Clinical trial NCT03114683
Conditions: Relapsed/Refractory Classical Hodgkin's Lymphoma
Keywords: Hodgkin Lymphoma
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2017-03-30; Completion date: 2019-11-30
Enrollment: 96 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is to evaluate ORR, CR, PR DCR DOR PFS and safety of IBI308 in treatment of patients with Relapsed/Refractory Hodgkin's Lymphoma.

Detailed description:
Patients with classical Hodgkin lymphoma(cHL) who relapse after autologous stem-cell transplantation(ASCT) or progress after multiple lines of chemotherapy have a poor prognosis, with a median survival of approximately 1.2 years.

CHL frequently harbors a spectrum of chromosome 9p24.1/PD-L1/PD-L2 alterations, leading to overexpression of the programmed death 1 ligands,PD-L1 and PD-L2.

Sintilimab is a humanized monoclonal antibody against PD-1 that blocks the interaction between PD-1 and its ligands and was approved for relapsed/refractory Hodgkin lymphoma in China in 2018.

This study is a single arm,phase 2 study designed to evaluate the clinical activity of sintilimab in Chinese patients with R/R

Arms: arm 1: None
Interventions: intervention 1: PD1
Intervention descriptions: intervention 1: IBI308 200mg/3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Study Protocol 
Title 
Efficacy and Safety Evaluation of IBI308 in 
Treatment of Patients With Relapsed/Refractory 
Classical Hodgkin's Lymphoma: a Multicenter, 
Single Arm, Phase II Study (ORIENT-1) 
Protocol No. 
CIBI308B201 
Version Date 
05Feb2018/Version2.0 
Investigational Product 
IBI308 
Study Phase 
Phase II 
Sponsor 
Innovent Biologics. Ltd 
 
This document contains confidential information belonging to Innovent.  Except as otherwise agreed to 
in writing, by accepting or reviewing this document, you agree to hold this information in confidence 
and not copy or disclose it to others (except where required by applicable law) or use it for unauthorized 
purposes.  In the event of any actual or suspected breach of this obligation, Innovent must be promptly 
notified. 
 
 
 
 




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Synopsis  
Protocol No. 
CIBI308B201 
Sponsor 
Innovent Biologics. Ltd 
Investigational 
Product 
IBI308 
Active Ingredient  
Recombinant humanized anti-programmed death receptor 1 (PD-1) 
monoclonal antibody 
Title 
Efficacy and Safety Evaluation of IBI308 in Treatment of Patients With 
Relapsed/Refractory Classical Hodgkin's Lymphoma: a Multicenter, Single 
Arm, Phase II Study (ORIENT-1) 
Study Phase 
Phase II 
Estimated 
Duration of Study 
36 months 
Objectives 
Primary Objectives 
• 
ORR of IBI308 monotherapy in relapsed or refractory cHL assessed by 
IRRC (Independent Radiological Review Committee). 
Secondary Objectives 
• 
ORR of IBI308 monotherapy in relapsed or refractory cHL assessed by 
investigator; 
• 
CR and PR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
DCR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
TTR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
DOR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
PFS and 6-month PFS rates of IBI308 monotherapy in relapsed or 
refractory cHL; 
• 
Evaluate the safety of IBI308 monotherapy in patients with relapsed or 
refractory cHL. 
• 
Evaluate PK/PD/immunogenicity of IBI308 monotherapy in patients 
with relapsed or refractory cHL. 
• 
Evaluate the quality of life of patients with relapsed or refractory cHL 
after IBI308 monotherapy (according to the EQ-5D-5L and EORTC 
QLQ-C30 scales). 
Exploratory Objectives 
Assess the relationship between PD-L1 expression, immune-related gene 
mRNA, and other potential biomarkers in relapsed or refractory cHL and 
IBI308 efficacy. 
Study Design 
This study is a multicenter, single-arm, phase II study to evaluate the 
efficacy and safety of IBI308 in relapsed or refractory classic Hodgkin's 
lymphoma. This study will enroll patients with relapsed or refractory cHL to 
receive intravenous (IV) IBI308 at 200 mg every three weeks (Q3W) for up 
to 24 months, or until disease progression, death, unacceptable adverse 
event(s), subject withdraws informed consent or other reasons specified in 
protocol. If the subject still has no disease progression after 24 months of 


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IBI308 treatment and the investigator judges that the subject will still benefit 
from the study drug, the subject should sign additional informed consent to 
continue receiving free IBI308 treatment. For subjects with first disease 
progression, if the clinical condition is stable, the investigator may let the 
subject continue to receive treatment until the total treatment time reaches 
24 months or until disease progression, death, unacceptable adverse 
event(s), subject withdraws informed consent, or other reasons specified in 
protocol. 
The primary endpoint of the study is overall response rate (ORR), defined as 
the percentage of subjects with optimal response to partial and complete 
response, evaluated according to the IWG 2007 criteria, and the Lugano 
2014 criteria as an adjunct to the standard, both evaluated by IRRC. 
Analysis of primary endpoints will be performed after the last subject who 
meets the statistical and imaging assessment requirements and completes up 
to 24 weeks of follow-up. Subjects will have a safety follow-up 90 days 
after the last dose of IBI308. 
Inclusion Criteria 
1. Histopathological confirmed classical Hodgkin's lymphoma (cHL). 
2. Relapsed/refractory cHL patients who have failed after at least two lines 
of therapy (including radiotherapy and autologous hematopoietic stem 
cell transplantation, ASCT); subject with no response to or with 
progression after ASCT is eligible for enrollment. 
3. At least one measurable disease (long axis>15 mm or short axis>10 
mm, with uptake on 18FDG-PET) 
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
0-2. 
5. Sign the informed consent form and be willing and able to comply with 
scheduled visits and other requirements of the study. 
6. Age ≥ 18. 
7. Life expectancy ≥ 12 weeks. 
8. Subjects of reproductive potential must be willing to use adequate 
contraception during the whole course of the study and through 90 days 
after the last dose of study medication. 
9. Adequate organ and bone marrow function: 
1) Count of Blood Cells: absolute neutrophil count (ANC) ≥ 0.75 × 
109 / L; platelet count (PLT) ≥ 50 × 109 / L; hemoglobin content 
(HGB) ≥ 8.0 g / dL; no granulocyte colony-stimulating factor, 
platelet or red blood cells infusion in the last 14 days. 
2) Liver function: total bilirubin (TBIL) ≤ 1.5 × normal upper limit 
(ULN); alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 2.5 × ULN. 
3) Renal function: serum creatinine (Cr) ≤ 1.5 × ULN 
4) Thyroid function: thyroid stimulating hormone (TSH) in normal 
range (TSH abnormalities due to non-autoimmune causes can be 
enrolled). 


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Exclusion Criteria 
1. Known nodular lymphocyte predominant Hodgkin lymphoma. 
2. Known central nervous system lymphoma. 
3. Received ASCT within 90 days before the first dose of study 
medication. 
4. Prior exposure to any anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody. 
5. Currently participating in another interventional clinical study, unless 
participating in an observational study or during follow-up period of 
another interventional study. 
6. Received any investigational agent within 4 weeks before the first dose 
of study medication. 
7. Received last dose of radiotherapy or anti-tumor therapy 
(chemotherapy, targeted therapy, tumor immunotherapy or arterial 
embolization) within 3 weeks before the first dose of study medication; 
received last dose of nitrosourea or mitomycin C within 6 weeks before 
the first dose of study medication. 
8. Received systemic treatment with corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 
4 weeks before first dose. Inhaled, nasal spray or topical steroids and 
adrenal replacement steroid doses are permitted in the absence of active 
autoimmune disease. 
9. Received a live vaccine within 4 weeks of the first dose of study 
medication or plan to receive live vaccine during study period. 
10. Underwent major operation (craniotomy, thoracotomy or laparotomy) 
within 4 weeks of the first dose of study medication or with open 
wound, ulcer or fracture. 
11. Activite, known or suspected autoimmune diseases or history of the 
disease with two years before enrollment. Vitiligo, psoriasis, hair loss, 
or Graves disease which do not need  systemic treatment in 2 years, or 
hypothyroidism which only need thyroid hormone replacement therapy, 
or type-1 diabetes which only need insulin replacement therapy is 
eligible for enrollment. 
12. Known primary immunodeficiency disorders. 
13. Active tuberculosis. 
14. Known history of allogeneic organ or allogeneic hemopoietic stem cell 
transplantation. 
15. Known allergy or hypersensitivity to any monoclonal antibodies or any 
components used in their preparation. 
16. Uncontrolled concomitant disease, including but not limited to : 
1) Human Immunodeficiency Virus (HIV) infection (HIV antibody 
positive) 
2) Active or poorly controlled severe infection 
3) Symptomatic congestive heart failure (New York Heart 
Association grade Ⅲ-IV) or symptomatic, poorly controlled 
arrhythmia 


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4) Poorly controlled arterial hypertension (SBP ≥ 160mmHg or 
DBP ≥ 100mmHg) with standard treatment 
5) Prior arterial thromboembolism event, including myocardial 
infarction, unstable angina, stroke or transient ischemic attack, 
within 6 months before enrollment 
6) Prior life-threatening blood loss or grade 3/4 
gastrointestinal/varicosity bleeding requiring blood infusion, 
endoscopic or surgical intervention within 3 months of 
enrollment 
7) Prior deep vein thrombosis, pulmonary embolism or any other 
severe thromboembolism events (implanted port or catheter 
caused thrombosis, or superficial vein thrombosis are not 
considered as severe thromboembolism events) within 3 months 
before enrollment 
8) History of uncontrolled metabolic disorder, non-malignant organ 
or systemic disease or secondary carcinomatous reaction, with 
high medical risk and/or uncertainty of survival evaluation 
9) With hepatic encephalopathy, hepato-renal syndrome or hepatic 
cirrhosis of Child-Pugh grade B or higher. 
10) History of intestinal obstruction or the following diseases: 
inflammatory bowel disease or extensive bowel resection (partial 
colonic resection or extensive small bowel resection, 
concomitant with chronic diarrhea), Crohn's disease, ulcerative 
colitis or chronic diarrhea 
11) Other acute or chronic diseases, mental illness, or abnormal 
laboratory test results that may lead to the following outcomes: 
increase the risk of participating in study or study drug 
administration, or interfere with the interpretation of the study 
results and considered by investigator as "NOT" eligible to 
participate in this study 
17. Known acute or chronic active hepatitis B infection (chronic HBV 
carrier or non-active HBsAg positive subject is eligible) or acute or 
chronic active hepatitis C (HCV antibody negative subject is eligible; 
HCV RNA examination is required for HCV antibody positive subject, 
subject is eligible for enrollment if result was negative) 
18. History of gastrointestinal perforation and /or fistula within 6 months 
before enrollment 
19. Subjects with interstitial lung disease 
20. Uncontrolled third space effusion, e.g. ascites or pleural effusion cannot 
be drained or controlled 
21. Other primary malignancy, with the exception of: 
1) Curable malignancy (e.g. papillary thyroid carcinoma) 
2) Without active disease in the last 5 years and with very low 
recurrence risk 


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3) Non-melanoma skin cancer or malignant freckle-like nevus with 
adequate treatment and no evidence of recurrence ; 
4) Adequately treated in-situ carcinoma 
22. Women who are pregnant or in lactation period. 
Drug 
Administration 
IBI308 100mg/10ml 
200 mg i.v. Q3W 
Evaluations 
Efficacy 
 
Efficacy is evaluated according to IWG 2007 and Lugano 2014 
by IRRC and the investigator, including ORR, DCR, TTR, DOR, 
PFS and PFS rate at 6 months. 
Safety 
 
Incidence, causality and severity of adverse events (AE), 
treatment emergent AEs, AEs of special interest, and serious AEs 
 
Vital sign, physical examinations, and laboratory examination, 
before, during and after treatment 
Immunogenicity 
 
Anti-drug antibody (ADA) and neutralizing antibody (NAB) 
PK/PD 
12 subjects from selected research sites are included in PK/PD analysis 
 
To describe PK profiles of single and multiple dose of IBI308. PK 
parameters include area under curve (AUC), Cmax, CL, V and t1/2 
 
PD analysis includes but not limited to PD-1 receptor occupancy 
Biomarker 
 
Samples will be collected for biomarker analysis, which includes 
but not limited to PD-L1 expression and other tumor related genes 
(IDO1, CXCL9, CXCL10, HLA-DRA, STAT1, IFNG massager 
RNA) 
Quality of life 
 
EQ 5D-5L and EORTC QLQ-C30 
Statistical Analysis 
Sample size estimated 
The study was a single arm study. The planned sample size of 80 patients 
provided 80% power to reject the null hypothesis that the proportion of 
patients achieving an objective response is 40% or fewer, assuming an 
objective response of 56% and given a two-sided alpha of 5%. Considering 
the possible drop-off of patients, 90 patients will be recruited to ensure at least 
80 evaluable patients.  
Hypothesis  
H0：ORR≤40% 
H1：ORR>40% 
α=0.05 (two-sided) and superiority test is based on confidence interval (CI).  
Interim analysis 
In this study, an interim analysis is planned to conduct at the time point when 
all the enrolled subjects finished two tumor assessments by IRRC. The 
purpose of the interim analysis is for conditional BLA submission at the early 


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stage, and the endpoint is the primary efficacy endpoint ORR according to 
IWG2007. 
Primary efficacy endpoint 
Binomial distribution will be applied to estimate ORR and 95% CI for 
superiority test. 
Secondary efficacy endpoint 
TTR, DOR, PFS: Kaplan-Meier will be used to estimate median values and 
95% 
CR, PR, DCR: Binomial distribution will be applied to estimate ORR and 
95% CI. 
Safety endpoint  
The safety analysis will be conducted by description of incidence rates and 
grades of AEs.  
Immunogenicity  
The positive rates of ADA antibody and NAB will be calculated, and the 
antibody levels of positive subjects will be described with listings. 
PK/PD 
Describe PK/PD parameters, such as AUC, Cmax, CL, V, t1/2 and PD-1 
receptor occupancy.  
Quality of life 
Describe results on EQ-5D-5L and EORTC QLQ-C30. 
Biomarker 
Describe PD-L1 expression, and other tumor related gene expression, and 
their potential relations with treatment efficacy. 
 
 
 


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Table 1 Schedule of Activities 
Protocol Activity 
Screen 
Treatment Period 
Treatment 
Disconinuation1 
Safety Visit 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 and after 
 
1 
2 
3 
4 
5 
6 
7 ~ N 
Early 
Termination/Treatment 
Discontinuation Visit 
 
 
-28~-1 
D 
Day 2 
Day 22 
（±3 
days） 
Day 43 
（±3 
days） 
Day 64 
（±3 
days） 
Day 85 
（±3 
days） 
Every 3 Weeks 
（±3 days） 
 
90 Days（±7）after 
last dosing 
Regular Activities 
 
Informed consent 1 
X 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographics/Medical 
History/Prior treatment2 
X 
 
 
 
 
 
 
 
 
Vital sign3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/weight4 
X 
 
 
 
 
 
 
X 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
 
12 lead ECG5 
X 
 
 
X 
 
X 
X 
X 
 
Clinical safety laboratory 
test6 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 7 
X 
 
 
 
 
 
 
X 
 
Thyroid function 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK9 
 
X 
X 
 
X 
 
X 
 
 


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Protocol Activity 
Screen 
Treatment Period 
Treatment 
Disconinuation1 
Safety Visit 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 and after 
 
1 
2 
3 
4 
5 
6 
7 ~ N 
Early 
Termination/Treatment 
Discontinuation Visit 
 
 
-28~-1 
D 
Day 2 
Day 22 
（±3 
days） 
Day 43 
（±3 
days） 
Day 64 
（±3 
days） 
Day 85 
（±3 
days） 
Every 3 Weeks 
（±3 days） 
 
90 Days（±7）after 
last dosing 
PD10 
 
X 
X 
 
 
 
X 
 
 
Immunogenicity 11 
 
X 
X 
 
X 
 
 
 
X 
HIV, HBV and HCV12 
X 
 
 
 
 
 
 
 
 
Adverse Event 13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy evaluation 
 
Bone marrow biopsy 14 
X 
 
 
 
 
 
 
 
 
Tumor radiological 
evaluation 15 
X 
 
 
X 
 
 
X 
 
 
Disease related symptom 
evaluation 16 
 
X 
X 
X 
X 
X 
X 
X 
 
Treatment administration 
 
IBI30817 
 
X 
X 
X 
X 
X 
X 
 
 
Quality of life evaluation 
 
EQ-5D-5L/ 
EORTC QLQ-C30 18 
 
X 
 
X 
 
 
X 
X 
 
Biomarker 
 
Archived or fresh tumor 
X 
 
 
 
 
 
 
 
 


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Protocol Activity 
Screen 
Treatment Period 
Treatment 
Disconinuation1 
Safety Visit 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 and after 
 
1 
2 
3 
4 
5 
6 
7 ~ N 
Early 
Termination/Treatment 
Discontinuation Visit 
 
 
-28~-1 
D 
Day 2 
Day 22 
（±3 
days） 
Day 43 
（±3 
days） 
Day 64 
（±3 
days） 
Day 85 
（±3 
days） 
Every 3 Weeks 
（±3 days） 
 
90 Days（±7）after 
last dosing 
sample collection 19 
Blood sample 20 
 
X 
 
X 
 
 
X 
 
 
Note： 
1. 
informed consent forms (ICF）is signed before any study procedure is taken. 
2. 
Prior treatment includes：treatments based on initial diagnosis, including chemotherapy, radiotherapy and surgery 
3. 
Vital sign includes body temperature, pulse rate, breathing, and blood pressure. 
4. 
Height and weight are measured at screening; weight is measured at treatment discontinuation visit. 
5. 
12 lead ECG is schedule at screening, every 2 cycle before dosing, and treatment discontinuation visit. 
6. 
CBC：red blood cell, HGB, white blood cell, PLT, lymphocyte count, ANC. Blood chemistry: liver function [TBIL, ALT, AST, γ-glutamyltransferase, alkaline phosphatase, albumin, 
total protein, lactic dehydrogenase]，renal function [blood urea nitrogen, Cr]，Na, K, Cl, Mg, Ca, P, lipase，fasting blood glucose, FBG. Urine routine： PH, urinary albumin, urine 
protein, urine red blood cell, urine glucose. The screening period, 7 days before the first study drug administration and the second cycle start every 3 days before the study drug 
administration and at the safety follow-up. Safety laboratory examination will be conducted at each research center. 
7. 
Women with fertility potential will have a urine or serum pregnancy check within 3 days prior to the first dose and at the end of the treatment visit. If the urine pregnancy test result 
cannot be confirmed as negative, a serum pregnancy test will be performed, which is based on the serum pregnancy result. Test will be conducted at each research center.  


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8. 
During the screening period, starting at the beginning of the second cycle, within 3 days before the study drug administration and at the safety follow-up. Screening period to check for 
triiodothyronine (T3), thyroxine (T4), free thiiodothronine (FT3), free tetraiodothyronine (free thiiodothronine) , FT4) and TSH, only check TSH at the beginning of the second cycle, if 
other abnormalities, consider checking other thyroid function indicators. Inspections will be conducted at each research center. 
9. 
PK: PK testing was performed in 12 subjects at designated research centers. The total number of PK blood collection points set in the first cycle is 8: 1 hour before the start of IBI308 
infusion, immediately after the end of infusion (+5min), 1h±5min after the end of infusion, 6h±15min, 24h±1h after the start of infusion. 48h±2h, 168h±8h (day 8), 336h±12h (day 15); 
if the administration is delayed on the first day of the second cycle due to AE or other reasons, the first cycle needs to be increased by 504h±24h ( Day 22) Sampling. From the second 
cycle, PK sample collection is performed every two cycles (the second, fourth, and sixth phase cycles, and so on). Except for the fourth cycle, the sampling time is: within 1 hour before 
the start of the infusion and the end of the infusion. Immediately (+5min). The fourth cycle (intensive sampling) blood collection time: within 1 hour before the start of the infusion, 
immediately after the end of the infusion (+5min), 1h ± 5min after the end of the infusion, 6h ± 15min, 24h ± 1h, 48h ± after the infusion 2h, 168h ± 8h (day 8), 336h ± 12h (day 15), 
504h ± 24h (day 22, ie, within 1 hour before the fifth cycle of administration).  
10. PD: PD testing was performed in 12 subjects in the designated study center. The total number of PD blood collection points set in the first cycle was 3: 1 h before the start of the IBI308 
infusion, 24 h ± 1 h after the start of the infusion, and 168 h ± 8 h (Day 8). At the beginning of the second cycle, sample collection is performed every four cycles (the second, sixth, 
tenth, fourteenth, etc., and so on). Blood collection point: within 1 hour before the start of the infusion.  
11. The immunogenicity test will be performed during the first cycle, the second cycle, the fourth cycle, and every 4 cycles (the 8th, 12th, and 16th cycles, etc.) within 1 hour before the 
IBI308 infusion and during the safety follow-up. The inspection will take place at the central laboratory.  
12. Five hepatitis B (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) tests, HBV DNA, HCV antibodies and HIV antibody tests are performed during the screening period. If HCV antibodies are 
positive, HCV RNA will be further examined. For hepatitis B virus carriers, it is recommended to monitor viral activity regularly during the study period. Inspections will be conducted 
at each research center. 
13. AE and laboratory safety assessments will be evaluated according to NCI CTCAE version 4.03. The definition, record, correlation judgment, severity judgment, reporting time limit and 
processing of AE and SAE are described in Section 7 of the scheme. 
14. For subjects with a positive baseline bone marrow biopsy, a bone marrow biopsy (completed within 2 weeks of imaging assessment) is required if there is a complete imaging remission 
during treatment; if the bone marrow biopsy biopsy cannot determine the nature, the immunization group is required. Confirmation; immunohistochemistry to determine no malignant 
components can be judged as complete remission, otherwise the efficacy is evaluated as partial remission. 


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15. Tumor imaging using enhanced CT (subject to hypersensitivity to CT contrast agents, MRI) and PET. Enhanced CT examination time is baseline (baseline assessment will be performed 
within 28 days prior to enrollment), 6/15/24 weeks (±7 days), every 12 weeks after 24 weeks (±14 days), and every 16 weeks after 48 weeks Week (±14 days), the examination site 
includes the neck, chest, abdomen, basin and other required anatomical sites until the start of new anti-tumor treatment, disease progression, withdrawal of ICF or death of the subject; 
The tester needs to confirm after 4~6 weeks; for patients who stop treatment except for the progress of imaging disease, it is still necessary to carry out imaging evaluation according to 
the program after stopping the drug until the start of new anti-tumor therapy, disease progression, subject withdrawal of ICF or death. PET examinations were performed at baseline, 
week 15 (±7 days), or early termination of study drug treatment. The requirements for PET examinations are detailed in the Image Acquisition Guide.  
16. Assessment of disease-related symptoms (including fever, night sweats, weight loss) before each cycle of medication, and complete elimination of disease-related symptoms is one of the 
conditions for evaluating CR 
17. IBI308 200 mg, administered intravenously, once every 3 weeks for up to 24 months, or until disease progression, death, intolerance, withdrawal of informed consent or other reasons as 
specified in the protocol. For the first time in which the disease progresses, if the clinical situation is stable, the investigator can continue to receive treatment until the total treatment 
time reaches 24 months or recurrence of disease progression, death, toxicity intolerance, withdrawal of informed consent. Or other reasons specified by the program. 
18. The quality of life assessment was assessed using the EQ-5D-5L and EORTC QLQ-C30 scales on the day of the first dose, each imaging assessment, and the end of treatment visit. 
19. Subjects who meet the inclusion criteria are required to provide archived tumor tissue at baseline or 4 unstained 4-5 micron sections prepared freshly during the screening period for PD-
L1 testing. For the detection of mRNA expression of immune-related genes, subjects should provide as much as possible of the archived tumor tissue at baseline or 4 unstained 4~5 
micron sections prepared freshly during the screening period.  
20. Subjects are required to provide 10 ml whole blood samples at the following time points: before the first dose, during the treatment period, and before the next treatment.  
21. Treatment termination: Treatment termination includes early termination (in addition to disease progression leading to discontinuation of the drug) and study treatment (end of disease 
leading to discontinuation of the drug), and treatment termination at the end of treatment. For patients who discontinued treatment for reasons other than imaging disease progression, an 
imaging evaluation was performed every 12 weeks (±7 days) after discontinuation of the drug until one of the following events occurred: initiation of new anti-tumor therapy, disease 
progression, subject withdrawal of ICF and death.


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Table of Contents 
Synopsis ............................................................................................................................................ 2 
Primary Objectives .................................................................................................................... 2 
Secondary Objectives ................................................................................................................ 2 
Exploratory Objectives ............................................................................................................. 2 
Table of Contents ............................................................................................................................ 10 
List of Abbreviations ....................................................................................................................... 17 
1 Background .................................................................................................................................. 19 
 Disease Background .......................................................................................................... 19 
 Tested Drug (IBI308) ........................................................................................................ 20 
 Mechanism of IBI308 ............................................................................................ 20 
 Results from IBI308 Clinical Studies ..................................................................... 21 
 Benefit/risk assessment ..................................................................................................... 22 
2 Trial Objectives ............................................................................................................................ 22 
 Primary Objectives ............................................................................................................ 22 
 Secondary Objectives ........................................................................................................ 22 
 Exploratory Objectives...................................................................................................... 23 
3 Study Design ................................................................................................................................ 23 
 Study Plan ......................................................................................................................... 23 
 Study Rationales ............................................................................................................... 24 
 Rationales of Single Arm Study Design ................................................................. 24 
 Rationales of Choosing 200 mg/kg Q3W............................................................... 24 
 Rationales of Primary Endpoint Analysis at Week 24 ............................................ 25 
 Rationales of Choosing ORR as the Primary Endpoint.......................................... 25 
 Rationales of Continuation of Treatment after Disease Progression ...................... 26 
4 Patient Eligibility Criteria ............................................................................................................ 26 
 Inclusion Criteria ............................................................................................................... 26 
 Exclusion Criteria ............................................................................................................. 27 
 Limitations During the Study Period ................................................................................ 30 
 Discontinue of Treatment/Withdrawal from Study ........................................................... 30 
5 Investigational Products ............................................................................................................... 32 
 Treatment Plan .................................................................................................................. 32 
 Treatment Administration ....................................................................................... 32 
 Continuation of Treatment after Disease Progression ............................................ 32 
 Study Treatment (IBI308) ................................................................................................. 33 
 Description of Study Treatment ............................................................................. 33 
 Label and Package.................................................................................................. 33 
 Storage ................................................................................................................... 33 
 Preparation and Administration .............................................................................. 34 
 Treatment Adjustment ....................................................................................................... 34 
 General Rules ......................................................................................................... 34 
 Adjustment of IBI308 ............................................................................................. 34 
 Principles of Handling Immune Checkpoints Inhibitor Toxicity ...................................... 36 


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 Concomitant Treatment ..................................................................................................... 36 
 Prohibited Treatment .............................................................................................. 36 
 Allowed Treatment ................................................................................................. 37 
 Drug-drug interaction ............................................................................................. 37 
 Treatment Compliance ...................................................................................................... 37 
 Drug Retrieve and Destroy................................................................................................ 37 
 Drug Record ...................................................................................................................... 37 
 Complaint .......................................................................................................................... 38 
6 Procedure ..................................................................................................................................... 38 
 Patient Recruitment ........................................................................................................... 38 
 Patient Recruitment ................................................................................................ 38 
 Handling of Wrong Patient Enrolled ...................................................................... 38 
 Study Plan and Schedule ................................................................................................... 39 
 Screening ................................................................................................................ 39 
 Baseline (Prior to Day 1 of Cycle 1) ...................................................................... 40 
 Treatment Visits ..................................................................................................... 40 
 Study Treatment Discontinuation Visit .................................................................. 41 
 Safety Follow-up .................................................................................................... 42 
 Pathological Diagnosis ...................................................................................................... 42 
 Radiographic Assessment.................................................................................................. 42 
 safety evaluation ............................................................................................................... 43 
 Laboratory Evaluation ............................................................................................ 43 
 Physical examination ............................................................................................. 43 
 12-lead ECG ........................................................................................................... 43 
 Vital signs ............................................................................................................... 44 
 Weight and height ................................................................................................... 44 
 Pregnancy test ........................................................................................................ 44 
 Other Safety Assessment: ....................................................................................... 45 
 Pharmacokinetics .............................................................................................................. 45 
 Pharmacodynamics ........................................................................................................... 45 
 Immunogenicity ................................................................................................................ 46 
 Quality of life assessment ................................................................................................. 46 
 Biomarker analysis .......................................................................................................... 47 
 Storage and destruction of biological samples ................................................................ 47 
7 Safety Reporting and Adverse Event Management ...................................................................... 47 
 Definition of adverse events .............................................................................................. 47 
 Definition of serious adverse events ................................................................................. 48 
 AE severity assessment ..................................................................................................... 49 
 Causality assessment ......................................................................................................... 49 
 AE record .......................................................................................................................... 50 
 AE collection period ............................................................................................... 50 
 Follow-up of AE ..................................................................................................... 50 
 Contents of AE records .......................................................................................... 50 
 SAE and pregnancy reporting process .............................................................................. 53 


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 Events with abnormal liver function ................................................................................. 55 
 Management of drug-related toxicity ................................................................................ 56 
 Immune-related adverse events .............................................................................. 56 
 Adverse Event of Special Interest Adverse Event of Special Interest (AESI) is the 
event needs special close monitoring for the better understanding of the safety for the IP. 
AESI may be non-serious event. ..................................................................................... 56 
8 Statistical considerations .............................................................................................................. 56 
 Statistical analysis plan ..................................................................................................... 56 
 Hypothesis testing ............................................................................................................. 57 
 Analysis populations ......................................................................................................... 57 
 Statistical Method ............................................................................................................. 57 
 General Statistical Method ..................................................................................... 57 
 Analysis of Primary Endpoints ............................................................................... 57 
 Analysis of Secondary Endpoints ........................................................................... 58 
 Biomarker assessment ............................................................................................ 59 
 Quality of life assessment ...................................................................................... 59 
 Safety analysis ........................................................................................................ 59 
 Immunogenic Endpoint .......................................................................................... 60 
 Compliance Analysis .............................................................................................. 60 
 Baseline characteristics of subjects ........................................................................ 61 
 Interim Analysis ................................................................................................... 61 
 Multiple comparison and multiplicity adjustment ................................................ 61 
 Subgroup Analysis ............................................................................................... 61 
 Listing of evaluable subjects ................................................................................ 62 
 Exploratory Analysis ............................................................................................ 62 
 Determination of sample size ............................................................................................ 62 
 Bias control ....................................................................................................................... 62 
 Randomization and blinding .................................................................................. 62 
 Evaluation of blinding maintenance ....................................................................... 62 
 Unblinding and emergency unblinding .................................................................. 62 
9 Quality Assurance and Quality Control ....................................................................................... 62 
 Clinical Audit .................................................................................................................... 63 
 Data Management / Coding .............................................................................................. 63 
 Quality Assurance Audit ................................................................................................... 65 
10 Ethics.......................................................................................................................................... 65 
 Ethics Committee ............................................................................................................ 65 
 Ethics of the study ........................................................................................................... 66 
 Subject Information and Informed Consent .................................................................... 66 
 Subject Data Protection ................................................................................................... 67 
11 Research Management ............................................................................................................... 67 
 Data Processing and Record Saving ................................................................................ 67 
 Raw Data / File Access Rights ........................................................................................ 67 
 Program revision ............................................................................................................. 67 
 Researcher Responsibilities ............................................................................................. 68 


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 Publication Policy ........................................................................................................... 68 
 Finance and Insurance ..................................................................................................... 69 
12 References .................................................................................................................................. 70 
 
 
 


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List of Abbreviations 
 
Abbreviation 
Definition 
%CV 
percent coefficient of variation 
%RE 
percent relative error 
abs 
absolute 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time profile 
AUCextrap% 
percent of AUCinf due to extrapolation 
AUCinf 
 
area under the plasma concentration-time profile from time zero extrapolated to 
infinite time 
AUClast 
AUC from time 0 to last quantifiable concentration 
BMI 
body mass index 
BP 
blood pressure 
CDK 
cyclin-dependent kinase 
CI 
confidence interval 
Clast 
last quantifiable concentration 
CLcr 
creatinine clearance 
CL/F 
apparent clearance  
CLu/F 
unbound CL/F 
Cmax 
maximum plasma concentration 
CO2 
carbon dioxide 
CRF 
case report form 
CRO 
contract research organization 
CRU 
Clinical Research Unit 
CYP3A4 
cytochrome P450 3A4 
DCT 
data collection tool 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
eNCA 
electronic non-compartmental analysis 
FDA 
Federal Drug Administration 
FL 
Florida 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HGB 
hemoglobin 
hr 
hour(s) 
ICD 
Informed Consent Document 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
K2EDTA 
dipotassium etheylendiaminetetraacetic acid 
 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond(s) 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PT 
prothrombin time 
QC 
quality control 
QT interval 
time from electrocardiogram Q-wave to the end of the T-wave corresponding to 
electrical systole 
QTc 
QT interval corrected for heart rate 
QTcF 
QTc using Fridericia’s formula 
RBC 
red blood cell 
SAE 
serious adverse event 
Scr, std 
serum creatinine measured with a standardized assay for serum creatinine 
SOP 
standard operating procedure 
SOC 
system organ class  
t½ 
terminal half-life 
TEAE 
treatment-emergent AE 
Tlast 
time of Clast 
Tmax 
time for Cmax 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
 
 


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1 Background 
Disease Background 
As a malignancy originating from the lymphatic hematopoietic system, lymphoma can 
be classified into two categories, namely Hodgkin lymphoma and non-Hodgkin 
lymphoma according to pathologic character. In 2015, 88000 estimated new cases of 
lymphoma were diagnosed in China [1]. Based on morphology and immunophenotype, 
Hodgkin lymphoma is divided into two categories: nodular lymphocyte predominant 
Hodgkin lymphoma and classical Hodgkin lymphoma (cHL). The latter is further 
divided into four types, i.e. lymphocyte rich, mixed cellularity, nodular sclerosing and 
lymphocyte depleted [4]. According to a pathological analysis of 10002 Chinese 
lymphoma patients, the proportion of Hodgkin lymphoma was 8.54%, of which cHL 
accounted for 93.56% [3]. The cure rate after first-line treatment of Hodgkin lymphoma 
is approximately 85% [4], and the rest 15% are considered refractory or have a tendency 
to relapse. For relapsed or refractory cHL, the second-line standard treatment in Europe 
and the United States is high-dose chemotherapy combined with autologous 
hematopoietic stem cell transplantation [5]. Due to the low acceptance of transplant 
therapy and limited medical resources in China, the second-line treatment for relapsed 
or refractory cHL patients is chemotherapy in general. According to historical data, the 
rate of non-treatment failure three years after second-line chemotherapy is 34%, and 
this rate three years after second-line high-dose chemotherapy in combination with 
autologous hematopoietic stem cell transplantation was 55% [6, 7]. High quality evidence 
is still lacking for third-line therapy or above [5]. Currently, monotherapy includes 
Brentuximab Vedotin [8], bendamustine [9], lenalidomide [10] and everolimus [11]. 
Brentuximab Vedotin showed an ORR of 75% and a PFS of 5.6 months in 102 patients 
who failed high-dose chemotherapy combined with autologous hematopoietic stem cell 
transplantation [8]. It has not been approved in China yet. Bendamustine had an ORR 
of 56% and a DOR of 5 months in 36 patients who had failed an average of four lines 
of therapy [9]. Lenalidomide demonstrated 19% of ORR and 4 months of PFS in 38 
patients who had failed an average of four lines of therapy [10]. Of the 19 patients who 
failed an average of six line treatment, everolimus showed an ORR of 47%, and time 
to progression of 7.2 months [11]. The ORR of the above single regimen was between 
19-56%, however, the disease control duration was short. Therefore, there is a 
significantly unmet clinical need for relapsed or refractory cHL which progress beyond 
second-line therapy in China. 


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The PD-1/PD-L1 pathway may play an important role in the onset and progression of 
cHL. The rate of  PD-L1 expression in Reed Sternberg cell (RS cell) of cHL was 65% 
in nodular sclerosing type (87/134), 81% in mixed cellularity type (60/74), 90% in 
lymphocyte rich type (9/10) and 67% in lymphocyte depleted type (4/6) [12]. High 
expression of PD-L1 in RS cells in cHL is usually caused by a copy number abnormality 
at the 9p24.1 site, which contains the PD-L1, PD-L2 and JAK2 genes. In a study of 108 
patients with cHL, FISH was used to detect PD-L1 and its copy number. Polyploid, 
copy number increase and copy number amplification were 5% (5/108), 61% (56/108) 
and 39% (36/108) respectively [13]. JAK2 activates downstream transcription factor 
STAT and further increases PD-L1 expression [14]. In addition, EB virus infection can 
also cause an increase in PD-L1 expression [15]. Since the expression of PD-L1 can 
cause immune escape of RS cells, blocking the signal pathway of PD-L1/PD1 may 
relieve immune suppression and promote the clearance of RS cells by immune system. 
Anti-PD-1 monoclonal antibodies Nivolumab and Pembrolizumab have shown 
significant efficacy in cHL [16, 17]. In patients who failed high-dose chemotherapy in 
combination with autologous hematopoietic stem cell transplantation and Brentuximab 
Vedotin, the ORR of Pembrolizumab was 72.5% (50/69). In patients who are not 
suitable for high dose chemotherapy or autologous hematopietic stem cell 
transplantation, the ORR of Pembrolizumab was 65.4% (53/81) after failure of 
Brentuximab Vedotin [18]. The ORR of Nivolumab in patients who failed high-dose 
chemotherapy in combination with autologous hematopoietic stem cell transplantation 
and Brentuximab Vedotin was 66.3% (53/80) [17]. Currently, Nivolumab has been 
approved by the US FDA for cHL patients who have failed high-dose chemotherapy 
combined with autologous hematopoietic stem cell transplantation and Brentuximab 
Vedotin. 
Nivolumab and Pembrolizumab have shown significant efficacy in cHL patients who 
have failed multi-line therapy, demonstrating the effectiveness of blocking PD-1/PD-
L1 pathway in relapsed and refractory cHL. To this end, this clinical trial is designed to 
evaluate the efficacy and safety of IBI308 in relapsed and refractory cHL. 
Tested Drug (IBI308) 
Mechanism of IBI308 
Immune checkpoints are a group of immunosuppressive molecules with the 
physiological function of regulating the intensity and breadth of immune response, 
thereby avoiding damage of normal tissues. Tumor cells can express these immune 
checkpoint molecules to escape immune attacks. Currently validated immune 
checkpoints include CTLA-4 and PD1/PD-L1. With its safety profile and broad 
indications, monoclonal antibody targeting PD1/PD-L1 pathway has shown promising 
prospect. 
PD-1 is mainly expressed on activated T cells, with two ligands being PD-L1 and PD-
L2. PD-L1 is its main ligand, which is expressed on activated T cells, antigen presenting 
cells and tumor cells as well [19]. The binding of PD-1/PD-L1 plays an important role 


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in regulation of T cell activation and peripheral immune tolerance. When not expressing 
PD-1, T cells interact with antigen-presenting cells, proliferate and secrete activating 
cytokines, and exert tumoricidal effect. After activation, T cells will express PD-1. 
When binding with PD-L1 on tumor cells, the inhibitory signal will prevent T cell from 
further activation and secretion of activating cytokines, causing immune escape and 
cancer progression. By blocking the interaction between PD-1 and PD-L1, the 
tumoricidal capability of T cell will be restored [20]. 
So far, the US FDA has approved the listing of three PD-1/PD-L1 products, namely 
Bristol-Myers Squibb (BMS) anti-PD-1 monoclonal antibody Nivolumab (trade name: 
OPDIVO), Merck Anti-PD-1 mAb Pembrolizumab (trade name: KEYTRUDA), and 
Genetech anti-PD-L1 monoclonal antibody Atezolizumab (trade name: Tecentriq). The 
indications include advanced melanoma, advanced NSCLC, advanced cHL, advanced 
renal cell renal cell carcinoma and urothelial carcinoma, advanced head and neck cancer. 
In addition, several other indications are currently under Phase III clinical trials or 
application. The listing of the above drugs has established the important position of PD-
1/PD-L1 immune checkpoint inhibitors in tumor immunotherapy. At present, there is 
no PD-1/PD-L1 immune checkpoint inhibitor listed in China. It is of great significance 
to develop such monoclonal antibodies to improve the outcome of advanced cancer 
patients in China. 
Recombinant human-derived anti-PD-1 monoclonal antibody injection (R&D code: 
IBI308) is a recombinant human-derived IgG4 monoclonal antibody, which has shown 
in vitro and in murine preclinical model to effectively block the PD-1/PD-L1 pathway 
and exhibit anti-tumor activity (for detailed results, please refer to the investigator's 
manual). 
Results from IBI308 Clinical Studies 
The Phase Ia dose escalation trial of IBI308 was initiated in September 2016, which 
was planned to enroll approximately 12-24 subjects with advanced solid tumors who 
had failed standard treatment. The dose escalation would follow the classic “3+3” 
design and 4 dose levels (1 mg/kg, 3 mg/kg, 200 mg and 10 mg/kg) would be evaluated. 
After completion of evaluation of the 1 mg/kg dose level, subjects would be randomized 
to either 3 mg/kg or 200 mg for independent evaluation. The dose-limiting toxicity 
(DLT) observation period was 28 days after the first dose in each dose level. After 
completion of DLT observation, the subjects are allowed to continue the subsequent 
IBI308 treatment (1 mg/kg, 3 mg/kg, and 10 mg/kg every 2 weeks or 200mg every 3 
weeks) until disease progression, intolerance, withdrawal of informed consent, or other 
reasons for discontinuation of the study (whichever occurs first). 
Pharmacokinetic evaluation of 1 mg/kg IBI308 was carried out in a multi-tumor subject 
(n=3). Preliminary results of single-dose administration showed that 1 mg/kg IBI308 
reached the maximum exposure of a single dose at the end of the infusion. After 
reaching the peak, the distribution was rapidly completed and elimination was slow 
(t1/2 was approximately 17.3d). It is a typical two compartment model of monoclonal 


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antibody, with a half-life similar to the physiological half-life of IgG4. 
Preliminary results of pharmacodynamic studies showed that IBI308 could rapidly (in 
24h) saturate the peripheral PD-1 receptor (95.8±2.3%) at a dose level of 1 mg/kg, and 
could maintain the occupancy of PD-1 receptor during the study phase of decreasing 
concentration (28d, C28d: 3.70 ± 0.15 μg/mL). Steady status is expected to be reached 
on Day 84 with continuous dose of 1 mg/kg Q2W (6 doses total). Provided no 
significant variation in drug clearance characteristics, the steady-state trough 
concentration is approximately 13μg/mL, which will sustainably maintain peripheral 
PD-1 receptor occupancy. 
Until February 8, 2017, three subjects each of the following dose levels, 1 mg/kg, 3 
mg/kg, and 200 mg, have completed DLT observation, with no DLT observed. 
Benefit/risk assessment 
Based on the mechanism of IBI308 and clinical safety profile of similar products, it is 
predicted that the major adverse events during clinical trial may be inflammations 
caused by activation of the immune system, including pneumonitis, colitis, hepatitis, 
renal dysfunction and inflammation of the endocrine system. According to the clinical 
data of the existing anti-PD-1 monoclonal antibodies, it is tolerated well despite of a 
relatively high incidence of adverse events, most of which will be alleviated after 
treatment. Only a small percentage of subjects have discontinued treatment due to 
severe adverse events. Since symptoms of immune related adverse events is atypical at 
early phase, researchers should pay close attention to early symptoms and signs, make 
timely judgments, adjust dose and give proper treatment per protocol section 5.4. 
Meanwhile, cautiously screen and exclude subjects with autoimmune diseases. 
In conclusion, the clinical pharmacology and safety data of IBI308 from Phase Ia 
clinical trial have demonstrated its pharmacological activity and safety in patients with 
advanced cancer. The efficacy of similar anti-PD-1 monoclonal antibody in cHL, 
supports the clinical trial of IBI308 in patients with relapsed or refractory cHL in China. 
2 Trial Objectives 
Primary Objectives 
• 
ORR of IBI308 monotherapy in relapsed or refractory cHL assessed by IRRC. 
Secondary Objectives 
• 
ORR of IBI308 monotherapy in relapsed or refractory cHL assessed by investigator; 
• 
CR and PR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
DCR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
TTR of IBI308 monotherapy in relapsed or refractory cHL; 
• 
DOR of IBI308 monotherapy in relapsed or refractory cHL; 


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• 
PFS and 6-month PFS rates of IBI308 monotherapy in relapsed or refractory cHL; 
• 
Evaluate the safety of IBI308 monotherapy in patients with relapsed or refractory 
cHL. 
• 
Evaluate PK/PD/immunogenicity of IBI308 monotherapy in patients with relapsed 
or refractory cHL. 
• 
Evaluate the quality of life of patients with relapsed or refractory cHL after IBI308 
monotherapy (according to the EQ-5D-5L and EORTC QLQ-C30 scales). 
Exploratory Objectives 
Assess the relationship between PD-L1 expression, immune-related gene mRNA, and 
other potential biomarkers in relapsed or refractory cHL and IBI308 efficacy. 
3 Study Design 
Study Plan 
This study is a multicenter, one-arm, phase II study to evaluate the efficacy and safety 
of IBI308 in relapsed or refractory classic Hodgkin's lymphoma. This study will enroll 
patients with relapsed or refractory cHL to receive intravenous (IV) IBI308 at 200 mg 
every three weeks (Q3W) for up to 24 months, or until disease progression, death, 
unacceptable adverse event(s), subject withdraws informed consent or other reasons 
specified in protocol. If the subject still has no disease progression after 24 months of 
IBI308 treatment and the investigator judges that the subject will still benefit from the 
study drug, the subject should sign additional informed consent to continue receiving 
free IBI308 treatment. . For subjects with first disease progression, if the clinical 
condition is stable, the investigator may let the subject continue to receive treatment 
until the total treatment time reaches 24 months or if disease progression, death, 
unacceptable adverse event(s), subject withdraws informed consent, or other reasons 
specified in protocol. 
The primary endpoint of the study is overall response rate (ORR), defined as the 
percentage of subjects with optimal response to partial and complete remission, 
evaluated according to the IWG 2007 criteria, and the Lugano 2014 criteria as an 
adjunct to the standard, both evaluated by IRRC. Analysis of primary endpoints will be 
performed after the last subject who meets the statistical and imaging assessment 
requirements and completes up to 24 weeks of follow-up. Subjects will have a safety 
follow-up 90 days after the last dose of IBI308. 
If the enrollment progressed slowly within the first 6 months after the start of the study 
(the number of subjects enrolled in the group within 6 months is less than 30), the 
sponsor may terminate the enrollment of the study early. 


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Study Rationales   
Rationales of Single Arm Study Design 
There is no high-quality evidence in three or more prior lines of systemic therapy to 
treat replaced/refactory cHL, and most evidence is monotherapy [5], including 
Brentuximab Vedotin 
[8], bendamustine 
[9], lenalidomide [10] and Vimos 
[11].  
Brentuximab Vedotin has not yet been listed in China. Bendamustine had an ORR of 
56% and a DOR of 5 months in 36 patients who had failed an average of four-line 
treatment [9]. The lenalidomide in the 38 patients who failed the average 4-line treatment 
had an ORR of 19% and a PFS of 4 months [10]. Of the 19 patients who failed the 
average 6-line treatment with everolimus, the ORR was 47% and the disease 
progression time was 7.2 months [11]. The sample size of the above studies is small and 
is not a recognized standard treatment. The ORR of Pembrolizumab and Nivolumab in 
patients with relapsed or refractory cHL who failed high-dose chemotherapy combined 
with autologous hematopoietic stem cell transplantation and Brentuximab Vedotin was 
72.5% (50/69) [18] and 66.3% (53/80) respectively[17]. The ORR of Pembrolizumab in 
patients who were not suitable to receive high-dose chemotherapy combined with 
autologous hematopoietic stem cell transplantation or Brentuximab Vedotin failed was 
65.4% (53/81) [18]. The above data indicate that anti-PD-1 monoclonal antibody alone 
has obvious curative effect on relapse or refractory cHL failure of multi-line treatment. 
Because of the lack of standard treatment in domestic third-line and above, this study 
chose a single-arm design. 
Rationales of Choosing 200 mg/kg Q3W 
This study is intended to be administered with 200 mg IBI308 Q3W. The choice of this 
mode of administration is based primarily on the ongoing Phase I (CIBI308A101) study 
of safety and exposure (concentration)-response (PD-1 receptor occupancy) 
relationship data, combined with preclinical in vitro/in vivo efficacy and other similar 
drugs’ data. 
The in vivo pharmacodynamic study of the SCID-Winn murine model and The MC38 
murine colon carcinoma model showed that the tumor suppressor ability of IBI308 
increased with dose escalation, and the 10 mg/kg IBI308 dose group significantly 
inhibited tumor growth. The equivalent dose in mankind was 0.8 Mg/kg. IBI308 can 
rapidly (24 hours ) saturate the peripheral PD-1 receptor (95.8±2.3%) at a dose of 
1mg/kg, and maintain peripheral PD-1 occupancy level during the period of IBI308 


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concentration continuously to decrease (28d, C28d: 3.70±0.15). The distribution of 
IBI308 in cynomolgus monkey’s different tissue showed that the IBI308 exposure of 
organs such as lung, liver, colon, small intestine, and lymph nodes was about 3.5-1/10 
of its in serum. Under the premise that the subject did not significantly change the drug 
clearance characteristics, IBI308 200 mg Q3W was expected to be administered to the 
steady state for 84 days (4 times), and the steady-state trough concentration was 
expected to be about 26 μg/mL. Under which IBI308 could continue to maintain 
peripheral and target organ PD-1 receptor occupancy. The above evidence supports the 
selection of IBI308 200 mg Q3W as a dosing regimen. 
Rationales of Primary Endpoint Analysis at Week 24 
One Study of the evaluations of Nivolumab monotherapy in a relapsed or refractory 
cHL patient study (Checkmate 205), of which one cohort enrolled patients failure from 
a high-dose chemotherapy combination with autologous stem cell transplantation and 
Brentuximab Vedotin. The results were published and the primary end point was ORR 
assessed by independent image review committee. The primary endpoint was analyzed 
at the time when all the 80 subjects were followed up for an average of 6 months. The 
ORR of the cohort was 65.3% (53/80), and the median time to first objective response 
was 2.1 months (IQR, 1.9-3.0 months). 31 cases had first objective response (58%, 
31/53) at 9.33 weeks (the first scheduled tumor evaluation time for the study was week 
9) [17]. In this study, the final analysis was performed at the time when the subject was 
followed up till maximum 24 weeks of treatment and at which the majority of objective 
mitigation events were expected to be observed. Because patients with response often 
have long-lasting duration of remission, and the reported median duration of response 
is 7.8 months in Checkmate205, subsequent assessments every 12 weeks can reduce 
unnecessary examinations for patients with remission [17]. 
Rationales of Choosing ORR as the Primary Endpoint 
In a study of 756 patients with relapsed/refractory cHL after failure of second-line 
standard therapy, the median progression-free survival was 1.3 years, with a median 
overall survival of 2.4 years [6].So for relapsed/refractory cHL, The Objective response 
rate is a common primary study end point in one-arm phase II study, as referring to the 
research design of the similar study (Brentuximab Vedotin [8], Nivolumab [17], 
Pembrolizumab [18]). We chose ORR as our study primary endpoint. 


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Rationales of Continuation of Treatment after Disease Progression 
Clinical data from listed products indicate that a small number of patients continue to 
receive immunotherapy may still receive clinical benefit despite prior evidence of 
disease progression (according to routine response criteria) before clinical objective 
response and/or disease stabilization [17, 21]. This phenomenon is currently explained 
with two reasons. First, increased inflammatory cells within the tumor may result in an 
increase in tumor volume, manifested as measurable lesion enlargement and the 
appearance of new, visible, immeasurable lesions. Over time, the malignant and 
inflammatory portions of the mass may shrink, resulting in significant imaging and 
clinical signs of improvement. Second, in some patients, the anti-tumor immune 
response is initiated slowly, and its early inhibition of tumors is less than tumor growth 
speed over time, anti-tumor activity will predominate and be manifested as an 
improvement in imaging response and clinical signs. In Checkmate 205, nine patients 
of the cHL who were re-administered after disease progressions, 6 of them were 
observed a further reduction in tumor burden [17]. Therefore, subjects treated with 
IBI308 will be allowed to continue to receive IBI308 if they are initially evaluated by 
IWG 2007 to have progressed disease, as the investigator confirm they will have 
clinical benefit and are tolerant to the study drug (see section 5.1.2). But they 
discontinue the study treatment after evidence of further progress. 
4 Patient Eligibility Criteria 
Inclusion Criteria 
10. Histopathological confirmed classical Hodgkin's lymphoma (cHL). 
11. Relapsed/refractory cHL, which failed second line and above therapy (including 
radiotherapy and autologous hematopoietic stem cell transplantation, ASCT); 
subject with no response to or with progression after ASCT is eligible. 
12. At least one measurable disease (long axis>15 mm or short axis>10 mm, with 
uptake on 18FDG-PET) 
13. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2. 
14. Signed written informed consent form and willing and able to comply with 
scheduled visits and other requirements of the study. 
15. Age ≥ 18. 
16. Life expectancy ≥ 12 weeks. 


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17. Subjects of reproductive potential must be willing to use adequate contraception 
during the course of the study and through 90 days after the last dose of study 
medication. 
18. Adequate organ and bone marrow function: 
5) Count of Blood Cells: absolute neutrophil count (ANC) ≥ 0.75 × 109 / L; 
platelet count (PLT) ≥ 50 × 109 / L; hemoglobin content (HGB) ≥ 8.0 g / dL; 
no granulocyte colony-stimulating factor, platelet or red blood cells infusion 
in the last 14 days. 
6) Liver function: total bilirubin (TBIL) ≤ 1.5 × normal upper limit (ULN); 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 
× ULN. 
7) Renal function: serum creatinine (Cr) ≤ 1.5 × ULN 
8) Thyroid function: thyroid stimulating hormone (TSH) in normal range (TSH 
abnormalities due to non-autoimmune causes can be enrolled). 
Exclusion Criteria  
23. Known nodular lymphocyte predominant Hodgkin lymphoma. 
24. Known central nervous system lymphoma. 
25. Received ASCT within 90 days of the first dose of study medication. 
26. Prior exposure to any anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody. 
27. Currently participating in an interventional clinical study, unless participating in 
observational study or during follow-up period of an interventional study. 
28. Received any investigational agent within 4 weeks of the first dose of study 
medication. 
29. Received last dose of radiotherapy or anti-tumor therapy (chemotherapy, targeted 
therapy, tumor immunotherapy or arterial embolization) within 3 weeks of the first 
dose of study medication; received last dose of nitrosourea or mitomycin C within 
6 weeks of the first dose of study medication. 
30. Received systemic treatment with corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 4 weeks of first dose. 


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Inhaled or topical steroids and adrenal replacement steroid doses are permitted in 
the absence of active autoimmune disease. 
31. Received a live vaccine within 4 weeks of the first dose of study medication or plan 
to receive live vaccine during study period. 
32. Underwent major operation (craniotomy, thoracotomy or laparotomy) within 4 
weeks of the first dose of study medication or with open wound, ulcer or fracture. 
33. Unrecovered toxicity (grade >1, according to NCI CTCAE 4.03) due to prior anti-
tumor therapy before the first dose of study medication. 
34. Known primary immunodeficiency. 
35. Active tuberculosis. 
36. Known history of allogeneic organ or allogeneic hemopoietic stem cell 
transplantation. 
37. Known allergy or hypersensitivity to any monoclonal antibodies or any 
components used in their preparation. 
38. Uncontrolled concomitant disease, including but not limited to : 
12) Human Immunodeficiency Virus (HIV) infection (HIV antibody positive) 
13) Active or poorly controlled severe infection 
14) Symptomatic congestive heart failure (New York Heart Association grade II-
IV) or symptomatic, poorly controlled arrhythmia 
15) Poorly controlled arterial hypertension (SBP ≥ 160mmHg or DBP 
≥ 100mmHg) with standard treatment 
16) Prior arterial thromboembolism event, including myocardial infarction, 
unstable angina, stroke and transient ischemic attack, within 6 months of 
enrollment 
17) Prior life-threatening blood loss or grade 3/4 gastrointestinal/varicosity 
bleeding requiring blood infusion, endoscopic or surgical intervention within 
3 months of enrollment 
18) Prior deep vein thrombosis, pulmonary embolism or any other severe 
thromboembolism events (implanted port or catheter caused thrombosis, or 


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superficial vein thrombosis are not considered as severe thromboembolism) 
within 3 months before enrollment 
19) History of uncontrolled metabolic disorder, non-malignant organ or systemic 
disease or secondary carcinomatous reaction, with high medical risk and/or 
uncertainty of life expectancy evaluation 
20) With hepatic encephalopathy, hepatorenal syndrome or hepatic cirrhosis of 
Child-Pugh grade B or higher. 
21) History of intestinal obstruction or the following diseases: inflammatory 
bowel disease or extensive bowel resection (partial colonic resection or 
extensive small bowel resection, concomitant with chronic diarrhea), Crohn's 
disease, ulcerative colitis or chronic diarrhea 
22) Other acute or chronic diseases, mental illness, or abnormal laboratory test 
results that may lead to the following outcomes: increase the risk of 
participating in study or study drug administration, or interfere with the 
interpretation of the study results and considered by investigator as "NOT" 
eligible to participate in this study 
39. Known acute or chronic active hepatitis B infection (chronic HBV carrier or non-
active HBsAg positive subject is eligible) or acute or chronic active hepatitis C 
(HCV antibody negative subject is eligible; HCV RNA examination is required for 
HCV antibody positive subject, subject is eligible if result was negative) 
40. History of gastrointestinal perforation and /or fistula within 6 months before 
enrollment 
41. Subjects with interstitial lung disease 
42. Uncontrolled third space effusion, e.g. ascites or pleural effusion cannot be drained 
or controlled 
43. Other primary malignancy, with the exception of: 
5) Curative malignancy (e.g. papillary thyroid carcinoma) 
6) Without active disease in the last 5 years and with very low recurrence risk 
7) Non-melanoma skin cancer or malignant freckle-like nevus with adequate 
treatment and no evidence of recurrence ; 


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8) Adequately treated in-situ carcinoma 
44. Women who are pregnant or nursing. 
Limitations During the Study Period  
Women with fertility potential were defined as women who had not undergone 
sterilization (ie, bilateral tubal ligation, bilateral salpingectomy, or total hysterectomy) 
or non-menopausal (menopausal defined as 12 months of amenorrhea without 
alternative medical reasons). 
Women who are menopausal for 12 months without alternative medical reasons are 
considered menopausal. Requirements are as below: 
Women <50 years of age can be considered menopausal women if they stop 
menstruating for 12 months or more after stopping exogenous hormone therapy and 
their lutein hormone and follicle stimulating hormone levels are within the recognized 
postmenopausal range. 
Woman ≥ 50 years of age can be considered menopausal if one of the following criteria 
is met: no menstruation for 12 months or more after stopping of all exogenous hormone 
therapy; underwent radiotherapy induced oophorectomy and the time from last 
menstruation >1 year; underwent chemotherapy induced menstruation and the time 
from last menstruation >1 year, underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy). 
Table 2. Effective contraception methods (required to use at least 2 methods) 
Barrier 
Intrauterine device 
Hormone therapy 
Male condom with spermicide 
Copper T-ring 
Implant 
Uterine cap with spermicide 
Progesterone-releasing T-ringa 
Hormone injectables or 
injections 
Barrier with spermicide 
levonorgestrel-releasing 
intrauterine device 
(eg.Mirena®)a 
Contraceptive compounds 
Low-dose oral contraceptive 
pills 
Contraceptive patchs 
a This is also considered as a hormonal method 
Discontinue of Treatment/Withdrawal from Study 
Subjects should terminate/exit the study in any of the following situations: 
1. Subjects who do not meet the inclusion/exclusion criteria, and the sponsor and 


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the investigator discuss and decide that they are not eligible to continue 
participating in the study; 
2. Subjects severely violated the study protocol, and the sponsor and the 
investigator discuss and decide that they are not eligible to continue 
participating in the study 
3. Subjects are enrolled in any other type of drug research which is considered to 
be incompatible with the scientific or medical science of the study. 
4. Subjects are lost to follow-up (the research center staff should contact the lost 
participant to determine the cause of the dropout and try to reschedule the visit. 
This contact date and the contact information used should be recorded in the 
research document). 
5. The researcher decides 
1) Based on the risk and benefit of the subject, the investigator believes that the 
subject should discontinue treatment or withdraw from the study. 
2) If the subject needs to receive another medication for any reason and it has 
demonstrated that the medication is effective in treating the indications for this 
study, the subject should withdraw from the study before using the new 
medication.  
3) Progress of the disease or what the investigator believes is not suitable to 
continue the treatment. 
4) Any treatment-related adverse events that are considered life-threatening, 
regardless of the severity. 
5) The toxicity of study drug meets the withdrawal criteria (see 5.4). 
6. The subject or his trustee (such as a parent or legal guardian) requests to 
withdraw from the study or discontinue the study drug (if the subject withdraws 
informed consent for treatment but does not withdraw informed consent for follow-up, 
he or she remains in long-term follow-up). 
7. The sponsor may terminate the study or discontinue the subject's participation 
in the study due to medical, safety or regulatory reason, or other reason related to laws, 
regulations, and good clinical practice (GCP). 
The reason and the date of the termination will be collected for all subjects. For subjects 


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who discontinue treatment, the relevant study procedures and study visits in the 
schedule of events should also be performed as much as possible. 
5 Investigational Products 
Treatment Plan 
Treatment Administration 
The study drug, IBI308, will be administrated intravenously at 200 mg Q3W until 
maximum of 24 months, or until disease progression, death, intolerable toxicity, 
withdrawal of informed consent, or other reasons per the protocol. Other drugs in the 
study were non-study drugs. 
Continuation of Treatment after Disease Progression 
Subjects can continue to receive IBI308 after first disease progression, by IWG 2007, 
if they met all the following criteria: 
1. Patients may receive clinical benefits and their conditions will not worsen 
rapidly, if continue to receive the study treatment, as assessed by the investigator; 
2. Able to tolerate study drugs; 
3. The ECOG PS is stable; 
4. Does not delay the treatment of serious complications requiring urgent 
intervention (such as central nervous system metastasis); 
5. Subjects need to be fully informed before continuing to receive treatment with 
IBI308, and the investigator needs to clarify all foreseeable risks or discomforts and 
alternative treatment options. 
Subject to the above criteria, the decision to continue treatment after progression 
requires the investigator to discuss the decision with the sponsor's medical manager and 
record it in the study record. 
Subject data those who continue to receive IBI308 after initial disease progression are 
to be collected and data variables are to be collected as described in Table 1. 
If the patient continues to receive the study drug after confirmation, the radiographic 
evaluation will continue at the frequency per protocol. Treatment can be continued until 
the total treatment time reaches 24 months or recurrence of disease progression, death, 


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toxicity intolerance, withdrawal of informed consent or other reasons per protocol. 
Subjects who continue treatment with IBI308 after initial disease progression are to be 
recorded as “clinical deterioration” if they discontinue the treatment due to worsening 
of clinical symptoms without radiographic confirmed recurrence of disease progression. 
 Study Treatment (IBI308) 
Description of Study Treatment 
The study drug was recombinant human-derived anti-programmed death receptor 1 
monoclonal antibody injection, referred as IBI308. 
The main active ingredient is a recombinant whole human anti-programmed death 
receptor 1 monoclonal antibody with a finished product size of 10 mL: 100 mg. IBI308 
does not contain any preservatives at a concentration of 10 mg/mL, excipients include 
140 mmol/L mannitol, 25 mmol/L histidine, 20 mmol/L sodium dihydrate, 50 mmol/L 
sodium chloride, 0.02 mmol/L disodium edetate (disodium edetate), 0.2 mg/mL 
polysorbate 80, pH 6.0. 
This product is a clear, colorless liquid with no foreign matter, no flocculation and 
precipitation. 
Manufacturer: Innovent Biologics (Suzhou) Co., Ltd. 
Label and Package 
The IBI308 minimum packaging unit is a box containing 1 IBI308 injection packed in 
a vial. The IBI308 box is printed with the drug name, drug number, dosage form, 
specifications, drug code, production batch number, expiration date, storage conditions, 
usage and dosage, precautions, and information about the sponsor. The same 
information is printed on the label of the vial and the box, but there is no information 
on the dosage form and precautions on the vial label. All boxes and vials are labeled 
"for clinical trial use only". 
Storage  
Stored in the dark at 2~8 °C, the effective period is 24 months. If there are quality 
problems such as turbidity and sedimentation in the injection, it should be sealed 
immediately and the sponsor will be notified immediately. 


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Preparation and Administration 
The preparation and infusion process of IBI308 is as follows: 
1. Two bottles of IBI308 injection are to be completely withdrawn and added to 
100 ml of 0.9% (w/v) sodium chloride sterile saline intravenous infusion bag, and the 
preparation start time is to be recorded. 
2. Gently invert the infusion bag to ensure uniformity of the drug in the infusion 
bag. 
3. Administration is to be done by an intravenous infusion tube containing a 0.2 to 
1.2 μm in-line filter (recommended infusion time was controlled for 30 to 60 minutes), 
and the administration start time and end time are to be recorded. 
Note: Before the configuration, make sure that IBI308 injection is transparent, no 
turbidity, sedimentation and other quality problems; ensure that the first bottle of 
IBI308 injection acupuncture extraction time to the end of the drug does not exceed 24 
hours (prepared infusion to be stored in refrigerator at 2~8°C); avoid mixing other drugs; 
avoid intravenous bolus. 
Treatment Adjustment 
General Rules 
Before the study drug is administered, the subject's hematology, liver and kidney 
function must meet all treatment requirements, and all toxic reactions must have been 
alleviated to CTCAE v4.03 grade 0-1 or baseline severity (except hair loss and fatigue). 
All treatment adjustment reasons and treatment should be recorded in the original 
medical record and electronic case report form (eCRF). 
Adjustment of IBI308 
The dose of IBI308 was not allowed to be adjusted throughout the study. The IBI308 
medication adjustment protocol (only for AEs judged by the investigator to be 
associated with IBI308) is shown in the table below. 
Table 1. IBI308 Adjustment Plan 
Adverse Event 
Severity 
Adjustment 
Pneumonitis  
Grade 2  
Suspend a 
Grade 3 or 4 
Terminate 


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Adverse Event 
Severity 
Adjustment 
Diarrhea/enterocolitis 
Grade 2 or 3 
Suspend a 
Grade 4 
Terminate 
Dermatitis 
Grade 3 
Suspend a 
Grade 4 
Terminate 
Hepatitis 
Grade 2 AST、ALT or TBIL increased 
Suspend a 
Grade 3 or 4 AST、ALT or TBIL increased 
Terminate 
Pituitary inflammation 
Grade 2 
Suspend a 
Grade 3 or 4  
Terminate 
Adrenal insufficiency 
Grade 2 
Suspend a 
Grade 3 or 4 
Terminate 
Hyperthyroidism 
Grade 3 or 4 
Terminate 
Type 1 diabetes 
Grade 3 hyperglycemia 
Suspend a 
Grade 4 hyperglycemia 
Terminate 
Renal insufficiency 
Grade 2 or 3 Cr increased 
Suspend a 
Grade 4 Cr increased 
Terminate 
Neurotoxicity 
Grade 2 
Suspend a 
Grade 3 or 4 
Terminate 
Infusion reaction 
Grade 3 or 4 
Terminate 
Other AE 
Other Grade 3 AE on first appearance  
Suspend a 
Same Grade 3 AE on second appearance 
Terminate 
Grade 3 AEs that cannot solve to Grade 0-2/ 
baseline in 7 days or to Grade 0-1/baseline in 
14 days 
Terminate 
Other Grade 4 AE 
Terminate c 
a：can resume treatment after AEs solve to grade 0-1 or baseline severity 
b：Pituitary inflammation, adrenal insufficiency, and type 1 diabetes can be re-administered with 
adequate control and only physiological hormone replacement therapy. 
c：For the abnormality of the results of the level 4 laboratory test, whether to terminate the drug should 
be decided according to the clinical symptoms/signs and according to the clinical judgment of the 
investigator. 
The maximum interval between drug pauses is 6 weeks. If the status of IBI308 can be 
re-used within 6 weeks, the subject permanently discontinues IBI308 and enters the 
follow-up phase. Except for the following two situations: 
Due to the use of glucocorticoids in the treatment of immune related adverse events 
(irAE), the glucocorticoid reduction process caused IBI308 to be suspended for more 
than 6 weeks. In this case, you need to discuss with the sponsor's medical manager to 
decide if you can continue IBI308 treatment. The imaging examination to evaluate the 
efficacy is planned as planned and is not affected by the suspension of medication. 


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IBI308 has been suspended for more than 6 weeks due to treatment of AEs that may or 
may not be related to IBI308. In this case, you need to discuss with the sponsor's 
medical manager to decide if you can continue IBI308 treatment. The imaging 
examination to evaluate the efficacy is planned as planned and is not affected by the 
suspension of medication. 
Principles of Handling Immune Checkpoints Inhibitor Toxicity 
IBI308 works through activating T cells, which can cause autoimmune hyperfunction, 
leading to multiple systemic autoimmune diseases. In the clinical application of other 
immune checkpoint inhibitors, e.g. ipilimumab, nivolumab, pembrolizumab and 
atezolizumab, autoimmune-related AEs, such as pneumonia, diarrhea/colitis, renal 
insufficiency, rash, hepatitis, endocrine diseases and peripheral or central neuritis were 
observed. Once any of the above mentioned AEs is observed in this study, investigators 
are to monitor patients’ symptoms and signs, conduct necessary exams to judge the 
causality of the AE.  
If no alternative causes (such as disease progression, concomitant medications and 
infections) 
are 
found 
and 
treatment 
with 
glucocorticoids 
and/or 
other 
immunosuppressive agents is required (except for endocrine events such as 
hyperthyroidism/hypertropy, pituitary inflammation, type 1 diabetes, and adrenal 
insufficiency, immunosuppressive therapy may not be used, but it is still thought to be 
related to autoimmune hyperactivity caused by IBI308) , the above AE should be 
considered to be related to immune system hyperactivity caused by IBI308, diagnosed 
as irAE. 
Concomitant Treatment 
 Prohibited Treatment 
• 
Other radiotherapy for the treatment of tumors (except palliative radiotherapy), 
chemotherapy, immunotherapy, targeted therapy and hormone therapy. 
• 
Immunosuppressive agents and high-dose glucocorticoids (i.e., more than 10 
mg/day of prednisone or equivalent doses of other glucocorticoids, except for the 
treatment of AE). 
• 
Immunoglobulin. 
• 
Live attenuated vaccines. 


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• 
ASCT. 
Allowed Treatment 
• 
Medications that allowed by the protocol, as judged by the investigators (e.g., for 
the treatment of disease-related symptoms and treatment-related AEs). 
• 
Local surgery or radiotherapy (radiation field does not include lungs) for isolated 
lesions (excluding target lesions) during study. 
• 
Subjects who need long-term medication for underlying diseases such as high 
blood pressure and diabetes can continue to take the drug. 
• 
Supportive treatment to relieve tumor-related symptoms. 
• 
Allow local glucocorticoids to be used, such as external skin, eye drops, nasal 
spray, inhalation, etc. 
Drug-drug interaction 
IBI308: There is no data on interaction with IBI308 drugs. 
Treatment Compliance  
Study treatment was performed at the research site, and medication compliance was 
monitored with drug delivery records, patient dairy, and eCRF. 
Drug Retrieve and Destroy 
In this study, containers, vials, infusion bags, and syringes of used and partially used 
research drugs can be destroyed at the research site, according to the guidance of the 
research site and local regulatory authorities, once confirmed by the clinical monitor.  
Any unused drug will be retrieved after the study is completed or terminated, or the 
drug expires, and destroyed by the sponsor. Designated clinical monitors will be in 
charge of drug retrieve and destroy. 
Drug Record 
The designated personnel of the research center shall promptly make relevant records 
of the receipt, distribution, use, inventory, destruction, recovery, damage, etc. of the 
research drug in accordance with the relevant regulations and guidelines and the 
requirements of the operational procedures of this test. 


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Complaint 
To ensure the safety and quality of the study participants and to assist with process and 
drug improvements, the sponsor will collect product complaints related to the study 
drug used in the clinical trial. 
Complaints related to the combined drug will be reported directly to the manufacturer 
based on the product description. 
The investigator or his designee is responsible for completing the following product 
complaint process in accordance with the relevant provisions of this study: 
• 
Use a research-specific complaint form to record the product complaints and 
related full descriptions. 
• 
Fax the completed product complaint form to the sponsor or its designated person 
within 24 hours. 
If the investigator is required to return the product for investigation, the investigator 
should return a copy of the product complaint form along with the product. 
6 Procedure 
Patient Recruitment 
Patient Recruitment 
The investigator will enroll the subjects as follows: 
1. Obtain informed consent with the subject's signature prior to any research-
related procedures. 
2. The principle investigator or the designated trained personnel to review the 
inclusion/exclusion criteria to formally determine the eligibility of the subject. 
Patients who did not meet the relevant criteria for this study (screening failure) could 
be rescreened. If a rescreening of the patient is considered, the investigator must contact 
the sponsor's medical manager. When rescreening, the patient must re-sign the ICF and 
will be reassigned a subject number. 
Handling of Wrong Patient Enrolled 
The inclusion criteria must be strictly adhered to. If a participant who does not meet the 
entry criteria is found, the sponsor's medical manager and investigator will discuss 


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whether to allow the subject to continue participating in the study, with or without the 
study drug. If the investigator believes that allowing the subject to continue 
participating in the study is appropriate for the subject from a medical perspective, and 
the sponsor's medical manager agrees with the investigator's decision, the subject may 
continue to participate in the study and accept study drug. If the investigator believes 
that the participant's continued participation in the study is medically appropriate, but 
the sponsor's medical manager disagrees with the investigator's decision, the subject 
may not continue to participate in the study (with or without study medication). The 
investigator was able to allow subjects who were accidentally enrolled in the study to 
continue to participate in the study only after receiving written approval from the 
sponsor. 
Study Plan and Schedule  
Screening 
The following research procedures must be completed during the screening period 
(Days -28~-1) to ensure that the subjects are eligible for this study: 
• 
Signing informed consent 
• 
Check the inclusion/exclusion criteria 
• 
Record demographics, medical history and prior medications 
• 
Record vital signs, height and weight 
• 
Physical examination 
• 
ECOG PS 
• 
12-lead ECG 
• 
CBC/ blood biochemistry / urine routine (within 7 days before the first dose) 
• 
Pregnancy test (within 3 days before the first dose) 
• 
Thyroid function 
• 
HIV antibody, hepatitis B two-and-a-half and HBV DNA, HCV antibodies (HCV 
antibody-positive patients need to detect HCV RNA) 
• 
Adverse event assessment 
• 
Concomitant medication 


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• 
Bone marrow biopsy 
• 
Tumor radiological assessment 
• 
Archived or fresh tumor tissue samples 
• 
Pathological diagnosis 
See Table 1 for the study screening period. 
See Sections 6.3, 6.4, and 6.5 for a detailed description of pathological diagnosis, tumor 
imaging assessment, and safety assessment. 
Baseline (Prior to Day 1 of Cycle 1) 
• 
Record vital signs  
• 
ECOG PS 
• 
PK 
• 
PD 
• 
Immunogenicity 
• 
Adverse event assessment 
• 
Concomitant medication 
• 
Disease related symptoms assessment 
• 
EQ-5D-5L and EORTC QLQ-C30 scale 
• 
Biomarker blood sample collection 
Treatment Visits 
• 
Record vital signs 
• 
Physical examination 
• 
ECOG PS  
• 
12-lead ECG 
• 
CBC / blood biochemistry / urine routine 
• 
Thyroid function 


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• 
PK 
• 
PD 
• 
Immunogenicity 
• 
Adverse event assessment 
• 
Concomitant medication 
• 
Tumor radiological assessment 
• 
Bone marrow biopsy: if the imaging is completely relieved, the bone marrow 
biopsy needs to be reviewed. 
• 
Disease related symptoms assessment 
• 
Study drug administration 
• 
Biomarker blood sample collection 
• 
EQ-5D-5L and EORTC QLQ-C30 
See Table 1 for study visits during the treatment period. 
Detailed descriptions of tumor radiological assessment, safety assessment, PK, PD, and 
immunogenic blood collection are provided in Sections 6.4, 6.5, 6.6, 6.7, and 6.8. 
Study Treatment Discontinuation Visit 
Study treatment discontinuation visit at the end of study treatment 
• 
Record vital signs and weight 
• 
Physical examination 
• 
ECOG PS 
• 
12-lead ECG 
• 
CBC / blood biochemistry / urine routine 
• 
Thyroid function 
• 
Pregnancy test 
• 
Adverse event assessment 
• 
Concomitant medication 


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• 
EQ-5D-5L and EORTC QLQ-C30 scale 
Safety Follow-up 
• 
Vital signs 
• 
CBC/ blood biochemistry / urine routine 
• 
Thyroid function 
• 
Adverse event assessment 
• 
Immunogenicity 
Pathological Diagnosis 
The pathological slides used for pathological diagnosis in the research site during 
screening should be provided to the central pathological laboratory for pathological 
diagnosis confirmation. If the central pathological laboratory requires further 
pathological slides (white films) or wax blocks, the research site needs to provide. The 
patients with central pathological laboratory confirmed diagnosis can continue the 
treatment. Patients without central pathological laboratory confirmed diagnosis will be 
discontinued from the study if agreed by the research site. Diagnosis confirmation from 
central pathological laboratory will not affect the patient recruitment. 
Radiographic Assessment 
The baseline assessment should be performed within 28 days prior to the first study. 
The investigator can collect radiographic results from the 28 days prior to enrollment 
for evaluation. 
Tumor radiography uses enhanced CT (MRI, for subjects who are allergic to CT 
contrast agents) and PET. Enhanced CT examination will be done at baseline (baseline 
assessment will be performed within 28 days prior to enrollment), weeks 6/15/24 (±7 
days), every 12 weeks after 24 weeks (±14 days), and every 16 weeks after 48 weeks 
Week (±14 days). The examination site includes the neck, chest, abdomen, basin and 
other required anatomical sites until the start of new therapy, disease progression, 
withdrawal of ICF or death. The first disease progression needs to confirm after 4~6 
weeks. For patients who discontinue treatment for other reasons than disease 
progression confirmed by radiology, it is still necessary to carry out radiological 
evaluation according to the protocol, after treatment discontinuation, until the start of 
new therapy, disease progression, subject withdrawal of ICF or death. PET 


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examinations were performed at baseline, week 15 (±7 days), or early termination of 
study treatment.  
The tumor assessment was based on the IWG 2007 and the Lugano 2014 as an auxiliary 
evaluation criterion. IRRC is to be set in the study. Specific radiological assessment and 
sampling requirements can be found in the Radiology Sampling Guide. 
safety evaluation 
Laboratory Evaluation 
Table 2. Laboratory Evaluation 
CBC 
RBC、HGB、WBC、PLT、LYM、ANC 
Blood 
Chemistry 
TBIL、ALT、AST、γ-GT 、ALP、ALB、TP、LDH、BUN、Cr、Na、K、
Cl、 Mg、Ca、P、Lipase、Amylase and FBG 
Urine routine 
PH、UALB、UPRO、URBC and UGLU 
Physical examination 
Complete physical examinations include: general condition, respiratory tract, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, throat), 
lymph nodes, thyroid, musculoskeletal (including spine and limbs), genitals/anus, and 
nerves System evaluation. 
Refer to Table 1 for examination schedule.  
12-lead ECG 
The 12-lead ECG will be analyzed at the local laboratory according to Table 1. 
A 12-lead ECG examination will be performed after the subject rests for at least 5 
minutes in the supine position. All 12-lead ECGs should be recorded while the subject 
is resting in a supine position. Further ECG examinations will be performed when there 
is a clinical need, for example, in the event of a cardiac related adverse event. The 
examiner completes the ECG assessment on the same day and records the results on the 
ECG. The same assessment method should be used throughout the study. 
The investigator should evaluate all ECGs based on clinically significant 
abnormalities/no clinically significant abnormalities. If it is an abnormal result of 
clinical significance, the investigator should record the result as an AE in eCRF. 


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Vital signs 
Vital signs examinations will be performed as described in Table 1. Vital signs include 
body temperature, pulse rate, respiratory rate, and blood pressure. 
Investigators may perform additional vital sign assessment based on standard clinical 
practice or on a clinical basis. 
Additional vital sign record values (if applicable) can be collected on the eCRF when 
AE/SAE occurs. The date and time of acquisition and measurement will be recorded in 
the appropriate section of the eCRF. 
6.5.4.1 Pulse and blood pressure 
After the subject rests for at least 5 minutes, the subject's supine posture blood pressure 
and pulse are to be measured. Two or more readings should be taken, with an interval 
of 2 minutes between measurements, taking the mean. If the first two systolic pressure 
readings differ by more than 5 mmHg, they should be measured again and averaged. 
The date and time of acquisition and measurement will be recorded in the appropriate 
section of the eCRF. 
It is necessary to measure pulse and blood pressure before the study drug is 
administered. 
6.5.4.2 Body Temperature and Breathing 
On the planned dosing day, body temperature and breathing should be taken prior to 
drug administration. 
Weight and height 
Height was measured only during the screening period, and body weight was measured 
during the screening period and at the end of treatment. 
Pregnancy test 
Women with fertility potential (as defined in 4.3) are tested for pregnancy in urine or 
serum human chorionic gonadotropin (β-HCG) samples within 3 days prior to the first 
dose of study drug. If the urine β-HCG is positive or cannot be determined to be 
negative, a serum β-HCG sample pregnancy test is performed. If the result is positive, 
the subject is not eligible for admission/must stop participating in the study. A 
pregnancy is suspected during the study and should be reviewed. 


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Other Safety Assessment: 
• 
Hepatitis B (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) and HBV DNA. 
• 
HIV antibody, HCV antibody (if HCV antibody is positive, HCV RNA will be 
checked) 
• 
Thyroid function: T3, T4, TSH, FT3 and FT4. 
Pharmacokinetics 
Twelve subjects in selected research sites will be chosen for PK analysis. The total 
number of PK blood collection in the first cycle is 8: within 1 hour before the start of 
IBI308 infusion, immediately after infusion (+5min), 1h±5min after infusion, 
6h±15min after the start of infusion, 24h±1h. 48h±2h, 168h±8h (day 8), 336h±12h (day 
15); if the administration is delayed on the first day of the second cycle due to AE or 
other reasons, the first cycle needs to include an 504h±24h ( Day 22) sampling. From 
the second cycle, PK sample collection is performed every two cycles (the second, 
fourth, and sixth phase cycles, and so on). Except for the fourth cycle, the sampling 
time is: within 1 hour before the start of the infusion and immediately (+5min) after 
infusion, 1h ± 5min after infusion, 6h ± 15min, 24h ± 1h, 48h ± after the infusion, 168h 
± 8h (day 8), 336h ± 12h (day 15), 504h ± 24h (day 22, ie, within 1 hour before the fifth 
cycle of administration). 
2 ml of blood is to be collected using a procoagulant vacuum blood collection tube, 
serum is separated, and frozen for storage for PK analysis. Sampling methods, sample 
storage, transportation and analysis are detailed in the Laboratory Manual provided by 
the sponsor's designated central laboratory. 
The concentration of IBI308 in the serum is analyzed by ELISA and tested by the 
sponsor's designated central laboratory. All subjects are required to measure plasma 
concentrations at the blood collection points per the protocol.  
Pharmacodynamics 
Twelve subjects in selected research sites will be chosen for PD analysis. The total 
number of PD blood collection in the first cycle is 3: within 1 hour before the start of 
the IBI308 infusion, 24 h ± 1 h after the start of the infusion, and 168 h ± 8 h (Day 8). 
At the beginning of the second cycle, sample collection is performed every four cycles 
(the second, sixth, tenth, fourteenth, etc., and so on). 


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An anticoagulated vacuum blood collection tube will be used to collect 1 ml of blood 
for PD-1 receptor occupancy analysis. Sampling methods, sample storage, 
transportation and analysis are detailed in the Laboratory Manual provided by the 
sponsor's designated central laboratory. 
Immunogenicity 
The immunogenicity test will be performed during the first cycle, the second cycle, the 
fourth cycle, and every 4 cycles (the 8th, 12th, and 16th cycles, etc.) within 1 hour 
before the IBI308 infusion and during the safety follow-up. The analysis will be done 
at the central laboratory. 
Anti-drug antibody (ADA) titers will be tested in each subject, and ADA-positive serum 
samples will continue to be tested for neutralizing antibodies (NAb). 
4 ml of whole blood will be collected using a coagulation vacuum blood collection tube, 
serum is separated, and frozen for storage for ADA and NAb analysis. 
Sampling methods, sample storage, transportation and analysis are detailed in the 
Laboratory Manual provided by the sponsor's designated central laboratory. 
Quality of life assessment 
The quality of life assessment is conducted using the EQ-5D-5L and EORTC QLQ-C30 
scales, on the first day of dosing, each radiographic assessment, and the end of treatment 
follow-up. 
The EQ-5D-5L is a standardized tool for self-reporting health status indicators. Subjects 
will fill out 5 levels (no problem, mild, moderate, severe, and extreme) about their 
current health status, 5 dimensions (mobility, self-care, daily activities, pain/discomfort, 
and anxiety/depression) questionnaire. After synthesizing the levels of the five 
dimensions, the unique EQ-5D health status is defined. In addition, patients will be 
marked with a visual analog scale (VAS) ranging from 100 (the best imaginable health 
condition) to 0 (the worst health condition imaginable) to illustrate their current health 
status.  
EORTC's QLQ-C30 is a core scale for all cancer patients. It has 30 entries and can be 
divided into 15 dimensions, with 5 functional dimensions (body, role, cognition, mood 
and social function), 3 symptoms dimensions (fatigue, pain, nausea and vomiting), 1 
overall health/quality of life dimension, and 6 single items. 


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Biomarker analysis 
Subject to the ethics committee, all subjects who meet the inclusion criteria are required 
to provide archived tumor tissue at baseline or 4 unstained 4-5 micron sections prepared 
freshly during the screening period for PD-L1 testing. 
For the detection of mRNA expression levels of immune-related genes, subjects are 
required to provide archived tumor tissue at baseline or 4 unstained 4-5 micron sections 
prepared freshly during the screening period. 
Subjects are required to provide 10 ml blood samples at the following time points: the 
screening period, the treatment period, and the efficacy evaluation before the next 
treatment. The following tests may be performed: dynamic analysis of peripheral blood 
mononuclear cells in the enrolled patients by analysis of surface markers of different 
subtypes of lymphocytes and circulating tumor cells (e.g., PD-L1, Tim-3, CSF1R, 
TIGIT, LAG-3) , OX40, 4-1BB, GITR, CTLA-4, FOXP3, PD-1, PD-L2, CD4, CD3, 
TAM-related markers, MDSC-related markers, B2M, B7-H3, B7-H4, VISTA, etc.), 
predict the efficacy and prognosis of patients with anti-PD-1 immunotherapy. 
For a detailed description of sample handling, disposal, and shipping, refer to the 
Laboratory Manual. 
Storage and destruction of biological samples 
The sample will be disposed or destroyed and merged and anonymized. Additional 
analysis of the anonymized, combined samples may be performed to further evaluate 
and validate the analytical method. Any results obtained from these analyses may be 
reported separately from the CSR. 
The sample reproducibility analysis (if performed) will be performed in parallel with 
the bioanalysis of the test sample. These findings will not be reported in the clinical 
study report, but will be given separately in a bioanalytical report. 
7 Safety Reporting and Adverse Event Management 
Definition of adverse events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have to have a causal relationship with this treatment. All adverse events 
should be reported since the consent form is signed until 90th day after last 


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administration of investigation products. AE includes but is not limited to the following 
situations:   
• 
Exacerbation of preexisting (before entering the clinical trial) medical 
condition/disease (including symptoms, signs, and abnormalities in laboratory 
tests) ; 
• 
Any new adverse medical conditions (including symptoms, signs, newly diagnosed 
diseases); 
• 
Abnormal laboratory test values or results which have clinical significance. 
Definition of serious adverse events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that: 
• 
Results in death, except for deaths caused by the progression of clinical indications; 
• 
Is life-threatening (The definition of “life-threatening” is the subject is at risk of 
death when AE occurs, but does not include AEs that may cause death if the event 
is aggravated); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
excluding the following: 
 
Rehabilitation institution 
 
Sanitarium 
 
Routine treatment in emergency room 
 
Day surgery (e.g. outpatient / day / ambulatory surgery) 
 
Hospitalization or prolongation of existing hospitalization that is not associated 
with AE aggravation. For example: The patient was hospitalized for clinical 
indication or preexisting indication, no new adverse events or no aggravation of 
preexisting indication (such as retest laboratory abnormalities that persisted); 
hospitalization for management reasons (such as annual routine Physical 
examination); hospitalization which specified in the protocol (e.g. as required 
by the protocol); elective hospitalization not associated with AE aggravation 
(e.g. elective surgery); scheduled treatment or surgery should be performed 
during clinical trial which recorded as baseline data; hospitalized for blood 
product use only. 
• 
Results in persistent or significant disability/incapacity; 
• 
Is a congenital anomaly/birth defect; 
• 
Is another important medical event. The definition of important medical events is 
AE that may not be immediately life-threatening or result in death or 


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hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
AE severity assessment 
Investigator will evaluate the severity for all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.03. 
For adverse event terms not included in NCI CTCAE version 4.03, the severity will be 
evaluated according to the general guideline of NCI CTCAE: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
ageappropriate instrumental ADL (Instrumental ADL refer to preparing 
meals,shopping for groceries or clothes, using the telephone, managing money, etc). 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL (Self care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridde) 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
Causality assessment  
The relationship between Investigation products and AE can be judged by the following 
classifications and criteria: 
Table 3. Causality assessment 
Causality 
Criteria for Causality assessment 
definitely 
related 
The onset date of AE and administration of Investigation product is reasonable; 
The administration of Investigation products can explains the adverse event more 
reasonably than other causes (e.g. the subject's preexisting disease, environmental or 
toxic factors, or other treatments received by the subject); 
AE disappeared or reduction after drug withdrawal or dosage reducing; 
AE type is known for the suspected drug or its similar drugs  
AE reappear after re-medication. 
Possible 
related 
The onset date of AE and administration of Investigation product is reasonable; 
The administration of Investigation product can also reasonably explains the adverse 
event than other causes (e.g. the subject's preexisting disease, environmental or toxic 
factors, or other treatments received by the subject); 
AE disappeared or reduction after drug withdrawal or dosage reducing; 


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Causality 
Criteria for Causality assessment 
Possible 
unrelated 
Another cause (e.g. the subject's preexisting disease, environmental or toxic factors, or 
other treatments received by the subject) can explains the adverse event more 
reasonably than Investigation products; 
AE still existed or no reduction after drug withdrawal or dosage reducing; 
AE dos not appear after re-medication.. 
Unrelated 
The onset date of AE and administration of Investigation product is unreasonable; or 
The adverse event has other apparent causes (eg, the subject's original disease, 
environmental or toxic factors, or other treatments the subject receives). 
Unable to 
judge 
The above information is not available, The Investigtor can’t assessment the causality 
according to the existing information and cannot get follow-up information. 
AE record 
Investigators should record AE or SAE using medical terminology/concept. Spoken and 
abbreviations should be avoided. All AEs (including SAE) should be recorded on the 
eCRF. 
AE collection period 
The investigator will collect AE via asking subject with non-inductive questions. 
All adverse events, including serious adverse events, will be collected since the consent 
form is signed until 90th day after last administration of investigation products, either 
observed by investigator or by the spontaneous reported by subjects. 
90 days after the last dose, the investigator should report serious adverse event 
associated with the study drug or procedure. 
Follow-up of AE 
Adverse events should be followed up until to baseline or grade 0~1 or the investigator 
believes that no further follow-up is required for reasonable reasons (if it cannot be 
recovered or has improved). If the adverse event cannot be recovered, a reasonable 
explanation should be recorded in the eCRF. Regardless of whether it is related to the 
study drug, the recovery condition and date of AE or SAE should be recorded in the 
subject’s eCRF and medical records. 
Contents of AE records 
Investigator should record adverse events completely, including diagnosis (if no 
diagnosis, record symptoms, signs including laboratory abnormalities), start date and 
end dates (if applicable), CTCAE severity grade and changes (level 3 or above), serious 


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adverse event or not, adverse event of special interest or not, action taken for 
investigation products, the treatments for AE and the result of AE, and the relationship 
between adverse events and investigation product. 
For serious adverse events, the investigator should also record the date on which the 
AE meets the SAE criteria, the date the investigator was informed of the SAE, the 
criteria for the AE meets SAE, the date of hospitalization, the date of discharge, the 
cause of death, the date of death, autopsy or not, and causal assessment with clinical 
procedure, causal assessment with other drugs, and other possible causes of SAE. The 
investigator should also provide a basis of causality assessment and the narrative of 
SAE. In the SAE narrative, the subject's number, age, gender, height, weight; the 
indications for study drug and disease staging, and related general conditions; SAE 
occurrence, development, outcome and clinical course; laboratory findings related to 
SAE (the time, unit and normal range must be provided); previous history of SAE, 
combined disease and its occurrence and duration; SAE-related medication history, 
combined drug and the start date, duration, and dosage of the treatment; the start date, 
duration, and dosage of investigation products. 
The items related to the AE recording are described as follows: 
Diagnosis, symptoms and signs 
If a diagnosis has been made, the diagnosis should be recorded on the eCRF rather than 
individual symptoms and signs (e.g. recording liver failure, not jaundice, elevated 
transaminase, and flapping tremor). If the symptoms and signs are not sure be caused 
by the diagnosis at the time of reporting, they should recorded as separate AE/SAE. If 
it is sure that the symptoms and signs are caused by the diagnosis, only the diagnosis is 
reported separately, and the symptoms and signs are included in the diagnosis. The AE 
recording needs to delete symptoms and signs, and the SAE needs to send a follow-up 
update report. 
Adverse events secondary to other events 
Often, adverse events secondary to other events (e.g, caused by other events or clinical 
sequelae) should record their primary events unless the secondary event is severe or a 
serious adverse event. However, secondary events with significant clinical significance, 
if different from the time of occurrence of the primary event, should be recorded as 
independent adverse events in the eCRF. If the association between the events is not 
clear, it should be recorded separately in the eCRF. 


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Persistent or recurrent adverse events 
A persistent adverse event is an adverse event that persists without a remission between 
the two evaluation time points. This adverse event should only be recorded once on the 
eCRF. The initial severity of the AE should be recorded and updated the severity when 
AE worsen. 
The AE of recurrence refers to an AE that has been alleviated between the two 
evaluation time points, but then occurred again. The reoccurred AE should be recorded 
separately in the eCRF. 
Abnormal laboratory test 
Clinically significant laboratory findings should be reported as AE. It is the 
responsibility of the investigator to review all laboratory abnormalities and to make 
medical judgments as to whether each laboratory should report an abnormality as an 
AE. 
Death 
All deaths that occurred during the entire trial period, including deaths occur during 90 
days after last administration of investigation products, whether or not related to the 
study drug, should be recorded in the death report form of the eCRF and reported to the 
sponsor timely. 
When a death event is recorded, the cause of death is recorded as an adverse event, and 
the result of the adverse event is death, and the death is reported as SAE; if the cause 
of death at the time of reporting is unknown, it should be recorded as “Death NOS” in 
eCRF and reported as a SAE. The exact cause of death should be further investigated. 
If death is clearly caused by tumor progression, it is not recorded and reported as an 
AE/SAE, but the investigator should record the death in the eCRF death report form 
and inform the sponsor timely. 
Preexisting Medical status 
Subjects' symptoms/signs during the screening period, only if there is a severity, 
frequency, or exacerbation of the disease (except for the worsening of the disease 
condition under study) should be recorded and reported as adverse events. Changes of 
preexisting medical status should be reflected in the record, such as "increased 
frequency of headache." 


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Hospitalization, prolongation of existing hospitalization or surgery 
Any adverse events that result in hospitalization or prolongation of existing 
hospitalization should be recorded and reported as SAE, except following e: 
Prolonged hospitalization or hospitalization according to the trial design requirements 
(e.g. for drug delivery, efficacy evaluation, etc.) 
The subject was hospitalized for medical conditions that existed before participating 
clinical trial. For example, elective surgery/treatment scheduled before participating in 
the study. 
However, if the preexisting disease aggravated, the aggravated preexisting disease 
should be recorded as AE/SAE. 
Disease progression 
Disease progression is defined the subject’s condition worsen caused by the primary 
tumor which as the indication of investigation product. A new lesion relative to the 
primary tumor or progression of the original lesion is considered to be disease 
progression. Disease progression is not reported as an AE, The symptoms and signs 
Disease progression which result death, life-threatening, requiring hospitalization or 
prolonged hospital stay, leading to permanent or severe disability/capacity loss, leading 
to congenital anomalies/birth defects and other important medical events are not 
reported as SAE. 
Overdose 
The dosage over the dose specified in the protocol is the drug overdose. Overdose will 
be recorded in the eCRF. 
SAE and pregnancy reporting process 
SAE report: 
SAE will be reported since the consent form is signed until 90th day after last 
administration of investigation products. If SAE occurs, whether it is initial report or 
follow-up report, the investigator must immediately completed SAE form with 
signature. The SAE should be reported sponsor, regulatory authority and the ethics 
committee within 24 hours of the investigator awareness. The contact details are shown 
in the table below. 
If a SAE occurred outside the above-mentioned period, the SAE should also be reported 


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to sponsor when there is a reasonable relationship between this SAE and investigation 
product. 
For SAEs that are life-threatening or death, the investigator should urgently follow up 
missing information and provide a complete SAE report to Sponsor, regulatory 
authority and ethics committees. 
Table 4. SAE Reporting contact form 
Organization 
Contact 
Fax/telephone/address 
Hospitals name 
Ethics committee 
Fax/telephone of hospitals 
Innovent 
Innovent PV  
fax：021-31652800 
mail：drugsafety@innoventbio.com 
China 
National 
Drug 
Administration 
 
 
address：Building 2, No. 26, Xuanwumen 
West Street, Xicheng District, Beijing  
zip code：100053 
phone：010-88330732 
fax：010-88363228 
National Health Commission 
of the People’s Republic of 
China 
 
 
address：No. 38, Lishi Road, Xicheng 
District, Beijing  
phone：010-68792001 
fax：010-68792734 
Provincial, 
autonomous 
region, 
municipal 
drug 
regulatory authority 
Refer to the reporting requirements of the regulatory authorities of 
provinces, autonomous regions, and municipalities directly under 
the Central Government. 
Pregnancy 
Similar drugs have a safety risk for embryotoxicity, and all subjects with fertility in 
clinical trials must take effective contraceptive measures. 
When a female subject is pregnant during a clinical trial, the subject is should be 
excluded, Investigator should report to sponsor within 24 hours of awareness of 
pregnancy, and complete Innovent Clinical Trial Pregnancy Report/Follow-up Form. 
When the male subject's partner is pregnant during the clinical trial, and the subject can 
still participate the clinical trial.  Investigator should report to sponsor within 24 hours 
of awareness of pregnancy, and complete Innovent Clinical Trial Pregnancy 
Report/Follow-up Form. 
The investigator should monitor the pregnancy and follow up the pregnancy results, 
until to 8 weeks after the mother delivers, and report the results to sponsor. 
If the pregnancy results is stillbirth, spontaneous abortion, fetal malformation (any 


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congenital anomaly / birth defects), and abortion with medical reason, this condition 
should be considered as SAE, need to report as SAE and timeline. 
If the subject has SAE at the same time during pregnancy, the Serious Adverse Event 
Report Form will be completed and reported in accordance with the SAE reporting 
procedure. 
Events with abnormal liver function 
If the AST and / or ALT levels are abnormal and the total bilirubin level is abnormally, 
the abnormal test can met following conditions and no other reason cause liver damage, 
this will be considered as drug-induced liver damage. Such conditions should always 
be considered an important medical event. 
Table 7. Liver function damage as required by SAE 
baseline 
Normal (AST/ALT and total 
bilirubin) 
abNormal (AST/ALT and total bilirubin) 
Treatment period 
ALT or AST≥ 3× ULN  
With Total bilirubin≥ 2× ULN 
And 
Alkaline phosphatase≤ 2× ULN 
And without hemolyse 
AST or ALT≥ 8× ULN 
With Total bilirubin≥ 1× ULN or ≥ 3× ULN 
Subjects should return to site for evaluation as soon as possible after receiving an 
abnormal result (preferably within 48 hours). The assessment should include laboratory 
tests, detailed medical history and physical assessment, and should consider the 
possibility of liver tumors (primary or secondary). 
In addition to repeated testing for AST and ALT, laboratory tests should be performed 
including albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-
glutamyltransferase, prothrombin time/international Standardized ratio, alkaline 
phosphatase. Detailed medical history collection should include: history of drinking, 
acetaminophen, soft drugs, various supplements, Chinese medicine, history of exposure 
to chemical drugs, family history, occupational exposure, history of sexual behavior, 
travel history, and history of contact with patients with jaundice, surgery, blood 
transfusion, history of liver disease or allergic disease, history of heart disease, history 
of immune disease, etc. Further examination may include detection of acute hepatitis 
A, B, C and E, liver imaging (eg, biliary tract), autoantibodies, and cardiac ultrasound. 
If repeated testing met the criteria in Table 7, the potential of drug-induced liver damage 
should be considered without any other reason explaining abnormal liver function 


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testing, no need to wait all liver nosetiology results. Such potential cases of drug-
induced liver damage should be reported as SAE. 
Management of drug-related toxicity 
Sponsor will conduct regular safety review during study. Detailed information, 
including the frequency of review and the type of data to be reviewed, will be recorded 
in a separate safety review plan for this trial. 
Immune-related adverse events 
As the mechanism of IBI308 is T cell activation and proliferation, immune-related 
adverse events (irAEs) may be observed during this study. For a detailed definition of 
irAE, see Section 5.4. The signs and symptoms of irAE should be monitored. 
The dose adjustment of IBI308 and adverse event management principles are detailed 
in Sections 5.3 and 5.4. The disposal guidelines for irAE are detailed in attachment 7 
(Tables 1 to 2). 
Adverse Event of Special Interest 
Adverse Event of Special Interest (AESI) is the event 
needs special close monitoring for the better 
understanding of the safety for the IP. AESI may be 
non-serious event. 
Adverse Event of Special Interest (AESI) of the trial included: 
• 
Infusion reaction which the grade is greater than or equal to 3 
• 
Diarrhea colitis, uveitis, interstitial pneumonia which the grade is greater than or 
equal to 2 
• 
Suspected immune-related adverse events which the grade is greater than or equal 
to 3 
8 Statistical considerations 
Statistical analysis plan 
Detailed statistical analysis plan (SAP) will be prepared after first patient enrolled and 
will be finalized before data base lock. 


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Hypothesis testing 
The primary efficacy endpoint of this study is ORR from IRRC according to IWG2007 
criteria. The hypothesis of one sample superiority test is: 
H0：ORR≤40% 
H1：ORR>40% 
Superiority test is based on confidence interval (CI). If the lower limit of the (1-α) % 
CI (α will be adjusted for interim analysis）is larger than 40%, it is statistically 
confirmed that IBI308 monotherapy is efficacious in patients with relapsed or refractory 
cHL. 
Analysis populations 
The following analysis populations will be defined: 
Safety set (SS): patients who received at least one dose of study drug. 
Full analysis set (FAS): patients who received at least one dose of study drug and with 
measurable disease at baseline. Patients that are not confirmed by IRRC as cHL will 
not be included in FAS population. 
Per protocol set (PPS): subset of FAS, with no major protocol deviation that affects 
efficacy evaluation, no prohibited concomitant medication defined by protocol, and 
good compliance. 
Statistical Method 
General Statistical Method 
Descriptive summary statistics are provided to summarize continuous data. Frequency 
and percentage are provided to summarize categorical data.  
SAS 9.2 (or higher version) will be used for all the statistical analysis. 
 Analysis of Primary Endpoints 
Per IWG 2007 criteria, ORR assessed by IRRC: 
*100%
Total Number of Subjects
CR
PR
ORR


, and the (1-α) % CI will be calculated 
using binomial distribution for confirmation of superiority. 


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Analysis of Secondary Endpoints 
Per IWG 2007 criteria, assessed by IRRC and investigators: 
 
ORR (Assessed by Investigators) 
*100%
Total Number of Subjects
CR
PR
ORR


 , and the 95% CI will be calculated 
using binomial distribution. 
 
TTR (Assessed by IRRC and Investigators) 
For subjects with complete remission or partial remission, the time to response is 
defined as time from the date of first dose to the date of the first objective response. 
Kaplan-Meier method will be used to obtain the median TTR and its 95%CI and the 
survival curves will be provided accordingly. 
 
DOR (Assessed by IRRC and Investigators) 
For subjects with complete remission or partial remission, the duration of response is 
defined as the time from the date of first remission to the date of disease progression or 
death whichever is earlier, and subjects with no disease progression or death will be 
censored on the date of the last imaging assessment.  
Kaplan-Meier method will be used to obtain the median DOR and its 95%CI and the 
survival curves will be provided accordingly. 
 
PFS (Assessed by IRRC and investigators) 
PFS: the time from the date of the first dose to the date of first disease progression 
(imaging), if subjects died due to any reason prior to the disease progression, PFS is the 
time from the date of first dose to the date of death. If subjects who did not die or had 
no disease progression, the censoring dates are the dates of the last imaging assessment 
dates. Subjects with no post-baseline imaging assessments will be censored on the date 
of enrollment. 
Kaplan-Meier method will be used for the analysis of PFS to evaluate the median PFS 
(mPFS) and its 95% CI and the survival curves will be provided accordingly.  
 
DCR (Assessed by IRRC and investigators) 
*100%
Total Number of Subjects
CR
PR
SD
DCR



 , and 95% CI will be calculated 


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using binomial distribution. 
Biomarker assessment 
Descriptive statistics will be summarized for different PD-L1 expression levels and 
explore its potential relations with treatment effect. 
Descriptive analyses will also be provided for tumor immune related genes and its 
distribution and explore its potential relations with treatment effect. 
The analysis not specified in this document may need to be done post hoc wisely. The 
analysis specified in this section may need to be done at discretion of the data 
availability.  
Quality of life assessment 
The score of EQ-5D-5L and EORTC QLQ-C30 at each assessment will be computed. 
The descriptive statistics for baseline value, values at each post-baseline assessment 
and the change from baseline will be summarized for each individual question score as 
well as the composite score. 
Safety analysis 
The safety analysis will be conducted on domains of Adverse Event, Clinical 
Laboratory 
Evaluation, 
Vital 
Sign 
Measurement, 
Electrocardiograms 
and 
Immunogenicity base on SS population.  
8.4.6.1 Treatment Exposure 
The study treatment exposure in doses and the treatment duration in days and cycles 
will be summarized for subjects. 
8.4.6.2 Adverse Event 
All AEs will be coded using MedDRA. 
The overall incidence rates of AEs, TEAEs, drug related AE, Immune-related AEs 
(irAE), AEs of Special Interest (AESI), SAEs, important AEs and AEs leading to early 
study termination will be summarized. and by SOC and PT according to MedDRA, and 
further by severity grade according to NCI CTCAE 4.03. 
A listing will be provided for subjects who discontinued the study drug due to AE, 
experienced at least one SAE, or died with information at least including AE’s start and 


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end date, severity grade, relation with study drug, action taken and outcomes. 
8.4.6.3 Clinical Laboratory Evaluation 
Hematology and Chemistry test results will be summarized with descriptive statistics 
for values of baseline, post-baseline and change from baseline. Shift tables will be 
provided for normality status of laboratory values changing from baseline to each post-
baseline assessment. 
Urinalysis will be analyzed by using shift tables with normality status changing from 
baseline to each post-baseline assessment. 
For subjects with abnormal laboratory values, the status of “Abnormal, clinically 
Significant” will be determined by investigator and the category will be summarized in 
frequencies and percentages. 
Subjects with abnormal post-baseline laboratory values with or without clinical 
significance will be provided in a listing. 
8.4.6.4 Electrocardiograms 
The ECG measurements at baseline, post-baseline and change form baseline will be 
summarized. The normality status changing from baseline to each post-baseline 
assessment will be also summarized in a shift table. Listings of ECG measurements will 
be provided as well.  
8.4.6.5 Vital Sign, Physical Examination and Other relevant assessments  
Vital sign will be summarized with descriptive statistics for baseline, post-baseline and 
change from baseline values. A listing will be provided for subjects who have post-
baseline abnormal assessment in physical examination. 
Immunogenic Endpoint 
The positive rates of ADA antibody and NAB will be calculated, and the antibody levels 
of positive subjects will be listed. 
Compliance Analysis 
Summarize the percentage and frequency of subjects who violate the expected drug 
regimen. 
The percentage of subjects who take the drug between 80% and 120% of the prescribed 


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dose in the study. 
The percentage of subjects who complete the entire study and that who completed 
different treatment cycles. 
Baseline characteristics of subjects 
Descriptive statistics will be used for the endpoints below: 
Demographic characteristics (gender and age), information about diagnosis and 
treatment of tumor (pathological diagnosis, clinical stage and previous treatment), 
baseline examination of tumor (target lesion, number of non-target lesion, location, 
total diameter, etc.); other baseline information (height, weight, body mass index, body 
surface area, vital signs, laboratory examinations, previous/concomitant/newly added 
medications, etc.). 
Interim Analysis 
In this study, an interim analysis is planned to conduct at the time point when all the 
enrolled subjects finished two tumor assessments as planned. The purpose of the interim 
analysis is for conditional BLA submission at the early stage, and the endpoint is the 
primary efficacy endpoint ORR according to IWG2007. 
Given a two-sided alpha of 0.03 at interim analysis, if the lower limit of 97% CI of 
ORR is greater than 40%, it can be considered as superiority confirmed. Regardless of 
results at interim analysis, the study will continue till the last subject finish at 24 weeks 
tumor assessment at which time final analysis will be conducted. An alpha level of two-
sided 0.05 is to be used in the final analysis if the study demonstrates superiority at the 
interim analysis, otherwise two-sided 0.036 level will be applied. 
Multiple comparison and multiplicity adjustment 
In this study, interim analysis is planned to be conducted once with an alpha level of 
two-sided 0.03. An alpha level of two-sided 0.05 is to be applied in the final analysis if 
the study demonstrated superiority at the interim analysis, otherwise two-sided 0.036 
level will be applied. 
Subgroup Analysis 
Efficacy analysis in PD-L1 positive subjects. 
Subgroup analysis of efficacy will also be conducted according to age and previous 


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treatment. 
Listing of evaluable subjects 
In addition to the overall listings of subjects, tumor evaluation of CR and PR (evaluation 
date, lesion status and evaluation results) and efficacy endpoints will be listed 
separately. 
PFS data of all subjects at the end of study. 
Exploratory Analysis 
Correlation between different expression levels of PD-L1 and treatment effect. 
Determination of sample size 
This is a phase II single-arm study. Assuming the null hypothesis of ORR is ≤ 40%, 
two-sided alpha as 0.05, a total sample size of 80 will provide 80% power to detect a 
16% difference for IBI308 monotherapy, that is, the ORR for IBI308 monotherapy 
reaches 56%. Considering a dropout rate as approximately 10%, the planned sample 
size is 90, to ensure at least 80 patients with available efficacy assessment (the EAS 
population). 
The null hypothesis of ORR 40% is based on clinical research results of relevant drug 
monotherapy on relapsed or refractory cHL [9-11]. It also takes into consideration of 
study designs of similar drugs in clinical research of cHL. 
Bias control 
Randomization and blinding 
This is a single arm, open label study, which does not involve randomization and 
blinding process. 
Evaluation of blinding maintenance 
Not applicable. 
Unblinding and emergency unblinding 
Not applicable. 
9 Quality Assurance and Quality Control 
In accordance with the guidelines of the GCP, it is the responsibility of the sponsor to 


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implement and maintain a quality assurance and quality control system in accordance 
with the appropriate standard operating procedures to ensure the implementation of 
clinical trials and the truthfulness of the data, and to collect, record and report 
compliance with the program, GCP and corresponding regulatory requirements.  
Clinical Audit 
The CRO authorized by the sponsor or sponsor will conduct a clinical audit of the study. 
The clinical monitor should conduct the audit according to the standard operating 
procedures of the sponsor or CRO and have the same rights and responsibilities as the 
sponsor's monitor. The auditor shall maintain regular communication with the 
investigator, the trial authorised personnel and the sponsor. 
Before the study begins, the auditor will assess the competency of each research center 
and report issues related to facilities, technical equipment, or medical staff to the 
sponsor. During the course of the study, the monitor will be responsible for monitoring 
whether the investigator has obtained written informed consent from all subjects and 
whether the data records are correct and complete. At the same time, the monitor will 
also compare the data input to the eCRF with the original data and inform the researcher 
of errors or omissions. The monitor will also control the compliance of the research 
center's program and test procedures, arrange for the supply of research drugs, and 
ensure that the drugs are kept in the proper conditions. 
The audit visit will be conducted in accordance with the requirements of relevant laws 
and regulations. From the time the subjects are enrolled, each center will receive regular 
monitoring visits. After each visit to the investigator, the auditor should submit a written 
report to the sponsor. 
Data Management / Coding 
This study will use an electronic data collection (EDC) system, and the research data 
will be entered into the eCRF by the investigator or authorized researcher. Researchers 
and authorized researchers will be properly trained and appropriate security measures 
will be taken for the equipment used, etc., prior to the start of the research center or data 
entry. 
Data entry for eCRF should be completed as soon as possible during or after the visit 
and updated at any time to ensure that it reflects the latest developments of the 
participants in the study. To avoid differences in outcome assessment by different 
evaluators, it is recommended that the same subject's baseline and all subsequent 


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efficacy and safety assessments be performed by the same individual. Researchers are 
required to review the data to ensure the accuracy and correctness of all data entered 
into the eCRF. If some assessments are not made during the study, or if certain 
information is unavailable, not applicable, or unknown, the investigator should record 
it in the eCRF. The investigator should electronically sign the verified data. 
The CRA will review the eCRF and assess its completeness and consistency, and the 
CRA will compare the eCRF with the original documents to ensure consistency of key 
data. All data entry, corrections and modifications will be the responsibility of the 
investigator or his designee. The data in the eCRF is submitted to the data server and 
any changes to the data are recorded in the audit trail, ie the reason for the change, the 
name of the operator, the time and date of the modification will be recorded. The roles 
and authorities of the staff responsible for data entry in the research center will be 
predetermined. If there is any data challenge, the CRA or data management staff will 
issue a challenge in the EDC and the research center staff will be responsible for the 
Q&A. The EDC system will record the audit trail of the challenge, including the name, 
time and date of the investigator. 
Unless otherwise stated, eCRF will only be used as a form to collect data, not as a 
source. The original document is used by the investigator or hospital, relevant to the 
subject, and demonstrates the presence, inclusion criteria, and all records of 
participation in the study, including laboratory records, ECG results, and pharmacy 
drug delivery records. , subject folder, etc. 
The investigator is responsible for maintaining all original documents and for CRA to 
monitor them at each visit. In addition, regardless of the length of time the enrolled 
subjects participated in the study, the investigator must submit a complete eCRF for 
each enrolled subject. The program number and subject number of all supporting 
documents (such as laboratory records or hospital records) submitted with eCRF should 
be carefully verified, and all personal privacy information (including the subject's name) 
should be deleted or made illegible. To protect the privacy of the subject. The researcher 
verifies that the record has been reviewed by an electronic signature record and that the 
data of the record is accurate. The electronic signature will be completed using the 
researcher's user ID and password. The system will automatically attach the date and 
time of the signature. The researcher must not share the user ID and password with 
other people. If you need to change the data in the eCRF, you should follow the 
workflow defined by the EDC system. All changes and reasons for the changes will be 


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recorded in the audit trail. 
Adverse events, concomitant diseases/history will be coded. The dictionary for coding 
will be described in the Clinical Research Summary Report (CSR). 
Quality Assurance Audit 
During the course of the study, the sponsor or the representative authorized by the 
sponsor may conduct quality assurance audits of the research center, research database 
and related research documents. At the same time, the corresponding regulatory agency 
may also inspect the research center, research database and related research documents 
at its own discretion. When the researcher receives the inspection notice from the 
regulatory body, he or she must immediately inform the sponsor. 
The quality assurance department of the sponsor conducts an audit of the clinical trial 
institution. The audit includes: the supply of the drug, the required test documents, the 
record of the informed consent process, and the consistency of the medical report form 
with the original documents. The content and scope of the audit can also be increased 
depending on the situation. After reasonable notice, the investigator shall allow the 
auditors commissioned by the sponsor to conduct inspections related to the trials and 
inspections conducted by the regulatory authorities. The primary purpose of an audit or 
inspection is to verify that the rights or health of the participants in the trial are protected, 
that the signing of the informed consent and the implementation of the trial process are 
carried out correctly, and that all data related to the study drug evaluation are processed 
and reported and pre-planned, The program, facility, ethical standard operating 
procedures, GCP and applicable regulatory requirements are consistent. Researchers 
should have direct access to all test files, original records, and raw data. 
10 Ethics 
Ethics Committee 
The sponsor or the representative authorized by the sponsor will prepare the relevant 
documents to be submitted to the Research Center's Ethics Committee (EC), including 
the trial protocol, informed consent, investigator's manual, subject recruitment 
materials or advertising and other regulatory requirements. Documents must be 
submitted to the appropriate EC for approval. Prior to the start of the study, written 
approval from the Research Center EC must be obtained and provided to the sponsor. 
The EC's approval must specify the name, serial number, version number and version 
number of the other study (e.g. informed consent) and the date of approval. The 


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investigator is required to notify the sponsor of the EC's written comments regarding 
delays, suspensions, and re-approval. 
The research center must follow the requirements of the Center's EC. It may include 
revision of the program, revision of the informed consent form, revision of the subject's 
recruitment materials, submission of the EC for approval, local safety report 
requirements, regular reporting and update in accordance with EC regulations, and 
submission of the final report. All the above documents and EC approvals must be 
provided to the sponsor or its designee. 
Ethics of the study 
Access to the research process and informed consent is subject to the Helsinki 
Declaration, relevant GCP requirements, and laws and regulations related to drug and 
data protection in China. 
GCP provides ethical, scientific, global quality standards for the design, 
implementation, documentation, and reporting of clinical studies involving human 
subjects. This study will be conducted in accordance with the GCP and relevant national 
regulations and in accordance with the relevant ethical principles of the Helsinki 
Declaration to protect the rights, safety and health of the subjects. 
The researcher is required to follow the procedures specified in this protocol and may 
not change it without the permission of the sponsor. Any program violation will be 
reported to the EC, the sponsor, or the regulatory body. 
Subject Information and Informed Consent 
Before the start of any research process, informed consent (ICF) is used to explain the 
risks and benefits of this study to potential participants, and the language of informed 
consent should be straightforward. The ICF statement should make it clear that 
informed consent is voluntary and clearly identifies the risks and benefits of 
participating in the study, and the subject may withdraw from the study at any time. The 
investigator can only enroll the subject if he or she fully explains the details of the study, 
the subject's question is satisfactorily answered, and sufficient time is given for 
consideration and the written consent of the subject or his legal representative is 
obtained. All signed informed consent must be in the investigator's document or in the 
subject's folder. 
The investigator is responsible for interpreting the informed consent of the subject and 


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obtaining informed and dated informed consent from the subject or his or her legal 
representative prior to the start of the study. After signing, the investigator should send 
the subject a copy of the signed informed consent form. The investigator is required to 
document the process of informed consent in the original test document. 
Subject Data Protection 
ICF will contain (or in some cases, together with separate files) information about data 
protection and privacy protection. 
Take precautions to ensure the confidentiality of the documents and prevent the 
identification of the subject. However, under special circumstances, some people may 
see the genetic data and personal identification number of a subject. For example, in 
the event of a medical emergency, the sponsor, his representative doctor, or the 
researcher knows the subject identification code and has access to the subject's genetic 
data. In addition, relevant regulatory agencies require access to relevant documents. 
11 Research Management 
Data Processing and Record Saving 
The documents in the clinical trial (plan and program revision, completed eCRF, signed 
ICF, etc.) are to be preserved and managed as required by the GCP. The research center 
should keep these documents for 5 years after the end of the study. 
Study documents should be reasonably preserved for future visits or data traceability. 
Security and environmental risks should be considered when saving files. 
No research documents may be destroyed without the written permission of the sponsor 
and the researcher. The investigator/research center may transfer the research 
documents to other parties who comply with the document retention requirements or 
transfer to other locations that meet the requirements only after notifying the sponsor 
and obtaining their written consent. 
Raw Data / File Access Rights 
The investigator agrees that the sponsor, CRO, and relevant authorized regulatory 
agencies have direct access to all research-related documents, including subject medical 
records. 
Program revision 
Any possible revisions to the program during the course of the study will be 


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communicated and agreed by the sponsor and the investigator. The sponsor should 
ensure that the program revision is submitted to the regulatory body in a timely manner. 
All revisions to the programme should be maintained as a supplement to the programme. 
Any changes to the program must be submitted to the Ethics Committee for approval 
or filing in accordance with the ethics committee's rules. If necessary, it should also be 
submitted to the regulatory authority for approval and approved by the EC and 
regulatory authorities (if required) (except for changes to the program to eliminate 
direct hazards to the test subjects). 
Researcher Responsibilities 
The researcher will follow the program, the ethical principles of the Helsinki 
Declaration, the Chinese GCP and the corresponding regulatory requirements for this 
study. 
The detailed responsibilities of the relevant researchers are listed in Chapter 5 
(Researcher's Responsibilities) of the Chinese GCP (Order No. 3). 
Publication Policy 
All data generated in this study are confidential information of the sponsor. The sponsor 
has the right to publish the research results. Information about sponsor and researcher 
publication policies will be described in the clinical trial protocol. 
All information about this trial (not limited to the following documents: program, 
researcher's manual) must be kept strictly confidential. Researchers must recognize that 
the scientific or medical information derived from this trial may be of commercial value 
to the sponsor. The researcher should keep the information and data related to this test 
confidential. If you want to publicly publish the information related to this test or the 
conclusions obtained from the test, you must consult with the sponsor in advance and 
obtain the written consent of the sponsor. In order to protect their rights and interests, 
the sponsor may require the researcher not to publish information about the trial before 
the trial product is approved for marketing. 
The sponsor has the right to publish or publish information or data related to the trial 
or to report it to the drug administration. If the sponsor needs to have the name of the 
researcher in the publication, publication or advertising content, the researcher's 
consent should be obtained. 


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Finance and Insurance 
The sponsor will purchase insurance for the participants in the study in accordance with 
local regulations and minimum requirements. Insurance related terms will be saved in 
the research folder. 
 
 
 


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