagulation therapy, oral contraceptives, and 
inhaled corticosteroids/mineralocorticoids can be used or continue their use during the study at 
the discretion of the investigator.   
 
5.10 
End of Treatment (EOT) 
An EOT Visit will be scheduled within 7days ±3 days after the last dose of study drug for all 
subjects, including those discontinuing treatment for any reason, except for patients lost to 
follow-up, death, or withdrawal of consent for study participation. The EOT Visit should be 
completed before starting any subsequent anticancer treatment. If a subject is unable to return 
to the site for the EOT Visit, the subject should be contacted to collect AEs and concomitant 
medications that occur up to 30± 7 days after the last dose of study drug.  
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug and that they should return to their primary physician to 
determine standard of care.  
 
5.11 
Follow-up 
For follow-up procedures see Schedule of Events. At least 30 days and no more than 37 days 
after discontinuation of treatment, subjects will return to undergo the assessments outlined in 
the Schedule of Events as well as a review of concomitant medications, vital signs, and 
assessment for resolution of any treatment related toxicity. Subjects continuing to experience 
toxicity at this point following discontinuation of treatment will continue to be followed at least 
every 4 weeks until resolution or determination, in the clinical judgment of the investigator, 
that no further improvement is expected.  
In the event a subject is unable to return to the clinic for the follow-up visit, telephone contact 
with the subject to assess AEs and concomitant medications and treatment is expected. If 
laboratory assessments are needed to follow-up unresolved AEs, retrieval of assessments 
performed at an institution local to the subject is acceptable.  


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To collect OS data, subjects will be contacted by telephone every 3 months (±7 days) post -
EOT visit. 
 
5.12 
Removal from Study Treatment and off-Study Criteria  
Participation in this research study is completely voluntary. Subjects are free to withdraw from 
this study at any time by informing the investigator.  If a subject, for whatever reason, no longer 
appropriate to continue receiving study therapy, they will be notified and withdrawn from the 
study.  Furthermore, if the subject is non-compliant (e.g. non-compliant with visits, 
concomitant medications.) they will be withdrawn from the study and a replacement subject 
may be recruited. 
Additionally, prior to removal from study, efforts must be made to have all subjects complete 
a safety visit approximately 30 days following the last dose of study therapy.  
 
5.12.1 Criteria for removal from study treatment 
If subjects are taken off study treatment, they will be followed until meeting the Off-Study 
criteria in Section 5.12.2. When subjects are off protocol therapy, data will be still collected to 
meet protocol objectives.  
Also, subjects who complete study treatment will be still followed for other study endpoints. 
Below are Criteria for removal from study treatment: 
 Death 
 EOT 
 Progressive disease 
 Participant requests to be withdrawn from active therapy 
 Unacceptable toxicity 
 Investigator discretion 
 Positive pregnancy test 
 
5.12.2 Off-Study Criteria 
Once a subject is taken off study, no further data can be collected.   
 Participant requests to be withdrawn from study 
 Subject withdrawal from the follow-up period 
 Subject completed all protocol required follow-ups 
 Death 
 Screen failure 
 
5.13 
Pregnancy/Contraception/Nursing 
5.13.1 Pregnancy Testing 
All women who are being considered for participation in the study, and who are not surgically 
sterilized or postmenopausal, will be tested for pregnancy within 72 hours before Cycle 1 
dosing and after the last dose of study drug. If a urine test is positive or borderline (unable to 


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confirm as negative), a serum β-hCG test will be required. Patients must be excluded in the 
event of a positive or borderline test result. The results of the pregnancy test will be recorded. 
 
5.13.2 Contraception 
IBI308 may have adverse effects on a fetus in utero. Furthermore, it is not known if IBI308 
has transient adverse effects on the composition of sperm. Non-pregnant, non-breast-feeding 
women may be enrolled if they are considered highly unlikely to conceive. Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered postmenopausal), 
or 3) amenorrheaic for <1 year without a hysterectomy or oophorectomy and with a 
documented FSH value in the postmenopausal range, or 4) not heterosexually active for the 
duration of the study, or 5) heterosexually active and willing to use 2 methods of birth control 
(which is also recommended for the female partners of male patients). The 2 birth control 
methods can be 2 barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy, used throughout the study starting with Visit 1 through 90 days after the last dose 
of study medication. Male patients enrolled in this study must also agree to use an adequate 
method of contraception starting with Visit 1 through 90 days after the last dose of study drug. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). Patients should be informed that taking the study medication may 
involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. 
In order to participate in the study they must adhere to the contraception requirement 
(described above) for the duration of the study. If there is any question that a patient will not 
reliably comply with the requirements for contraception, that patient should not be entered into 
the study. 
 
5.13.3 Use in Pregnancy 
IBI308 may have adverse effects on a fetus; therefore, women with a positive pregnancy test 
at screening will not be eligible for enrollment. If a female subject inadvertently becomes 
pregnant while on treatment with IBI308, the subject will immediately be removed from the 
study. The site will contact the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the SPONSOR without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). If a male patient’s partner becomes 
pregnant on study the pregnancy must be reported to the SPONSOR. The study investigator 
will make every effort to obtain permission to follow the outcome of the pregnancy and report 
the condition of the fetus or newborn to the SPONSOR. See Section 9.6 for the details of 
pregnancy reporting. 
 


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5.13.4 Use in Nursing Women 
It is unknown whether IBI308 is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrollment. 
 
6. STUDY ASSESSMENT AND EVALUATIONS 
6.1 Specimen Collection and Evaluations 
6.1.1 Pharmacokinetics (PK) 
Intensive PK blood samples will be drawn from first 6 subjects in cohort 1 and first 12 subjects 
in cohort 2, PPK will be drawn from other subjects at the time points indicated in Table-2. 
Blood samples should be drawn from a site other than the infusion site on days of infusion. If 
the infusion is interrupted, the reason for interruption will also be documented on the CRF. 
Blood samples will be processed to collect serum and stored preferably at -70oC. Serum 
samples will be analyzed for IBI308 by a validated method. For each time point, 2 ml whole 
blood sample needs to be collected for PK testing. Further details on PK sample collection and 
processing will be provided to the site in a procedure manual. 
 
6.1.2 Immunogenicity 
Blood samples for anti-drug antibody (ADA) analyses will be collected at predose in Cycle 1 
and Cycle 2 and then in every other subsequent cycle, and at the mandatory Safety Follow-up 
Visit or until start of a new anti-cancer therapy, whichever occurs first. Analysis will be 
performed by a central laboratory. For each time point, 4 ml whole blood sample needs to be 
collected, further details on ADA sample collection and processing will be provided to the site 
in a procedure manual. 
 
6.1.3 Biomarkers 
A variety of factors that could potentially predict clinical response to IBI308 will be 
investigated in tumor specimens obtained at screening, and in peripheral blood taken both at 
screening (prior to first dose of study drug) and during the study, from all subjects as outlined 
in Schedule of Events. Data from these investigations will be evaluated for associations with 
objective response, survival (OS, PFS).  
 
6.1.3.1 Peripheral Blood Biomarkers  
Serum will be obtained from all subjects prior to first dose of study drug, and during the study 
at every other cycle. Biomarkers measured in blood will focus on blood TMB and Serum-
Soluble Factors. 
To understand the prevalence of circulating proteins and the impact they may have on the 
clinical activity of IBI308, the protein concentrations of a panel of cytokines, chemokines, and 
other relevant immunomodulatory, serum-soluble factors will be evaluated by ELISA, serum 
chemistry, and/or other relevant multiplex-based protein assay methods. Examples of analytes 


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to be assessed include but are not limited to factors induced by IFNγ signaling (e.g. T cell 
chemoattractants CXCL9; CXCL10), antibodies to tumor-associated antigens, and soluble PD-
L1 (PD-L1), which may play an important role in immune tolerance and disease progression. 
For each time point, 10 ml whole blood sample needs to be collected for blood biomarkers 
testing. Further details on blood biomarker sample collection and processing will be provided 
to the site in a procedure manual. 
 
6.1.3.2 Tissue Biomarkers  
Before entry into study, every subject in cohort 1 must have testing for TMB by FoundationOne 
and the information of TMB level must be available. The FoundationOne assay was approved 
by The U.S. Food and Drug administration on Nov 30, 2017, and it was validated to detect 
genetic mutations in 324 genes and two genomic signatures in any solid tumor type. Average 
sequencing depth of coverage was greater than 250x, with >100x at >99% of exons. For TMB, 
the number of somatic mutations detected on NGS (interrogating 1.2 Mb of the genome) are 
quantified and that value extrapolated to the whole exome using a validated algorithm. 
Alterations likely or known to be bona fide oncogenic drivers and germline polymorphisms are 
excluded. TMB is measured in mutations per megabase (Mb). In this study, only patients with 
TMB levels > 10 mut/Mb are eligible.  
For FoundationOne testing specimens should follow the established FoundationOne Specimen 
Instruction documentation provided by Foundation Medicine. In summary the sample should 
either be a formalin-fixed, paraffin-embedded tumor tissue block and 1 original H&E slide, or 
10 unstained 4-5 micron thick slides with 1 H&E slide. The surface area of the specimen should 
be 5-25 mm2. The tumor content of the specimen should be 20-30% estimated based on nuclei 
count. Cut formalin-fixed paraffin-embedded slides are stable for this analysis for at least 6 
months. 
Acceptable samples include formalin-fixed paraffin-embedded specimens, including core-
needle biopsies, ne-needle aspirates, and effusion cytologies. Use standard fixation methods to 
preserve nucleic acid integrity. 10% neutral-buffered formalin for 6–72 hours is industry 
standard. Do not use other fixatives (Bouins, B5, AZF, Holland’s). Do not decalcify. When 
decalcifcation is required, EDTA is recommended. Do not use strong acids (e.g., hydrochloric 
acid, sulfuric acid, picric acid). 
For other biomarkers, a formalin-fixed, paraffin-embedded tumor tissue block or unstained 
slides (minimum 10 requested) of tumor sample (archival or recent) for biomarker evaluation 
will be obtained prior to subject enrollment. A reference laboratory will receive the samples 
for immunohistochemistry (IHC)-based analyses aimed at determining the abundance of the 
immunoregulatory proteins such as PD-L1. Additional immunohistochemical analysis may be 
completed to determine the abundance of other protein markers associated with TILS. The 
abundance of each protein monitored (or combinations of proteins) will be correlated with 
clinical endpoints. FFPET may be evaluated also by fluorescent in-situ hybridization (FISH), 
genetic mutation detection methods, and/or by RT-QPCR as part of additional exploratory 
analyses of putative biomarkers thought to be associated with response or resistance to 
therapeutics. Such analyses will be completed retrospectively and within the scope of informed 
consent.  
 
 
 


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Tumor samples: (meeting any of the following requirements) 
Sample Type 
Sample Collecting 
Storage 
Temperature 
Transportation 
Remarks 
Paraffin-embedded 
tissue 
(FFPE) 
10~15 copies for 
surgical biopsy, at 
least 5 copies; >15 
copies for puncture 
biopsy; 
Paraffin 
block 50mg (bean-
size) 
<37℃ 
Room temperature 
is acceptable 
Paraffin unstained 
samples within 6 
months. 
Puncture biopsy 
2 
punctures 
recommended or at 
least once. 1-2mm 
diameter and more 
than 0.5cm length 
for each sample. 
With 
preservation 
solution:<25℃ 
Without 
preservation 
solution:<-20℃ 
With dry ice 
Try not to keep in 
formalin 
Fresh tissue 
No less than 60mg 
(bean-size) 
With 
preservation 
solution:<25℃ 
Without 
preservation 
solution:<-20℃ 
With dry ice 
Please ensure the 
tissue 
sample 
is 
completely 
immersed in liquid 
once 
preservation 
solution was used 
 
6.1.4 Safety Laboratory Evaluations 
Safety labs will be drawn to assess AEs. CBC with differential, blood chemistry, thyroid tests 
(TSH, free T3 and T4), urine analysis will be obtained prior to each dosing. Coagulation tests 
(INR, aPTT) will be obtained within 7 days prior to first dosing on Day 1. 
AEs will be graded according to the CTCAE v4.03. Investigators will report whether an AE is 
potentially immune related (irAE). 
7. DATA COLLECTION AND MANAGEMENT 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
Hardcopies of the study visit worksheets will be used as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. All source documents should be completed in a neat, legible manner 
to ensure accurate interpretation of data.   
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into EDC, which is a 21 CFR, Part 
11-compliant data capturing system. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
Only individuals who have received training on the EDC are allowed to make eCRF entries, 
corrections, and alterations. Training must be documented and a log of all EDC users and their 
rights within the system be maintained. The data management team will raise queries in the 


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EDC system to resolve discrepancies. The Investigator must verify that all data entries in the 
eCRFs are accurate and correct. 
Any outstanding entries must be completed immediately upon notice. No blank sections should 
be left on CRF and explanations have to be recorded for all missing data. All source documents 
should be retained. All essential documents should only contain subject coded identifiers and 
no personal identifying information should be transmitted. 
 
7.1 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, study manuals, or 
ICH GCP requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
 Compliance with Protocol  
 Quality Assurance and Quality Control  
 Noncompliance 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 
working days of the scheduled protocol-required activity.  All deviations must be addressed in 
study source documents and if applicable, in eCRFs and study reports, in coordination with the 
sponsor or their designated CRO.  Protocol deviations must be sent to the reviewing IRB per 
their policies. The site investigator is responsible for knowing and adhering to the requirements 
of the reviewing IRB. 
 
7.2 Publication and Data Sharing 
Both the use of data and the publication policy are detailed within the clinical study agreement.  
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the Institution and the Sponsor or their designee.   
 
8. HUMAN SUBJECT PROTECTION AND REGULATORY 
OVERSIGHT 
8.1 Informed Consent Processes and Documentation 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should 
adhere to ICH GCP. Prior to the beginning of the trial, the investigator should have the IRB’s 
written approval for the protocol and the written ICFs and any other written information to be 
provided to the participants. Participants will be asked to read and review IRB-approved ICFs 
and other written information.  ICF should include detailed description of study procedures, 
risk and benefits, directions, participant’s rights, compensation if applicable, and contact of 


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Human Subject Protection Services.  Additionally, investigator will explain the research study 
to the participant in terms suited to the participant’s comprehension and answer any questions 
that may arise. Investigator should explain their rights as research participants, study 
procedures, risk and benefits, anticipated adverse effects.  Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. 
ICF should be signed prior to any interventions for the study. Participants must be informed 
that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. Participant will be given a copy of the signed consent form and the original consent 
form will be kept as a permanent record. Obtaining ICF should be documented in the source 
document.  
 
8.2 Institutional Review Board Approval 
The Sponsor/Investigator will obtain prospective approval of the clinical protocol and 
corresponding informed consent form(s), and any other written information to be provided to 
the participants from Institutional Review Board (IRB). Additionally, any modifications to the 
clinical protocol and corresponding informed consent forms, and advertisements (i.e., directed 
at potential research subjects) for study recruitment also requires IRB approval.   
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent forms may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject.  In such circumstances, the 
Sponsor/Investigator will promptly notify the IRB of the deviation.  
The Sponsor/Investigator has to operate in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
In the event of modification of the protocol the sponsor/investigator will submit (i.e., in 
advance of implementing the change) a protocol amendment to the IND describing any change 
to the protocol that significantly affects the safety of subjects, the scope of the investigation, or 
the scientific quality of the study.  Examples such changes requiring a protocol amendment 
include: 
 Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
 Any significant change in the design of the protocol (such as the addition or deletion of 
a control group). 
 The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or adverse event; or the dropping of a test intended to 
monitor the safety of the investigational drug. 
 
8.3 Case Report Forms (CRFs) 
The Principal Investigator and/or appropriate designated staff, will prepare CRFs, and maintain 
adequate and accurate participant case histories with observations and data pertinent to the 
study.  Study specific CRFs will document safety and treatment outcomes for safety monitoring 
and data analysis.  All study data will be entered into standardized eCRFs in accordance with 
the study calendar, using single data entry with a secure access account.  The Clinical Research 


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Team will complete the CRFs as soon as possible upon completion of the study visit; the 
Investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
study personnel.  All source documentation should be kept in separate research folders for each 
patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  
At study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Case report forms (CRFs) should capture information on all immune-
mediated adverse events, i.e.: 
a) The criteria (under case definitions) which resulted in classification of an AE as an 
immune-mediated adverse reaction 
b) The treatment administered, including specific drugs, doses, and duration of 
immunosuppressive treatment 
c) Information on dose modifications of, to include date when dose is modified, date dosing is 
resumed, and drug dose if reductions occur. 
 
8.4 Confidentiality and Privacy 
Participant’s identification is concealed and a number is used as the identifier instead of the 
patient’s name.  Patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. Following the 
discussions, participants will be asked to sign HIPAA form and informed consent documents. 
The original signed document will become part of the patient’s medical records, and each 
patient will receive a copy of the signed document. Some designated research staff involved in 
the trial will have access to data. Therefore, the study protocol, documentation, data, and all 
other information generated will be held in strict confidence.  No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval 
of the sponsor. 
 
8.5 Conflict of Interest 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in 
the design and conduct of this trial. 
 


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9. SAFETY REPORTING 
9.1 Definitions 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug that occurs during the course of the clinical trial whether or not the event is 
considered related to the treatment or clinically significant.  
For this clinical trial, AEs will include any events reported by the patient, any new medical 
conditions, symptoms, any new abnormal findings on physical examination or laboratory 
evaluation. Additionally, any worsening of a pre-existing condition or abnormality will also be 
considered as an AE. 
AEs will be collected by the investigator from Informed Consent Form signed through 30 days 
after the last dose of study medication, or prior to initiate of new anti-cancer therapy whichever 
is earlier.  AEs that occur outside of 30 days, following cessation of the study treatment, must 
also be reported within the same timeframe if considered related to study medication or 
procedure. All AEs must be recorded on CRF/eCRF. All AEs must be followed return to 
baseline or stabilizes. 
 
Serious adverse events (SAE): 
A serious adverse event is defined as any adverse experience that meets any of the following 
criteria:  
 Results in death; death due to disease progression is not considered as SAE.  
 Is life-threatening  
 Requires hospitalization or prolongation of existing hospitalization. Additionally, 
complications occurring during hospitalization are also considered AEs.  
 Results in persistent or significant disability or incapacity (This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a substantial 
disruption.);  
 Consists of a congenital anomaly or birth defect  
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  
 
9.2 Causality AE 
Causality assessment has become a common routine procedure in pharmacovigilance. 
Causality assessments can decrease disagreement between assessors, classify relationship 
likelihood and improvement of scientific evaluation. 
 Limitations of causality assessment are following:  
 It can NOT assess accurate quantitative measurement of relationship likelihood 
 It can NOT distinguish valid from invalid cases 
 It can NOT prove the connection between drug and event 


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 It can NOT quantify the contribution of a drug to the development of an adverse event 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 2 categories 
below. In a clinical trial, the study product must always be suspect. 
 Related:  The AE is known to occur with the study product, there is a reasonable 
possibility that the study product caused the AE, or there is a temporal relationship 
between the study product and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study product and the AE. 
 Not Related:  There is not a reasonable possibility that the administration of the 
study product caused the event, there is no temporal relationship between the study 
product and event onset, or an alternate etiology has been established. 
 
 
Protocol Deviation  
Any change, divergence, or departure from the IRB-approved research protocol.   
 
Non-compliance  
The failure to comply with applicable IRB and other regulatory requirements, or regulatory 
requirements for the protection of human research subjects. 
 
Unanticipated Problem 
Any incident, experience, or outcome that: 
 Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
 Is related or possibly related to participation in the research; AND 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
9.3 Categorizations of AEs 
All AEs and clinically significant laboratory abnormalities will be graded according to 
Common Terminology Criteria for AEs, Version 4.03 dated 14 June 2010. For any term that is 
not specifically listed on the CTCAE scale, intensity will be assigned a grade of 1 through 5 
using the following CTCAE guidelines: 
Grade1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated. 
Grade2: Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living. 


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Grade3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living. 
Grade4: Life-threatening consequences; urgent intervention indicated. 
Grade5: Death related to AE. 
 
9.4 Reporting of SAEs  
Any SAE, including death resulting from any cause, which occurs to any subject participating 
in this study must be reported to sponsor (and/or IRB as required) within 24 hours of first 
becoming aware of the SAE. SAEs will be collected by the investigator from Informed Consent 
Form signed through 90 days after the last dose of study medication, or prior to initiation of 
new anti-cancer therapy, whichever is earlier. SAEs that occur outside of 90 days, following 
cessation of the study treatment, must also be reported within the same timeframe, if considered 
related to study medication or procedure. Any SAE that is judged by the investigator to be 
related to the study medication must be reported regardless of the amount of time since the last 
dose received. Follow-up information collected for any initial report of an SAE must also be 
reported to the sponsor (or its designee) within 24 hours of receipt by the investigator. All SAEs 
will be followed until resolution, stabilization of condition, or until follow-up is no longer 
possible. 
To fully understand the nature of any SAE, obtaining follow-up information is important. 
Whenever possible, relevant medical records such as discharge summaries, medical 
consultations, reports of radiographic studies, and clinical laboratory reports should be obtained.  
In the event of death, regardless of cause, all attempts should be made to obtain the death 
certificate and any autopsy report, if performed. These records should be reviewed in detail, 
and the investigator should comment on any event, lab abnormality, or any other finding, noting 
whether it should be considered a serious or non-serious AE, or whether it should be considered 
as part of the subject’s history. In addition, all events or other findings determined to be SAEs 
should be identified on the follow-up SAE form and the investigator should consider whether 
the event is related or not related to study drug. All events determined to be non-serious should 
be reported on the eCRF. 
 
9.5 IRB Reporting 
The investigators will report to the IRB the following according to the requirements of 
reviewing IRB: 
 All SAEs, except deaths due to progressive disease  
 Non-compliance to GCP or protocol deviations as required by IRB 
IND Safety Reports and any unexpected incidences or problems during the trial may be also 
reportable to the IRB as per IRB requirement.  
 
9.6 Reporting of Pregnancy  
  


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For pregnancy including female subject pregnancy and male subject’s female partner 
pregnancy, the investigator shall complete Pregnancy Report Form and submit the report to 
Innovent/ Innovent representative within 24 hours of the aware of pregnancy.   
Maternal exposure  
If a female subject becomes pregnant during the course of the study or within 120 days of the 
last dose of IBI308, the treatment must be discontinued immediately. The investigator or 
other site personnel must inform the appropriate Innovent representatives immediately but no 
later than 24 hours of when he or she becomes aware of it. The designated Innovent 
representative works with the investigator to ensure that all relevant information should be 
provided to the Innovent. Pregnancy is not regarded as an AE, however ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death must be 
reported and handled as SAEs. The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) and normal 
birth/ congenital abnormality must be followed up 60 days after outcome of pregnancy, all 
related information should be documented even if the subject was discontinued from the 
study.   
Paternal exposure  
If a male subject’s female partner becomes pregnant during the course of the study or within 
120 days of the last dose of IBI308, The subject continued the treatment. Pregnancy of male 
subject’s female partner is not considered to be an AE. However, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death must be 
reported and handled as SAEs. The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) and normal 
birth/ congenital abnormality must be followed up 60 days after outcome of pregnancy, all 
related information should be documented even if the subject was discontinued from the 
study.   
Related information about a pregnancy from the partner of a male subject should be 
captured. If so, the male subject’s partner consent must be obtained to collect information 
related to the pregnancy and outcome; the male subject should not be asked to provide this 
information. A consent form specific to this situation must be used.   
 
10. STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS 
10.1 
General Statistical Consideration 
Descriptive statistics will be utilized for all safety, efficacy, immunogenicity, and 
pharmacokinetic parameters. Data will be summarized using descriptive statistics (number of 
subjects, mean, median, standard deviation, minimum, and maximum) for continuous variables 
and using frequencies and percentages for discrete variables. Time-to-event variables will be 
summarized using Kaplan-Meier methods and figures for the estimated median time. All data 
collected will be presented in subject listings. All data will be summarized by investigational 
drug dose level received. ORR will be calculated based on the full analysis set (FAS), including 
all patients who received at least one dose of drug. 


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10.2 
Data Analysis 
 
10.2.1 Pharmacokinetic Data 
PK parameters will include, but not be limited to, AUC, Cmax, Cmin trough, t1/2, CL, and Vss. 
The concentration-time data will be summarized by descriptive statistics (n, mean, 
standard deviation, coefficient of variation, median, minimum, maximum, and geometric 
mean). PK parameters will be estimated using a non-compartmental method with 
WinNonlin (Pharsight Corp, Cary, North Carolina). Individual and mean serum 
concentration of investigational drug versus time data will be tabulated and plotted by dose 
level.   
 
10.2.2 Immunogenicity  
 
All samples will first be analyzed for ADAs in a screening assay. Study samples with results 
below the screening cut-off will be reported as negative for ADAs. In the event of a positive 
result in the screening assay, samples will be analyzed in the confirmatory assay. All samples 
confirmed positive will be reported as positive, and will be analyzed for presence of 
neutralizing antibodies (nAb).  
 
The incidence of ADA will be summarized for all subjects who received at least one 
administration of investigational drug. Impact of ADAs on PK, efficacy/safety of 
investigational drug will be evaluated, if applicable.    
 
10.2.3 Efficacy 
ORR and the associated 2-sided 95% exact confidence limits will be provided. The proportion 
of subjects who have experienced best response as CR, PR, SD or disease progression (PD) 
will be calculated. PFS and OS data will be analyzed by Kaplan-Meier method. 
 
10.3 
Determination of Sample Size 
For cohort 2: Assuming the true ORR in advanced/metastatic endometrial cancer patients 
receiving IBI308 is 25%, there is an approximately 80% chance to observe 8 or more than 8 
responders in a total of 40 patients (i.e. observed ORR≥20%). With observing at least 8/40 
responders, this study will approximately 96% confidence to exclude ORR≤10%. A 
preliminary evaluation of efficacy will be conducted after approximately 20 evaluable patients 
with at least post baseline 2 tumor assessments. If overwhelming efficacy is observed, this 
cohort might be further expanded beyond planned 40 patients to confirm the efficacy observed.  
 
10.4 
Subject Replacement Policy 
In this study subject replacement is not permitted. 


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10.5 
Safety Evaluations 
Safety will be assessed by physical examinations, vitals, ECG, laboratory tests, AE monitoring, 
and concomitant medication usage monitoring (see Schedule of Events). AEs are graded 
according to the CTCAE v4.03. Investigators will report whether an AE is potentially immune 
related (irAE). irAEs are defined as AEs of unknown etiology potentially associated with an 
immune phenomenon. Follow up for SAEs assessed as at least possibly related late irAEs will 
occur until 3 months after the last dose of IBI308. The overall safety of IBI308 will be assessed 
by the Safety Monitoring Committee (SMC). SMC will be responsible for safety oversight, 
dose-escalation decisions, and other critical study decisions. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRATM). 
 
10.6 
Efficacy Evaluations 
Tumor assessment will be performed at baseline, every 2 cycles thereafter, and at the end of 
treatment by the investigator per RECIST v1.1 (Appendix 11.2). Efficacy evaluations will 
include the following: CT/MRI, physical examination, and other procedures as necessary. 
Adequate/preferred imaging assessments include high resolution CT with contrast or contrast-
enhanced MRI for evaluating radiographic tumor response. In subject with known severe 
contrast allergies, where pre-medication is not an option a non-contrast scan will suffice.  
Appearance of new malignant lesions denotes disease progression during the consistent 
scanning techniques.  If a patient is classified as having disease progression at a post-baseline 
tumor assessment, then confirmation by a second scan in the absence of rapid clinical 
deterioration is required. If a lesion is identified on during the study in an anatomical location 
that was not scanned at baseline is will be considered as a new lesion and will indicate disease 
progression. Treatment response will also be assessed by iRECIST v1.1 criteria to assess the 
potential for pseudo progression. 
Anti-cancer activity parameters that will be assessed include determination of the following: 
1) 
Best overall response [complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease] 
2) 
Objective response rate (ORR) (CR + PR) 
3) 
Duration of response (DOR) or duration of SD 
4) 
Disease control rate (DCR) (CR, PR or SD) 
5) 
Progression-free survival (PFS) and overall survival (OS) efficacy Evaluations 
 
10.7 
Population Analysis 
 
10.7.1 Safety Population  
The safety analyses population will include all subjects who receive at least one dose of the 
investigational drug. The safety analyses population will be the primary population for 
evaluating treatment administration, compliance and safety in the study. 
 


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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10.7.2 Efficacy Population  
The efficacy population will include all subjects who complete at least 1 cycle of treatment and 
have at least 1 post baseline tumor assessment of efficacy or discontinue study early due to 
progressive disease. 
 
10.7.3 PK Population  
The PK population will include all subjects who have at least one blood sample providing 
evaluable PK data. 
 
10.8 
Tabulation of Individual Participation Data 
 
Data tabulations will summarize the following subject numbers: 
 
Enrolled 
 
Investigational drug treatment dose received 
 
Evaluable for safety and efficacy 
 
Protocol violations 
 
Protocol completions 
 
Withdraw from study due to: 
 
Adverse event 
 
Physician’s recommendation 
 
Withdrew consent 
 
Lost to Follow-up 
Other reasons as collected on the case report form.  
 
11. STUDY MANAGEMENT  
  
11.1 
Quality Assurance and Quality Control  
  
Quality control (QC) procedures will be implemented to assure that any missing data will be 
communicated with sites for clarification and resolution.  
  
Standard Operating Procedures (SOPs) should be available to monitors. Monitors will verify 
that all the clinical trial procedures are conducted, documented and reported in compliance 
with the protocol, ICH, GCP, GLP, GMP and other applicable regulatory requirements.  
  


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities.  
  
11.2 
Clinical Monitoring Plan  
  
Monitors are qualified by training and experience to monitor the progress of clinical trials. 
Personnel monitoring this study will not be affiliated in any way with the trial conduct  
  
Site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with ICH GCP, and with applicable regulatory requirements.  
  
A sponsor representative will meet with the investigator and his/her staff prior to the entrance 
of the first subject to review study procedures and methods of recording study data. After 
enrollment of the first subject, a sponsor representative will be assigned to periodically 
monitor each investigator site for study progress and to verify that standards of Good 
Clinical Practice (GCP) and/or ICH guidelines were followed.  
  
The investigator is expected to prepare for the monitor visit, ensuring that all source 
documents, completed CRFs, signed consent forms and other study related documents are 
readily available for review.  
  
As a sponsor for clinical trials, FDA regulations require the Investigators to facilitate 
monitoring process. Monitors will evaluate adherence to the protocol, regulations, SOPs, 
human subject protection, study data, specifically data that could affect the interpretation of 
primary study endpoints. This is done through independent verification of study data with 
source documentation focusing on:  
● 
Informed consent process  
● 
Eligibility confirmation  
● 
Drug administration and accountability  
● 
Adverse events monitoring  
● 
Response assessment  
● 
Safety Monitor  
  
11.3 
Study Closure  
  
The investigator may terminate the study at any time in the interest of subject welfare. The 
sponsor may terminate the study prematurely at any time. Reasons for the closure of an 
investigational site or termination of a study may include:  


Sponsor: Innovent Biologics (Suzhou) Co. Ltd. 
 
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● 
The Investigator fails to comply with the protocol or ICH/GCP guidelines  
● 
Safety concerns  
● 
Inadequate recruitment of subjects by the investigator  
● 
Completion of the study  
  
If the clinical study is prematurely terminated or suspended, the sponsor or CRO 
representative will inform the investigator and the regulatory authorities of the termination/ 
suspension and the reasons for the termination/suspension as appropriate. The investigator 
should promptly notify the IEC/IRB of the termination or suspension and provide reasons. 
The sponsor reserves the right to close the investigational site or terminate the study in its 
entirety at any time, for reasonable cause.  
  
Premature termination of the study by either PI or sponsor will be governed under the terms 
of the contract between both parties.  
 
 
 


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12. REFERENCES  
 
KEYTRUDA® [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 
2014.  
 
OPDIVO® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company: 2014  
 
FoundationOne CDx™ Technical Information, Cambridge, MA: Foundation Medicine, Inc. 
n.d 
 
American Cancer Society (ACS).   About Endometrial Cancer. February 29, 2016. 
https://www.cancer.org/content/dam/CRC/PDF/Public/8609.00.pdf . Accessed December 
15 2017. 
 
Lee WL, Yen MS, Chao KC, Yuan CC, Ng HT, Chao HT, Lee FK, Wang PH. Hormone 
therapy for patients with advanced or recurrent endometrial cancer. J Chin Med Assoc. 
2014 May;77(5):221-6. doi: 10.1016/j.jcma.2014.02.007. Epub 2014 Mar 30. 
 
Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 
human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 
2017 Apr 19;9(1):34. doi: 10.1186/s13073-017-0424-2. 
 
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel 
MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, 
Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz 
LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen 
AC, Socinski MA; CheckMate 026 Investigators. First-Line Nivolumab in Stage IV or 
Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. 
doi: 10.1056/NEJMoa1613493. 
 
Goodman AM1, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, 
Daniels GA, Kurzrock R. Tumor Mutational Burden as an Independent Predictor of 
Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther. 2017 
Nov;16(11):2598-2608. doi: 10.1158/1535-7163.MCT-17-0386. Epub 2017 Aug 23. 
 
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et 
al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who 
have progressed following treatment with platinum-based chemotherapy: a single-arm, 
multicentre, phase 2 trial. Lancet. 2016; 387:1909–20. 
 
 


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13. GENERAL APPENDICES  
13.1 
Appendix 1 Eastern Cooperative Status Oncology Group Performance Status 
Score  
ECOG Performance Status Scale 
Grade 
Descriptions 
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 self-care 
Totally confined to bed or chair 
5 
Dead 
 
 
 


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13.2 
Appendix 2 Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1  
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Measurable 
Tumor Burden 
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified at 
baseline and measured through the course of therapy. 
Minimum Size of 
Measurable 
Lesions 
≥10 mm in longest diameter (LD) and 2X the slice thickness for extranodal lesions. 
≥15 mm in short axis diameter (SAD) for nodal lesions. 
≥10 mm in LD for clinical lesions (must be measured using electronic calipers). 
≥20 mm in LD for chest X-ray (if clearly defined and surrounded by aerated lung); CT is 
preferable. 
Ultrasound (US) cannot be used to measure lesions. 
Lymph Nodes 
Lymph nodes are considered pathologically enlarged if >10 mm in SAD. To be 
measurable, nodal lesions must be ≥15 mm in SAD. 
Nodal lesions with SAD >10 mm and <15 mm are non- measurable.  
The sum of the diameters (LD for extranodal target lesions, SAD for nodal lesions) is 
followed through the course of therapy. 
Bone Lesions 
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed on 
CT/MRI can be measurable if the minimum size criteria are met. 
Blastic bone lesions and bone lesions assessed on bone scan, positron emission therapy 
(PET) or plain films are non-measurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts are not 
malignant. 
Cystic lesions thought to be metastases can be measurable if they meet the minimum 
size criteria. Non-cystic lesions are preferable. 
Lesions with 
Prior Local 
Treatment 
Too Small To 
Measure 
Lesions in previously irradiated areas (or areas treated with local therapy) are not 
measurable unless the lesion has progressed since therapy. 
If a target lesion becomes too small to measure, a default value of 5 mm is assigned. If 
the lesion disappears, the measurement is recorded as 0 mm. 
Lesions That 
Split or Coalesce 
If extranodal target lesions fragment, the LDs of the fragmented portions are added to 
calculate the sum. 
If target lesions coalesce and cannot be distinguished, the LD of the coalesced lesion 
is added to the sum. 
Definition of 
Complete 
Response (CR) 
CR requires the disappearance of all extranodal lesions, the regression of all nodal 
lesions to <10 mm SAD and the normalization of tumor marker level. 
Definition of 
Progressive 
Disease (PD) 
PD is assessed if the sum of the diameters has increased by ≥20% and ≥5 mm from 
nadir (including baseline if it is the smallest sum). Patients with measurable disease: 
for "unequivocal progression" based on non- target disease, there must be an overall 
level of substantial worsening that merits discontinuation of therapy (if target disease 
is SD/PR). Patients without measurable disease: for "unequivocal progression" of 
non-target disease, the increase in overall tumor burden must be comparable to the 
increase required for PD of measurable disease. 
Assessment of 
New Lesions 
New lesions should be unequivocal and not attributable to differences in scanning 
technique or findings which may not be tumor (ie, 'new' bone lesions may be healing 
or flare of pre- existing lesions). If on is equivocal, repeat scans are needed to confirm. 
If confirmed, PD is assessed at the date of the initial scan. Lesions identified in 
anatomic locations not scanned at baseline are considered new. New lesions on US 
should be confirmed on CT/MRI. 
FDG-PET 
New lesions can be assessed using FDG-PET:(-) PET at baseline and (+) PET at 
follow-up is PD based on a new lesion. No PET at baseline and (+) PET at follow-up 
is PD if the new lesion is confirmed on CT. If a subsequent CT confirms the new lesion, 
the date of the PD is the date of the initial PET scan. No PET at baseline and (+) PET 


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at follow-up corresponding to pre-existing lesion on CT that is not progressing; not PD. 
Recurrence of 
Lesions 
For a patient with SD/PR, a lesion which disappears and then reappears will 
continue to be measured and added to the sum. Response will depend upon the status 
of the other lesions. For a patient with CR, reappearance of a lesion would be 
considered PD. 
 
 
Overall 
Response 
One overall response table integrates target, non-target and new lesions and 
another table integrates non-target and new lesions for the assessment of subjects 
without measurable disease. 
Confirmation of 
Response 
Confirmation of PR/CR is ONLY required for non-randomized trials where 
response is the primary endpoint. In these trials, subsequent confirmation of PR 
with one interim timepoint of SD is acceptable. 
 
Link:  
https://www.sciencedirect.com/science/article/pii/S0959804908008733/pdfft?md5=14893671e2bb1311c1f
e32 ab44638208&pid=1-s2.0-S0959804908008733-main.pdf  
 
 
 


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13.3 
Appendix 3 modified RECIST 1.1 for immune based therapeutics (iRECIST)  
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour 
burden, or the appearance of new lesions, does not reflect true tumour progression. 
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be recorded 
separately. 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is 
seen as evidenced by one or more of the following: 
 Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
 Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
 Continued unequivocal progression in non-target disease with an increase in tumour 
burden 
 Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions. 
 RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.  
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). As can be seen in table 2, the prior documentation of 
iUPD does not preclude assigning iCR, iPR, or iSD in subsequent time-point assessments or 
as best overall response (BOR) providing that iCPD is not documented at the next assessment 
after iUPD. 
New lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 


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Date: 01/07/2019 
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short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New Lesion-
Non-Target (NLNT) to allow clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of measures 
of original target lesions identified at baseline. Rather, these measurements will be collected 
on a separate table in the case record form. 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from 
iUPD with either an increase of at least 5 mm in the absolute value of the sum of NLT OR an 
increase (but not necessarily unequivocal increase) in the size of NLNT lesions OR the 
appearance of additional new lesions. 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-
iCR/Non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-
iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-
iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR 
decrease 
from last 
TP 
iUPD with 
no change 
OR 
decrease 
from last 
TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5 mm in 
SOM for NLT or any increase for NLNT) 
or number. If no change in NLs (size or 
number) from last TP, remains iUPD 
iSD，iPR，
iCR 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based in further increase in size of NT 
disease (need not meet RECIST 1.1 criteria 
for unequivocal PD) 
iUPD 
Non-
iCR/Non-
iUPD；iCR 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based on: 
o further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed 
based on further increase in: 
o previously identified T lesion iUPD SOM 
≥5 mm and / or 
o NT lesion iUPD (prior assessment - need 
not be unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed 
based on further increase in: 
o previously identified T lesion iUPD ≥5 
mm and / or 
o previously identified NT lesion iUPD 
(need not be unequivocal) and /or 


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o size or number of new lesions previously 
identified 
Non-
iUPD/PD 
Non-
iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed 
based on 
o increase in size or number of new lesions 
previously identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, 
PR and SD would be the same. ** in any lesion category. *** previously identified in assessment 
immediately prior to this TP. 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
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PROTOCOL CIBI308A102 
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Document: 
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Version Date: 
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STATISTICAL ANALYSIS PLAN 
CIBI308A102 
AN OPEN-LABEL, PHASE 1B MULTICENTER STUDY OF IBI308 IN SUBJECTS WITH 
ADVANCED/METASTATIC SOLID MALIGNANCIES 
 
AUTHOR: CHERYL LEE 
VERSION NUMBER AND DATE: V2.2, 05JAN2020 


 
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Version Date: 
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reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V2.2 (Dated 05Jan2021) for Protocol CIBI308A102 version 6, dated 7Jan2019. 
 
Name 
Signature 
Date 
Author: 
Cheryl Lee 
 
 
 
Position: 
Biostatistician 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Winnie Leung 
 
 
 
Position: 
Clinical Project Manager 
 
Company: 
Innovent Biologics (Suzhou) Co. Ltd. 
 
Approved By: 
Xing Sun 
 
 
 
Position: 
Biostatistician 
 
Company: 
Innovent Biologics (Suzhou) Co. Ltd. 
 


 
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OUTPUT TEMPLATES SIGNATURE PAGE 
Output Templates V2.2 (Dated 05Jan2021) for Protocol CIBI308A102 version 6, dated 7Jan2019. 
 
 
Name 
Signature 
Date 
Author: 
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Position: 
Biostatistician 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Output Templates, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Winnie Leung 
 
 
 
Position: 
Clinical Project Manager 
 
Company: 
Innovent Biologics (Suzhou) Co. Ltd. 
 
Approved By: 
Xing Sun 
 
 
 
Position: 
Biostatistician 
 
Company: 
Innovent Biologics (Suzhou) Co. Ltd. 
 


 
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MODIFICATION HISTORY 
 
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Cheryl Lee 
Not Applicable – First Version 
0.2 
12Jul2019 
Cheryl Lee 
- The department and position of the responsible person 
have been changed. 
- Updates made due to protocol amendment. 
- The efficacy population is replaced with full analysis set 
for all efficacy analysis.  
- Removed the preliminary evaluation due to sponsor 
strategy. 
- Added protocol deviations/violations categories. 
- The medical history and concomitant illness will be 
summarized by body system instead of MedDRA. 
1.0 
13Jan2020 
Cheryl Lee 
Finalized Version 
2.0 
20Mar2020 
Cheryl Lee 
- Added derivations for Time Since Initial Diagnosis and 
Time Since Current Diagnosis. 
- Added ATC2/ATC3 for prior and concomitant medications 
summary. 
- Removed variable of duration of stable disease (DOS).  
- Added CTCAE grade criteria and shift table of laboratory 
test results from baseline to worst CTCAE Grade. 
- Added summary and derivation for QTcF. 
- Added summary and derivations for Treatment-Induced 
ADA, Treatment-Boosted ADA, and ADA incidence. 
- Added summary and criteria of abnormalities for vital sign.  


 
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2.1 
15May2020 
Cheryl Lee 
- Added 2nd final analysis due to COVID-19 issue. 
2.2 
05Jan2021 
Cheryl Lee 
- Added the PFS rate at 12-week, 24-week, and 36-week. 
- Converted into SI unit for height and weight. 
- Updated WHO-DDE version. 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................ 9 
2. 
STUDY OBJECTIVES ..................................................................................................................... 9 
2.1. 
Primary Objective ........................................................................................................................................9 
2.2. 
Secondary Objectives ..................................................................................................................................9 
2.3. 
Exploratory Objectives ................................................................................................................................9 
3. 
STUDY DESIGN ........................................................................................................................... 10 
3.1. 
General Description ................................................................................................................................... 10 
3.2. 
Determination of Sample Size ................................................................................................................... 11 
3.3. 
Schedule of Events..................................................................................................................................... 11 
3.4. 
Changes to Analysis from Protocol ............................................................................................................ 11 
4. 
PLANNED ANALYSES ................................................................................................................ 11 
4.1. 
Final Analysis ............................................................................................................................................. 12 
5. 
ANALYSIS SETS ........................................................................................................................... 12 
5.1. 
Enrolled Analysis Set [ENR] ........................................................................................................................ 12 
5.2. 
Safety Analysis Set [SAF] ........................................................................................................................... 12 
5.3. 
Full Analysis Set [FAS] ................................................................................................................................ 12 
6. 
GENERAL CONSIDERATIONS ................................................................................................. 13 
6.1. 
Reference Date and Study Day .................................................................................................................. 13 
6.2. 
Baseline ..................................................................................................................................................... 13 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 13 


 
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6.4. 
Windowing Conventions ............................................................................................................................ 14 
6.5. 
Statistical Tests .......................................................................................................................................... 14 
6.6. 
Common Calculations ................................................................................................................................ 14 
6.7. 
Software Version ....................................................................................................................................... 14 
6.8. 
Missing data .............................................................................................................................................. 14 
7. 
OUTPUT PRESENTATIONS ..................................................................................................... 15 
8. 
DISPOSITION AND WITHDRAWALS .................................................................................... 15 
9. 
PROTOCOL DEVIATIONS/VIOLATIONS ............................................................................. 15 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 16 
10.1. Derivations ................................................................................................................................................ 18 
11. 
MEDICAL HISTORY AND CONCOMITANT ILLNESS ......................................................... 19 
12. 
MEDICATION AND PROCEDURES ......................................................................................... 19 
12.1. Prior and Concomitant Medications .......................................................................................................... 19 
12.2. Prior and Concomitant Non-Drug Treatments (Procedures) ...................................................................... 20 
12.3. Prior and Concurrent Anti-Cancer Therapies and Surgeries ....................................................................... 20 
13. 
STUDY MEDICATION EXPOSURE .......................................................................................... 21 
13.1. Derivations ................................................................................................................................................ 22 
14. 
EFFICACY OUTCOMES .............................................................................................................. 22 
14.1.1. 
Best Overall Response ..............................................................................................................................22 
14.1.2. 
Objective Response Rate (ORR) ................................................................................................................24 
14.1.3. 
Disease Control Rate (DCR).......................................................................................................................24 
14.1.4. 
Duration of Response ...............................................................................................................................25 
14.1.5. 
Progression Free Survival (PFS).................................................................................................................25 
14.1.6. 
Overall Survival (OS) .................................................................................................................................25 


 
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15. 
SAFETY OUTCOMES .................................................................................................................. 25 
15.1. Adverse Events .......................................................................................................................................... 26 
15.1.1. 
All TEAEs ...................................................................................................................................................26 
15.1.1.1. 
Severity .............................................................................................................................................26 
15.1.1.2. 
Relationship to Study Medication.....................................................................................................27 
15.1.2. 
Immune Related Adverse Events (irAE) ....................................................................................................27 
15.2. Deaths ....................................................................................................................................................... 27 
15.3. Laboratory Evaluations .............................................................................................................................. 27 
15.3.1. 
Laboratory Specific Derivations ................................................................................................................28 
15.3.2. 
CTC Grading for Laboratory Data ..............................................................................................................28 
15.4. 12-Lead Electrocardiogram (ECG) Evaluations ........................................................................................... 28 
15.4.1. 
12-Lead Electrocardiogram (ECG) Specific Derivations ............................................................................29 
15.5. Immunogenicity Assessments .................................................................................................................... 29 
15.5.1. 
Immmunogenicity Assessments Specific Derivations ...............................................................................29 
15.6. Vital Signs .................................................................................................................................................. 30 
15.6.1. 
Vital Signs Markedly Abnormal Criteria ....................................................................................................30 
15.7. Physical Examination ................................................................................................................................. 31 
15.8. ECOG Performance Status ......................................................................................................................... 31 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ........................................... 33 
IQVIA Output Conventions .................................................................................................................................... 33 
Dates & Times ....................................................................................................................................................... 33 
Spelling Format ..................................................................................................................................................... 33 
Presentation of Timepoints ................................................................................................................................... 33 
APPENDIX 2. PARTIAL DATE CONVENTIONS .......................................................................... 34 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 34 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 36 
APPENDIX 3. NCI CTCAE V5.0 LAB GRADES ............................................................................. 38 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy 
and safety data for Protocol CIBI308A102. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed. This statistical analysis plan (SAP) is based on 
protocol CIBI308A102 version 6, dated 7Jan2019. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate preliminary anti-tumor activity (objective response rate, ORR) of 
IBI308 monotherapy in subjects with advanced/metastatic solid malignancies. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are 
 To measure progression-free survival rate (PFS). 
 To measure duration of response (DOR). 
 To measure overall survival rate (OS). 
 To obtain safety and toxicity data. 
 To further evaluate pharmacokinetics (PK) of IBI308. 
 To further evaluate immunogenicity of IBI308. 
2.3.  EXPLORATORY OBJECTIVES 
The exploratory objectives are 
 To explore the relationship between baseline markers (PD-L1, TMB etc.) and clinical 
response 
 To explore the relationship between exposure and efficacy/safety 
 To assess the impact of ADA on PK, efficacy/safety 


 
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3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is an open-label, phase 1b multicenter study of IBI308 in subjects with advanced/metastatic solid 
malignancies. The trial will recruit 2 cohorts: cohort 1 consisting of subjects with advanced/metastatic 
cancer subjects with TMB>10 mutations per megabase (mut/Mb) and cohort 2 consisting of advanced 
endometrial cancer subjects (refer to Study Design Scheme, and Table B for sample sizes). Sponsor has 
made strategic decisions to stop enrollment in cohort 1 in this protocol amendment. In each cohort a fixed 
dose of 200 mg IBI308 will be administered Q3W to the subjects. Additional cohorts may be added to this 
study via a new IND package or will be added with a protocol amendment submission during the clinical 
trial stage. 
Table A: 
Scheme of The Study design 
 


 
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Table B: 
Study population, sample size and treatment dose 
Cohort 
Number 
Indication 
Patient Number 
IBI308 Dose 
Cohort 1 
Advanced/metastatic cancers with TMB level >10mut/Mb 
2 enrolled as of 7Jan2019 
200 mg 
Cohort 2 
Advanced/Metastatic Endometrial Cancer 
40 
200 mg 
3.2. DETERMINATION OF SAMPLE SIZE 
For cohort 2: Assuming the true ORR in advanced/metastatic endometrial cancer subjects receiving 
IBI308 is 25%, there is an approximately 80% chance to observe 8 or more than 8 responders in a total of 
40 subjects (i.e. observed ORR≥20%). With observing at least 8/40 responders, this study will have 
approximately 96% confidence to exclude ORR≤10%. A preliminary evaluation of efficacy will be 
conducted after approximately 20 evaluable subjects with at least post baseline 2 tumor assessments. If 
overwhelming efficacy is observed, this cohort might be further expanded beyond planned 40 subjects to 
confirm the efficacy observed.  
3.3. SCHEDULE OF EVENTS 
Schedule of events can be found in Table-1 of the protocol. 
3.4. CHANGES TO ANALYSIS FROM PROTOCOL 
PK analysis defined in the protocol secondary objectives is not awarded to IQVIA. Date of 
acknowledgement of the change is 4May2018. 
FAS will be considered for all efficacy analysis. Definition of FAS is same as Efficacy population stated in 
protocol.  
Hematology and Biochemistry laboratory quantitative parameters will be graded according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 for shift from 
baseline table.  
4. PLANNED ANALYSES 
The following formal analysis is planned for the study:  


 
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4.1. FINAL ANALYSIS  
Two final analyses will be performed by IQVIA Biostatistics following sponsor authorization of the final 
SAP. 
The 1st final analysis will be performed based on 1st database lock on 21May2020. Not all of the data is 
clean as there is a lack of site accessibility due to Coronavirus (COVID-19) pandemic.  
The 2nd final analysis will to be performed based on 2nd database lock when all source data verified, which 
will be an update with results from both final analyses being addressed in clinical study report. 
5. ANALYSIS SETS 
All summaries will be presented by assigned cohort. Protocol Table-A contains a detailed presentation of 
each study cohort. 
5.1. ENROLLED ANALYSIS SET [ENR] 
The enrolled population will contain all subjects who signed Informed consent.  
5.2. SAFETY ANALYSIS SET [SAF] 
The safety population will contain all eligible subjects who receive at least one dose of investigational drug. 
The safety population will be the primary population for evaluating treatment administration, compliance 
and safety data in the study. 
If there is any doubt whether a subject was treated, they will be assumed treated for analysis purpose.  
5.3. FULL ANALYSIS SET [FAS] 
The full analysis set will include all subjects who complete at least 1 cycle of treatment and have at least 1 
post baseline tumor assessment of efficacy or discontinue study early due to progressive disease. 


 
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6. GENERAL CONSIDERATIONS 
6.1. REFERENCE DATE AND STUDY DAY 
Study Day will be calculated from the reference date, and will be used to show start/stop day of 
assessments and events.  
Reference date is defined as the day of the first dose of study medication (Day 1 is the day of the first 
dose of study medication), and will appear in every listing where an assessment date or event date 
appears.  
 If the date of the event is on or after the reference date, then:  
STUDY DAY = (DATE OF EVENT – REFERENCE DATE) + 1. 
 If the date of the event is prior to the reference date, then:  
STUDY DAY = (DATE OF EVENT – REFERENCE DATE). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the 
listings. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date (including unscheduled assessments). In the case where the last non-missing 
measurement and the reference start date coincide, that measurement will be considered pre-baseline, 
but Adverse Events (AEs) and medications commencing on the reference start date will be considered 
post-baseline, i.e., treatment-emergent or concomitant (“worst case” approach). 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the best/worst case value 
where required (e.g. shift table).  
In the case of a retest (same visit number assigned), the latest available measurement for that visit will be 
used for by-visit summaries.  
For any subject with early withdrawal assessments available, all early withdrawal assessments related to 
the specific subject are to be considered in chronological order and are to be: 


 
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 
Considered as unscheduled.  
 
Not summarized in the by-visit summaries. 
 
Only listed in the by-subject data listings. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study. 
6.5. STATISTICAL TESTS 
No formal statistical tests will be performed for this study. The default significance level will be 5%; 95% 
confidence intervals (CI) will be presented unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
 Test Value at Visit X – Baseline Value. 
The time from Date of Event A to Date of Event B (years) is calculated as: 
 (Date of Event B - Date of Event A + 1)/365.25. 
The time from Date of Event A to Date of Event B (months) is calculated as: 
 (Date of Event B - Date of Event A + 1)/30.4375. 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
6.8. MISSING DATA 
Neither missing safety nor efficacy data will be imputed, with the exception of section 10.1 (demographic 
data), 12.1 (prior and concomitant medication data), 12.2 (prior and concomitant non-drug treatment data), 


 
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15.1 (adverse event data).  
7. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format 
and content of the summary tables, figures and listings to be provided by IQVIA Biostatistics. 
8. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition and withdrawals will be presented for all eligible subjects. 
9. PROTOCOL DEVIATIONS/VIOLATIONS 
Protocol deviation will be collected by clinical team and entered into clinical trial management system 
(CTMS).  The protocol deviation will be presented in listing including date, severity and type and will be 
further summarized for SAF. The type of protocol deviations may include the following categories based 
on IQVIA SOP:  
 
Informed Consent Criteria 
 
Eligibility and Entry Criteria 
 
Concomitant Medication Criteria 
 
Laboratory Assessment Criteria 
 
Study Procedures Criteria 
 
Serious Adverse Event Criteria 
 
Visit Schedule Criteria 
 
Investigation Produce Compliance 
 
Efficacy Criteria 
 
Administrative Criteria 
 
Source Document Criteria 
 
Regulatory or Ethics Approvals Criteria 


 
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 
Other criteria- Monitor to enter description 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the SAF. 
The following demographic and other baseline characteristics will be reported for this study: 
 Age (years) - calculated relative to date of consent 
 Sex 
o Female 
o Male 
 Is the subject a woman of childbearing potential 
o No 
o Yes 
 Reasons for no childbearing potential for woman subject 
o Menopausal 
o Sterilized 
o Other 
 Ethnicity 
o Hispanic or Latino 
o Not Hispanic or Latino 
o Not Reported 
o Unknown 
 Race  
o American Indian or Alaska Native 
o Asian 
o Black or African American 
o Naive Hawaiian or Other Pacific Islander 
o White 
o Other 
 Baseline Weight (kg) 


 
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 Baseline Height (cm) 
 Baseline Body Mass Index (BMI) (kg/m2) 
 Baseline Coagulation 
o Was Coagulation Performed: Yes/No 
o Activate Partial Thromboplastin Time (aPTT) 
o International Normalized Ratio (INR) 
 Hepatitis and HIV Screen 
o Was Hepatitis and HIV Testing Performed: Yes/No 
o HBsAg: Positvie/Negative 
o HBsAb: Positive/Negative 
o HBcAb: Positive/Negative 
o Hep C RNA (copies/mL) 
o HIV: Positive/Negative 
 Baseline Cardiac Assessment (ECHO or MUGA) 
o Was ECHO or MUGA Examination Performed: Yes/No 
o ECHO or MUGA: ECHO/MUGA 
o LVEF (%) 
o Result: Normal/Abnormal, Not Clinically Significant/Abnormal, Clinically Significant 
 Baseline Bone Scan 
o Was Bone Scan Performed: Yes/No 
o Any Bone Metastases: Yes/No 
o Location of Metastases: XXX/XXX/XXX 
o Total Number of Lesions(s): 0/1/2/>=3 
 Time Since Initial Diagnosis (months)  
 Initial Disease Stage 
o Stage I 
o Stage II 
o Stage III 
o Stage Iva 
o Stage IVb 
 Time Since Current Diagnosis (months)  


 
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 Current Disease Stage 
o Stage I 
o Stage II 
o Stage III 
o Stage Iva 
o Stage IVb 
 Histologic Types of Cancer 
 Histologic Grading of Cancer 
 Value of Tumor Mutational Burden (TMB) (mut/Mb) 
 Tumor Mutational Burden (TMB) Level 
o >10 and <15 mut/Mb 
o >=15 and =<20 mut/Mb 
o >20 mut/Mb 
o NA – Cohort 2 
 MMR Status (For Cohort 2 Only) 
o dMMR 
o iMMR 
o Unknown 
 MSI Status (For Cohort 2 Only) 
o MSI-H 
o MSI-L 
o Unknown 
 POLE-ultra-mutates Status (For Cohort 2 Only) 
o Yes 
o No 
o Unknown 
10.1. DERIVATIONS 
 Height (cm) = height (inches) x 2.54 
 Weight (kg) = weight (lbs) x 0.454 


 
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 BMI (kg/ m2) = weight (kg)/ [height (cm)/100]2 
 For all durations calculated relative to the date of informed consent, the following formula 
will be used. Age calculation is automatically performed in the EDC system: 
o Duration (Years) = (Date of Informed Consent Signed – Date of Event + 1)/365.25 
o For partially missing dates, the above calculation will be based on imputed values. For all 
calculation elements, if the date part is missing while year and month present, the 15th 
of the month will be used. If both date and month part are missing while year is present, 
July 1 will be used for imputation. 
 Time Since Initial Diagnosis (months) = (Date of Informed Consent Signed – Date of initial 
diagnosis date)/30.4375. 
 Time Since Current Diagnosis (months) = (Date of Informed Consent Signed – Date of current 
diagnosis date)/30.4375. If current diagnosis date is later than date of informed consent 
signed, the time since current diagnosis will be imputed as 0. 
 
11. MEDICAL HISTORY AND CONCOMITANT ILLNESS 
Medical history and concomitant illness will be presented for the SAF.  
Medical history and concomitant illness data are captured on the ‘Medical History’ CRF page.  
Medical history is defined as those conditions which stop prior to initial treatment of IBI308; concomitant 
illnesses are conditions which started prior to the date of initial treatment of IBI308 and stopped at or after 
the date of initial treatment of IBI308.  
The summary of medical history and concomitant illness tables will be presented by number and 
percentage of subjects by body system; each subject could have medical histories under multiple body 
systems; each subject will be counted only once within each body system.  
12. MEDICATION AND PROCEDURES 
12.1. PRIOR AND CONCOMITANT MEDICATIONS 
Medications used from signed informed consent through visit of safety follow-up 30 days after last dose of 
study drug will be collected on CRF page “Concomitant/Prior Medications”. Concomitant medications are 


 
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defined as medications administered after the first administration of the IBI308 or are ongoing at the time 
of start of treatment.  
Medications with the stop dates prior to the date of first dose of the IBI308 will be considered prior 
medications. All other medications will be considered concomitant. 
Prior and concomitant medications will be coded using World Health Organization Drug Dictionary 
Enhanced (WHO-DDE), Version 01MAR2019.  
Prior and concomitant medications will be summarized by ATC Level 3, ATC Level 2, and preferred WHO-
DDE drug name and listed for the SAF respectively.  
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define 
a medication as prior, concomitant, post concomitant, the medication will be classified by the worst case; 
i.e. concomitant.  
12.2. PRIOR AND CONCOMITANT NON-DRUG TREATMENTS (PROCEDURES)  
Procedures performed from signed informed consent through visit of safety follow-up 30 days after last 
dose of study drug are captured on CRF page “Concomitant Non-Drug Treatment”.  Medical Dictionary for 
Regulatory Activities (MedDRA) central coding dictionary, Version 22.0 (MedDRA 22.0) will be used for 
coding. 
Non-drug treatments (procedures) with the stop dates prior to the date of first dose of the IBI308 will be 
considered prior non-drug treatments (procedures). All other non-drug treatments (procedures) will be 
considered concomitant. 
Relevant information for non-drug treatments (procedures) will be listed for the SAF. 
12.3. PRIOR AND CONCURRENT ANTI-CANCER THERAPIES AND SURGERIES 
Prior and concurrent anti-cancer therapies includes prior/concurrent anti-cancer radiotherapy, 
prior/concurrent anti-cancer treatment regimens and prior/concurrent anti-cancer surgical procedures.  
Data will be captured on ‘Prior Anti-Cancer Radiotherapy’, ‘Prior Anti-Cancer Treatment Regimens’, ‘Prior 
Anti-Cancer Surgical Procedures’ CRF pages when only therapies and procedures starting prior to 
screening visit will be collected. Otherwise the therapy will be presented together with concomitant 
medications whilst procedures will be considered concomitant procedures in ‘Anti-Cancer Radiotherapy’, 
‘Anti-Cancer Treatment Regimens’, and ‘Anti-Cancer Surgical Procedures’ CRF pages, respectively.  
All prior and concurrent anti-cancer therapies will be presented in listing. The following information for 
prior and concurrent anti-cancer therapies will be summarized:  


 
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 Prior and Concurrent Anti-Cancer Radiotherapy  
o Was Any Prior Radiation Performed 
o Radiation Therapy Type 
o Treatment Intent 
o Setting 
o Modality Type 
o Radiation Relative Location(s) Category 
o Best Overall Response 
 Prior and Concurrent Anti-Cancer Treatment Regimens 
o Were Any Prior Cancer Treatment Regimens Taken 
o Type of Treatment 
o If Chemotherapy or Immunotherapy or Biotherapy or Targeted Agents or Hormonal 
Therapy, Type of Treatment Administered 
o Number of Lines of Treatment 
o Best Response 
o Medication Term 
o Reason for Discontinuing This Prior Treatment 
 Prior and Concurrent Anti-Cancer Surgical Procedures 
o Were Any Prior Surgical, Therapeutic or Diagnostic Procedures Performed 
o Reported Name of Procedure 
o Purpose of Procedure 
o Any Residual Disease Left After the Procedure Performed 
13. STUDY MEDICATION EXPOSURE 
A fixed dose of 200 mg IBI308 will be administered as IV infusion on day 1 for every three weeks (Q3W) 
to the patient until disease progression or intolerable toxicity, death, withdrawal of consent, or end of study 
up to 2 years, whichever occurs first. The date of first study medication administration will be taken from 
the eCRF “Administration of IBI308” form. The date of last study medication will be taken from the eCRF 
“End of Treatment” form.  
The following dosage information will be summarized for the SAF. 
 Total number of IBI308 infusion received 
 Total cumulative dose (mg) 


 
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 Duration of IBI308 (cycle) 
 Dose intensity (mg/cycle) 
 Relative dose intensity of IBI308 (%) 
13.1. DERIVATIONS 
 The total cumulative dose (mg) is defined as the sum of all recorded (scheduled or 
unscheduled) doses. 
 The duration of IBI308 (cycle) is defined as (Date of last dose of IBI308 - date of first dose of 
IBI308 + 21)/21. 
 The dose intensity (mg/cycle) is defined as the total cumulative dose (mg) / duration of 
IBI308 (cycle). 
 The relative dose intensity of IBI308 (%) is defined as the dose intensity of IBI308 defined in 
the preceding formula divided by 200 mg per cycle (i.e., the planned dose as assigned in the 
protocol) multiply by 100. 
14. EFFICACY OUTCOMES  
Treatment efficacy will be evaluated using the following anti-cancer activity parameters. 
 Best overall response (BOR) [complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease]   
 Objective response rate (ORR) (CR + PR) 
 Duration of response (DOR)  
 Disease control rate (DCR) (CR, PR or SD) 
 Progression-free survival (PFS) and overall survival (OS) 
Tumor assessment will be performed at baseline, every 2 cycles thereafter, and at the end of treatment by 
the investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Treatment response will 
also be assessed by immune RECIST (iRECIST) criteria to assess the potential for pseudo progression. 
Anti-cancer activity parameters will be presented by cohort and total group on the FAS. 
14.1.1. BEST OVERALL RESPONSE  
The BOR is defined as the best response from the date of first study drug administration until documented 


 
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RECIST progression, irrespective of whether subjects discontinued treatment. In the absence of RECIST 
progression, BOR is determined using visit responses up until the last evaluable overall visit response. CR 
or PR response(s) after receiving subsequent anti-cancer therapy will not be included. 
A subject’s BOR will be determined as the best response across all time points following CR> PR> SD> 
PD. When SD is believed to be best response, it must also meet the specified minimum time from 
Baseline (at least 6 weeks from treatment initiation). If the minimum time is not met when SD is otherwise 
the best time point response, the subject’s best response depends on the subsequent assessments. For 
example, a subject who has SD at first assessment, PD at second and does not meet minimum duration 
for SD, will have a best response of PD. The same subject lost to follow-up after the first SD assessment 
would be considered unevaluable.  
In addition, the following special scenario shall be considered for the determination of BOR: if a subject 
receives new anti-cancer treatment(s), for that subject, tumor assessments after the first new anti-cancer 
treatment (same day inclusive) will be considered inadequate thus not counted towards the determination 
of BOR. 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable at that 
time-point.  
Tumor responses data are captured on ‘Tumor Assessments’ of CRF Folder, including “Tumor Result: 
Targeted Lesion”, “Tumor Result: Targeted Lesion Follow Up”, “Tumor Result: Non-Targeted Lesion”, 
“Tumor Result: Non-Targeted Lesion Follow Up”, “Tumor Result: New Lesion” and “Disease Response 
(RECIST v1.1)”, “Disease Response (iRECIST v1.1)”. The numbers and the percentages of subjects 
achieving each category of BOR (CR, PR, SD, PD, NE) will be summarized for the efficacy population.  
The tumor location, the assessment methods of target lesion, and the overall response for each cycle will 
also be presented in listing. 
According to RECIST v1.1, in non-randomized trials where response is the primary endpoint, confirmation 
of PR and CR is required to ensure responses identified are not result of measurement error.  
Confirmed responses (CR or PR) are those responses which are confirmed at a repeat tumor evaluation 
at least 4 weeks (28 days) after being first observed. The detail derived logic is presented as below, 
according to the revised RECIST v1.1.  
Best Overall Response Based on RECIST v1.1 when Confirmation of CR and PR Required 
Overall 
response 
First time 
point 
Overall 
response 
Subsequent 
time point 
 
BEST overall response 
 
CR 
CR 
 
CR 
CR 
PR 
 
SD, PD or PRa 
CR 
SD 
 
SD provided minimum criteria for SD 
duration met, otherwise, PD 


 
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CR 
PD 
 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
 
SD provided minimum criteria for SD 
duration met, otherwise NE 
CR 
NE followed 
by CR 
 
CR 
PR 
CR 
 
PR 
PR 
PR 
 
PR 
PR 
SD 
 
SD 
PR 
PD 
 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
One or more 
NE/SD 
followed by 
PR 
 
PR 
NE 
NE 
 
NE 
Note: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, and 
NE=not evaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent time 
point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR). Best response would depend on whether minimum duration for 
SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact the subject had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
14.1.2. OBJECTIVE RESPONSE RATE (ORR) 
Objective response rate will be the proportion of subject with a BOR of confirmed CR or confirmed PR. 
The ORR and its 95% confidence interval (CI) will be presented. The 95% exact (Clopper-Pearson) CI will 
be calculated based on the binomial method. 
14.1.3. DISEASE CONTROL RATE (DCR) 
Disease control rate is defined as the proportion of subjects who achieve confirmed CR, confirmed PR, 
and durable SD based on RECIST v1.1. The DCR as well as 95% exact CI will be estimated. 


 
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14.1.4. DURATION OF RESPONSE  
Duration of response for responders (subjects with confirmed CR or confirmed PR) is defined as the time 
interval between the date of the earliest qualifying response and the date of disease progression or death 
for any cause, whichever occurs earlier. For subjects who are alive without disease progression following 
the qualifying response, duration of response will be censored on the date of last evaluable tumor 
assessment. 
Kaplan Meier methodology will be used to estimate median duration of response or duration of stable 
disease and its 95% confidence interval. 
14.1.5. PROGRESSION FREE SURVIVAL (PFS) 
Progression-free survival is defined as the time from the date of first study dose to disease progression or 
death whichever occurs first in subjects. Subjects without event (no disease progression or death) will be 
censored at the date of ‘last tumor assessment’. Subjects for whom no post-baseline tumor assessments 
are available are censored at the time of first dose. 
Kaplan Meier methodology will be used to estimate median PFS and its 95% confidence interval, also for 
the survival rates at week 12, 24 and 36. Kaplan Meier curves will be constructed to provide a visual 
description of the PFS change with time. 
14.1.6. OVERALL SURVIVAL (OS) 
Overall survival is defined as the time from the date of the first study dose to the date of death (any cause). 
Subjects who were alive at the time of analysis or end of study will be censored at the date of the last 
available visit. 
Kaplan-Meier methodology will be used to estimate the median survival time and its 95% confidence 
interval, also for the survival rates at week 6, 12, 18, 24, 30 and 36. Kaplan Meier curves will be 
constructed to provide a visual description of the OS change with time. 
15. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section.  


 
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15.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA, Version 22.0. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on 
or after the first dose of study medication. 
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to determine an 
AE as treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of AEs table will be provided as specified in the templates. The overall summary of 
AEs table will include the frequency (number and percentage) of subjects with each of the following by 
cohort and total group: 
o 
TEAEs 
o 
Treatment-Related TEAEs 
o 
Grade ≥ 3 TEAEs 
o 
Grade ≥ 3 Treatment-Related TEAEs 
o 
Serious TEAEs 
o 
Serious Treatment-Related TEAEs  
o 
Infusion Related Reaction (IRR) 
o 
Immunotherapy-Related Adverse Events (irAE) 
o 
TEAEs Leading to Drug Interrupted 
o 
TEAEs Leading to Drug Withdrawn 
o 
TEAEs Leading to Death 
Listings will include TEAEs and Non-TEAEs. 
15.1.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also 
broken down further by maximum severity and relationship to study medication. 
15.1.1.1. 
Severity 
The severity of all TEAEs will be graded according to 5 grades (Grade 1 to Grade 5) (increasing severity) 
in accordance with the national cancer institute common terminology criteria for adverse event (NCI-
CTCAE) V4.03. If a subject reports a TEAE more than once within that SOC/ PT, the AE with the worst 


 
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case severity will be used in the corresponding severity summaries. 
15.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as ”Not Related”, “Related” (increasing severity 
of relationship). TEAEs with a missing relationship to study medication will be regarded as “Related” to 
study medication. If a subject reports the same AE more than once within that SOC/ PT, the AE with the 
worst case relationship to study medication will be used in the corresponding relationship summaries.  
15.1.2. IMMUNE RELATED ADVERSE EVENTS (IRAE) 
Checkpoint inhibition is associated with a wide spectrum of side effects defined as immune-related 
adverse events (irAE). IrAEs may include gastrointestinal, hepatic, endocrine, dermatologic and 
inflammatory events. IrAEs are defined as AEs of unknown etiology potentially associated with an immune 
phenomenon.  
IrAE can be identified on the Adverse Event CRF page with question “Was this an immunotherapy-related  
adverse event (irAE)?”. Summaries of incidence rates (frequencies and percentages) of irAE by SOC and 
PT will be prepared. 
15.2. DEATHS 
If any subjects die during the study as recorded on the “Death Detail” page of the CRF, the information will 
be presented in a data listing. 
15.3. LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for Hematology including 
CBC with differential, blood chemistry, thyroid tests (TSH, free T3 and T4), urine pregnancy test, urine 
analysis. The following laboratory parameters will be reported for this study: 
o 
Hematology: Haemoglobin, White Blood Cell Count, Neutrophil (absolute value), Lymphocyte (absolute 
value), Monocytes (absolute value), Basophil (absolute value), Eosinophil (absolute value), Red Blood Cell 
Count, Hematocrit, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration 
(MCHC), Mean Corpuscular Volume (MCV), Platelet Count 
o 
Blood chemistry: Alkaline Phosphatase, ALT, AST, Total Bilirubin, BUN, Creatinine, Total Protein, Albumin, 
Fasting Glucose, Potassium, Sodium, Chloride, Uric Acid, Lactate Dehydrogenase, LDL, Total Cholesterol, 
Triglycerides, Amylase, Lipase 
o 
Thyroid Function Tests: Thyroid Stimulation Hormone (TSH), Free T3 and Free T4 
o 
Urine Pregnancy Test (HCG) 
o 
Urine Analysis: pH (quantitative value only), Red Blood Cells, White Blood Cells, Protein, Glucose 


 
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Presentations will use SI Units. Unit conversions will be performed by Data Manager in the database 
where necessary. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), 
or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of 
quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
 Actual and change from baseline by visit (for quantitative measurements) 
 Incidence of abnormal values according to normal range criteria 
 Shift from baseline according to normal range criteria (for quantitative measurements and 
categorical measurements) 
 Shift from baseline according to Common Toxicity (CTC) grading system (for measurements 
applicable based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0) 
15.3.1. LABORATORY SPECIFIC DERIVATIONS 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
SI units and categorized as: 
 Low: Below the lower limit of the laboratory reference range  
 Normal: Within the laboratory reference range (upper and lower limit included) 
 High: Above the upper limit of the laboratory reference range 
15.3.2. CTC GRADING FOR LABORATORY DATA 
Hematology and Biochemistry laboratory quantitative parameters will be graded according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria (see 
Appendix 3), where applicable, and shift from baseline based on the classification will be presented.  
15.4. 12-LEAD ELECTROCARDIOGRAM (ECG) EVALUATIONS 
ECG data collected in 12-Lead ECG eCRF page will be included in the reporting of this study.  
The following ECG parameters will be reported for this study, change from baseline will be prepared for 
quantitative parameters and summary by each visit will be display for qualitative parameter. The overall 
result of ECG shift from baseline to maximal on-treatment value during the on-treatment period will be 
summarized by cohort. 


 
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 Heart Rate (bpm) 
 PR Interval (msec) 
 RR Interval (msec) 
 QRS Interval (msec) 
 QT Interval (msec) 
 QTcF (msec) [derived] 
 Overall Result of ECG (Investigator’s judgment): 
o Normal 
o Abnormal, Not Clinically Significant (ANCS) 
o Abnormal, Clinically Significant (ACS) 
o Unevaluable 
15.4.1. 12-LEAD ELECTROCARDIOGRAM (ECG) SPECIFIC DERIVATIONS 
 Fridericia’s Correction (msec) 
 
15.5. IMMUNOGENICITY ASSESSMENTS 
Blood samples for anti-drug antibody (ADA) analyses will be collected at predose in Cycle 1 and Cycle 2 
and then in every other subsequent cycle, and at the mandatory Safety Follow-up Visit or until start of a 
new anti-cancer therapy, whichever occurs first. All samples will first be analyzed for ADAs in a screening 
assay. Study samples with results below the screening cut-off will be reported as negative for ADAs. In 
the event of a positive result in the screening assay, samples will be analyzed in the confirmatory assay. 
All samples confirmed positive will be reported as positive and will be further analyzed for presence of 
neutralizing antibodies (NAb).  
The incidence of ADA will be summarized for all subjects who received at least one administration of 
investigational drug.  
The immunogenicity results will be listed for ADA and NAb for each patient and time point. 
15.5.1. IMMMUNOGENICITY ASSESSMENTS SPECIFIC DERIVATIONS 
 Treatment-induced ADA: defined as any post-treatment positive ADA assay response when 


 
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the baseline ADA result is negative. 
 Treatment-boosted ADA: defined as any post-treatment positive ADA assay response that is 
greater than or equal to 4-fold over baseline titer level when baseline is ADA positive in the 
ADA assay. 
 ADA Incidence: sum of both treatment-induced and treatment-boosted  
15.6. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 Height (cm) 
 Weight (kg) 
 Systolic Blood Pressure (mmHg) 
 Diastolic Blood Pressure (mmHg) 
 Respiratory Rate (resp/min) 
 Pulse Rate (bpm) 
 Temperature (F) 
The following summaries will be provided for vital signs data: 
 Actual and change from baseline by visit  
 Incidence of abnormalities: Normal/Abnormal 
15.6.1. VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with the 
following predefined markedly abnormal criteria: 
Vital 
Signs 
Markedly Abnormal Criteria 
Note 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
≥120 bpm and increase from baseline≥20 bpm 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
To be applied for all positions (including 
missing) except STANDING. 
≥160 mmHg and increase from baseline ≥20 mmHg 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
≥110 mmHg and increase from baseline ≥10 mmHg 
Weight 
≥5% increase from baseline  
FDA Feb 2007. 


 
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15.7. PHYSICAL EXAMINATION 
The following physical examination parameters will be reported for this study: 
 General Conditions 
 Respiratory System 
 Cardiovascular System 
 Abdomen 
 Skin and Mucous Membranes 
o Head and Neck (including Eyes, Ears, Nose and Throat) 
o Thyroid 
o Lymph Nodes 
o Genitourinary System 
o Muscles and Bones (including Spine and Limbs) 
o Nervous System 
The following summaries will be provided for physical examination data: 
 Incidence of abnormalities: Normal/Abnormal, Not Clinically Significant (ANCS)/Abnormal, 
Clinically Significant (ACS)  
15.8. ECOG PERFORMANCE STATUS 
The following summaries of ECOG Performance Status will be reported for this study: 
 0 
 1 
 2 
 3 
 4 
 5  
The ECOG shift from baseline to highest score during the on-treatment period will be summarized by 
cohort. 


 
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References  
Protocol - CIBI308A102 Version 6, 7Jan2019 
CRF - CIBI308A102 Version 03.00, 13Mar2019 
 
 


 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
The following conventions will be applied for reporting descriptive statistics of all continuous data: 
• 
Mean, Median, Q1, Q3, Minimum, and Maximum will have the one more digit than RAW/SDTM 
data for non-derived data (e.g. weight).  
• 
SD will be presented with one digit more than mean.  
• 
Statistics on derived data (e.g. treatment exposure time in days) will be rounded to reasonable 
number of digits. Maximal digits should be available in ADaM datasets.  
Outputs will be presented according to the following Global Bios > Processes > GBIOS Processes - 
Implementation Guidelines and Templates > General Guidelines and Templates > Output Conventions.   
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TIMEPOINTS 
For outputs, treatment cycles will be represented as follows and in the order shown. Visits will be 
displayed as carried in the raw data, unless otherwise specified in the analysis dataset specifications. The 
number of visits and cycles will vary across subjects. 
Long Name 
Short Name (default for presentations) 
Cycle x Day y 
CxDy 
Example: 
Cycle 1 Day 1 
Cycle 2 Day 1 
Cycle 2 Day 1 – Unscheduled 01 
Example: 
C1D1 
C2D1 
C2D1 UNS01 


 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If study med start date ≤ AE start date ≤ the later of (study 
med stop +30 days or the safety follow-up visit), then TEAE 
If the later of (study med stop +30 days or the safety follow-
up visit) < AE start date, then not TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If study med start date ≤ AE start date ≤ the later of (study 
med stop +30 days or the safety follow-up visit), then TEAE 
If the later of (study med stop +30 days or the safety follow-
up visit) < AE start date, then not TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If study med start date ≤ AE start date ≤ the later of (study 
med stop +30 days or the safety follow-up visit), then TEAE 
If the later of (study med stop +30 days or the safety follow-
up visit) < AE start date, then not TEAE 
 
 
 
Partial, but known 
components show that 
it cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not TEAE 
If study med start ≤ AE stop date ≤ the later of (study med 


 
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START DATE 
STOP DATE 
ACTION 
stop +30 days or safety follow-up visit), then TEAE 
If the later of (study med stop +30 days or safety follow-up 
visit) < AE stop date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If study med start ≤ AE stop date ≤ the later of (study med 
stop +30 days or the safety follow-up visit), then TEAE 
If the later of (study med stop +30 days or the safety follow-
up visit) < AE stop date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If study med start ≤ AE stop date ≤ later of (study med stop 
+30 days or the safety follow-up visit date), then TEAE 
If the later of (study med stop +30 days or safety follow-up 
visit date) < AE stop date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If study med start ≤ AE stop date ≤ the later of (study med 
stop +30 days or safety follow-up visit date), then TEAE 
If the later of (study med stop +30 days or safety follow-up 
visit date) < AE stop date, then TEAE 
 
Missing 
Assumed TEAE 
 


 
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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant  
If stop date >= study med start date and start date > end of 
treatment, assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 


 
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START DATE 
STOP DATE 
ACTION 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 


 
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APPENDIX 3. NCI CTCAE V5.0 LAB GRADES 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Albumin 
(hypalbuminaemia) 
g/L 
[30, LLN) 
[20, 30) 
[0, 20) 
 
Alkaline Phosphatase 
increased 
IU/L 
(ULN, 2.5*ULN]  
if baseline is normal; 
[2*BL, 2.5*BL]  
if baseline is abnormal 
(2.5*ULN, 5*ULN] 
if baseline is abnormal; 
[2.5*BL, 5*BL]  
if baseline is abnormal 
(5*ULN, 20*ULN] 
if baseline is abnormal; 
[5*BL, 20*BL]  
if baseline is abnormal 
>20*ULN  
if baseline is abnormal; 
>20*BL  
if baseline is abnormal 
 
ALT (Alanine 
Aminotransferase) 
increased 
IU/L 
(ULN, 3*ULN]  
if baseline is normal; 
[1.5*BL, 3*BL]  
if baseline is abnormal 
(3*ULN, 5*ULN] 
if baseline is abnormal; 
[3*BL, 5*BL]  
if baseline is abnormal 
(5*ULN, 20*ULN] 
if baseline is abnormal; 
[5*BL, 20*BL]  
if baseline is abnormal 
>20*ULN  
if baseline is abnormal; 
>20*BL  
if baseline is abnormal 
 
AST (Aspartate 
Aminotransferase) 
increased 
IU/L 
(ULN, 3*ULN]  
if baseline is normal; 
[1.5*BL, 3*BL]  
if baseline is abnormal 
(3*ULN, 5*ULN] 
if baseline is abnormal; 
[3*BL, 5*BL]  
if baseline is abnormal 
(5*ULN, 20*ULN] 
if baseline is abnormal; 
[5*BL, 20*BL]  
if baseline is abnormal 
>20*ULN  
if baseline is abnormal; 
>20*BL  
if baseline is abnormal 
 
Blood Bilirubin 
increased 
umol/L 
(ULN, 1.5*ULN]  
if baseline is normal; 
[1*BL, 1.5*BL]  
if baseline is abnormal 
(1.5*ULN, 3*ULN] 
if baseline is abnormal; 
[1.5*BL, 3*BL]  
if baseline is abnormal 
(3*ULN, 10*ULN] 
if baseline is abnormal; 
[3*BL, 10*BL]  
if baseline is abnormal 
>10*ULN  
if baseline is abnormal; 
>10*BL  
if baseline is abnormal 
 
Cholesterol high 
umol/L 
(ULN, 7.75] 
(7.75, 10.34] 
(10.34, 12.92] 
>12.92 
Creatinine increased 
umol/L 
(ULN, 1.5*ULN] 
(1.5*ULN, 3*ULN]; 
(1.5*BL, 3*BL] 
(3*ULN, 6*ULN]; 
(3*BL, 6*BL] 
>6*ULN 
 
Glucose decreased 
(Hypoglycemia) 
mmol/L 
[3, LLN) 
[2.2, 3) 
[1.7, 2.2) 
[0, 1.7) 
 
Potassium increased 
(Hyperkalaemia)  
mmol/L  
(ULN, 5.5] 
(5.5, 6] 
(6, 7]  
>7  
Potassium decreased 
(Hypokalaemia)  
mmol/L  
[3, LLN) 
 
[2.5, 3)  
[0, 2.5)  
Sodium increased 
(hypernatremia) 
mmol/L  
(ULN, 150] 
(150, 155] 
(155, 160] 
>160 
 
Hemoglobin 
decreased 
g/L 
[100, LLN) 
[80, 100) 
<80 
 
Hemoglobin increased 
g/L 
Increase in >0 - 20 g/L 
above ULN or above 
baseline 
if baseline is above ULN 
Increase in >20 - 40 g/L 
above ULN or above 
baseline 
if baseline is above ULN 
Increase in >40 g/L 
above ULN or above 
baseline if 
baseline is above ULN 
- 
 
Platelet decreased 
10^9/L 
[75, LLN) 
[50, 75) 
[25, 50) 
[0, 25) 
 
WBC decreased 
10^9/L 
[3, LLN) 
[2, 3) 
[1, 2) 
[0, 1) 
 
Leukocytosis 
10^9/L 
- 
- 
>100 
 
Lymphocytes 
decreased 
10^9/L 
[0.8, LLN)  
[0.5 - 0.8) 
[0.2 - 0.5) 
[0, 0.2) 
 
Lymphocyte increased 
10^9/L 
- 
(4, 20] 
>20 
- 
 
Neutrophil decreased 
10^9/L 
[1.5, LLN) 
[1, 1.5) 
[0.5, 1) 
[0, 0.5) 
 
- Grade 0: if Value is not missing and >= Normal Range Lower Limit [Decreased]; if Value is not missing    
   and <= Normal Range Upper Limit [Increased] 
- LLN=Lower Limit of Normal; ULN=Upper Limit of Normal; BL=Baseline 
- Qualitative criteria will be ignored