Clinical trial NCT03116152
Conditions: Esophageal Squamous Cell Carcinoma
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2017-05-10; Completion date: 2019-10-02
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Efficacy and safety evaluation of IBI308 versus paclitaxel/irinotecan in patients with advanced/metastatic esophageal squamous cell carcinoma after failure of first-line treatment: a randomized, open-label, multicenter, phase 2 study

Detailed description:
Efficacy and safety evaluation of IBI308 versus paclitaxel/irinotecan in patients with advanced/metastatic esophageal squamous cell carcinoma after failure of first-line treatment: a randomized, open-label, multicenter, phase 2 study (ORIENT-2)

Arms: arm 1: IBI308 200mg Intravenous drip every three weeks arm 2: paclitaxel 175mg/㎡ Intravenous drip every three weeks； irinotecan 180mg/㎡ Intravenous drip every two weeks
Interventions: intervention 1: IBI308 intervention 2: paclitaxel/ irinotecan
Intervention descriptions: intervention 1: IBI308 200mg Intravenous drip every three weeks； intervention 2: paclitaxel 175mg/㎡ Intravenous drip every three weeks or irinotecan 180mg/㎡ Intravenous drip every two weeks

Protocol documents:
Prot_SAP_000.pdf: 
Investigational product: IBI308 
Innovent Biologics (Suzhou) Co., Ltd 
CIBI308A201 
May 19, 2019, Version 2.1 
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Clinical Study Protocol 
Study title: 
A Randomized, Open-label, Multi-center, Phase II Study 
to Evaluate the Efficacy and Safety of IBI308 versus 
Paclitaxel 
or 
Irinotecan 
in 
Patients 
with 
Advanced/Metastatic 
Esophageal 
Squamous 
Cell 
Carcinoma 
After 
Failure of First-line Treatment 
(ORIENT-2) 
Protocol ID: 
CIBI308A201 
Version Number and 
Date: 
May 19, 2019/Version 2.1 
Product name: 
IBI308 
Phase of study: 
Phase II 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd 
168 Dongping Street, Suzhou Industrial Park, Jiangsu 
Province, China 
Sponsor’s Contact: 
WANG Yan, Senior Medical Director 
+ 86 021-31652896 
hui.zhou@innoventbio.com 
 
Confidentiality Statement 
This document contains confidential information of Innovent Biologics (Suzhou) Co., Ltd. 
The contents of this document may not be disclosed to any persons other than the investigator 
(s), study advisor (s) or related personnel, Institutional Review Board/Independent Ethics 
Committee. 
The information contained herein may not be used for any purpose other than the evaluation or 
conduct of this clinical study without prior written approval of the sponsor. 
 
 




Investigational product: IBI308 
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Synopsis 
Protocol ID 
CIBI308A201 
Sponsor 
Innovent Biologics (Suzhou) Co., Ltd 
Investigational 
Product 
IBI308 
Active 
Ingredient 
Recombinant fully human anti-programmed cell death receptor 1 (PD-1) 
monoclonal antibody 
Study Title  
A Randomized, Open-label, Multi-center, Phase II Study to Evaluate the 
Efficacy and Safety of IBI308 versus Paclitaxel or Irinotecan in Patients with 
Advanced/Metastatic Esophageal Squamous Cell Carcinoma After Failure of 
First-line Treatment (ORIENT-2) 
Phase 
II 
Estimated 
Duration of 
Study  
27 months estimated 
Study 
Objectives 
Primary objective: 
 To evaluate the overall survival (OS) for IBI308 versus Paclitaxel or 
Irinotecan in patients with advanced/metastatic esophageal 
squamous cell carcinoma after failure of first-line treatment. 
Secondary objectives: 
 To evaluate progression-free survival (PFS), objective response rate 
(ORR), disease control rate (DCR) and duration of response (DoR) 
for IBI308 versus Paclitaxel or Irinotecan in patients with 
advanced/metastatic esophageal squamous cell carcinoma after 
failure of first-line treatment; 
 To evaluate the safety of IBI308 versus Paclitaxel or Irinotecan in 
patients with advanced/metastatic esophageal squamous cell 
carcinoma after failure of first-line treatment; 
 To evaluate the quality of life (QoL) for IBI308 versus Paclitaxel or 
Irinotecan in patients with advanced/metastatic esophageal 
squamous cell carcinoma after failure of first-line treatment. 
Exploratory objectives: 


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 
To evaluate the relationship between PD-L1 expression / immune-
related gene mRNA expression and efficacy in patients with 
advanced/metastatic esophageal squamous cell carcinoma. 
 
To evaluate the relationship between the dynamic expression of 
PD-L1 on the surface of circulating tumor cells (CTCs) / ctDNA 
results and efficacy in the IBI308 group. 
 
To explore the iPFS, iORR, iDCR and iDoR assessed per Immune-
modified Response Evaluation Criteria in Solid Tumors 
(iRECIST) in the IBI308 group. 
Study Design 
This is a randomized, open-label, multi-center, phase II study designed to 
evaluate the efficacy and safety of IBI308 versus paclitaxel or irinotecan in 
patients with advanced/metastatic esophageal squamous cell carcinoma after 
failure of first-line treatment. It is planned to enroll about 180 subjects with 
advanced/metastatic esophageal squamous cell carcinoma after failure of first-
line treatment, and the subjects will be randomized using central 
randomization stratified by Eastern Cooperative Oncology Group 
performance status (ECOG PS) score of 0 or 1. 
Subjects in this study will be randomized into an IBI308 group or single-agent 
chemotherapy group in a 1:1 ratio. The IBI308 group will be administered 
with IBI308 200 mg IV Q3W, until disease progression, death, intolerable 
toxicity, withdrawal of consent, or occurrence of other protocol-specified 
situations. For a subject who experienced disease progression initially, if the 
subject is clinically stable, the decision is left to the discretion of the 
investigator as to whether IBI308 treatment should be continued or not (see 
5.1.2 for details). The treatment regimen for the chemotherapy group, 
determined by the investigator based on prior first-line regimen, is Paclitaxel 
175 mg/m2 IV Q3W or Irinotecan 180 mg/m2 IV Q2W, until disease 
progression, death, intolerable toxicity, withdrawal of consent, or occurrence 
of other protocol-specified situations. In this study, Response Evaluation 
Criteria in Solid Tumors 1.1 (RECIST v1.1) is used for response assessment 
and iRECIST is adopted as the exploratory response assessment criteria. 
After discontinuation of study treatment, the subjects will be followed for 
safety and survival (every 60 days). 
The primary endpoint of this study is OS, defined as the time from 
randomization to the date of death, and subjects who did not die will be 
censored at the most recent known date of survival. 
Inclusion 
Criteria 
1. 
Histologically or cytologically confirmed locally advanced unresectable 
or metastatic esophageal squamous cell carcinoma (excluding mixed 
adenosquamous carcinoma and other pathological types). 


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2. 
Imaging evidence (e.g. CT scan) or clinical evidence (e.g. cytological 
report of new ascites or pleural effusion) of disease progression during 
or after first-line chemotherapy; Subjects have to receive at least one dose 
of first-line treatment, permitting discontinuation or dose reduction of 
one drug or exchange of fluorouracil drugs used during first-line 
treatment, and patients discontinuing first-line treatment due to 
intolerable toxicity are allowed to be enrolled; Neoadjuvant or adjuvant 
therapy (chemotherapy or chemo-radiotherapy) should be regarded as 
first-line treatment if there is disease progression during treatment or 
within 6 months after treatment discontinuation. 
3. 
At least one measurable lesion according to RECIST v1.1. 
4. 
ECOG PS score of 0 or 1. 
5. 
Subjects who have signed the written informed consent form and are able 
to follow the visit schedule and relevant procedures as specified in the 
study protocol. 
6. 
Age ≥ 18 and ≤ 75 years. 
7. 
Life expectancy ≥ 12 weeks. 
8. 
Female subjects of childbearing potential or male subjects with sexual 
partners of childbearing potential should use effective contraception 
throughout and within 6 months after treatment (see Section 4.3). 
9. 
Adequate organ and bone marrow functions, defined as follows: 
1) 
Hematology: absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet 
(PLT) count ≥ 100×109/L; Hemoglobin (HGB) ≥ 9.0 g/dL. 
2) 
Liver function: serum total bilirubin (TBIL) ≤ 1.5×upper limit of normal 
(ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤2.5×ULN; Serum albumin ≥ 28 g/L. 
3) 
Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine 
clearance (Ccr) ≥ 40 mL/min (calculated using the standard Cockcroft -
Gault formula): 
Females: CrCl = (140-age) x body weight (kg) x 0.85 
72 x serum creatinine (mg/dL) 
Males: CrCl = (140-age) x body weight (kg) x 1.00 
72 x serum creatinine (mg/dL) 
Exclusion 
Criteria 
1. 
Prior exposure to any anti-PD-1 or anti-PD-L1 antibody. 
2. 
Concurrent participation in another interventional clinical study, except 
for observational (non-interventional) clinical studies or in the follow-up 
phase of an interventional study. 


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3. 
Receipt of any investigational products within 4 weeks prior to the first 
dose of study treatment. 
4. 
Receipt of the last dose of anti-tumor therapy (chemotherapy, targeted 
therapy, tumor immunotherapy, tumor embolization) within 3 weeks 
prior to the first dose of study treatment. 
5. 
Radiotherapy within 4 weeks prior to the first dose of study treatment. 
6. 
Receipt of immunosuppressive agents within 4 weeks prior to the first 
dose of study treatment, excluding topical glucocorticoids for intranasal, 
inhalation or other routes of administration, or physiological doses of 
systemic glucocorticoids (i.e., no more than 10 mg/day prednisone or 
equivalent doses of other glucocorticoids). 
7. 
Receipt of a live attenuated vaccine within 4 weeks prior to the first dose 
of study treatment or planned receipt of a live attenuated vaccine during 
the study. 
8. 
Subjects who have undergone major surgical procedures (craniotomy, 
thoracotomy or laparotomy) within 4 weeks prior to the first dose of 
study treatment or have unhealed wound, ulcers or bone fracture. 
9. 
Presence of toxicities induced by previous anti-tumor therapy that have 
not recovered to Grade 0 or 1 as assessed per NCI CTCAE 4.03 (National 
Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.03) prior to the first dose of study treatment, excluding 
alopecia, and non-clinically significant and asymptomatic laboratory 
abnormalities. 
10. Known symptomatic metastases to central nervous system (CNS) and/or 
carcinomatous meningitis. Subjects previously treated for brain 
metastasis are eligible for the study provided the brain metastasis has 
remained stable for at least 4 weeks before first dose of study treatment; 
Neurological symptoms must be recovered to grade 0 or 1 as per NCI 
CTCAE version 4.03. 
11. Active, known or suspected autoimmune diseases (refer to Appendix 6) 
or a history of such disease in the past 2 years (patients with vitiligo, 
psoriasis, alopecia or Grave's disease requiring no systemic treatment in 
the past 2 years, patients with hypothyroidism requiring only thyroid 
hormone replacement therapy and patients with type I diabetes requiring 
only insulin replacement therapy can be enrolled). 
12. Known history of primary immunodeficiency. 
13. Known active tuberculosis (TB). 


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14. Known history of allotransplantation and allogeneic hematopoietic stem 
cell transplantation. 
15. Known hypersensitivity to any component of the monoclonal antibody, 
paclitaxel or irinotecan formulation. 
16. Uncontrolled concurrent diseases, including but not limited to: 
 
HIV infection (HIV antibody positive). 
 
Active or clinically uncontrolled severe infections. 
 
Symptomatic congestive heart failure (New York Heart 
Association Class II-IV) or symptomatic or poorly controlled 
arrhythmia. 
 
Uncontrolled arterial hypertension (systolic blood pressure ≥ 
160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite 
standard treatment. 
 
Any arterial thromboembolism events within 6 months prior to 
inclusion for treatment, including myocardial infarction, 
unstable angina, cerebrovascular accident or transient ischemic 
attacks. 
 
Significant malnutrition, if intravenous nutrient solution 
supplement is required; Except for malnutrition corrected for 
more than 4 weeks before first dose of study treatment. 
 
Tumor invasion into surrounding vital organs (e.g., aorta and 
trachea) or a risk for esophagotracheal fistula or esophagopleural 
fistula. 
 
Post esophageal or intratracheal stenting. 
 
History of deep vein thrombosis (DVT), pulmonary embolism, 
or any other serious thromboembolism within 3 months prior to 
enrollment (implanted venous access port or catheter-related 
thrombosis, or superficial venous thrombosis is not considered 
as "serious"thromboembolism). 
 
Uncontrolled metabolic disorders or other non-malignant 
organic or systemic diseases or reactions secondary to cancer, 
which can result in high medical risks and/or uncertainty in 
survival evaluations. 
 
Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh 
class B or even more severe cirrhosis. 
 
History of intestinal obstruction or the following diseases: 
inflammatory bowel disease or extensive bowel resection 


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(partial colectomy or extensive resection of the small intestine, 
concurrent chronic diarrhea), Crohn's disease, ulcerative colitis, 
or chronic diarrhea. 
 
Other acute or chronic diseases, mental disorders or abnormal 
laboratory findings that may lead to the following results: 
increase risks associated with study participation in the study or 
use of the study drug, or interfere with the interpretation of study 
results, and render the patient ineligible for the study at the 
investigator’s discretion. 
17. Known acute or chronic active hepatitis B (HBsAg positive and HBV 
DNA ≥200 IU/mL or ≥ 103 copies/mL) or acute or chronic active 
hepatitis C (HCV antibody positive and positive for HCV RNA test). 
18. History of gastrointestinal perforation and/or fistula within 6 months 
prior to study inclusion. 
19. Presence of interstitial lung disease. 
20. Clinically uncontrollable effusion of the third space, such as pleural 
effusion and ascites that can not be controlled by drainage or other 
methods before enrollment. 
21. History of other primary malignancies, excluding: 
 
A malignancy with complete remission for at least 2 years before 
enrollment and requiring no other treatment during the study; 
 
Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of relapse; 
 
Adequately treated carcinoma in situ without evidence of 
relapse. 
22. Pregnant or breastfeeding women. 
Study Drugs, 
Strength and 
Route of 
Administration 
 
IBI308 
- 
Strength: 10 ml: 100 mg 
- 
Route of administration: 200 mg IV Q3W 
 
Paclitaxel 
- 
Strength: 16.7 ml: 100 mg or 5 ml: 30 mg 
- 
Route of administration: 175 mg/m2 IV Q3W  
 
Irinotecan  
- 
Strength: 2 ml: 40 mg or 5 ml: 0.1g 


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- 
Route of administration: 180 mg/m2 IV Q2W 
Evaluation 
Criteria 
Efficacy evaluation: 
 
To evaluate OS, 6-month overall survival rate, PFS, ORR, DCR and 
DoR after treatment. 
Safety Evaluation: 
 
The incidences and severity of all adverse events (AE), treatment-
emergent adverse events (TEAE), adverse events of special 
interest (AESI) and serious adverse events (SAE), as well as their 
relationship to the investigational product. 
 
Changes in vital signs, physical examination findings, and 
laboratory results before, during, and after study treatment. 
Immunogenicity evaluation (IBI308 group only): 
 
Perform testing for anti-drug antibody (ADA) and neutralizing 
antibody (NAb). 
Biomarker evaluation: 
 
Tumor tissue samples were collected for analysis of tumor 
biomarkers, including but not limited to the expression of PD-L1 
and the expression of immune-related genes (including but not 
limited to the expression of IDO1, CXCL9, CXCL10, HLA-DRA, 
STAT1, IFNG messenger RNA). 
 
For subjects treated with IBI308, blood samples will be collected 
for analysis of circulating tumor cells (CTCs) (including but not 
limited to PD-L1 dynamic expression) and ctDNA analysis. 
Quality of life (QoL) assessment: 
 
To assess quality of life (QoL) and health status for the subjects 
treated with IBI308 and chemotherapy respectively as measured by 
the EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-OES18. 
Statistical 
Methods 
Estimation of sample size: 
Since this study is a phase II clinical study with overall survival (OS) as the 
primary measure, assuming a two-sided  level of 0.2, power of 80% and a 
hazard ratio (HR) of 0.7 for the IBI308 group compared with the 
chemotherapy group, a number of 142 subjects with OS events is required. 
Further, presuming 21% of the patients are censored, an estimated number of 
180 subjects will be enrolled, with about 90 subjects in the IBI308 and 
chemotherapy groups each, respectively (35 sites, with 0.7 subjects enrolled 
per month in every site, the expected duration of this study is 27 months). 


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Considering a possible delay of OS benefit with the anti-tumor therapy and 
based on an estimated median OS of approximately 8.7 months for IBI308, it 
should be ensured that the subjects have been followed up for about 10 months 
(from randomization) by the time of OS analysis. 
Hypothesis test: 
H0: HR≥1; H1: HR<1;  = 0.2 (two-sided) for analysis of the primary efficacy 
endpoint, stratified log-rank test for OS for the IBI308 group compared with 
the chemotherapy group. 
Primary efficacy endpoints: 
Overall survival (OS); Kaplan-Meier estimator will be used to estimate the 
median survival and its 95% CI, survival curves will be plotted, and stratified 
Log-Rank test will be utilized for comparison between groups. In addition, 
stratified Cox proportional-hazards model will be employed for estimating 
HRs and their 95% CIs. The 6-month and 1-year survival rates will be 
estimated using Kaplan-Meier method. Meanwhile, the comparison of OS 
between groups will be performed by the RMST method. 
Secondary efficacy endpoints: 
Survival data: analyses of PFS and DoR will be performed using the same 
method as OS analysis. 
For analyses of ORR and DCR, Fisher's exact test will be used for inter-group 
comparison. 
Safety data: 
The incidence and severity of adverse events were summarized by group, and 
abnormal changes in laboratory test indicators were described. 
Immunogenicity data: 
The positive rates of anti-drug antibody (ADA) and neutralizing antibody 
were summarized 
Quality of life (QoL): 
Variations of QoL scale scores as assessed per EQ 5D-5L, EORTC QLQ-C30 
and EORTC QLQ-OES18 will be described by group and visit, so as to 
evaluate the QoL and health status of the subjects treated by IBI308 and 
chemotherapy, respectively. 
Biomarkers: 
The results and distribution of PD-L1 expression and immune-related gene 
expression were summarized descriptively, and the potential relationship 
between the above indicators and efficacy was investigated. 


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Table 1. Visit Schedule 
Period 
Screening 
Period 
Treatment period 
Safety follow-up19 
Survival follow-
up20 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
thereafter 
Visit 
1 
2 
3 
4 
5 ~ N 
First 
Second 
Day 
-28~-1 
1 
22 (±3 days) 
43 (± 3 days) 
Every 3 weeks (± 
3 days) 
Day 30 (± 7 days) 
after treatment 
discontinuation 
visit or  
the last dose 
Day 90 (± 7 
days) after 
the last dose 
Every 60 days (± 
7 days) 
General Study Procedures 
 
Written ICF1 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics/past medical 
history/ 
past medications2 
X 
 
 
 
 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
 
Body weight/height4 
X 
X 
X 
X 
X 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
 
ECOG PS score 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG5 
X 
 
 
X 
X 
X 
X 
 
Hematology/blood 
biochemistry/urinalysis6 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test7 
X 
 
 
 
 
X 
 
 


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Period 
Screening 
Period 
Treatment period 
Safety follow-up19 
Survival follow-
up20 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
thereafter 
Visit 
1 
2 
3 
4 
5 ~ N 
First 
Second 
Day 
-28~-1 
1 
22 (±3 days) 
43 (± 3 days) 
Every 3 weeks (± 
3 days) 
Day 30 (± 7 days) 
after treatment 
discontinuation 
visit or  
the last dose 
Day 90 (± 7 
days) after 
the last dose 
Every 60 days (± 
7 days) 
Thyroid function8 
X 
 
X 
X 
X 
X 
 
 
Immunogenicity9 
 
X 
X 
 
X 
 
X 
 
HIV, HBV and HCV10 
X 
 
 
 
 
 
 
 
AE assessment11 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
Survival status 
 
 
Subsequent anti-tumor 
treatment 
 
 
 
 
 
X 
X 
X 
Efficacy Evaluation 
 
Radiologic evaluation of 
tumor12 
X 
 
 
X 
X 
 
 
 
Randomization 
 
IWRS13 
 
X 
 
 
 
 
 
 
Study Drug Infusion 
 
IBI308 group: IBI30814 
 
X 
X 
X 
X 
 
 
 
Chemotherapy group: 
Paclitaxel or irinotecan15 
 
X 
X 
X 
X 
 
 
 


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Period 
Screening 
Period 
Treatment period 
Safety follow-up19 
Survival follow-
up20 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
thereafter 
Visit 
1 
2 
3 
4 
5 ~ N 
First 
Second 
Day 
-28~-1 
1 
22 (±3 days) 
43 (± 3 days) 
Every 3 weeks (± 
3 days) 
Day 30 (± 7 days) 
after treatment 
discontinuation 
visit or  
the last dose 
Day 90 (± 7 
days) after 
the last dose 
Every 60 days (± 
7 days) 
QoL Assessment16 
 
EQ 5D-5L/ 
EORTC QLQ-C30/ 
EORTC QLQ-OES18 
questionnaires 
 
X 
 
X 
X 
X 
 
 
Biomarker Evaluation 
 
Archived or fresh 
tumor tissue samples17 
X 
 
 
 
 
 
 
 
Blood samples18 
 
X 
 
X 
X 
 
 
 
Remarks: 
1. 
The signing of the ICF should precede any protocol-specified procedures. 
2. 
Past medication includes treatments for initial diagnosis, including chemotherapy, radiotherapy and surgical treatment. 
3. 
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. 
4. 
Height and weight measurements are only performed during the screening period. 
5. 
12-lead ECG is performed at the following time points: during screening period, prior to administration of study drug every 2 cycles (excluding Cycle 1) and at safety follow-up. 
6. 
Hematology includes: red blood cell count (RBC), HGB, white blood cell count (WBC), PLT, WBC differential [lymphocyte count (LYM), ANC]. Blood biochemistry includes: liver 
function [TBIL, ALT, AST, gamma-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), lactate dehydrogenase (LDH)], renal function [blood urea 


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nitrogen (BUN), Cr], blood electrolytes (Na, K, Cl, Mg, Ca, P), lipase, amylase and fasting blood glucose (FBG). Urinalysis includes pH, urine albumin (UALB), urine protein (UPRO), 
urine red blood cell (URBC) and urine glucose (UGLU). Hematology, blood biochemistry and urinalysis are performed during the screening period, within 7 days before each dose and at 
safety follow-up. The test will be performed at various sites. 
7. 
For women of child-bearing potential, urine or serum pregnancy test will be performed within 3 days prior to the first dose and at the first safety follow-up visit. If negative cannot be 
confirmed with the result of urine pregnancy test, serum pregnancy test is required and the result of serum pregnancy test should prevail. The test will be performed at various sites. 
8. 
This test will be performed at screening, within 3 days prior to administration of study drug in each cycle since Cycle 2, and at the first safety follow-up visit. During the screening period, 
the test will cover thyroid stimulating hormone (TSH), triiodothyronine (T3), tetraiodothyronine (T4), free triiodothyronine (FT3) and free tetraiodothyronine (FT4). Only TSH will be 
examined since Cycle 2, and if any abnormalities, examination of other thyroid function parameters will be considered. The test will be performed at various sites. Thyroid function test 
will be performed for all subjects during the screening period. However, test results not older than 28 days prior to randomization at the site are acceptable, and thyroid function test is only 
limited to the IBI308 group since Cycle 2. 
9. 
Immunogenicity test will be performed only for the IBI308 group, within 1 hour before IBI308 infusion in Cycle 1, Cycle 2, Cycle 4 and then every 4 cycles (Cycles 8, 12, 16 and so on), 
and at the 2nd safety follow-up visit. The test will be performed at the central laboratory. 
10. Hepatitis B testing (HBsAg, HBsAb, HBcAb, HBeAg and HBeAb), and HCV antibody/HIV antibody test are performed during the screening period. If HBsAg test reports positive, HBV 
DNA test will be further performed. If HCV antibody test reports positive, HCV RNA test will be further performed. Test results not older than 28 days prior to randomization at the site 
are acceptable. For hepatitis B virus carriers, it is recommended to provide subjects randomized to chemotherapy with prophylactic antiviral therapy in reference to the guidelines and to 
monitor viral activity regularly during the study. The test will be performed at various sites. 
11. AE assessment and evaluation of laboratory findings will be performed according to NCI CTCAE 4.03. The definitions, documentation, relationship judgment, severity judgment, 
reporting time-line and handling of AEs and SAEs are subject to description in Section 7 of the protocol. 
12. Tumor assessment includes evaluation per RECIST v1.1 and evaluation per iRECIST. For the same subject, the imaging technique used should remain unchanged throughout this study. 
Baseline assessment will be performed within 28 days prior to enrollment, and the investigators may collect imaging results not older than 28 days prior to enrollment for assessment. 
Tumor imaging evaluation will be performed every 6 weeks (± 7 days) in the first 24 weeks following the first dose of study drug, and then every 9 weeks (± 7 days) after Week 24, until 
initiation of new anti-tumor treatment, disease progression, withdrawal of ICF, or death. For subjects treated by IBI308 who developed disease progression initially, radiographic 
confirmation needs to be performed intervals of 4~6 weeks. If the patient is clinically stable, the decision is left to the discretion of the investigator as to whether IBI308 treatment should 
be continued or not (see 5.1.2). For subjects who continue treatment beyond disease progression, radiologic evaluation should be continued. For patients who discontinued treatment for 
reasons other than radiographic disease progression, imaging evaluations should, wherever possible, be performed every 6 weeks (± 7 days) after discontinuation, until occurrence of any 


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of the following: initiation of new anti-tumor therapy, disease progression, withdrawal of ICF, and death. For subjects treated by IBI308 who have a disease progression as assessed per 
RECIST v1.1, radiologic evaluation should be continued as per iRECIST assessment requirements and the frequency of follow-up, wherever possible. 
13. Eligible subjects will be randomized into the IBI308 or chemotherapy group in a 1:1 ratio prior to the first dose in the treatment period, stratified by ECOG PS score (0 or 1). 
14. IBI308 200 mg, administered via intravenous infusion every 3 weeks (Q3W), until disease progression, death, intolerable toxicity, withdrawal of consent, or occurrence of other 
protocol-specified situations. Some subjects meeting specific conditions can continue treatment beyond disease progression (refer to Section 5.1.2 in the protocol). Cycle 1/Day 1 dosing 
must occur within 3 working days of randomization. 
15. Paclitaxel 175 mg/m2 IV Q3W or Irinotecan 180 mg/m2 IV Q2W, until disease progression, death, intolerable toxicity, withdrawal of consent, or occurrence of other protocol-specified 
situations. Cycle 1/Day 1 dosing must occur within 3 working days of randomization. 
16. QoL assessment: will be performed using EQ 5D-5L, EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires on the day of the first dose, and at each radiographic evaluation and 
the first safety follow-up visit. 
17. Subjects are required to provide archived or fresh tumor tissue samples meeting the testing requirements at the time of screening for PD-L1 and immune-related gene mRNA assays. 
18. Subjects need to provide 10 ml of whole blood specimen at the following time points: prior to the first dose, and before each efficacy evaluation prior to start of the next treatment. Only 
for the IBI308 group. 
19. Two safety follow-ups will be performed. The first takes place at the treatment discontinuation visit or on Day 30 (± 7 days) after the last dose, and the second on Day 90 (± 7 days) after 
the last dose. 
20. Survival follow-up: takes place every 60 days (± 7 days) after safety follow-up, and telephone follow-up is acceptable.


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Table of Contents 
Synopsis ............................................................................................................................................ 3 
Table of Contents ............................................................................................................................ 16 
LIST OF TABLES .......................................................................................................................... 18 
LIST OF FIGURES ........................................................................................................................ 19 
Abbreviations and Definitions of Terms ......................................................................................... 20 
1 Study Background ........................................................................................................................ 23 
 Disease Background .............................................................................................................. 23 
 Study Drug (IBI308) ............................................................................................................. 26 
 Risk/Benefit Assessment ....................................................................................................... 28 
2 Study Objectives .......................................................................................................................... 29 
 Primary Objective ................................................................................................................. 29 
 Secondary Objectives ............................................................................................................ 29 
 Exploratory Objectives ......................................................................................................... 29 
3 Overall Study Design ................................................................................................................... 29 
 Overall Design ...................................................................................................................... 29 
 Design Rationale ................................................................................................................... 31 
4 Study Population .......................................................................................................................... 33 
 Inclusion Criteria................................................................................................................... 33 
 Exclusion Criteria ................................................................................................................. 35 
 Restrictions throughout Study ............................................................................................... 38 
 Discontinuation of Treatment/Withdrawal of Subjects from Study ...................................... 39 
5 Study Drug and Other Treatments ............................................................................................... 40 
 Treatment Regimen ............................................................................................................... 40 
 Study Drug (IBI308) ............................................................................................................. 42 
 Study drug (paclitaxel and irinotecan) .................................................................................. 43 
 Dose Adjustments ................................................................................................................. 44 
 Principles for Management of Toxicities Associated with Immune Checkpoint Inhibitors .. 48 
 Concomitant Treatment ......................................................................................................... 49 
 Treatment Compliance .......................................................................................................... 52 
 Drug Recovery and Destruction ............................................................................................ 52 
 Documentation of Study Drug .............................................................................................. 52 
 Handling of Complaints ...................................................................................................... 52 
6 Study Evaluations and Procedures ............................................................................................... 53 
 Subject Enrollment and Randomization Process .................................................................. 53 
 Study Plan and Schedule ....................................................................................................... 54 
 Efficacy Evaluation ............................................................................................................... 57 
 Safety Assessment ................................................................................................................. 58 
 Immunogenicity .................................................................................................................... 60 
 Quality of Life Assessments.................................................................................................. 60 
 Biomarker Analysis ............................................................................................................... 61 
 Storage and Destruction of Biological Samples .................................................................... 61 
7 Safety Report and AE Management ............................................................................................. 61 
 Definition of Adverse Events ................................................................................................ 61 


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 Definition of Serious Adverse Events ................................................................................... 62 
 Criteria for AEs Severity Judgment ...................................................................................... 63 
 Judgment on Correlation between AEs and Study Drug ....................................................... 63 
 Recording of AEs .................................................................................................................. 64 
 Expedited reporting of SAEs and pregnancies ...................................................................... 68 
 Liver function abnormality events ........................................................................................ 70 
 Management of drug related toxicities .................................................................................. 71 
8 Statistical Considerations ............................................................................................................. 71 
 Statistical Analysis Plan ........................................................................................................ 71 
 Hypothesis Test ..................................................................................................................... 71 
 Statistical Analysis Population .............................................................................................. 72 
 Statistical Analysis Methods ................................................................................................. 72 
 Sample Size Determination ................................................................................................... 77 
 Measures for Bias Control .................................................................................................... 77 
9 Quality Assurance and Quality Control ....................................................................................... 78 
 Clinical Monitoring ............................................................................................................... 78 
 Data Management/Coding .................................................................................................... 78 
 Quality Assurance Audit ....................................................................................................... 80 
10 Ethics.......................................................................................................................................... 80 
 Ethics Committee ................................................................................................................ 80 
 Ethics of the Study .............................................................................................................. 81 
 Subject Information and Informed Consent ........................................................................ 81 
 Protection of Subject Data .................................................................................................. 82 
11 Study Management .................................................................................................................... 82 
 Data Processing and Record Preservation ........................................................................... 82 
 Access to Source Data/Documents ...................................................................................... 83 
 Protocol Modification ......................................................................................................... 83 
 Investigator’s Responsibilities ............................................................................................ 83 
 Publication Policy ............................................................................................................... 83 
 Finance and Insurance ......................................................................................................... 84 
12 REFERENCES .......................................................................................................................... 85 
13 Appendix .................................................................................................................................... 87 
Appendix 1: Investigator Signature Page ........................................................................................ 87 
Appendix 2: ECOG PS Scoring Criteria ......................................................................................... 88 
Appendix 3: Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) .............. 89 
Appendix 4: Response Evaluation Criteria in Immune Solid Tumors (iRECIST)........................ 100 
Appendix 5: Liver Function Abnormality Monitoring and Follow-up Report Form .................... 105 
Appendix 6: List of Autoimmune Diseases Present Before Inclusion .......................................... 107 
Appendix 7: IBI308 Dose Modification and Toxicity Management Guidelines .......................... 108 
 
 
 


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LIST OF TABLES 
Table 1. Visit Schedule .................................................................................................................... 11 
Table 2. Effective contraception methods (must use 2 methods) .................................................... 39 
Table 3. Dose and regimen .............................................................................................................. 40 
Table 4. Recommended pre-medication for chemotherapy ............................................................. 43 
Table 5. Dose adjustment scheme of IBI308 ................................................................................... 44 
Table 6. Recommended dose adjustment of irinotecan monotherapy ............................................. 48 
Table 7. Routine laboratory safety evaluations ............................................................................... 58 
Table 8. Judgment on correlation between AE and study drug ....................................................... 63 
Table 9. Contact information for SAE reporting ............................................................................. 68 
Table 10. Liver impairment that should be reported as SAE .......................................................... 70 
 


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LIST OF FIGURES 
Figure 1. Schematic diagram of study design and dosing regimen of CIBI308A201 
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Abbreviations and Definitions of Terms 
Abbreviation 
Full English 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALB 
Albumin 
ALP  
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST  
Aspartate aminotransferase 
AUC 
Drug exposure 
BUN 
Urea nitrogen 
CCr 
Creatinine clearance 
CI  
Confidence interval 
Cmax  
Observed maximum concentration 
Cr 
Serum creatinine 
CR  
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
CT  
Computed tomography 
CTC 
Circulating tumor cells 
CTCAE  
Common Terminology Criteria for Adverse Events 
ctDNA 
Tumor circulating deoxyribonucleic acid 
CTLA-4  
Cytotoxic T lymphocyte antigen-4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
ECG  
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire Core 30 
EORTC QLQ-OES18 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Esophageal Cancer 18 
EQ 5D-5L 
EuroQol Five Dimensions Questionnaire-5 Levels 
FAS 
Full analysis set 
FBG 
Fasting blood glucose 
FFPE  
Formalin-fixed paraffin-embedded 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP  
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 


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HCV 
Hepatitis C 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Signed informed consent 
ICH 
International Council for Harmonisation 
IgG 
Immunoglobulin G 
irAE  
Immune-related adverse event 
IRR 
Infusion-related reactions 
iRECIST  
Immune-Related Response Evaluation Criteria in Solid Tumors 
IV  
Intravenous infusion 
LDH 
Lactic dehydrogenase 
LYM 
Lymphocyte count 
MedDRA  
Medical Dictionary for Regulatory Activities 
mOS 
Median overall survival 
mPFS 
Median progression free survival 
MRI  
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NAb 
Neutralizing antibody 
NCI  
National Cancer Institute 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect level 
ORR  
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamic Properties 
PD-1  
Programmed death 1 
PD-L1  
Programmed death-ligand 1 
PFS  
Progression-free survival 
PH 
pH 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PLT 
Platelet count 
PR 
PR 
PVC 
Polyvinyl chloride 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
SAE 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SS 
Safety Analysis Set 
t½ 
Half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBIL 
Total bilirubin 


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TEAE 
Treatment-emergent adverse events 
TP 
Total protein 
TSH 
Thyroid-stimulating hormone 
UWBC 
White blood cells in urine 
UGLU 
Urine glucose 
ULN 
Upper limit of normal 
UPRO 
Urine protein 
URBC 
Urine red blood cell 
WBC 
White blood cell 
γ-GT 
Gamma-glutamyl transferase 
 
 
 


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1 Study Background 
Disease Background 
With the increase in human average life span and changes in lifestyle, malignant tumors 
have become the most important life-threatening disease that poses a serious threat to 
the health of Chinese people. Globally, esophageal cancer has the 8th highest incidence 
and the 6th highest mortality among malignancies, mostly in developing countries[1]. 
China has the greatest number of esophageal cancer cases in the world, with both 
incidence and mortality of esophageal cancer higher than the mean global levels. It is 
estimated that there were 4.29 million cases of new cancer in China, with 2.81 million 
cases of new cancer death in 2015[2]. Among all causes of cancer death, esophageal 
cancer has the 3rd and 4th highest incidence and mortality, with 0.478 million and 0.375 
million cases of morbidity and mortality, respectively[2]. Though there are certain 
advances in the treatment of esophageal cancer, there is still a huge unmet medical need. 
Esophageal cancer refers to malignancy of esophageal epithelial origin between 
hypopharynx and esophagogastric junction. In China, most esophageal cancer cases 
originate from upper and middle segments of esophagus, with the main pathology of 
squamous cell carcinoma, which accounts for approximately 90% in upper, middle and 
lower segments of esophagus, while adenocarcinoma accounts for less than 2%. There 
are great differences in primary sites and pathology of esophageal cancer between 
China and developed countries in Europe and America[3], indicating that clinical 
diagnosis and treatment of esophageal cancer should be explored based on actual 
situation in China. 
A surgery is the main treatment method for early- and - middle-stage esophageal cancer. 
However, there may be local relapse and/or metastasis after surgery, with poor overall 
prognosis. A study of clinical data from 1,510 patients with esophageal cancer 
surgically treated in Shanxi Tumor Hospital reported cumulative survival rates of 78%, 
38% and 30% at post-operative 1, 5 and 10 years, respectively, with a median survival 
time of 2.68 years. Prognosis is even worse for patients with locally advanced and 
advanced esophagus cancer. Mean survival time is less than 1 year for advanced 
patients[4]. 
Advanced esophageal cancer is rarely investigated in randomized controlled studies, 
and often investigated together with gastric cancer. First-line treatment is primarily 
platinum-based dual or triple chemotherapy[5-10]. In a randomized controlled phase 


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III clinical study (REAL-2) to evaluate the efficacy of capecitabine versus fluorouracil 
and oxaliplatin versus cisplatin in patients with advanced first-line gastric cancer and 
esophageal cancer, 1,002 patients were randomized at 1:1:1:1 ratio to 4 treatment 
groups of ECF (epirubicin + cisplatin + fluorouracil), ECX (epirubicin + cisplatin + 
capecitabine), EOF (epirubicin + oxaliplatin + fluorouracil) or EOX (epirubicin + 
oxaliplatin + capecitabine). Each treatment group included 30-40% esophageal cancer 
and approximately 10% squamous cell carcinoma. Median survival time was 9.9, 9.9, 
9.3 and 11.2 months in ECF, ECX, EOF and EOX treatment groups, respectively, and 
one-year survival rate was 37.7%, 40.8%, 40.4% and 46.8%, respectively[5]. In a 
randomized controlled phase III study (REAL-3) investigating EOX regimen versus 
EOX + panitumumab, panitumumab did not increase survival time. A total of 275 
subjects were enrolled in EOX treatment group, including 40% of subjects with 
esophageal cancer, and 99% of subjects with adenocarcinoma. Overall survival was 
11.3 months in EOX treatment group[6]. In a phase II clinical study to evaluate the 
efficacy of docetaxel plus cisplatin in first-line esophageal squamous cell carcinoma, 
39 subjects were enrolled, objective response rate was 33.33%, progression free time 
was 5 months and overall survival was 8.5 months[7]. In a single-arm phase II clinical 
study evaluating the efficacy of paclitaxel plus cisplatin and fluorouracil in advanced 
esophageal cancer, 61 subjects were enrolled, including 30 subjects with squamous cell 
carcinoma. ORR was 48% (48% for adenocarcinoma , 50% for squamous cell 
carcinoma) and OS was 10.8 months[8]. In a randomized controlled study to evaluate 
the efficacy cisplatin plus fluorouracil versus cisplatin plus fluorouracil and cetuximab 
in first-line esophageal squamous cell carcinoma, 30 subjects received cisplatin plus 
fluorouracil, resulting in objective response rate of 13%, disease control rate of 57%, 
PFS of 3.6 months and OS of 5.5 months[9]. In a single-arm study evaluating the 
efficacy of paclitaxel plus cisplatin in Chinese patients with first-line esophageal 
squamous cell carcinoma, 39 subjects were enrolled, objective response rate was 48.6%, 
and OS was 13 months[10]. 
There is no large-scale randomized controlled clinical study of second-line treatment 
for advanced esophageal cancer. Docetaxel[11, 12], paclitaxel[13] and irinotecan 
monotherapy[14-16] have demonstrated certain efficacy in several single-arm studies, 
and are commonly used as second-line treatment of esophageal cancer in clinical 
practice (recommended by NCCN guideline)[17]. In a single-arm clinical study to 
evaluate the efficacy of paclitaxel monotherapy in advanced esophageal cancer, 102 
subjects were enrolled, PR was 13%, duration of response was 172 days, and mean 


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survival time was 274 days[13]. In a study evaluating the efficacy of irinotecan 
monotherapy in patients with advanced esophageal cancer failing cisplatin-based 
chemotherapy, 14 patients were enrolled. Among 13 subjects evaluable for efficacy, 2 
subjects reached partial response, and 3 subjects remained stable disease. Median time 
to disease progression was 2 months, and overall survival was 5 months[14]. In a study 
evaluating the efficacy of irinotecan monotherapy in advanced gastric and esophageal 
cancer, 46 patients were enrolled, objective response rate was 14% and median survival 
time was 6.4 months[15]. In a study evaluating the efficacy of irinotecan monotherapy 
in patients with unresectable esophageal cancer, 13 subjects (10 subjects with squamous 
cell carcinoma and 3 subjects with adenocarcinoma) were enrolled, and 2 subjects 
reached partial response (1 with squamous cell carcinoma and 1 with adenocarcinoma). 
Median time to disease progression was 3.8 months, and median survival time was 6.1 
months[16]. 
Several studies reported the PD-L1 expression in esophageal cancer and the relationship 
between PD-L1 expression and prognosis of esophageal cancer, but study conclusions 
were inconsistent. In a case analysis including 288 cases of esophageal squamous cell 
carcinoma, PD-L1 positive rate was 50.7%. The PD-L1 expression and prognosis 
varied with tumor staging and status of lymph node metastasis. In patients with stage 
IV disease and patients without lymph node metastasis, PD-L1 expression was 
negatively correlated with disease free survival and overall survival, while there was 
no significant correlation in stage III-IV patients[18]. In another case study including 
162 cases of esophageal squamous cell carcinoma, PD-L1 positive rate was high in 
patients with stage IV disease, lymph node metastasis and local treatment failure. PD-
L1 positive patients had poor response to treatment and poor prognosis[19]. In a report 
including 41 cases of esophageal cancer, PD-L1 positive was associated with poor 
prognosis, with stronger association in cases at later disease stage[20]. PD-L1 
expression was variable in esophageal cancer. In a study comparing PD-L1 expression 
in tumor tissue before and after neoadjuvant therapy in 28 patients with esophageal 
cancer ( 19 patients for concurrent chemoradiotherapy,  9 patients for chemotherapy), 
PD-L1 expression in tumor tissue significantly increased after concurrent neoadjuvant 
chemoradiotherapy, but significantly decreased after neoadjuvant chemotherapy[21]. 
In a phase Ib clinical study (KEYNOTE-028) of Pembrolizumab in patients with 
advanced esophageal cancer (PD-L1 expression >1%) who had failed or were 
intolerable to at least one line of systemic treatment, ORR was 30% (95% CI, 13-
53)[22]. In a phase II clinical study of Nivolumab in patients with advanced esophageal 


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cancer who had failed or were intolerable to at least one line of systemic treatment, 
ORR was 17.2% and mOS was 12.1 months[23]. Based on efficacy observed in early 
trials, phase III studies evaluating the efficacy of Nivolumab[24] and 
Pembrolizumab[25] versus chemotherapy in second-line esophageal cancer are 
currently ongoing. 
Study Drug (IBI308) 
Mechanism of Action of IBI308 
Immune checkpoints are a class of immunosuppressive molecules. Their physiological 
function is to modulate intensity and extent of immune response, so as to avoid injury 
and damage of normal tissues. Tumor cells often utilize the property of immune 
checkpoints to escape attack from immune cells. At present, clinically verified immune 
checkpoints include CTLA-4 and PD-1/PD-L1. Due to good safety and extensive 
indications, immune checkpoint inhibitors targeting PD-1/PD-L1 are more promising 
in clinical practice. 
PD-1 is mainly expressed on activated T cells and has two ligands: PD-L1 and PD-L2, 
of which PD-L1 is its main ligand and is expressed in activated T cells, antigen-
presenting cells, and tumor cells[26]. PD-1/PD-L1 binding plays an important role in 
regulating T cell activation and maintaining peripheral immune tolerance. When there 
is no PD-1 expression in T cells, T cells interact with antigen presenting cells, resulting 
in activation, proliferation of T cells and secretion of active cytokines, which act on 
tumor cells, leading to tumor cell killing; The activated T cells begin to express PD-1. 
When they bind to antigen-presenting cells or ligand PD-L1 on tumor cells, the 
inhibitory signal transmitted by PD-1 inhibits the proliferation of T cells and the 
secretion of active cytokines, diminishing the T cell function. Most tumor cells utilize 
this mechanism to escape attack from immune cells; If the interaction between PD-1 
and PD-L1 is blocked by medications, the activity of T cells can be restored and the 
ability to kill cancer cells can be improved[27]. 
Up to date, three PD-1/PD-L1 products have been approved for marketing by the US 
FDA, i.e., anti-PD-1 monoclonal antibody Nivolumab (trade name: OPDIVO) of BMS, 
anti-PD-1 monoclonal antibody Pembrolizumab (trade name: KEYTRUDA) of Merck, 
and anti-PD-L1 monoclonal antibody Atezolizumab (trade name: Tecentriq) of 
Genetech, under the indications for advanced melanoma, advanced NSCLC, advanced 
classical Hodgkin lymphoma, advanced renal cell carcinoma, advanced urothelial 


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carcinoma, and advanced head and neck tumors. In addition, many indications are 
currently under phase III clinical studies or NDA submissions. The marketing of the 
above drugs has established the important position of PD-1/PD-L1 immune checkpoint 
inhibitors in cancer immunotherapy. For the moment, there is no PD-1/PD-L1 immune 
checkpoint inhibitor marketed in China. Therefore, it is of great significance to actively 
develop such inhibitors to provide better treatment options for Chinese patients with 
advanced tumors. 
Recombinant fully human anti-PD-1 monoclonal antibody injection (R&D code: 
IBI308) is a recombinant fully human IgG4 monoclonal antibody. The effect of 
blocking PD-1 pathway with IBI308 has been investigated in various preclinical in vitro 
tests, and the anti-tumor activity of the murine analogue of IBI308 has been 
demonstrated in several non-immunocompromised mouse tumor models (refer to the 
Investigator's Brochure for detailed study results). The results of preclinical studies 
suggested a promising future for the development of IBI308 for PD-1 blockade. 
Results of IBI308 Clinical Study 
In September 2016, a phase Ia dose-escalation trial of IBI308 was initiated. The phase 
Ia was planned to enroll approximately 12 to 24 subjects with advanced solid tumors 
who had failed standard of care, to evaluate IBI308 at four dose levels (1 mg/kg, 3 
mg/kg, 200 mg, and 10 mg/kg), with the dose escalation decision based on the classic 
“3+3” design. After completion of the 1 mg/kg dose group, subjects were randomized 
to the 3 mg/kg and 200 mg dose groups at a 1:1 ratio for independent evaluation. There 
was a 28-day DLT observation period for the two dose groups each after initial dosing, 
and only subjects who completed the DLT observation period could enter the 
subsequent treatment period to receive IBI308 Q2W (1 mg/kg, 3 mg/kg and 10 mg/kg) 
or Q3W (200 mg), until disease progression, intolerable toxicity, withdrawal of consent, 
or occurrence of other conditions that require discontinuation of study treatment, 
whichever occurs first. 
Preliminary pharmacokinetic results of IBI308 in subjects with various tumors (n=3) 
showed that maximum exposure after a single dose was achieved at the end of 1 mg/kg 
IBI308 infusion; after the peak exposure, the drug was rapidly distributed and slowly 
eliminated (t1/2 was approximately 17.3d), demonstrating typical 2-compartment PK 
characteristics of monoclonal antibody drugs, with elimination half life similar to 
physiological half life of IgG4. 


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Preliminary pharmacodynamic results showed that, at the dose of 1 mg/kg, IBI308 
rapidly (24h) occupied peripheral PD-1 in saturation (95.8±2.3%), and maintained PD-
1 occupation during the study when concentration continued to decrease (28d, C28d: 
3.70± 0.15 μg/mL). It is expected that steady state will be achieved after continuous 
administration of 1 mg/kg Q2W for 84 days (6 doses). If there is no significant variation 
of drug elimination characteristics, trough concentration at steady state is expected to 
be approximately 13 μg/mL, which can persistently maintain occupation of peripheral 
PD-1 receptor. 
As of February 8, 2017, enrollment of 3 patients each and protocol specified 
observation of dose limiting toxicities had been completed in 1 mg/kg, 3 mg/kg and 
200 mg dose groups in phase Ia, with no occurrence of dose limiting toxicity. 
Risk/Benefit Assessment 
Based on the mechanism of action of this product and on the clinical safety information 
of products with the same mechanism, adverse events expected to possibly occur with 
this product during the clinical trial are mainly various immune-mediated 
inflammations caused by activation of the immune system, such as pneumonia, colitis, 
hepatitis, renal insufficiency and inflammation of the endocrine system. According to 
available clinical data of anti-PD-1 monoclonal antibody drugs, although the incidence 
of adverse reactions is high, the drugs were well tolerated, with only a small portion of 
subjects discontinuing treatment due to adverse reactions, most of which resolved after 
appropriate treatment. As the early symptoms of immune-related adverse reactions are 
variable, the investigator(s) should pay special attention to the early symptoms and 
signs of various immune-related reactions in the clinical study, make appropriate 
judgment in a timely fashion, and perform dose adjustment and appropriate effective 
treatment as described 5.4.2 of the protocol to reduce the risks of drug use for the 
patients. In addition, the investigator(s) should exclude patients with autoimmune 
diseases during the clinical trial to avoid worsening of pre-existing diseases as a result 
of immune system activation. 
The phase Ia clinical pharmacology and safety data for IBI308 show that IBI308 has 
clear pharmacological activity and is well tolerated in patients with advanced tumors. 
The above data preliminarily indicates that IBI308 has good safety and pharmacological 
activity, and drugs of the same class have significant anti-tumor activity in patients with 
advanced esophageal cancer, supporting clinical studies in Chinese patients with 


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advanced esophageal cancer. 
2 Study Objectives 
Primary Objective 
 
To evaluate the overall survival (OS) for IBI308 versus Paclitaxel or 
Irinotecan in patients with advanced/metastatic esophageal squamous cell 
carcinoma after failure of first-line treatment. 
Secondary Objectives 
 To evaluate progression-free survival (PFS), objective response rate (ORR), 
disease control rate (DCR) and duration of response (DoR) for IBI308 versus 
Paclitaxel or Irinotecan in patients with advanced/metastatic esophageal 
squamous cell carcinoma after failure of first-line treatment; 
 To evaluate the safety of IBI308 versus Paclitaxel or Irinotecan in patients 
with advanced/metastatic esophageal squamous cell carcinoma after failure of 
first-line treatment; 
 To evaluate the quality of life (QoL) for IBI308 versus Paclitaxel or Irinotecan 
in patients with advanced/metastatic esophageal squamous cell carcinoma 
after failure of first-line treatment. 
Exploratory Objectives 
 To evaluate the relationship between PD-L1 expression / immune-related gene 
mRNA expression and efficacy in patients with advanced/metastatic 
esophageal squamous cell carcinoma. 
 To evaluate the relationship between the dynamic expression of PD-L1 on the 
surface of circulating tumor cells (CTCs) / ctDNA results and efficacy in the 
IBI308 group. 
 To explore the iPFS, iORR, iDCR and iDoR assessed per Immune-modified 
Response Evaluation Criteria in Solid Tumors (iRECIST) in the IBI308 group. 
3 Overall Study Design 
Overall Design 
This is a randomized, open-label, multi-center, phase II study designed to evaluate the 
efficacy and safety of IBI308 versus paclitaxel or irinotecan in patients with 


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advanced/metastatic esophageal squamous cell carcinoma after failure of first-line 
treatment. It is planned to enroll 180 subjects with advanced/metastatic esophageal 
squamous cell carcinoma after failure of first-line treatment, and the subjects will be 
randomized using central randomization stratified by Eastern Cooperative Oncology 
Group performance status (ECOG PS) score of 0 or 1. 
Subjectswill be randomized into an IBI308 group or chemotherapy group in a 1:1 ratio. 
The IBI308 group will be administered with IBI308 200 mg IV Q3W, until disease 
progression, death, intolerable toxicity, withdrawal of consent, or occurrence of other 
protocol-specified situations. For a subject who experienced disease progression 
initially, if the subject is clinically stable, the decision is left to the discretion of the 
investigator as to whether IBI308 treatment should be continued or not (see 5.1.2 for 
details). The treatment regimen for the chemotherapy group, determined by the 
investigator based on prior first-line regimen, is Paclitaxel 175 mg/m2 IV Q3W or 
Irinotecan 180 mg/m2 IV Q2W, until disease progression, death, intolerable toxicity, 
withdrawal of consent, or occurrence of other protocol-specified situations. In this study, 
Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) is used for response 
assessment and iRECIST is adopted as the exploratory response assessment criteria. 
After discontinuation of study treatment, the subjects will be followed for safety and 
survival (every 60 days). 
The primary endpoint of this study is OS, defined as the time from randomization to 
the date of death, and subjects who did not die will be censored at the most recent 
known date of survival. 


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Figure 1. Schematic diagram of study design and dosing regimen of CIBI308A201 
Design Rationale 
Rationale for Selection of Open-label Study Design 
As IBI308 has a different mechanism of action from paclitaxel and irinotecan, subjects 
may experience different AEs. IBI308 may induce immune related AEs, which may 
involve various tissues and organs. Adverse event profile of paclitaxel mainly includes 
myelosuppression and neurotoxicity, while adverse event profile of irinotecan mainly 
includes myelosuppression and diarrhea. Even for AEs involving the same tissue or 
organ, IBI308 and chemotherapy have different mechanisms to induce AEs, requiring 
different dose adjustment and rescue treatment. IBI308-induced AEs are mainly 
immune related, and require treatment with glucocorticoid in most cases. If this trial is 
blinded, treatment of AEs may be delayed or there may be injury of subjects. 
Additionally, different treatment adjustment rules (no dose reduction of IBI308, while 
doses of paclitaxel and irinotecan can be reduced) and different drug-drug interaction 
profile also increase complexity, making it difficult to use any blinding strategy. 
Therefore, this study selects an open-label study design. 
Screening 
Patients with pathologically confirmed 
esophageal squamous cell carcinoma failing 
first-line chemotherapy (N=180) 
Randomization (1:1 ratio to IBI308 group or 
chemotherapy group) 
Stratification factor: ECOG 0 vs. ECOG 1 
IBI308 group 
IBI308 200 mg IV Q3W 
Chemotherapy group 
Paclitaxel 175 mg/m2 Q3W or irinotecan 180 
mg/m2 Q2W 
Safety Follow-up 
Safety follow-up 1st: 30 days after treatment 
discontinuation visit or the last dose 
Safety follow-up 2nd: 90 days after the last 
dose 
Survival Follow-up 
Every 60 days after safety follow-up 


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Rationale for Selection of Treatment Regimen of 200 mg Every 3 Weeks 
It is planned to administer 200 mg IBI308 Q3W in this study. Selection of this 
administration mode is mainly based on data of safety and exposure (concentration)-
response (PD-1 receptor occupation) relationship from a currently ongoing phase I 
study (CIBI308A101), in conjunction with pre-clinical in vitro/ in vivo 
pharmacodynamic data and comparative data of similar drugs. 
In vivo pharmacodynamic studies in mouse SCID-Winn model and MC38 mouse colon 
cancer model indicated that anti-tumor ability of IBI308 increased with dose, and tumor 
growth was significantly inhibited at 10 mg/kg IBI308 dose, which was equivalent to 
0.8 mg/kg dose in human. In human, IBI308 1 mg/kg can rapidly (24h) occupy 
peripheral PD-1 in saturation, and maintain peripheral PD-1 occupation level during 
the study when concentration continues to decrease. Results of IBI308 tissue 
distribution in cynomolgus monkeys showed IBI308 exposure in lung, liver, colon, 
small intestine and lymph node was approximately 3.5-1/10 of serum exposure. If there 
is no significant variation of drug elimination characteristics in subjects, it is expected 
that steady state will be achieved after continuous administration of IBI308 200 mg 
Q3W for 84 days (4 doses), and mean steady state trough concentration is expected to 
persistently maintain occupation of peripheral and target organ PD-1 receptor. The 
above evidence supports selection of IBI308 200 mg Q3W as dosing regimen. 
Rationale for Selection of Paclitaxel or Irinotecan as Control 
There is no large-scale randomized controlled clinical study of second-line treatment 
for advanced esophageal cancer. Docetaxel[11, 12], paclitaxel[7, 13] and irinotecan 
monotherapy[14-16] have demonstrated certain level of efficacy in several single-arm 
studies, and are commonly used as second-line treatment for esophageal cancer in 
clinical practice (recommended by NCCN guideline)[17]. In a single-arm clinical study 
evaluating the efficacy of paclitaxel monotherapy in previously untreated advanced 
esophageal cancer patients, treatment regimen was 150-280 mg/m2 D1 Q3W. A total of 
52 subjects were enrolled, and ORR was 32%[7]. In a single-arm clinical study 
evaluating the efficacy of paclitaxel monotherapy in advanced esophageal cancer, 
treatment regimen was 80 mg/m2 QW. A total of 102 subjects were enrolled, PR was 
13%, duration of response was 172 days, and mean survival time was 274 days[13]. In 
a study evaluating the efficacy of irinotecan monotherapy in patients with advanced 
esophageal cancer failing cisplatin-based chemotherapy, treatment regimen was 100 
mg/m2 D1, 8, 15 in a 28-day cycle. A total of 14 patients were enrolled. In 13 subjects 


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evaluable for efficacy, 2 subjects reached partial response, and 3 subjects remained 
stable disease. Median time to disease progression was 2 months, and median overall 
survival was 5 months[14]. In a study evaluating the efficacy of irinotecan monotherapy 
in advanced gastric and esophageal cancer, treatment regimen was 125 mg/m2 D1, 8, 
15, 22 in a 42-day cycle. A total of 46 patients were enrolled, objective response rate 
was 14% and median survival time was 6.4 months[15]. In a study evaluating the 
efficacy of irinotecan monotherapy in patients with unresectable esophageal cancer, 
treatment regimen was 125 mg/m2 D1, 8, 15, 22 in a 42-day cycle. A total of 13 subjects 
(10 subjects with squamous cell carcinoma and 3 subjects with adenocarcinoma) were 
enrolled, and 2 subjects reached partial response (1 with squamous cell carcinoma and 
1 with adenocarcinoma). Median time to disease progression was 3.8 months, and 
median survival time was 6.1 months[16]. 
Rationale for Treatment after Disease Progression 
Clinical data of marketed products indicate that a few patients receiving 
immunotherapy may still obtain clinical benefit in spite of preliminary evidence of 
disease progression (as per routine response criteria) before clinical objective response 
and/or stable disease[28]. At present, this phenomenon is hypothetically due to two 
reasons. First, aggravated inflammation within tumor may cause increased tumor 
volume, manifested as enlarged measurable lesion and new visible non-measurable 
lesion. Over time, malignant portion and inflammatory portion of mass may diminish, 
resulting in significant radiological response and improvement of clinical signs. Second, 
in some patients, anti-tumor immune response has a slow onset, with early tumor 
inhibition lower than tumor growth kinetics. Over time, anti-tumor activity will become 
predominant, manifested as radiological response and improvement of clinical signs. 
Therefore, for IBI308-treated subjects, if they are assessed as clinical benefit and 
tolerable to study drug, the subjects will be allowed to continue with the study treatment 
after preliminary assessment of disease progression by the investigator as per RECIST 
v1.1 (see Section 5.1.2). 
4 Study Population 
Inclusion Criteria 
1. Histologically or cytologically confirmed locally advanced unresectable or 
metastatic esophageal squamous cell carcinoma (excluding mixed adenosquamous 
carcinoma and other pathological types). 


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2. Imaging evidence (e.g. CT scan) or clinical evidence (e.g. cytological report of new 
ascites or pleural effusion) of disease progression during or after first-line 
chemotherapy; Subjects have to receive at least one dose of first-line treatment, 
permitting discontinuation or dose reduction of one drug or exchange of 
fluorouracil drugs used during first-line treatment, and patients discontinuing first-
line treatment due to intolerable toxicity are allowed to be enrolled; Neoadjuvant 
or adjuvant therapy (chemotherapy or chemo-radiotherapy) should be regarded as 
first-line treatment if there is disease progression during treatment or within 6 
months after treatment discontinuation. 
3. At least one measurable lesion according to RECIST v1.1. 
4. ECOG PS score of 0 or 1. 
5. Subjects who have signed the written informed consent form and are able to follow 
the visit schedule and relevant procedures as specified in the study protocol. 
6. Age ≥ 18 and ≤ 75 years. 
7. Life expectancy ≥ 12 weeks. 
8. Female subjects of childbearing potential or male subjects with sexual partners of 
childbearing potential should use effective contraception throughout and within 6 
months after treatment (see Section 4.3). 
9. Adequate organ and bone marrow functions, defined as follows: 
1) Hematology: Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet (PLT) count 
≥ 100 × 109/L; Hemoglobin (HGB) ≥ 9.0 g/dL. 
2) Liver function: serum total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN; 
Serum albumin ≥ 28 g/L. 
3) Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance (Ccr) 
≥ 40 mL/min (calculated using the standard Cockcroft -Gault formula): 
Females: CrCl = (140-age) x body weight (kg) x 0.85 
72 x serum creatinine (mg/dL) 
Males: CrCl = (140-age) x body weight (kg) x 1.00 
72 x serum creatinine (mg/dL) 


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Exclusion Criteria 
1. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody. 
2. Concurrent participation in another interventional clinical study, except for 
observational (non-interventional) clinical studies or in the follow-up phase of an 
interventional study. 
3. Receipt of any investigational products within 4 weeks prior to the first dose of 
study treatment. 
4. Receipt of the last dose of anti-tumor therapy (chemotherapy, targeted therapy, 
tumor immunotherapy, tumor embolization) within 3 weeks prior to the first dose 
of study treatment. 
5. Radiotherapy within 4 weeks prior to the first dose of study treatment. 
6. Receipt of immunosuppressive agents within 4 weeks prior to the first dose of study 
treatment, excluding topical glucocorticoids for intranasal, inhalation or other 
routes of administration, or physiological doses of systemic glucocorticoids (i.e., 
no more than 10 mg/day prednisone or equivalent doses of other glucocorticoids). 
7. Receipt of a live attenuated vaccine within 4 weeks prior to the first dose of study 
treatment or planned receipt of a live attenuated vaccine during the study. 
8. Subjects who have undergone major surgical procedures (craniotomy, thoracotomy 
or laparotomy) within 4 weeks prior to the first dose of study treatment or have 
unhealed wound, ulcers or bone fracture. 
9. Presence of toxicities induced by previous anti-tumor therapy that have not 
recovered to Grade 0 or 1 as assessed per NCI CTCAE 4.03 (National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.03) prior to 
the first dose of study treatment, excluding alopecia, and non-clinically significant 
and asymptomatic laboratory abnormalities. 
10. Known symptomatic metastases to central nervous system (CNS) and/or 
carcinomatous meningitis. Subjects previously treated for brain metastasis are 
eligible for the study provided the brain metastasis has remained stable for at least 
4 weeks before first dose of study treatment; Neurological symptoms must be 
recovered to grade 0 or 1 as per NCI CTCAE version 4.03. 


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11. Active, known or suspected autoimmune diseases (refer to Appendix 6) or a history 
of such disease in the past 2 years (patients with vitiligo, psoriasis, alopecia or 
Grave's disease requiring no systemic treatment in the past 2 years, patients with 
hypothyroidism requiring only thyroid hormone replacement therapy and patients 
with type I diabetes requiring only insulin replacement therapy can be enrolled). 
12. Known history of primary immunodeficiency. 
13. Known active tuberculosis (TB). 
14. Known history of allotransplantation and allogeneic hematopoietic stem cell 
transplantation. 
15. Known hypersensitivity to any component of the monoclonal antibody, paclitaxel 
or irinotecan formulation. 
16. Uncontrolled concurrent diseases, including but not limited to: 
 
HIV infection (HIV antibody positive). 
 
Active or clinically uncontrolled severe infections. 
 
Symptomatic congestive heart failure (New York Heart Association Class 
II-IV) or symptomatic or poorly controlled arrhythmia. 
 
Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or 
diastolic blood pressure ≥ 100 mmHg) despite standard treatment. 
 
Any arterial thromboembolism events within 6 months prior to inclusion 
for treatment, including myocardial infarction, unstable angina, 
cerebrovascular accident or transient ischemic attacks. 
 
Significant malnutrition, if intravenous nutrient solution supplement is 
required; Except for malnutrition corrected for more than 4 weeks before 
first dose of study treatment. 
 
Tumor invasion into surrounding vital organs (e.g., aorta and trachea) or a 
risk for esophagotracheal fistula or esophagopleural fistula. 
 
Post esophageal or intratracheal stenting. 
 
History of deep vein thrombosis (DVT), pulmonary embolism, or any other 
serious thromboembolism within 3 months prior to enrollment (implanted 


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venous access port or catheter-related thrombosis, or superficial venous 
thrombosis is not considered as "serious"thromboembolism). 
 
Uncontrolled metabolic disorders or other non-malignant organic or 
systemic diseases or reactions secondary to cancer, which can result in high 
medical risks and/or uncertainty in survival evaluations. 
 
Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or 
even more severe cirrhosis. 
 
History of intestinal obstruction or the following diseases: inflammatory 
bowel disease or extensive bowel resection (partial colectomy or extensive 
resection of the small intestine, concurrent chronic diarrhea), Crohn's 
disease, ulcerative colitis, or chronic diarrhea. 
 
Other acute or chronic diseases, mental disorders or abnormal laboratory 
findings that may lead to the following results: increase risks associated 
with study participation in the study or use of the study drug, or interfere 
with the interpretation of study results, and render the patient ineligible for 
the study at the investigator’s discretion. 
17. Known acute or chronic active hepatitis B (HBsAg positive and HBV DNA ≥200 
IU/mL or ≥ 103 copies/mL) or acute or chronic active hepatitis C (HCV antibody 
positive and positive for HCV RNA test). 
18. History of gastrointestinal perforation and/or fistula within 6 months prior to study 
inclusion. 
19. Presence of interstitial lung disease. 
20. Clinically uncontrollable effusion of the third space, such as pleural effusion and 
ascites that cannot be controlled by drainage or other methods before enrollment. 
21. History of other primary malignancies, excluding: 
 
A malignancy with complete remission for at least 2 years before enrollment 
and requiring no other treatment during the study; 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of relapse; 
 
Adequately treated carcinoma in situ without evidence of relapse. 


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22. Pregnant or breastfeeding women. 
Restrictions throughout Study 
Women of childbearing potential who are sexually active with male partners not 
surgically sterilized must begin to use 2 acceptable effective contraception methods (see 
Table 2) from screening phase, and must agree to continue with these contraception 
measures for 6 months after the last dose of the study drug; After this time point, they 
should discuss with a responsible physician about discontinuation of contraception 
measures. Periodic abstinence, safe period contraception and coitus interruptus are not 
acceptable contraception methods. 
Women of childbearing potential are defined as women not surgically sterilized (i.e. 
bilateral tubal ligation, bilateral salpingectomy or total hysterectomy) or 
postmenopausal (defined as amenorrhea for 12 months without an alternative medical 
cause). 
Women with amenorrhea for 12 months without an alternative medical cause are 
considered to have menopause. Requirements by age are as follows: 
 
If women ≥50 years have amenorrhea for 12 months or more after stopping 
treatment with exogenous hormones, and levels of luteinizing hormone and 
follicle stimulating hormone are within recognized postmenopausal range, 
they are considered as postmenopausal women. 
 
If women <50 years have amenorrhea for 12 months or more after stopping 
treatment with exogenous hormones, radiotherapy induced oophorotomy and 
the last menses occurred >1 year ago, chemotherapy induced amenorrhea and 
the time from the last menses was >1 year, or have undergone surgical 
sterilization (bilateral oophorotomy or hysterectomy), they are considered as 
postmenopausal women. 


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Table 2. Effective contraception methods (must use 2 methods) 
Barrier methods 
Intrauterine device (IUD) 
methods 
Hormonal methods 
Male condoms with 
spermicide 
T-ring with copper 
Implants 
Cervical cup plus spermicide 
Progesterone-containing T-ring a 
Contraceptive injections 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine systems (e.g., 
Mirena®) a 
Combined contraceptives 
Low-dose oral contraceptive 
pills 
Birth control patches 
a This is also regarded as a hormonal method 
Discontinuation of Treatment/Withdrawal of Subjects from Study 
Subjects should discontinue/withdraw from the study if any of the following situations 
occurs: 
1. The subject does not meet inclusion/exclusion criteria, and the investigator 
determines the subject is not suitable to continue participation in this study 
after discussion with the sponsor; 
2. The subject deviates seriously from the study protocol, and the investigator 
determines the subject is not suitable to continue participation in this study 
after discussion with the sponsor. 
3. The subject has been enrolled in another study of any type of drugs 
scientifically or medically not appropriate to be concurrent with this study. 
4. The subject is lost to follow-up (the study site personnel should contact the 
subject to determine the reason for lost to follow-up and re-schedule visit as 
far as possible. The site should document the date of the subject to be 
contacted and the contact information used in the study file). 
5. Investigator Decision 
 
The investigator considers the subject should discontinue treatment or 
study based on the subject's safety and benefit. 
 
If the subject needs another drug treatment for any reason, and the drug has 
been demonstrated to effectively treat the study indication, the subject 
should discontinue this study before use of the new drug. 


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 
Disease progression or the investigator considers the subject is not suitable 
to continue with treatment. 
 
Occurrence of any life-threatening treatment-related events, regardless of 
severity. 
 
Study drug meets discontinuation criteria due to toxicity (see 5.4). 
6. The subject or his/her representative (e.g. parents or legal guardian) requests 
withdrawal from this study or discontinuation of study drug (if the subject 
withdraws informed consent for treatment but not informed consent for 
follow-up, he or she may still enter into long-term follow-up). 
7. The sponsor may terminate the study or discontinue subject's participation in 
this study for other medical, safety, regulatory or applicable laws, 
regulations and Good Clinical Practice (GCP) related reasons. 
Reason and date for study discontinuation will be collected for all subjects. For subjects 
discontinuing treatment, relevant study procedures specified in schedule of study visits 
will also be performed as far as possible. 
5 Study Drug and Other Treatments 
Treatment Regimen 
Treatment Regimen 
Study drug in this study refers to IBI308, paclitaxel and irinotecan. Other drugs used in 
the study are non-study drugs. Treatment regimen is shown in the table below. For 
paclitaxel and irinotecan pretreatment, refer to Section 5.3.1 of the protocol. 
Table 3. Dose and regimen 
Cohort 
Treatment Regimen 
Dosage time 
IBI308 group 
IBI308 200 mg IV, Day 1, Q3W  
Until disease progression, death, 
intolerable toxicity, withdrawal of 
consent, or occurrence of other 
protocol-specified situations; 
Eligible subjects can continue 
IBI308 treatment beyond initial 
disease progression (see Section 
5.1.2). 


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Chemotherapy 
groupa 
Paclitaxel 175 mg/m2 IV, Day 1, Q3W 
or 
Irinotecan 180 mg/m2 IV, Day 1, Q2W 
At the investigator's discretion based 
on previous first-line treatment 
regimen 
Until disease progression, death, 
intolerable toxicity, withdrawal of 
consent, or occurrence of other 
protocol-specified situations. 
a This study site will determine actual drug dose the subject should receive by calculating the 
subject’s body surface area on the day of scheduled administration in each cycle. The maximum 
body surface area used in the protocol is 2.0 m2. For subjects whose body surface area is >2.0 m2, 
the study site personnel will calculate based on the body surface area of 2.0 m2. To facilitate 
administration, the protocol allows a deviation of ±5% for each calculated overall infusion dose.  
Re-administration after Disease Progression 
During IBI308 treatment, subjects initially assessed as disease progression (initial 
disease progression) per RECIST v1.1 have to meet all the following criteria to continue 
IBI308 treatment: 
1. 
The investigator considers the continuation of study treatment may be 
expected to lead to clinical benefits and no rapid disease progression; 
2. 
IBI308 was tolerated; 
3. 
ECOG PS score is stable; 
4. 
Any urgent intervention for serious complications (e.g. central nervous 
system metastasis) will not be delayed ; 
5. 
The subject should be sufficiently informed and the investigator should 
explain all predictable risks or discomfort and other alternative treatment 
methods in details before continuation of IBI308 treatment. 
If all the above criteria are met, the investigator has to discuss with the sponsor's 
medical manager to make the decision on continued treatment after disease progression, 
and the decision should be documented on study record. 
The data of subjects continuing IBI308 treatment after initial disease progression have 
to be collected refering to Table 1. Treatment will be continued until death, intolerable 
toxicity, withdrawal of consent, no clinical benefit evaluated by the investigator, or 
initiation of new anti-tumor therapy (whichever occurs first). 


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If there is worsening of clinical symptoms, IBI308 treatment should be discontinued 
for subjects continuing IBI308 treatment after initial disease progression, and 
“worsening of clinical symptoms” should be documented. 
Study Drug (IBI308) 
Description 
The study drug is recombinant fully human anti-programmed cell death receptor 1 
monoclonal antibody injection, referred to as IBI308. 
Its main active ingredient is recombinant fully human anti-programmed cell death 
receptor 1 monoclonal antibody, with the finished product supplied in strength of 10 
mL: 100 mg. IBI308 is free of preservatives at a concentration of 10 mg/mL, and 
contains the following excipients: mannitol 140 mmol/L, histidine 25 mmol/L, sodium 
citrate dihydrate 20 mmol/L, sodium chloride 50 mmol/L, edetate disodium (disodium 
edetate) 0.02 mmol/L, and polysorbate 80 0.2 mg/mL, with a pH value of 6.0. 
The product is a clear colorless liquid, free of foreign matters, floccules and precipitates. 
Manufacturer: Innovent Biologics (Suzhou) Co., Ltd (hereinafter referred to as 
Innovent). 
Labeling 
IBI308 is supplied in the minimum packaging unit of boxes, with per box containing 2 
pieces of IBI308 injection packaged in a vial. Printed on the packaging boxes of IBI308 
are drug name, drug number, dosage form, strength, drug code, lot number, shelf life, 
storage conditions, usage and dosage, precautions and sponsor information. The same 
information is also printed on the labels for the vials and packaging boxes, except for 
dosage form and precautions information, which is not provided on the vial labels. The 
labels of all packaging boxes and vials are clearly indicated with "For clinical trial only".  
Storage conditions 
It is stored at 2 to 8℃, protect from light, shelf life of 24 months. If the injection has 
quality issue of opacity or precipitation, it should be sealed immediately, and the 
sponsor is informed immediately. 
Preparation and infusion 
IBI308 is prepared and infused according to procedures as follows: 


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1． Completely draw 2 vials of IBI308 injection into an intravenous infusion bag 
containing 100 mL of 0.9% (weight/volume) sodium chloride-sterile normal saline, 
and record the start time of preparation. 
2． Gently invert the infusion bag for mixing to ensure the homogeneity of drug 
in the infusion bag, and avoid foaming from violently shaking. 
3． Administer infusion intravenously via an IV pump installed with a 0.2-1.2 μm 
on-line filter (it is recommended that the infusion be completed within 30-60 
minutes), and record the start time and end time of infusion. 
Precautions: drug products from different batches should not be mixed for a single 
infusion; Before preparation, confirm IBI308 injection is clear, without quality issue of 
opacity or precipitation; Ensure the time from drawing of the first vial of IBI308 
injection to the end of administration will not exceed 24 hours (prepared drug will be 
stored at 2-8℃ in a refrigerator); Avoid mixture with other drugs; Avoid intravenous 
bolus injection. 
Study drug (paclitaxel and irinotecan) 
Both paclitaxel and irinotecan are approved anti-tumor drugs, and will be centrally 
supplied by the sponsor after additional re-labeling. The study site has to store, prepare 
and administer drugs according to approved labels. The following information is 
provided for reference. 
Pre-medication for chemotherapy 
For details of pre-medication regimen for chemotherapy, please refer to requirements 
in package insert and local clinical practice. The table below lists recommended pre-
medication for chemotherapy. 
Table 4. Recommended pre-medication for chemotherapy 
Paclitaxel 
Dexamethasone 
20 mg divided into 2 doses, orally administered 12 h and 6 h before 
chemotherapy 
Diphenhydramine 50 mg, intravenous injection 30-60 min before chemotherapy (or other 
similar drugs of equivalent dose) 


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Cimetidine or 
ranitidine 
Cimetidine (300 mg) or ranitidine (50 mg), intravenous injection 30-60 
min before chemotherapy 
Irinotecan 
Antiemetics 
Recommended prophylactic use, per routine practice at each study site 
Atropine 
If the subject develops cholinergic syndrome, consider prophylactic 
atropine in subsequent treatment cycles 
Dose Adjustments 
General Principles 
 The subjects must have adequate hematologic, hepatic, and renal functions 
prior to Day 1 of each drug administration cycle, and all toxicities must have 
resolved to NCI CTCAE 4.03 grade 0-1 or baseline (excluding alopecia, 
fatigue). 
 All dosage modifications should be documented, including the reason and the 
method(s) used. 
Dose adjustment for IBI308 
No dose reduction for IBI308 is allowed throughout the study. The dosage modification 
scheme for IBI308 (only for AEs judged as IBI308-related by the investigator) is 
presented in the table below. 
Table 5. Dose adjustment scheme of IBI308 
Adverse reaction 
Seriousness 
Dose 
Modifications 
Pneumonia 
Grade 2 pneumonitis 
Interruptiona 
Grade 3 or 4 pneumonitis 
Permanent 
discontinuation 
Diarrhea/enterocolitis 
Grade 2 or 3 diarrhea or enterocolitis 
Interruptiona 
Grade 4 diarrhea or enterocolitis 
Permanent 
discontinuation 
Dermatitis 
Grade 3 dermatitis 
Interruptiona 
Grade 4 dermatitis 
Permanent 
discontinuation 


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Adverse reaction 
Seriousness 
Dose 
Modifications 
Hepatitis 
Grade 2 AST, ALT or TBIL elevation 
Interruptiona 
Grade 3 or 4 AST, ALT or TBIL elevation 
Permanent 
discontinuation 
Hypophysitis 
Grade 2 hypophysitis 
Interruptionb 
Grade 3 or 4 hypophysitis 
Permanent 
discontinuation 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Interruptionb 
Grade 3 or 4 adrenal insufficiency 
Permanent 
discontinuation 
Hyperthyroidism 
Grade 3 or 4 hyperthyroidism 
Permanent 
discontinuation 
Type 1 diabetes 
Grade 3 hperglycaemia 
Interruptionb 
Grade 4 hperglycaemia 
Permanent 
discontinuation 
Renal insufficiency 
Grade 2 or 3 elevated Cr 
Interruptiona 
Grade 4 elevated Cr 
Permanent 
discontinuation 
Neurotoxicity 
Grade 2 neurotoxicity 
Interruptiona 
Grade 3 or 4 neurotoxicity 
Permanent 
discontinuation 
Infusion reactions 
Grade 3/4 infusion reaction 
Permanent 
discontinuation 
Other AEs 
First occurrence of other grade 3 AEs 
Interruptiona 
Second occurrence of the same grade 3 AEs 
Permanent 
discontinuation 
Grade 3 AEs that did not return to grade 0 - 2 or the 
baseline level within 7 days or did not resolve to 
grade 0/1 or the baseline level within 14 days 
Permanent 
discontinuation 
Grade 4 AEs 
Permanent 
discontinuationc 
a: The drug may be resumed after the symptoms resolve to grade 0 - 1 or the baseline level. 
b: The drug may be resumed after hypophysitis, adrenal insufficiency, and/or type 1 diabetes 
mellitus is adequately controlled, only requiring physiological hormone replacement therapy (HRT). 
c: For grade 4 laboratory abnormalities, discontinuation of treatment should be based on 
concomitant clinical symptoms/signs and the investigator’s clinical judgment. 
The maximum permitted duration of temporary discontinuation is 6 weeks. If the 
abnormalities do not return to a status allowing for resumption of IBI308 within 6 
weeks, the subject will permanently discontinue IBI308 treatment and proceed to 
follow-up period. Except for the following two situations: 


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 
Glucocorticoid is used for treatment of irAE and tapering of glucocorticoid 
causes temporary discontinuation of IBI308 for more than 6 weeks: In this case, 
the investigator should discuss with the sponsor's medical manager to 
determine whether IBI308 treatment can be resumed. Radiological 
examination assessing efficacy will be performed as scheduled, not influenced 
by temporary discontinuation. 
 
Treatment of AEs unlikely related or unrelated to IBI308 results in temporary 
discontinuation of IBI308 for more than 6 weeks: In this case, the investigator 
should discuss with the sponsor's medical manager to determine whether 
IBI308 treatment can be resumed. Radiological examination assessing efficacy 
will be performed as scheduled, not influenced by temporary discontinuation. 
Dose adjustment of paclitaxel 
Hematological toxicity 
The next cycle of paclitaxel treatment can be started only if ANC is recovered to ≥1.5 
x 109/Land PLT is recovered to ≥100 x 109/L. If severe neutropenia (ANC ≤0.5 x 109/L 
lasting for one week or more) or febrile neutropenia occurs during paclitaxel treatment, 
dose of paclitaxel should be reduced by 20% in subsequent treatment. 
If there is platelet count <25 x 109/L or <50 x 109/L with bleeding or requiring 
transfusion in the previous treatment cycle, dose of paclitaxel should be reduced by 20% 
in subsequent treatment. 
Once dose of chemotherapeutic drug is reduced due to febrile neutropenia or 
thrombocytopenia (platelet <25 x 109/L or <50 x 109/L with bleeding or requiring 
transfusion), it is not permitted to restore the original dose. If dose reduction is required 
again due to febrile neutropenia or thrombocytopenia, dose of paclitaxel should be 
further reduced by 20%. If the subject develops a condition requiring dose reduction 
for the third time, chemotherapy should be discontinued immediately. 
The maximum permitted delay of chemotherapy is 3 weeks. If ANC is not ≥1.5 x 109/L 
or platelet is not ≥100 x 109/L on pre-specified Day 1 of chemotherapy after a 3-week 
delay, the subject should permanently discontinue chemotherapy; If the above values 
are met, the next cycle of chemotherapy can be continued. 
The investigator should carefully monitor subjects for toxicities, particularly early and 
obvious signs of myelosuppression/infection/febrile neotropenia, so as to appropriately 


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treat these complications in time. 
Dose adjustment is not necessary for anemia, but the study physician should provide 
treatment according to routine practice at each study site. 
Neurotoxicity 
In case of severe peripheral neuropathy (G3-4), temporarily discontinue till the subject 
is recovered to grade 1, and dose of paclitaxel should be reduced by 20% in subsequent 
treatment. Once dose is reduced due to neurotoxicity, it is not allowed to restore the 
original dose. If toxicity is not recovered to grade 1 after temporary discontinuation for 
3 weeks, paclitaxel should be permanently discontinued. 
Allergic reaction hypersensitivity 
If allergic reaction is re-induced in subjects with previous mild to moderate 
hypersensitivity, prophylactic medication (see below) is recommended, with close 
monitoring of vital signs. 
 Mild symptoms: complete paclitaxel infusion. Bedside observation, not 
required for treatment. 
 Moderate symptoms: stop paclitaxel infusion, provide intravenous 
administration of diphenhydramine 25-50 mg and dexamethasone 10 mg. 
After resolution of symptoms, resume infusion of paclitaxel at low rate (20 
mL/hr infusion for 15 min, followed by 40 mL/hr for 15 min; after that, if 
there is no allergic reaction/hypersensitivity, complete infusion at normal 
infusion rate). If the same symptoms recur, stop paclitaxel infusion and 
permanently discontinue subsequent cycles of paclitaxel infusion. 
 Severe life-threatening symptoms: stop paclitaxel infusion, provide 
intravenous administration of diphenhydramine and dexamethasone (as 
above). If indicated, add epinephrine or bronchodilator. Permanently 
discontinue subsequent cycles of paclitaxel infusion. 
Other toxicities 
In case of other grades 3-4 toxicities not mentioned previously, temporarily discontinue 
infusion of chemotherapeutic drug till resolution of symptoms or recovery of toxicities 
to grade 1. Then resume infusion at 20% dose (not restored to the original dose 
thereafter). If toxicity is not recovered to grade 1 after temporary discontinuation for 3 


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weeks, chemotherapy should be permanently discontinued. For grades 1 and 2 toxicities, 
no dose adjustment is recommended. 
Dose adjustment of irinotecan 
The next cycle of irinotecan treatment can be started only if ANC is recovered to ≥1.5 
x 109/L, PLT is recovered to ≥100 x 109/L, and treatment related diarrhea completely 
resolved. Treatment should be delayed by 1-2 weeks to allow recovery of related 
toxicities. If the patient is not recovered after delay of 2 weeks, permanent 
discontinuation of irinotecan chemotherapy should be considered. 
If the subject develops toxicities listed in the table below, dose of irinotecan for the next 
cycle should be reduced by a decrement of 30 mg/m2. 
Table 6. Recommended dose adjustment of irinotecan monotherapy 
Toxicity grade 
Dose for the next cycle 
Neutropenia 
 
- 
Grade 1-2 neutropenia 
Maintain the original dose level 
- 
Grade 3-4 neutropenia 
Reduce by 1 dose level 
Febrile neutropenia 
Reduce by 1 dose level 
Diarrhoea 
 
- 
Grade 1-2 diarrhoea 
Maintain the original dose level 
- 
Grade 3 diarrhea  
Reduce by 1 dose level 
- 
Grade 4 diarrhea  
Reduce by 2 dose level 
Other non-hematological toxicities 
 
- 
Other grade 1 non-hematological toxicities 
Maintain the original dose level 
- 
Other grade 2-4 non-hematological 
toxicities 
Reduce by 1 dose level 
Principles for Management of Toxicities Associated with Immune 
Checkpoint Inhibitors 
IBI308 pharmacologically promotes the activation and proliferation of T cells to cause 
immune hyperfunction, thereby leading to autoimmune disorders of multiple systems. 
Immune-related adverse events were reported with clinical application of other immune 
checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab and atezolizumab), 


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including immune-related pneumonia, diarrhea/enterocolitis, renal insufficiency, rash, 
hepatitis, endocrine disorders, and peripheral or central neuritis. If the subject 
experiences any of the above AEs in this study, the subject’s symptoms and signs should 
be monitored, related examinations performed, and causes identified. If no alternative 
causes (e.g., disease progression, concomitant medication and infection) are identified 
and treatment with glucocorticoids and/or other immunosuppressive agents is required 
(except for endocrine events such as hyperthyroidism/hypothyroidism, hypophysitis, 
type 1 diabetes and adrenal insufficiency, which may not be treated with 
immunosuppressive therapy but are still considered related to immune hyperfunction 
caused by IBI308), the above AEs should be considered related to immune 
hyperfunction caused by IBI308 and diagnosed as irAEs. 
Guidelines on dose adjustment and toxicity management for potential major irAEs, 
potential other irAEs and infusion-related reactions are provided in Appendix 7. 
Concomitant Treatment 
Prohibited Medications 
 
Other chemotherapy, immunotherapy, targeted therapy and hormone therapy 
for treatment of tumor. 
 
Immunosuppressive agents and high-dose glucocorticoids (excluding those 
for AEs). 
 
Immunoglobulins. 
 
Live attenuated vaccine. 
Permitted Medications 
 
Medications that comply with the protocol requirements in the investigator’s 
judgment (e.g., concomitant medications for disease-related symptoms and 
treatment-related AEs). 
 
Long-term medications that are required for management of underlying 
diseases such as hypertension and diabetes. 
 
During study treatment, local surgery or radiotherapy (radiation field 
excluding lung) will be used for isolated lesions (excluding target lesions). 
 
Supportive treatment to relieve tumor related symptoms is permitted, such as 
bisphosphonates for bone metastasis. 


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 
Glucocorticoids that are intended for topical use, such as topical skin 
application, eye application, nasal spray and inhalation. 
 
Carriers of hepatitis B virus are permitted to receive prophylactic anti-viral 
treatment. For specific dosage and administration, refer to applicable 
guidelines. 
Drug-Drug Interactions 
 
IBI308: at present, there is no data on drug interaction with IBI308. 
 
Paclitaxel: 
- 
Cytochrome P450 isoenzymes CYP2C8 and CYP3A4 promote 
metabolism of paclitaxel. When paclitaxel is used concurrently with 
known substrates, inducers (e.g. rifampicin, carbamazepine, phenytoin, 
efavirenz and nevirapine) or inhibitors (e.g. erythromycin, fluoxetine and 
gemfibrozil) of cytochrome P450 isoenzymes CYP2C8 and CYP3A4, 
pharmacokinetics of paclitaxel will be changed, and caution is 
recommended. 
- 
Interaction between paclitaxel and substrates of CYP3A4 and protease 
inhibitors acting as substrates or inhibitors of CYP3A4 (ritonavir, 
saquinavir, indinavir and nelfinavir) has not been confirmed in a clinical 
study. 
- 
In vitro, many drugs (ketoconazole, verapamil, apauvin, quinidine, 
dexamethasone, cyclosporine, teniposide, etoposide and vincristine) can 
inhibit metabolism of paclitaxel into 6α-hydroxy paclitaxel, but 
concentrations used exceed normal in vivo therapeutic doses. 
Testosterone, 17α-ethinyloestradiol, retinoic acid and CYP2C8 specific 
inhibitor quercetin can also inhibit generation of 6α-hydroxy paclitaxel in 
vitro. 
 
Irinotecan: 
- 
Neuromuscular blocking agents: interaction between irinotecan 
hydrochloride and neuromuscular blocking agents cannot be excluded. 
Since irinotecan hydrochloride has cholinesterase inhibitor activity, drugs 
with cholinesterase inhibiting activity may prolong the neuromuscular 
blocking effects of suxamethonium chloride and the neuromuscular 


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blockade of non-depolarising drugs may be antagonised. 
- 
Anticonvulsants: concomitant use of CYP3A induced anticonvulsants 
(e.g. carbamazepine, phenobarbital or phenytoin) may result in decreased 
exposure of SN-38. For patients requiring anticonvulsant treatment, 
consider initiate or switch to non-enzyme induced anticonvulsants at least 
one week prior to initial dose of irinotecan hydrochloride. 
- 
Ketoconazole: concomitant ketoconazole treatment will significantly 
reduce clearance of irinotecan hydrochloride, resulting in increased 
exposure to its active metabolite SN-38. Ketoconazole should be stopped 
at least one week prior to initiation of irinotecan hydrochloride. Also, it 
should not be used concomitantly with irinotecan hydrochloride. 
- 
St. John’s Wort (Hypericum perforatum): the exposure to active 
metabolite SN-38 is reduced in patients concomitantly treated with 
Hypericum perforatum. Hypericum perforatum should be stopped at least 
one week prior to initial dose of irinotecan hydrochloride. Also, it should 
not be used concomitantly with irinotecan hydrochloride. 
- 
Atazanavir: concomitant use of atazanavir, an inhibitor of CYP3A4 and 
UGT1A1, may increase exposure of SN-38. This should be considered 
when these drugs are used concomitantly. 
- 
Dexamethasone: lymphocyte decreased has been reported in patients 
treated with irinotecan hydrochloride, which may be aggravated when 
dexamethasone is used as antiemetic. However, no serious opportunistic 
infection or any complication due to lymphopenia has been found. 
Increased blood glucose has been reported in patients using this product. 
This usually occurs in patients with a history of diabetes or impaired 
glucose tolerance before treatment with this product. Increased blood 
glucose in some patients may be due to dexamethasone. 
- 
Prochlorperazine: in a clinical study of monotherapy using weekly 
regimen, incidence of akathisia was higher in patients receiving 
prochlorperazine on the same day of irinotecan hydrochloride treatment 
(8.5%, 4/47 patients), and lower when the two drugs were administered 
on different days (1.3%, 1/80 patient). However, the incidence of 
akathisia 8.5% was still within the reported range of akathisia when 


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prochlorperazine was used as pre-medication for other chemotherapies. 
- 
During treatment with this product, concomitant use of laxatives may 
increase severity or incidence of diarrhea. However, there is no relevant 
study. 
- 
Diuretics: as there is potential risk of dehydration secondary to vomiting 
and/or diarrhea, physicians should avoid use of diuretics during treatment 
with irinotecan hydrochloride as well as diarrhea or vomiting. 
Treatment Compliance  
Study treatment is administered at the study site, and treatment compliance is monitored 
using drug receipt &amp; dispensing records, medical records and eCRFs. 
Drug Recovery and Destruction 
In this study, the used and partially used containers, bottles, infusion bags, and syringes 
of the study drug may be destroyed on site according to the applicable guidelines and 
operating procedures established by the study site and local authorities after 
confirmation by the clinical research associate (CRA). 
All unused study drugs will be returned to the sponsor for central destruction after study 
completion/termination or beyond expiration date. The clinical research associate 
designated by the sponsor will be responsible for return of study drugs. 
Documentation of Study Drug 
The designated site personnel should keep a record of the receipt, dispensing, use, 
inventory, loss, recovery and destruction of the study drugs in time according to the 
requirements of relevant regulations and guidelines as well as the operating procedures 
of this trial. 
Handling of Complaints  
To ensure safety of study participants, monitor quality, and promote improvement of 
flow process and drug product, the sponsor will collect product complaints related to 
study drugs used in the clinical trial. 
Complaints involving concomitant drugs will be reported directly to the manufacturers 
according to product label. 
The investigator or the designee will be responsible to complete the following flow 


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process of product complaint according to relevant specifications in this study: 
 
Use study specific complaint form to document reported product complaint 
and relevant complete description. 
 
Fax the completed product complaint form to the sponsor or the designee 
within 24 hours. 
If the investigator is required to return the product for investigation, the investigator 
should return a copy of product complaint form along with the product. 
6 Study Evaluations and Procedures 
Subject Enrollment and Randomization Process 
Subject Enrollment and Randomization 
The investigator(s) will enroll subjects according to the following procedures: 
1. Obtain the signed ICF from the subject prior to initiation of any study-related 
procedures. 
2. The principal investigator (PI) or the appropriately trained designee formally 
should confirm the subject’s eligibility according tothe inclusion/exclusion 
criteria. 
3. IWRS system will be used for randomization at 1:1 ratio, stratified by ECOG 
PS score (0 or 1). 
Re-screening may be performed for patients who do not meet the relevant criteria for 
this study (screening failure). If re-screening is considered, the investigator must 
contact the sponsor’s medical manager. Each patient can be re-screened once. At re-
screening, the patient must re-sign the ICF and will be reassigned with an identification 
number. 
Handling Procedures for Wrongly Enrolled Subjects 
Inclusion/exclusion criteria must be strictly followed. If an enrolled subject is found not 
meeting inclusion/exclusion criteria, the sponsor’s medical manager and the 
investigator should discuss to determine whether the subject should continue in the 
study, and whether study drug should be used. If the investigator considers it medically 
appropriate for the subject to continue in the study, and agreed by the sponsor's medical 
manager, the subject can continue in the study and receive study drug. If the investigator 


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considers is medically appropriate for the subject to continue in the study, but not agreed 
by the sponsor’s medical manager, the subject cannot continue in the study (whether 
receive study drug or not). The investigator may allow the accidentally enrolled subject 
to continue participation in the study only after receiving written approval from the 
sponsor. 
Study Plan and Schedule 
Screening Period 
The following study procedures must be completed during the screening period (Day -
28 - -1) to ensure the subject’s eligibility for the study: 
 
Signing ICF 
 
Inclusion/exclusion criteria 
 
Demographics, past medical history and previous medication 
 
Vital signs, height and weight 
 
Physical Examination 
 
ECOG PS score 
 
12-lead electrocardiogram 
 
Hematology/blood biochemistry/urinalysis (within 7 days prior to the first 
dosing) 
 
Pregnancy test (within 3 days prior to the first dose) 
 
Thyroid function (test results not older than 28 days prior to randomization at 
the site are acceptable) 
 
HIV antibody, hepatitis B panel (for HBsAg positive patients, further test 
HBV DNA) and HCV antibody (for HCV antibody positive patients, further 
test HCV RNA), test results not older than 28 days prior to randomization at 
the site are acceptable 
 
Adverse event assessment 
 
Concomitant medications 
 
Tumor imaging evaluation 


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 
Archived or fresh tumor tissue sample 
For details of tumor radiological assessment and safety assessment, refer to Sections 
6.3 and 6.4. 
Baseline (Prior to Dosing on Cycle 1/Day 1) 
 
IWRS randomization (first dose must occur within 3 working days of 
randomization) 
 
Vital signs 
 
Weight 
 
ECOG PS score 
 
Immunogenicity (IBI308 group only) 
 
Adverse event assessment 
 
Concomitant medications 
 
EQ 5D-5L questionnaires 
 
EORTC QLQ-C30 questionnaires 
 
EORTC QLQ-OES18 questionnaires 
 
Biomarker blood sample collection (IBI308 group only) 
Treatment Visits 
 
Vital signs 
 
Weight 
 
Physical Examination 
 
ECOG PS score 
 
12-lead electrocardiogram 
 
Hematology/blood biochemistry/urinalysis 
 
Thyroid function (IBI308 group only) 
 
Immunogenicity (IBI308 group only) 
 
Adverse event assessment 


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 
Concomitant medications 
 
Tumor imaging evaluation 
 
Administration of study drug (for visits requiring tumor radiological 
assessment, the assessment will be completed before dosing) 
 
EQ 5D-5L questionnaires 
 
EORTC QLQ-C30 questionnaires 
 
EORTC QLQ-OES18 questionnaires 
 
Biomarker blood sample collection (IBI308 group only) 
 
Survival status 
The flow chart of study treatment visits is provided in Table 1. 
For details of tumor radiological assessment, safety assessment and immunogenicity 
blood sample collection, refer to Sections 6.3, 6.4 and 6.5. 
Safety Follow-up 
Two safety follow-ups will be performed. The first takes place at the treatment 
discontinuation visit or on Day 30 (± 7 days) after the last dose, and the second on Day 
90 (± 7 days) after the last dose. Include: 
 
Vital signs 
 
Physical Examination 
 
ECOG PS score 
 
12-lead electrocardiogram 
 
Hematology/blood biochemistry/urinalysis 
 
Thyroid function (only the 1st one, IBI308 group only) 
 
Pregnancy test (only the 1st one) 
 
Immunogenicity (only the 2nd one, IBI308 group only) 
 
Adverse event assessment 
 
Concomitant medications 
 
Subsequent anti-tumor treatment (if applicable) 


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 
Survival status 
 
EQ 5D-5L questionnaires (only the 1st one) 
 
EORTC QLQ-C30 questionnaires (only the 1st one) 
 
EORTC QLQ-OES18 questionnaires (only the 1st one) 
Survival Follow-up 
After the 2nd safety follow-up, subjects will be contacted every 60 days (±7 days) 
(phone visit is acceptable). Information about survival, any subsequent systemic anti-
tumor treatment and disease progression will be obtained as far as possible. Long-term 
follow-up will be continued till subject's death or the end of study. 
Efficacy Evaluation 
The method used for baseline tumor burden assessment must be consistent with the 
method used for each subsequent follow-up assessment. Other involved sites will be 
examined as suggested by each subject’s symptoms and signs. Baseline assessment 
should be performed within 28 days prior to the first dose of study drug. The 
investigators may collect imaging results within 28 days prior to enrollment for 
assessment. 
Tumor imaging evaluation will be performed every 6 weeks (± 7 days) in the first 24 
weeks following the first dose of study drug, and then every 9 weeks (± 7 days) after 
Week 24, until initiation of new anti-tumor treatment, disease progression, withdrawal 
of ICF, or death. For patients with initially documented radiological progression in 
IBI308 treatment group, radiological confirmation is required at an interval of 4-6 
weeks. Some subjects meeting specific conditions can continue treatment beyond 
disease progression (refer to Section 5.1.2 in the protocol). For subjects who continue 
treatment beyond disease progression, radiologic evaluation should be continued. For 
patients who discontinued treatment for reasons other than radiographic disease 
progression, imaging evaluations should, wherever possible, be performed every 6 
weeks (± 7 days) after discontinuation, until occurrence of any of the following: 
initiation of new anti-tumor therapy, disease progression, withdrawal of ICF, and death. 
If the investigator cannot determine whether there is the disease progression or not, 
particularly uncertain about non-target lesions and new lesions, the subject can continue 
treatment. Disease status will be re-assessed in case of clinical signs or at the next 
scheduled assessment time point. If repeated scan confirms disease progression, the 


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date of progression should be the date of initial discovery. 
The primary analysis in this study is based on tumor assessment of the study site using 
RECIST v1.1. See Attachment 3 for assessment methods. For subjects treated by 
IBI308 who have a disease progression as assessed per RECIST v1.1, radiologic 
evaluation should be continued as per iRECIST (Attachment 4) assessment 
requirements and the frequency of follow-up, wherever possible. 
Safety Assessment 
Routine Laboratory Safety Evaluations 
Table 7. Routine laboratory safety evaluations 
Hematology 
RBC, HGB, WBC, PLT, LYM, ANC 
Blood 
Biochemistry 
TBIL, ALT, AST, γ-GT ALP, ALB, TP, LDH, BUN, Cr, Na, K, Cl, Mg, Ca, P, 
Lipase, Amylase and FBG 
Urine 
Routine 
PH, UWBC, UPRO, URBC 和UGLU 
Physical Examination and ECOG PS Score 
Complete physical examination includes: general condition, respiratory, cardiovascular, 
abdominal, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, 
thyroid, musculoskeletal (including spine and limbs), genital/anal and neurological 
assessments. 
Refer to Table 1 visit schedule for the specific time of physical examination. Refer to 
Appendix 2 for ECOG PS scoring system. 
12-lead Electrocardiogram 
Resting 12-lead ECG will be analyzed at a local laboratory according to Table 1 visit 
schedule.  
A 12-lead ECG is performed for each subject after a rest of minimum 5 minutes in 
recumbent position. All 12-lead ECGs should be recorded with the subject in a 
recumbent position. Further ECG will be performed as clinically indicated, e.g., when 
there is an occurrence of cardiac-related AE. The investigator completes ECG 
assessment on the day of the examination and write down the results of assessment on 
the electrocardiogram. The same assessment method(s) should be used throughout the 


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study. 
The investigator should assess all ECGs according to the category of clinically 
significant abnormality/not clinically significant abnormality. If the abnormality is 
clinically significant, the investigator should record this result as an AE in the eCRF. 
Vital Signs 
Vital signs examination will be performed as described in Table 1 study visit schedule. 
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. 
Additional monitoring of vital signs may be performed at the discretion of the 
investigator based on standard clinical practice or as clinically indicated. 
In the event of an AE/SAE, additional vital sign values may be collected from the eCRF 
(if appropriate). The date(s) and time of collection and measurement will be recorded 
in the appropriate section of the eCRF. 
Pulse and Blood Pressure 
Blood pressure (BP) and pulse rate are measured with the subject a supine position after 
a rest of at least 5 minutes. Two ore more readings should be obtained with 
measurement performed at intervals of two minutes, and the mean of the measurements 
is calculated. If the first two systolic blood pressure readings differ by more than 5 
mmHg, another measurement should be performed to calculate the mean value. The 
date(s) and time of collection and measurement will be recorded in the appropriate 
section of the eCRF. 
Measurement of pulse and blood pressure measurements needs to be performed prior 
to administration of the study drug. 
Body Temperatureand Respiratory Rate 
Blood temperature and respiratory rate should be collected prior to infusion on the 
scheduled dosing day(s). 
Body Weight and Height 
Body height is measured only during the screening period. 
Body weight measurement needs to be performed at screening and prior to each 
scheduled dosing throughout this study. 


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Pregnancy Test 
For women of childbearing potential (see 4.3 for definition), a pregnancy test using 
urine or serum human chorionic gonadotropin (hCG) samples should be performed 
within 3 days prior to the first dose of study drug. If urine hCG test reports positive or 
negative cannot be confirmed, a pregnancy test using serum β-hCG samples should be 
performed, and the result of serum pregnancy test should prevail. If the pregnancy test 
is positive, the subject is not eligible for enrollment/must be discontinued from the study. 
In the event of suspected pregnancy during the study, a test should be repeated for 
confirmation. 
Other Safety Tests 
 
Hepatitis B: hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb), if 
HBsAg positive, further test HBV DNA. 
 
HIV antibody, HCV antibody (if HCV antibody positive, further test HCV 
RNA). 
 
Thyroid function (except screening period, other time points for IBI308 group 
only): TSH, T3, T4, FT3 and FT4. 
Immunogenicity 
Immunogenicity test will be performed only for the IBI308 group, within 1 hour before 
IBI308 infusion in Cycle 1, Cycle 2, Cycle 4 and then every 4 cycles (Cycles 8, 12, 16 
and so on), and at the 2nd safety follow-up visit. The test will be performed at the central 
laboratory. 
Testing on anti-drug antibody titer will be performed for each subject, and ADA-
positive serum specimens will be further tested for neutralizing antibodies (NAbs). 
Four (4) mL of whole blood will be collected into a coagulation-promoting vacuum 
tube, then separated serum, split and frozen for ADA and NAb analysis. 
For details of sampling method, sample preservation, shipping and analysis, refer to the 
Laboratory Manual provided by the sponsor designated central laboratory. 
Quality of Life Assessments 
QoL assessment will be performed using EQ 5D-5L, EORTC QLQ-C30 and EORTC 
QLQ-OES18 questionnaires on the day of the first dose, and at each radiographic 
evaluation and the first safety follow-up visit. For details of assessment questionnaires 


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and requirements, refer to Quality of Life Assessment Manual provided by the sponsor. 
Biomarker Analysis  
As permitted by the Ethics Committee, all subjects meeting inclusion criteria have to 
provide diagnosed tumor tissue at baseline. Acceptable tumor tissues include 10 
unstained 4-5 micron slides prepared from archived tumor tissue or freshly collected in 
screening period, which will be used for tumor tissue PD-L1 testing and mRNA 
expression analysis of immune related genes (including but not limited to mRNA 
expression of IDO1, CXCL9, CXCL10, HLA-DRA, STAT1, IFNG). 
Subjects in IBI308 group have to provide 10 ml of whole blood samples at the following 
time points: screening period, at each efficacy evaluation before initiation of the next 
treatment in treatment period, for analysis of circulating tumor cell (CTC) (including 
but not limited to dynamic change of PD-L1) and ctDNA sequencing. 
For details of sampling method, sample preservation, shipping and analysis, refer to the 
Laboratory Manual provided by the sponsor designated central laboratory. 
Storage and Destruction of Biological Samples 
Samples will be anonymized and pooled. In addition, they will be disposed of or 
destroyed appropriately. Additional analyses may be performed for the anonymized, 
pooled samples to further assess and validate the analytical methods. Any results 
obtained from these analyses may be reported separately from the CSR. 
Sample reproducibility analysis (if performed) will be performed in parallel with the 
bioanalysis of the test samples. The assessment results will be separately reported in a 
bioanalysis report rather than in the clinical study report. 
7 Safety Report and AE Management 
Definition of Adverse Events 
An adverse event (AE) is defined as any adverse medical event that occurs from the 
clinical trial subject’s signing of the informed consent form to 90 days after the last 
dose of study drug regardless of causality with the study drug. AEs include but are not 
limited to the following situations: 
 
Worsening of preexisting medical conditions/diseases (including worsening 
of symptoms, signs and laboratory abnormalities); 


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 
Any new adverse medical conditions (including symptoms, signs and newly 
diagnosed diseases); 
 
Clinically significant abnormal laboratory test values or results.  
Definition of Serious Adverse Events 
A Serious Adverse Event (SAE) refers to an AE that meets at least one of the following 
criteria: 
 
Results in death, excluding deaths due to disease progression from the 
studied indication. 
 
Life-threatening (a “life-threatening” AE in the definition refers to an AE 
whose occurrence will have the subject under the risk of death, excluding 
AEs that may cause death if aggravated). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
with the exception of the following: 
 Rehabilitation facility 
 Nursing home 
 Conventional emergency room admission and treatment 
 Day surgery (e.g. outpatient/same-day/ambulatory surgery) 
 Hospitalization or prolonged hospitalization itself unrelated to AE 
deterioration is not an SAE, such as hospitalization due to the original 
disease without the occurrence of new adverse events or aggravation of 
the original disease (e.g.: for examination of laboratory test abnormalities 
that have persisted from before the trial to the present); hospitalization for 
administrative reasons (e.g.: routine yearly physical examination); 
hospitalization stipulated by the trial protocol during the clinical trial (e.g.: 
operations as required by the trial protocol); elective hospitalization 
unrelated to the deterioration of adverse events (e.g.: elective surgery); 
pre-defined treatment or surgery should be recorded in the entire trial 
protocol 
and/or 
the 
subject’s 
personal 
baseline 
information; 
hospitalization only for the use of blood products. 
 
Leading to persistent or significant disability/incapacity. 


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 
Leading to congenital anomalies/birth defects. 
 
Other significant medical events: defined as events that jeopardize the 
subject, or require medical intervention to prevent any of the above 
situations. 
Criteria for AEs Severity Judgment 
The investigator(s) will assess the severity of AEs according to the five-grade judgment 
criteria as established in NCI CTCAE v4.03. 
AEs that are not included in NCI CTCAE v4.03 will be graded according to the 
following CTCAE principles: 
 
Grade 1 mild; No symptom or slight sign; Only clinical or diagnostic 
observation; Medical intervention not indicated. 
 
Grade 2 moderate; Minimal, local or non-invasive intervention indicated; 
Limiting age-appropriate instrumental activities of daily living (ADL, e.g., 
preparing meals, shopping for groceries, using the telephone, managing 
money, etc.). 
 
Grade 3 severe or clinically significant, but not immediately life-threatening; 
Hospitalization or prolonged hospitalization; With disability; Limiting daily 
activities (e.g. bathing, dressing, eating, toileting and drug use), but not bed-
ridden. 
 
Grade 4 life-threatening consequences; Urgent intervention indicated. 
 
Grade 5 death related to AEs 
Judgment on Correlation between AEs and Study Drug 
The relationship of the study drug with the AEs or the role it plays in the occurrence of 
AE can be judged using the following classification and criteria: 
Table 8. Judgment on correlation between AEs and study drug 
Correlation 
Criteria 
Definitely 
related 
 
There exists a reasonable temporal consequence in use of the study drug 
with occurrence of the AEs; 
 
The AEs can be more reasonably explained by the investigational drug 
than other causes (e.g., the subject's preexisting disease, environmental or 
toxic factors or other treatments the subject received, etc.); 


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Correlation 
Criteria 
 
The AEs disappear or are mitigated after treatment discontinuation or dose 
reduction; 
 
It falls into the known AEs types of the suspected drug or similar drugs; 
 
The adverse event appears again after resumption of the drug; 
Possibly 
related 
 
There exists a reasonable temporal consequence in use of the study drug 
with occurrence of the AEs; 
 
The AEs can be reasonably explained by the investigational drug as well as 
by other causes (e.g., the subject's preexisting disease, environmental or 
toxic factors or other treatments the subject received, etc.); 
 
The AEs disappear or are mitigated after treatment discontinuation or dose 
reduction (if applicable). 
Unlikely 
related 
 
The AEs can be more reasonably explained by other reasons (e.g., the 
subject's preexisting disease, environmental or toxic factors or other 
treatments the subject received, etc.) than the investigational drug; 
 
It is unknown whether the AEs disappear or are mitigated after treatment 
discontinuation or dose reduction (if applicable); 
 
It is unknown whether the AEs appear again or not after resumption of the 
drug. 
Definitely 
unrelated 
 
There does not exist a reasonable temporal consequence in use of the drug 
with occurrence of the AEs, or 
 
There are other obvious explanations for the AEs (e.g., the subject's 
preexisting disease, environmental or toxic factors or other treatments the 
subject received, etc.). 
Unable 
to 
judge 
 
The above information is unknown; the investigator considers it impossible 
to judge based on available information and is unable to obtain further 
follow-up information. 
Recording of AEs 
The investigator(s) should record AEs or SAEs using medical terminology/concepts. 
Use of colloquialisms and abbreviations should be avoided. All AEs (including SAEs) 
should be recorded on the adverse event form of the eCRF. 
Collection of AEs and Time Period 
The investigator is aware of AEs by asking the subjects non-inductive questions. 
All AEs (including SAEs), whether observed by the investigator or spontaneously 
reported by the subjects, should be collected from the signing of the ICF through 90 
days after the last dose. 
Beyond 90 days after the last dose, the investigator should report SAEs that are 


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considered related to the study drug or procedures.  
Follow-up of AEs 
All AEs should be followed up until they resolve to baseline or grade 0 - 1 or the 
investigator consider further follow-up unnecessary for good justification (e.g, the AEs 
cannot resolve or has improved). If the AEs cannot resolve, the reasonable 
explanation(s) should be recorded on the eCRF. The outcomes of AEs or SAEs in the 
subjects and their dates should be documented on the eCRF and medical records, 
irrespective of their relationship with the study drug. 
AEs Records 
The investigator should keep a complete record of any adverse event, including 
diagnosis (if no diagnosis, record the symptoms and signs including abnormal 
laboratory findings), start and end dates and time (if applicable), CTCAE severity grade 
and change (Grade 3 events and above), whether it is an SAE, whether it is an AESI, 
actions taken for the study drug, treatment administered due to the AE and the outcome 
of the event, and the relationship of AE with the study drug. 
For an SAE, the investigator should also provide the following details: the date on 
which the AE is judged to meet the criteria for an SAE, the date the investigator became 
aware of the SAE, rationale for determining the AE as an SAE, the date of 
hospitalization, the date of discharge, the possible cause(s) of death, the date of death, 
whether an autopsy was performed, the assessment of causality with the study 
procedures, assessment of causality with other drugs, and other possible explanations 
for the SAE. The investigator should also provide the rationale for correlation judgment 
and a description of the SAE. SAE description should also include subject number, age, 
gender, height and body weight; Indication of study treatment, disease stage and 
relevant systemic condition; Clinical disease course including onset, development and 
outcome of SAE; Laboratory results associated with SAE (test time, unit and normal 
range must be provided); Past history, concurrent disease associated with SAE, as well 
as onset time and duration; Medication history, concomitant drug associated with SAE, 
as well as treatment start, duration, dosage and administration; Details of start, duration, 
dosage and administration of study drug treatment. 
The items of AEs records are described as follows: 
Diagnosis, symptoms and signs 


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If a diagnosis has been made, the diagnosis should be recorded in the eCRF rather than 
the individual signs and symptoms (e.g., record liver failure other than jaundice, 
elevated transaminases, and asterixis). If symptoms and signs cannot be determined to 
be a result of the diagnosis at the time of reporting, they should be recorded as a separate 
AE/SAE. If the symptoms and signs are determined to be a result of the diagnosis, only 
the diagnosis is reported separately, with the symptoms and signs included in the 
diagnosis. For an AE, the records of signs and symptoms need to be deleted; for an SAE, 
the updated follow-up report needs to be sent. 
AEs secondary to other events 
For adverse events secondary to other events (e.g. caused by other events or clinical 
sequelae), their primary events should be documented in general, unless such a 
secondary event is of high severity or an SAE. However, a secondary event of great 
clinical significance should be recorded as a separate AE in the eCRF provided it 
occurred at different time from the primary event. If the correlation between the events 
is unclear, the events should be recorded separately in the eCRF. 
Persistent or recurred AE 
A persistent AE refers to an AE that persists and does not resolve between two 
evaluations for the subject. 
A recurred AE refers to an AE that resolved between two evaluations but occurred later 
again. The occurrence of such events should be recorded separately on the eCRF. 
Abnormal laboratory findings 
Clinically significant abnormal laboratory findings should be reported as AEs. It is the 
responsibility of the investigator to review all abnormal laboratory findings and make 
medical judgment on each abnormal laboratory finding as to whether they should be 
reported as an AE. 
Death 
All deaths that occurred throughout the trial, including the 90-day follow-up period that 
begins from the last dose, should be recorded on the death report form on the eCRF and 
reported to the sponsor in a timely manner, irrespective of relationship with the study 
drug. 
When recording death, if cause of death is determined, it will be recorded as AE with 


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outcome of death, and the event will be reported as SAE; If cause of death is unclear at 
the time of report, “unexplained death” should be recorded on AE page of eCRF. 
“Unexplained death” will be reported as SAE, followed by further investigation to 
determine the cause of death. 
If the death is clearly due to tumor progression, it will not be recorded and reported as 
AE/SAE, but the investigator should keep a record of the death on the death report form 
on the eCRF and inform the sponsor timely. 
Preexisting medical conditions 
The preexisting symptoms/signs a subject has already presented in the screening period 
of the trial should be recorded and reported as AE only when there is worsening in 
severity, frequency and nature (excluding worsening of the medical condition studied) 
after entry into the trial. Changes from the previous state should be reflected in the 
record, e.g., “increased frequency of headache”. 
Hospitalization, prolonged hospitalization, or surgery 
All AEs resulting in hospitalization or prolonged hospitalization should be recorded and 
reported as SAE, except the following: 
 
Scheduled hospitalization or prolonged hospitalization as requirement of the 
protocol (e.g. for administration, efficacy assessment, etc.) 
 
Hospitalization for medical condition pre-existing before participation in the 
study without any change. For example, elective surgery/treatment scheduled 
before participation in the study. 
However, the required elective surgery and treatment due to condition deterioration of 
the existing disease during the study shall be considered as AE. 
Disease progression 
Progressive disease (PD) is defined as worsening of a subject’s condition due to the 
primary tumor the investigational drug is targeted on. Appearance of new lesions 
relative to the primary tumor or progression of the original lesions is considered as PD. 
PD is not reported as an AE. Death due to signs and symptoms of disease progression, 
events that were life-threatening, required inpatient hospitalization or prolongation of 
existing hospitalization, resulted in persistent or significant disability/incapacity, or 
were a congenital anomaly/birth defect, and other important medical events warrant 


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expedited reporting as SAE. 
Overdose 
Overdose is defined as use beyond the protocol-specified dose. Overdose will be 
recorded in eCRF. 
Expedited reporting of SAEs and pregnancies 
Reporting of SAEs: 
The time limit of SAE reporting is from signing of the ICF to 90 days (including Day 
90) after the last dose. In case of an SAE during this period of time, the investigator 
must immediately fill out, sign and date "CFDA Serious Adverse Event Report Form", 
and submit the completed form to the sponsor, National Medical Products 
Administration and the Ethics Committee no later than 24 hours after awareness, 
regardless of an initial report or a follow-up report. Detailed contact information on 
SAE reporting is provided in the Table below. 
If any serious adverse event occurred beyond the above - mentioned time limit is 
considered as related to the study drug, it should also be reported to the sponsor. 
The investigator must submit the completed SAE report form to the sponsor as soon as 
possible and within 24 hours after awareness of an SAE. For deaths or life-threatening 
serious adverse events, the investigator should immediately follow up missing 
information and provide a complete SAE report. 
Meanwhile, the investigator should report to the drug regulatory authorities, health 
administrative department and the Ethics Committee according to regulatory 
requirements. 
Table 9. Contact information for SAE reporting 
Unit 
Contact 
Fax/Phone/Address 
Hospital name 
Ethics Committee 
Fax/Phone of each hospital 
Innovent Biologics (Suzhou) 
Co., Ltd. 
Clinical 
Research 
Department PV 
Fax: 021-31652800 
Email: drugsafety@innoventbio.com 
Division of Drug Research 
Supervision, Department of 
Drug 
and 
Cosmetics 
 
Address: 
Building 
2, 
No.26 
Xuanwumen West Street, Xicheng 


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Registration, CFDA 
District, Beijing. P.R. China 
Postcode: 100053 
Tel.: 010-88330732 
Fax: 010-88363228 
The 
Bureau 
of 
Health 
Administration, the National 
Health Commission 
 
Address: No. A38 Lishi Road, Xicheng 
District, Beijing, P.R. China 
Tel.: 010-68792001 
Fax: 010-68792734 
Provincial, autonomous region 
and municipal drug regulatory 
authorities 
Refer to reporting requirements of provincial, autonomous 
region and municipal drug regulatory authorities  
Pregnant women 
Considering embryotoxicity risks are reported for similar drugs, all clinical trial 
participants of childbearing potential must take effective contraceptive measures. 
If any female subject becomes pregnant during the clinical trial, the subject should be 
withdrawn from the study, and the investigator should report the pregnancy to the 
sponsor within 24 hours after awareness, and fill out the Innovent Clinical Trial 
Pregnancy Report/Follow-up Form. 
If any partner of a male subject becomes pregnant during the clinical trial, the subject 
may continue the clinical trial, and the investigator should report the pregnancy to the 
sponsor within 24 hours after awareness, and fill out the Innovent Clinical Trial 
Pregnancy Report/Follow-up Form. 
The investigator shall follow up the outcome of the pregnant subject until 8 weeks after 
childbirth, and shall report the outcome to the Sponsor. 
If the outcome of pregnancy is stillbirth, spontaneous abortion, fetal malformation (any 
congenital anomaly/birth defect), or induced abortion for medical reasons, it should be 
considered as SAE and reported according to the procedures and time limit for SAE 
reporting. 
If a subject experienced a concurrent SAE during pregnancy, CFDA Serious Adverse 
Event Report Form should also be completed for reporting according to the SAE 
reporting procedures. 


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Liver function abnormality events 
If there is abnormal AST and/or ALT with abnormally elevated total bilirubin meeting 
the following criteria, without alternative cause of liver injury, this should be considered 
as drug induced liver injury. Such condition should always be regarded as important 
medical events. 
Table 10. Liver impairment that should be reported as SAE 
Baseline 
Normal 
(AST/ALT 
and 
total 
bilirubin) 
Abnormal 
(AST/ALT 
and 
total 
bilirubin) 
Treatment period 
ALT or AST ≥3x ULN  
With total bilirubin ≥2×ULN 
And 
alkaline 
phosphatase 
≤2×ULN 
And no hemolysis 
AST or ALT ≥8×ULN 
With total bilirubin increase ≥1×ULN 
or value ≥3×ULN 
Subjects should return to the study site for evaluation as soon as possible (preferably 
within 48 hours) after discovery of abnormal result. This evaluation should include 
laboratory tests, detailed medical history and physical assessment, and the possibility 
of hepatic neoplasia (primary or secondary) should be considered. 
In addition to repeating AST and ALT, laboratory tests should also include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time/international normalized ratio and alkaline phosphatase. 
Detailed medical history collection should include: alcohol history, acetaminophen, soft 
drugs, various supplements, traditional Chinese medicine, history of chemical drug 
exposure, family history, occupational exposure, history of sexual behavior, travel 
history, history of contact with jaundice patient, surgery, blood transfusion, liver disease 
or allergic disease history, cardiac disease history and immune disease history. Further 
tests may also include tests of acute hepatitis A, B, C and E, liver imaging (e.g. biliary 
tract), autoantibody and cardiac ultrasound. If repeated test still meets laboratory 
criteria in Table 10, without alternative cause of liver function test abnormality, 
possibility of potential drug induced liver injury should be considered, with no need for 
results of all liver function etiological tests. Such cases of potential drug induced liver 
injury should be reported as SAE, and Attachment 5 "Monitoring of liver function 
abnormality and follow-up report form "will be submitted to the sponsor. 


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Management of drug related toxicities 
The sponsor will perform periodic safety review at trial level during the trial. Details 
concerning frequency of review and type of reviewed data will be documented in a 
separate trial-level safety review plan. 
Immune-related adverse events 
Given that IBI308 pharmacologically acts to cause activation and proliferation of T 
cells, immune-related adverse events (irAEs) may be observed during this study. The 
definition of irAE is provided in Section 5.5 of the protocol. Subjects should be 
monitored for signs and symptoms of irAEs. 
For details of IBI308 dose adjustment and principles of AE management, refer to 
Sections 5.4.2 and 5.5 of the protocol. Guidelines for the handling of irAEs are provided 
in Appendix 7 (Tables 1 - 2). 
Adverse events of special interest 
An adverse event of special interest (AESI) refers to an AE that needs to be closely 
monitored to better understand the safety profile of the investigational drug, and 
therefore AESI can be non-serious events. 
AESI includes: 
 ≥Grade 3 infusion related reactions 
 ≥Grade 2 diarrhea, colitis, uveitis, interstitial pneumonia 
 ≥ Grade 3 suspected irAEs 
8 Statistical Considerations 
Statistical Analysis Plan 
A detailed statistical analysis plan (SAP) will be written after enrollment of the first 
subject and finalized before database lock. The SAP will provide a full presentation of 
all statistical analyses and their results. 
Hypothesis Test 
This study is a superiority design comparing test drug and reference drug using 
superiority hypothesis test: 
H0: HR≥1; Ha: HR< 1 


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For primary efficacy endpoint, =0.2 (two-sided). Stratified log-rank test will be used 
for the comparison of OS between IBI308 group and chemotherapy group. 
Statistical Analysis Population 
The analysis population includes safety analysis set (SS), full analysis set (FAS), and 
per-protocol set (PPS): 
1) SS: the population of subjects who received at least one dose of the study drug. 
2) FAS: the population of randomized subjects. 
3) PPS: a subset of the FAS, defined as the population of subjects with good compliance 
who constituted no gross protocol violations, without major protocol violations and 
used no concomitant medications prohibited by the protocol. 
Statistical Analysis Methods 
General Methods Forstatistical Analysis 
Measurement data are presented by mean, standard deviation, median, maximum and 
minimum; Count data are described by frequency and percentage. 
All statistical analyses will be completed using SAS 9.2 (or a higher version). 
Except primary efficacy endpoint, nominal test significance level for other inter-group 
comparisons: =0.05 (two-sided). If P value ≤0.05, inter-group difference is considered 
statistically significant. 
Analysis of Primary Endpoint 
Overall survival (OS): the time from randomization to the death of the subject, when 
the subject is still alive at the end of the study, with the known "date the subject was 
last alive" as the censoring date. 
For OS analysis, Kaplan-Meier will be used to estimate median OS (mOS) and its 95% 
CI. Survival curve will be plotted. Comparison between groups will be performed by 
the stratified log-rank test. Stratified Cox proportional-hazards model will be employed 
for estimating HR. Stratification factors of randomization will be included in the model. 
Meanwhile, the comparison of OS between groups will be performed by the RMST 
method. 
The 6-month and 1-year overall survival rates will be estimated using Kaplan-Meier 
method. 


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Analysis of secondary endpoints 
All efficacy evaluations will be based on RECIST v1.1: 
 Progression free survival (PFS) 
PFS: the time from randomization to the first occurrence of disease progression 
(radiographic), or the time from randomization to death if a patient died of any cause 
before disease progression. For subjects without disease progression or death, the 
censoring date is the last date of imaging evaluation. Subjects without imaging 
evaluation after baseline will be censored at the date of randomization. 
For PFS analysis, median PFS (mPFS) and its 95% CI will be estimated by the Kaplan-
Meier. Survival curve will be plotted. Comparison between groups will be performed 
by the stratified log-rank test. 
 Objective response rate (ORR) 
𝑂𝑅𝑅=
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓𝐶𝑅 + 𝑃𝑅 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠∗100%, its 95% CI, inter-group difference and its 
95% CI will be calculated by using the binomial distribution. Fisher exact probability 
will be used for inter-group comparison. 
 
Disease control rate (DCR) 
𝐷𝐶𝑅=
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓𝐶𝑅+𝑃𝑅+𝑆𝐷 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠
∗100%, its 95% CI, inter-group difference and its 
95% CI will be calculated by using the binomial distribution. Fisher exact probability 
will be used for inter-group comparison. 
 
Duration of response (DoR) 
For subjects achieving response (CR or PR), duration of response is the time from date 
of first response to time of disease progression or death. Subjects without disease 
progression or death will be censored at the date of last imaging evaluation. 
Median DoR (mDoR) and its 95% CI will be estimated by Kaplan-Meier. Survival 
curve will be plotted. Comparison between groups will be performed by the stratified 
log-rank test. 
Quality of Life Scale Analyses 
Variations of QoL scale scores as assessed per EQ 5D-5L, EORTC QLQ-C30 and 
EORTC QLQ-OES18 will be described by group and visit, so as to evaluate the QoL 


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and health status of the subjects treated by IBI308 and chemotherapy, respectively. 
Biomarker Analysis 
 Tumor tissue samples will be collected for the analysis of tumor biomarkers, 
including but not limited to the expression of PD-L1 and the expression of 
immune-related genes (including but not limited to the expression of IDO1, 
CXCL9, CXCL10, HLA-DRA, STAT1, IFNG messenger RNA). The relationship 
between these markers and efficacy will be analyzed 
 For subjects in IBI308 group, blood samples will be collected for the analysis of 
circulating tumor cells (CTCs) (including but not limited to PD-L1 dynamic 
expression) and ctDNA analysis. 
Safety Analysis 
The safety analysis will be performed using the SS population. Safety indicators include 
AEs, laboratory tests, vital signs, ECGs and immunogenicity. 
Drug exposure 
The exposure and duration (cycles) of the study drug in the subjects during the study 
period will be summarized. 
Adverse events 
All adverse events will be coded using MedDRA. 
Incidence (frequency) of AEs, TEAEs, ADRs, irAEs, AESIs, SAEs and AEs leading to 
study discontinuation will be summarized separately; Severity distribution of TEAEs, 
ADRs, irAEs and AESIs will be summarized by MedDRA SOC and PT per NCI 
CTCAE v4.03. 
Subjects who discontinued treatment due to AE, subjects who experienced SAEs and 
subjects who died will be tabulated (at least including the start date, end date and 
severity of AE, relationship with drug, actions taken, and outcome). 
Laboratory tests 
For hematology and blood biochemistry, the measured values and values of change 
before and after treatment will be described using mean ± SD, maximum, minimum 
and median, and cross classification table will be employed for describing normal and 
abnormal changes before and after treatment. 


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Urinalysis: cross classification table will be used to describe the normal and abnormal 
changes before and after treatment. 
The percentage of subjects with abnormal changes evaluated as “abnormal and 
clinically significant” will be described. The investigator judges whether the 
abnormality is clinically significant or not. 
A list of subjects with abnormal changes (clinically significant or not clinically 
significant) after treatment will be provided. 
ECG examination 
The changes of ECG indicators from baseline will be descriptively described. The 
normal and abnormal changes before and after treatment will be described by the cross-
classification table, and a data list will be provided 
Vital signs, physical examination and other safety-related examinations 
The results of vital signs examination and changes from baseline will be summarized 
descriptively. 
Subjects with abnormal changes from baseline in physical examination will be 
summarized by tabulation. 
Immunogenicity Measures 
Positive rates of ADA and neutralizing antibody will be calculated, and antibody level 
of positive subjects will be tabulated. 
Compliance Analysis 
The following will be summarized: the percentage and number of subjects with a 
violation of the intended dosing regimen 
Percentage of subjects who have used the study drug at 80% - 120% of the dose 
specified in the protocol 
Percentage of subjects having completed the study, and percentage of subjects having 
completed different treatment cycles. 
Baseline Characteristics of Subjects 
Descriptive statistics of subject demographics (gender, age); Information on diagnosis 
and treatment of tumor (pathological diagnosis, clinical stage, previous treatment); 


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Baseline tumor testing (number, site and total long diameter of target lesions and non-
target lesions); Other baseline information: height, body weight (body mass index, body 
surface area), vital signs, laboratory tests, previous/ongoing/new concomitant 
medications. 
Interim Analysis 
This study is a phase II clinical study. Due to limited sample and potential delayed 
overall survival benefit of anti-tumor immunity, no interim analysis is planned in this 
study. 
Subgroup Analysis 
Efficacy analysis in PD-L1 positive subjects; 
Subgroup analyses based on randomization stratification factors (e.g. PS score); 
Subgroup 
analyses 
based 
on 
subjects’ 
baseline 
characteristics, 
different 
chemotherapeutic drugs (paclitaxel or irinotecan), previous treatment (drug, best 
response), and other factors of potential clinical significance. 
Multiple Comparison and Multiplicity Adjustment 
Formal statistical test will be performed only for primary efficacy endpoint in this study. 
Multiple comparison is not applicable. 
Data Listing of Valid Subjects 
In addition to subject data listing, tumor evaluation (date of evaluation, lesion condition, 
evaluation result) and efficacy parameters of CR and PR subjects will be listed 
separately. 
PFS and OS data of all subjects by the end of study (date of disease progression, date 
of death, PFS, OS) 
Exploratory Analysis 
Relationship between PD-L1 expression level and efficacy; 
Clinical benefit evaluation based on iRECIST in IBI308 group, including iPFS, iORR, 
iDCR and iDoR (see Section 8.4.3 for analysis methods); 
Relationship between biomarker levels and efficacy parameters. 


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Sample Size Determination 
Since this study is a phase II clinical study with overall survival (OS) as the primary 
endpoint, assuming a two-sided  level of 0.2, power of 80% and a hazard ratio (HR) 
of 0.7 for the IBI308 group compared with the chemotherapy group, a number of 142 
subjects with OS events is required. Further, presuming 21% of the patients are 
censored, an estimated number of about 180 subjects should be enrolled, with about 90 
subjects in the IBI308 and chemotherapy groups each, respectively (35 study sites, with 
0.7 subjects enrolled per month, the expected duration of this study is 27 months). 
Considering a possible delay of OS benefit with the anti-tumor therapy and based on 
an estimated median OS of approximately 8.7 months for IBI308, it should be ensured 
that the subjects have been followed up for about 10 months (from randomization) by 
the time of OS analysis. 
Measures for Bias Control 
Randomization and Blinding 
In this study, the subjects will be randomized by an interactive web response system 
(IWRS), and the randomization stratification factor is ECOG PS score (0 or 1). The 
investigator or qualified designee will enter the interactive web response system with 
their own passwords, assign each subject a unique randomization number, and obtain 
the subject's corresponding study drug group from the IWRS: IBI308 group or 
chemotherapy group. If randomized into IBI308 group, the subject will receive IBI308 
treatment. If the subject is randomized into chemotherapy group, the investigator 
should determine if paclitaxel or irinotecan will be used based on the subject's previous 
anti-tumor therapy. The independent statistician responsible for randomization will use 
block randomization method to generate a randomization table (subject randomization 
number) at 1:1 (IBI308:chemotherapy) ratio. Subject randomization numbers will be 
submitted to the randomization system as an electronic document. 
This study is an open-label study without blinding of study drug. 
Evaluation of Blinding Maintenance 
Drugs will not be blinded in this study. 
Unblinding and Emergency Unblinding 
N/A. 


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9 Quality Assurance and Quality Control 
Pursuant to GCP guidelines, the sponsor has the responsibility to implement and 
maintain the quality assurance and quality control systems for this study according to 
corresponding standard operating procedures (SOPs) to ensure that the implementation 
of the clinical trial, data authenticity, and the collection, recording and reporting of data 
comply with the protocol, GCP and corresponding regulatory requirements. 
Clinical Monitoring 
The sponsor or the sponsor-authorized CRO will conduct clinical monitoring of the 
study. The clinical research associate (CRA) should conduct monitoring according to 
the standard operating procedures of the sponsor or CRO, and have the same rights and 
responsibilities as the sponsor's monitor. The monitor (CRA) should hold regular 
communications with the investigator, the authorized study personnel and the sponsor. 
Prior to the initiation of the study, the CRA will assess the competence of each study 
site and report problems regarding facilities, technical equipment, and/or medical 
personnel to the sponsor. During the study, the CRA will be responsible for monitoring 
whether the investigator has obtained the signed written ICFs from all subjects and 
whether the data records are correct and complete. Meanwhile, the CRA will also check 
the data entries in the eCRF against the source data and inform the investigator of any 
errors or omissions. The CRA will also control the site’s compliance with the protocol 
and study procedures, arrange for supplies of the study medications, and ensure that the 
drugs are stored under the specified conditions. 
Monitoring visits will be conducted in accordance with applicable laws and regulations. 
Each site will receive regular monitoring visits from the start of subject enrollment. 
After each visit to the investigator, the CRA should submit a written report to the 
sponsor. 
Data Management/Coding 
An electronic data capture (EDC) system will be used for this study and study data will 
be entered into the eCRF by the investigator or the authorized study personnel. Prior to 
site initiation or data entry, appropriate training will be provided to the investigator and 
the authorized study personnel, and appropriate security measures will be taken for 
computers and other equipment used in the study. 
Data entry into the eCRF should be completed during or as soon as possible after a visit 


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and updated promptly to ensure that it reflects the latest status of the subjects 
participating in the study. To avoid differences in the assessment of the results by 
different assessors, it is recommended that the baseline and all subsequent efficacy and 
safety assessments be completed by the same person. The investigator must review the 
data to ensure the accuracy and correctness of all data entered into the eCRF. If some 
assessments are not performed or some information is unavailable, inapplicable, or 
unknown during the study, the investigator should record it in the eCRF. The 
investigator should electronically sign the verified data. 
The CRA will review the eCRFs and assess their completeness and consistency. In 
addition, the CRA will check the eCRFs against the source documents to ensure the 
consistency of key data. The entry, correction and modification of all data will be in the 
charge of the investigator or his/her designee. The data in the eCRF will be submitted 
to the data server, and any changes to the data will be recorded in the audit trail, i.e. the 
reason for the change, the name of the operator, the time and date of the change will all 
be recorded. The roles and authorities of the site staff responsible for data entry will be 
determined in advance. In case of any data query, the CRA or the data manager will 
send a query in the EDC system and the site staff is responsible for answering the query. 
The EDC system will document the audit trails of the queries, including the 
investigator’s name, time and date. 
Unless otherwise specified, the eCRF will be used only as a form for collecting data 
rather than as source materials. Source documents refer to all records that are used by 
the investigator or hospital and related to the subjects and can prove the subjects’ 
existence and their eligibility per the inclusion and exclusion criteria as well as 
participation in this study, including laboratory records, ECG results, pharmacy 
dispensing records, subject folder, etc. 
The investigator is responsible for maintaining all source documents and providing 
them to the CRA for monitoring at each visit. In addition, the investigator must submit 
a complete eCRF for each enrolled subject, regardless of the duration of their study 
participation. The protocol number and subject number on all supporting documents 
(e.g., laboratory records or hospital records) submitted together with the eCRF should 
be carefully verified, and all personal privacy information (including the subject's name) 
in these documents should be deleted or made illegible to protect the subject's privacy. 
The investigator uses electronic signature to testify that he or she has reviewed the 
record, and guarantees the accuracy of the data recorded. The electronic signature will 


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be completed through the investigator’s user ID and password, and the data and time of 
signature will be generated by the system automatically. The investigator shall not share 
his/her user ID and password with other personnel. Any changes to the data in the eCRF, 
if necessarily required, should be made according to the work procedures as defined in 
the EDC system. All changes and the reasons for such changes will be documented on 
the audit trails. 
Adverse events and accompanying diseases/medical history will be coded. The 
dictionary used for coding will be described in the Clinical Study Report (CSR). 
Quality Assurance Audit 
During the process of the study, the sponsor or its authorized representative may 
perform quality assurance audits of the study site, the study database and related study 
documents. Moreover, the appropriate regulatory authorities may conduct inspections 
of the study site, the study database and related study documents at their discretion. The 
investigator should notify the sponsor immediately upon receipt of an inspection 
notification from the regulatory authority. 
The sponsor's quality assurance department will audit the clinical trial institution. 
Audits include the supply of drugs, trial documents required, documentation of the 
informed consent process, and consistency of case report forms with source documents. 
The content and scope of the audits may also be increased as appropriate. After 
reasonable notice, the investigator should allow the auditors entrusted by the sponsor 
to conduct trial-related audits and regulatory authorities to conduct inspections. The 
main purpose of the audit or inspection is to confirm that the rights or health of the 
subjects participating in the trial are protected, the informed consent is signed and the 
trial is carried out correctly, all data related to the evaluation of the study drug are 
handled and reported in accordance with the pre-planned arrangements, the protocol, 
facilities, ethical standard operating procedures, GCP and applicable regulatory 
requirements. The investigator should allow them to directly access all trial documents, 
source records and source data. 
10 Ethics 
Ethics Committee 
The sponsor or the sponsor’s authorized representative will prepare relevant documents 
to be submitted to the study site’s Ethics Committee (EC), including study protocol, 


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informed consent form, investigator’s brochure, subject recruitment materials or 
advertising and other legally required documents which should be submitted to the 
corresponding EC for review and approval. Written approval of the site EC must be 
obtained and provided to the sponsor prior to initiation of the study. The EC’s approval 
letter must clearly indicate the study protocol title, number, version number and other 
documents’ version number (e.g., ICF) and approval date. The investigator should 
inform the sponsor of the EC’s written opinion on delay, suspension or re-approval. 
The site must observe the requirements of the site’s EC, which may include submission 
of protocol modifications, modifications to the ICF and modifications to subject 
recruitment materials to the EC for review and approval, local safety reporting 
requirements, periodical reporting and updates according to the EC provisions, and 
submission of final report. All the above documents and EC approval letters must be 
provided to the sponsor or its designee. 
Ethics of the Study 
The study process and acquisition of informed consent should follow the Declaration 
of Helsinki, relevant GCP requirements and Chinese laws and regulations on drugs and 
data protection. 
The GCP provides a scientific global quality standard in line with ethical requirements 
for the design, implementation, recording and reporting of clinical studies involving the 
participation of human subjects. This study will be conducted in accordance with the 
GCP and relevant national regulations, and follow relevant ethical principles in the 
Declaration of Helsinki so as to protect the rights, safety and health of subjects. 
The investigator should follow the trial protocol’s stipulated process, and may not 
change it without the sponsor’s permission. Any protocol deviation will be reported to 
the EC, the sponsor or regulatory agencies. 
Subject Information and Informed Consent 
Prior to initiation of any study procedures, the possible risks and benefits of this study 
will be explained to subjects who may participate in the study using the informed 
consent form (ICF), which should be written in plain language. The ICF statement 
should clarify that signing the ICF is voluntary, explain the possible risks and benefits 
associated with participation in this study, and that the subjects are free to withdraw 
from the study at any time. The investigator may enroll a subject only after the 
investigator has fully explained the details of the study, the subject’s questions have 


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been answered satisfactorily, the subject has been given adequate time to think over, 
and written consent has been obtained from the subject or his/her legal representative. 
All signed ICFs must be kept in the investigator file or subject folder. 
The investigator is responsible for explaining the contents of the informed consent to 
the subjects and obtaining the signed and dated ICFs from the subjects or their legal 
representatives prior to initiation of the study. The investigator should provide each 
subject with a copy of the signed ICF. The investigator should record the informed 
consent process in the original trial documents. 
Protection of Subject Data 
The ICF will contain (or in some cases, together with the use of separate documents) 
information on data protection and privacy protection. 
Additional preventive measures should be taken to ensure the confidentiality of the 
documents and prevent the identification of subjects. However, under special 
circumstances, the genetic data and personal identification code of a certain subject may 
be accessed by some personnel. For example, in the event of a medical emergency, the 
sponsor, its representative physician or the investigator will be aware of the subject’s 
identification code and have access to the genetic data of the subject. In addition, 
relevant regulatory authorities require access to relevant documents. 
11 Study Management 
Data Processing and Record Preservation 
Documents in the clinical trial (protocol and protocol modifications, completed eCRF, 
signed ICF, etc.) should be preserved and managed according to the GCP requirements. 
The study site should preserve these documents for 5 years after the end of the study. 
Study documents should be reasonably preserved for future access or data tracing. 
Security and environmental risks should be taken into account for document 
preservation. 
Without the sponsor’s and the investigator’s written approval, no study documents may 
be destroyed. Only after the sponsor is notified and its written consent is obtained can 
the investigator/study site hand over the study documents to other parties following the 
document preservation requirements or transfer them to other locations meeting the 
requirements for preservation. 


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Access to Source Data/Documents 
The investigator agrees that the sponsor, CRO and relevant authorized regulatory 
authorities may directly access all study-related documents, including the subjects’ 
medical records. 
Protocol Modification 
In the course of the study, any possible appropriate modifications made to the protocol 
shall be communicated and approved by the sponsor and the investigator. The sponsor 
should ensure timely submission of protocol modifications to the administrative 
authorities. 
All modifications to the protocol should be preserved as protocol addenda. Any 
modification to the protocol should be submitted to the Ethics Committee, and approved 
or filed according to the Ethics Committee’s provisions. If necessary, the modification 
should also be submitted to the regulatory authorities for review and approval, and can 
be implemented only after approval by the EC and regulatory authorities (if needed) 
(except for changes to the protocol in order to eliminate direct harms to the trial 
subjects). 
Investigator’s Responsibilities 
The investigator will conduct this study in accordance with the protocol, ethical 
principles that have their origins in Declaration of Helsinki, Chinese GCP and the 
corresponding regulatory requirements. 
The detailed responsibilities of relevant investigators are listed in Chapter 5 
(Investigator’s Responsibilities) of the Chinese GCP (CFDA Order No. 3). 
Publication Policy 
All data generated from this study are confidential information of the sponsor. The 
sponsor has the right to publishstudy results. Information about the sponsor’s and the 
investigator’s publication policy will be described in the clinical trial agreement. 
All information related to this trial (not merely limited to the following documents: 
protocol, investigator’s brochure) must be kept strictly confidential. The investigator 
must aware that the scientific or medical information derived from the trial may be of 
commercial value for the sponsor. The investigator should keep information and data 
related to this trial confidential. If information related to this trial or conclusion obtained 


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from the trial is to be published to the public, it is required to negotiate with the sponsor 
in advance and obtain the sponsor’s written consent. In order to protect its own rights 
and interests, the sponsor may require the investigator not to publish any trial-related 
information until the investigational product is approved for marketing. 
The sponsor has the right to publish or publicate information or data related to this trial, 
or submit the information or data to the drug administrative authorities. If the sponsor 
needs to include the investigator’s name in the published, publicated or advertised 
content, consent from the investigator should be obtained. 
Finance and Insurance 
The sponsor will purchase insurance for subjects participating in the study according to 
local regulations and the minimum requirements. Relevant insurance clauses will be 
preserved in the study folder. 


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Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 
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Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med 2014,371:2499-2509. 
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Guodong Li. Analysis of survival rate and prognostic factors of 1510 surgically treated 
esophageal cancer patients.. Master's Thesis 2016. 
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Cunningham  D, Okines  AFC, Ashley  S. Capecitabine and Oxaliplatin for Advanced 
Esophagogastric Cancer. New England Journal of Medicine 2010,362:858-859. 
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Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AFC, Wotherspoon A, et al. 
Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with 
previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label 
phase 3 trial. The Lancet Oncology 2013,14:481-489. 
7. 
Ajani JA, Ilson DH, Daugherty K, Pazdur R, Lynch PM, Kelsen DP. Activity of taxol in 
patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer 
Inst 1994,86:1086-1091. 
8. 
Ilson DH, Ajani J, Bhalla K, Forastiere A, Huang Y, Patel P, et al. Phase II trial of paclitaxel, 
fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 
1998,16:1826-1834. 
9. 
Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, et al. 
Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line 
metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the 
Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2009,20:1667-1673. 
10. 
Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients 
with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol 2008,31:29-33. 
11. 
Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, et al. Phase II 
studies on docetaxel alone every third week, or weekly in combination with gemcitabine in 
patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol 
2007,24:407-412. 
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Ford HER, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel 
versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-
02): an open-label, phase 3 randomised controlled trial. The Lancet Oncology 2014,15:78-86. 
13. 
Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion 
in advanced esophageal cancer. Ann Oncol 2007,18:898-902. 
14. 
Burkart C, Bokemeyer C, Klump B, Pereira P, Teichmann R, Hartmann JT. A phase II trial of 
weekly irinotecan in cisplatin-refractory esophageal cancer. Anticancer Res 2007,27:2845-
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Enzinger PC, Kulke MH, Clark JW, Ryan DP, Kim H, Earle CC, et al. A phase II trial of 
irinotecan in patients with previously untreated advanced esophageal and gastric 
adenocarcinoma. Dig Dis Sci 2005,50:2218-2223. 
16. 
Muhr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, et al. A 
pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or 
metastatic esophageal carcinoma. Int J Colorectal Dis 2003,18:330-334. 
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<NCCN esophageal.pdf>. 


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18. 
Jiang D, Song Q, Wang H, Huang J, Wang H, Hou J, et al. Independent prognostic role of PD-
L1expression in patients with esophageal squamous cell carcinoma. Oncotarget 2016. 
19. 
Chen MF, Chen PT, Chen WC, Lu MS, Lin PY, Lee KD. The role of PD-L1 in the radiation 
response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell 
immunosuppression. Oncotarget 2016,7:7913-7924. 
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Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of 
programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human 
esophageal cancer. Clin Cancer Res 2005,11:2947-2953. 
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Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, et al. Changes in tumour expression of 
programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with 
squamous oesophageal cancer. Eur J Cancer 2016,52:1-9. 
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Toshihiko Doi SAP-P, Shadia Ibrahim Jalal, Hieu Mai-Dang, Sanatan Saraf, Minori Koshiji, 
Ildiko Csiki, Jaafar Bennouna. Updated results for the advanced esophageal carcinoma cohort 
of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol 34, 2016 
(suppl 4S; abstr 7). 
23. 
Takashi Kojima HH, Kensei Yamaguchi, Shuichi Hironaka, Satoru Iwasa, Ken Kato, Takahiro 
Tsushima, Hirofumi Yasui, Takashi Ura, Kei Muro, Taroh Satoh, Yuichiro Doki, Atsushi 
Ohtsu, Yasuo Hamamoto, Yuko Kitagawa. Phase II study of nivolumab (ONO-4538/BMS-
936558) in patients with esophageal cancer: Preliminary report of overall survival. J Clin 
Oncol 34, 2016 (suppl 4S; abstr TPS175). 
24. 
Study of ONO-4538 in Unresectable Advanced or Recurrent Esophageal Cancer. 
https://clinicaltrials.gov/ct2/show/NCT02569242?term=nivolumab&cond=Esophageal&rank
=1. 
25. 
Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for 
Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed 
After First-Line Therapy (MK-3475-181/KEYNOTE-181) 
https://clinicaltrials.gov/ct2/show/NCT02564263. 
26. 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 2008,8:467-477. 
27. 
Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. Journal 
of Clinical Investigation 2015,125:3384-3391. 
28. 
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009,15:7412-7420. 
 
 
 


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13 Appendix 
Appendix 1: Investigator Signature Page  
Protocol Title: A Randomized, Open-label, Multi-center, Phase II Study to 
Evaluate the Efficacy and Safety of IBI308 versus Paclitaxel or Irinotecan in 
Patients with Advanced/Metastatic Esophageal Squamous Cell Carcinoma After 
Failure of First-line Treatment(ORIENT-2)  
 
Protocol Number:   CIBI308A201  
This protocol is a trade secret of Innovent Biologics (Suzhou) Co., Ltd. I have read 
and fully understand this protocol and will conduct this study in accordance with its 
requirements and Good Clinical Practice, and in accordance with applicable laws, 
regulations and the Declaration of Helsinki. At the same time, I promise not to give 
any confidential information about this study to any third party without written 
consent from Innovent Biologics (Suzhou) Co., Ltd.  
Guidance for the Investigator: Please sign and date this signature page, print the 
Investigator's name, title, and name of site conducting the study and return to 
Innovent Biologics (Suzhou) Co., Ltd. after signing.  
 
I have read all the contents of this study protocol and guarantee to conduct this study 
as required:  
Investigator's Signature:          _    Date:    _  
Print Name:           ___________________________  
Investigator Title:      ___________________________  
Site Name/Address:     ___________________________  
______________________________________________________  


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Appendix 2: ECOG PS Scoring Criteria  
Score  
Activity level  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
REFERENCES  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity 
and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-
655.  
 
 
 
 


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Appendix 3: Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1)  
The following is an excerpt from the RECIST v1.1. 
 
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
1.1.1 Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm by conventional instruments in clinical exam (lesions which cannot be accurately 
measured by calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Malignant lymph nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15mm in short axis by CT scan (CT scan slice thickness no greater than 5 mm). 
At baseline and during follow-up, only the short axis will be measured and followed. 
 
1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodule 
with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses that 
cannot be diagnosed and followed by reproducible imaging techniques, and cystic lesions. 
 
1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 


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 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts; 
 Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
 
1.2 Specifications by methods of measurements 
1.2.1. Measurements of lesions 
All measurements should be recorded in metric notation when clinically assessed. All baseline 
measurements of tumor lesions should be performed as close as possible to the treatment start and 
must be within 28 days (4 weeks) before the beginning of the treatment. 
1.2.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion being followed cannot be imaged 
but is assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter (e.g. skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is 
more objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. Lesions on 
chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound should not be used as a method of measurement to assess lesion size. 


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Ultrasound examinations cannot be reproduced for review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm CR when biopsies are obtained or to determine 
relapse in trials where recurrence following CR or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a subject to be 
considered in complete response. Because tumor markers are disease-specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific guidelines 
for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 
cancer), have been published. In addition, the Gynecologic Cancer Intergroup has developed CA-
125 progression criteria which are to be integrated with objective tumor assessment for use in first-
line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse 
effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or SD) and PD. 
 
2. Tumor Response Evaluation 
2.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only subjects with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. In studies where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if entry is restricted to those 
with measurable disease or whether subjects having non-measurable disease only are also eligible. 
 
2.2 Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in instances 
where subjects have only one or two organ sites involved a maximum of two and four lesions 
respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. On occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 


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reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained 
(for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, 
saggital or coronal). The smaller of these measures is the short axis. For example, an abdominal 
node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. 
Nodes with short axis ≥ 10 mm but < 15 mm should not be considered target lesions. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference for baseline level of disease. 
All other lesions including pathological lymph nodes should be identified as non-target lesions and 
should also be recorded at baseline. These lesions should be followed as "present", "absent", or in 
rare cases "unequivocal progression". Multiple target lesions involving the same target organ may 
be recorded as a single item (e.g. "multiple enlarged pelvic lymph nodes" or "multiple liver 
metastases"). 
 
2.3 Response Criteria 
2.3.1 Evaluation of target lesions 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
 
2.3.2 Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the "sum" of lesions may not be zero even if complete response criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm Electronic CRFs or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 


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SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which are recorded 
as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being "too small to measure". When this occurs 
it is important that a value be recorded on the case report form. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned. (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well). This default 
value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, 
even if it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions "fragment", the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter should be the maximal longest 
diameter for the coalesced lesion. 
 
2.3.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response of non-
target lesions. While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points specified in the 
protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Unequivocal progression of existing non-target lesions. Note: the appearance of one or more 
new lesions is also considered progression. 
 
2.3.4 Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: When 
the subject also has measurable disease. In this setting, to achieve "unequivocal progression" on the 
basis of the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest "increase" in the size of one or 


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more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the face of 
SD or PR of target disease will therefore be extremely rare. 
When the subject only has non-measurable disease: This circumstance arises in some phase III trials 
when it is not a criterion of study entry to have measurable disease. The same general concepts 
apply here as noted above, however, in this instance there is no measurable disease assessment. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions are 
truly non-measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare PD 
for measurable disease: i.e. an increase in tumor burden representing an additional 73% increase in 
"volume" (which is equivalent to a 20% increase diameter in a measurable lesion). Examples include 
an increase in a pleural effusion from "trace" to "large", an increase in lymphangitic disease from 
"localized" to "widespread", or may be described in protocols as "sufficient to require a change in 
therapy". Examples include an increase in a pleural effusion from "trace" to "large", an increase in 
lymphangitic disease from "localized" to "widespread", or may be described in protocols as 
"sufficient to require a change in therapy". If "unequivocal progression" is seen, the subject should 
be considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the increase must be substantial. 
 
2.3.5 New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal. For example, 
progression should not be attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some "new" 
bone lesions may be simply healing or flare of pre-existing lesions) This is particularly important 
when the subject’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a "new" cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the subject who has visceral 
disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible "new" disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 


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If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, 
the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
 
2.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The 
subject’s best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. Furthermore, it depends 
on the nature of the study, protocol requirements, and results. Specifically, in non-randomized trials 
where response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 
"best overall response". 
 
2.4.1 Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for subjects who 
have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 
2.4.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually 
the case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response. 
This would be most likely to happen in the case of PD. For example, if a subject had a baseline sum 
of 50 mm with three measured lesions and at follow-up only two lesions were assessed, but those 
gave a sum of 80 mm, the subject will have achieved PD status, regardless of the contribution of the 
missing lesion. 
 
2.4.3 Best overall response: all time points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in trials where confirmation of complete or partial response is not 
required: Best response in these trials is defined as the best response across all time points (for 
example, a subject who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must also 
meet the protocol specified minimum time from baseline. If the minimum time is not met when SD 
is otherwise the best time point response, the subject’s best response depends on the subsequent 


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assessments. For example, a subject who has SD at first assessment, PD at second and does not meet 
minimum duration for SD, will have a best response of PD. The same subject lost to follow-up after 
the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of CR or PR is required: CR or PR may 
be claimed only if the criteria for each are met at a subsequent time point as specified in the protocol 
(generally 4 weeks later). In this circumstance, the best overall response can be interpreted as in 
Table 3. 
 
2.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to "normal" size 
(< 10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that subjects with CR may not have a 
total sum of "zero" on the eCRF. 
In trials where confirmation of response is required, repeated "NE" time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD at that time should be reported as "symptomatic deterioration". Every 
effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy. The objective response status of such subjects is to be determined by evaluation of 
target and non-target disease as shown in Table 1 to Table 3. 
Conditions that define "early progression, early death and inevaluability" are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends upon this determination, a biopsy of the residual lesion 
is recommended before assigning a status of complete response. FDG-PET may be used to upgrade 
a response to a CR in a manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease specific medical 
literature for the indication. However, it must be acknowledged that FDG-PET and biopsy may lead 
to false positive CR due to limitations of both approaches (resolution/sensitivity). 
 
 


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Table 1 Time point response: subjects with target (with or without non-target) disease. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-Cr/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete 
response 
PR = partial response 
SD = stable 
disease 
PD = progressive disease NE = 
inevaluable 
 
Table 2 Time point response: subjects with non-target disease only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: "Non-CR/non-PD" is preferred over "stable disease" for non-target disease. Since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign Non-CR/non-PD 
when no lesions can be measured is not advised.  
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected.  
 
Table 3 Best overall response when confirmation of CR and PR required. 
Overall 
response first 
time point 
Overall response 
subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 


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Overall 
response first 
time point 
Overall response 
subsequent time point 
Best overall response 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
and NE = inevaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent 
time point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR). Best response would depend on whether minimum duration for 
SD is met. However, sometimes "CR" may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the subject had PR, not CR at the first time point. Under these circumstances, 
the original CR should be changed to PR and the best response is PR. 
 
2.5 Frequency of Tumor Re-Evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to the 
type and schedule of treatment. However, in the context of Phase 2 studies where the beneficial 
effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) 
is reasonable. The protocol should specify which organ sites are to be evaluated at baseline (usually 
those most likely to be involved with metastatic disease for the tumor type under study) and how 
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each 
assessment. In selected circumstances certain non-target organs may be evaluated less frequently. 
For example, bone scans may need to be repeated only when complete response is identified in 
target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the trial 
has as a goal the response rate or the time to an event (progression/death). If "time to an event" (e.g. 
time to progression, disease-free survival, progression-free survival) is the main endpoint of the 
study, then routine scheduled re-evaluation of protocol specified sites of disease is warranted. In 
randomized comparative trials in particular, the scheduled assessments should be performed as 
identified on a calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months 
after treatment) and should not be affected by delays in therapy, drug holidays or any other events 
that might lead to imbalance in a treatment arm in the timing of disease assessment. 
 
2.6 Confirmatory Measurement/Duration of Response 
2.6.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also permit 


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appropriate interpretation of results in the context of historical data where response has traditionally 
required confirmation in such trials. However, in all other circumstances, i.e. in randomized trials 
(Phase 2 or 3) or studies where stable disease or progression are the primary endpoints, confirmation 
of response is not required since it will not add value to the interpretation of trial results. However, 
elimination of the requirement for response confirmation may increase the importance of central 
review to protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
 
2.6.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The duration 
of overall complete response is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
2.6.3 Duration of SD 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of SD varies in different studies and diseases. If the proportion of subjects 
achieving stable disease for a minimum period of time is an endpoint of importance in a particular 
trial, the protocol should specify the minimal time interval required between two measurements for 
determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account many 
parameters including disease types and stages, treatment periodicity and standard practice. However, 
these limitations of the precision of the measured endpoint should be taken into account if 
comparisons between trials are to be made 
 
2.7 PFS/TTP 
2.7.1. Phase 2 trials 
This guideline is focused primarily on the use of objective response endpoints for Phase 2 trials. In 
some circumstances, "response rate" may not be the optimal method to assess the potential 
anticancer activity of new agents/regimens. In such cases PFS/PPF at landmark time points, might 
be considered appropriate alternatives to provide an initial signal of biologic effect of new agents. 
It is clear, however, that in an uncontrolled trial, these measures are subject to criticism since an 
apparently promising observation may be related to biological factors such as subject selection and 
not the impact of the intervention. Thus, Phase 2 screening trials utilizing these endpoints are best 
designed with a randomized control. Exceptions may exist where the behavior patterns of certain 
cancers are so consistent (and usually consistently poor), that a non-randomized trial is justifiable. 
However, in these cases it will be essential to document with care the basis for estimating the 
expected PFS or proportion progression-free in the absence of a treatment effect.  


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Appendix 4: Response Evaluation Criteria in Immune Solid Tumors 
(iRECIST)  
IRECIST: Efficacy Assessment Guidelines for Use in Clinical Trials Evaluating Immunotherapy 
(Appendix) (excerpt)  
3. 
IRECTIST Efficacy Assessment  
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in infiltration 
of immune cells leading to transient increase in the size in malignant lesions, or undetectable lesions 
becoming detectable. The criteria are identical to those of RECIST 1.1 in many respects but have 
been adapted to account for instances where an increase in tumor burden, or the appearance of new 
lesions, does not reflect true tumor progression.  
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately.   
3.1 Confirmed Progression  
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD.  
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen as 
evidenced by one or more of the following:   
 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions   
 
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum   
 
Continued unequivocal progression in non-target disease with an increase in tumour 
burden   
 
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions.  
 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.   


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If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not preclude 
assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall response (BOR) 
providing that iCPD is not documented at the next assessment after iUPD. 
3.2 New lesions  
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow 
clear differentiation from baseline target and non-target lesions.  
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions should NOT be included in the sum of measures of original target 
lesions identified at baseline. Rather, these measurements will be collected on a separate table in the 
case record form.  
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional new 
lesions 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined Table 3.  
 
4. 
Time to Response and Stable Disease (RECIST 1.1 and iRECIST)  
Time to response will be calculated from the time when the criteria for CR/PR or iCR/iPR are met 
(whichever occurs first) until relapse or disease progression, while minimum measurements 
(including baseline) during the study will also be recorded as reference.  
Time to stable disease will be calculated from the start of treatment until disease progression, and 
the minimum measurement during the study (including baseline) will also be recorded as the 
reference.  
Table 1. RECIST 1.1 and iRECIST  
 
RECIST 1.1  
IRECIST  


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Definition 
of 
measurable 
and 
non-measurable 
lesions; 
number 
and location of 
target lesions  
Measurable lesions ≥ 10 mm in 
long diameter (15 mm for nodal 
lesions); up to 5 lesions (2 per 
organ); non-target lesions (≥ 10 
mm short axis for nodal lesions)  
No change; however, new lesions will 
be recorded separately on the case 
report form according to RECIST 1.1 
criteria (will not be included in the 
sum of target lesion measurements at 
baseline)  
CR, PR, or SD  
PD cannot be documented until 
CR, PR, or SD  
IUPD (one or more) but no iCPD 
before iCR, iPR or iSD  
Confirmed 
CR, 
PR  
Required for non-randomized trials 
only  
Same as RECIST 1.1  
Confirm SD  
Not necessary  
Same as RECIST 1.1  
New lesions  
Will be assessed as PD but no 
measurements required  
IUPD will be assessed, and iCPD will 
be recorded when the following 
conditions are met at the next 
assessment  
 
Appearance of other new 
lesions or  
 
Increase in size of new lesions 
(increase in sum of new target 
lesion measurements by ≥ 5 
mm or increase in any new non-
target lesion)  
ICPD can also be confirmed by new 
lesions 
that 
have 
never 
been 
previously recorded  
Independent Blind 
Review 
and 
Central 
Image 
Acquisition  
Recommended in some cases  
Image collection is recommended for 
all studies (but not for independent 
review)  
Confirmed PD  
Non-essential (unless ambiguous)  Required  
Consider 
patient 
clinical status  
Not considered in assessment  
Continued use after iUPD should take 
into account whether the patient is 
clinically stable (see definitions)  
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; iCR: 
complete immune response; iPR: partial immune response; iSD: stable immune disease; iUPD: 
immunologically unconfirmed progression; iCPD: immunologically confirmed progression;  
 
Table 2: iRECIST Response Record by Assessment Point  
This efficacy evaluation  
Target 
Lesions *  
Non-target 
lesions *  
New 
lesions *  
Efficacy Assessment Results  
No 
prior 
Previous iUPD*, *  


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iUPD*  
ICR  
ICR  
No  
ICR  
ICR  
ICR  
Non-
iCR/Non-
iUPD  
No  
IPR  
IPR  
IPR  
Non-
iCR/Non-
iUPD  
No  
IPR  
IPR  
ISD  
Non-
iCR/Non-
iUPD  
No  
ISD  
ISD  
IUPD 
unchanged 
or 
reduced 
from 
last 
assessment  
IUPD 
unchanged 
or reduced 
from 
last 
assessment  
YES  
NA  
ICPD was confirmed if new lesions had been 
previously identified and increased in size 
(increase in SOM of new target lesions by ≥ 
5 mm or increase in new non-target lesions). 
If new lesions remain unchanged (volume or 
number) from last assessment, they remain 
iUPD  
ISD, 
iPR, 
iCR  
IUPD  
No  
IUPD  
An increase in the size of non-target lesions 
(unequivocal PD per RECIST 1.1 is not 
required) confirms iCPD, otherwise they 
remain iUPD  
IUPD  
Non-
iCR/Non-
iUPD; iCR  
No  
IUPD  
ICPD shall be confirmed if:  
 
Increase in SOM of ≥ 5 mm in target 
lesions, other cases remain iUPD  
IUPD  
IUPD  
No  
IUPD  
ICPD shall be confirmed if:  
 
Previously noted increase in target 
lesion SOM of ≥ 5 mm in iUPD 
and/or  
 
Increase in non-target lesions for iUPD 
(previous assessment - unequivocal PD 
was not required)  
IUPD  
IUPD  
YES  
IUPD  
ICPD shall be confirmed if:  
 
Previously noted increase in target 
lesion SOM of ≥ 5 mm in iUPD 
and/or  
 
Increase in non-target lesions for iUPD 
(where unequivocal PD is not required) 
and/or  
 
Increase in volume or number of 
previously identified new lesions  
Non-
iUPD/PD  
Non-
iUPD/PD  
YES  
IUPD  
ICPD shall be confirmed if:  
 
Increase in volume or number of 
previously identified new lesions  


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* Refer to RECIST 1.1 principles. In the absence of pseudoprogression, CR, PR, and SD are 
defined consistently by RECIST 1.1 and iRECIST. * for any type of lesion. * Found at the last 
assessment prior to this assessment.  
ICR: complete immune response; iPR: partial immune response; iSD: stable immune disease; iUPD: 
immune unconfirmed progression; iCPD: immune confirmed progression; SOM: sum of 
measurements; NA: not applicable; NE: not evaluable  
Table 3. Best overall response according to iRECIST criteria  
Best overall response  
1st 
Assessment  
2nd Assessment  
3rd Assessment  
4th 
Assessment  
5th 
Assessment  
Optimal 
overall 
immune 
response  
ICR  
ICR, iPR, iUPD, 
NE  
ICR, iPR, iUPD, 
NE  
IUPD  
ICPD  
ICR  
IUPD  
IPR, iSD, NE  
ICR  
ICR, iUPD, 
NE  
ICR, 
iPR, 
iSD, iUPD, 
iCPD, NE  
ICR  
IUPD  
IPR  
IPR, iSD, iUPD, NE  IPR, 
iSD, 
iUPD, NE, 
iCPD  
IPR, 
iSD, 
iUPD, NE, 
iCPD  
IPR  
IUPD  
ISD, NE  
IPR  
IPR, 
iSD, 
iUPD, NE  
IPR, 
iSD, 
iUPD, 
iCPD, NE  
IPR  
IUPD  
ISD  
ISD, iUPD, NE  
ISD, iUPD, 
iCPD, NE  
ISD, iUPD, 
iCPD, NE  
ISD  
IUPD  
ICPD  
Any  
Any  
Any  
ICPD  
IUPD  
IUPD 
(without 
iCPD)  
ICPD  
Any  
Any  
ICPD  
IUPD  
NE  
NE  
NE  
NE  
IUPD  
 
For example only - more cases may exist but follow the same principles  
 
This table assumes a randomized study design and does not require confirmation of CR or 
PR  
 
For patients with only non-target lesions at baseline, the evaluation at each time point was 
only recorded as iCR or non-CR/non-PD, but was not reflected in the table for ease of 
presentation  
ICR: complete immune response; iPR: partial immune response; iSD: stable immune disease; iUPD: 
immune unconfirmed progression; iCPD: immune confirmed progression; SOM: sum of 
measurements; NA: not applicable; NE: not evaluable  
 


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Appendix 5: Liver Function Abnormality Monitoring and Follow-up Report 
Form  
Please report to Innovent PV:  
Fax: 021-31652800                        Email: drugsafety@innoventbio.com  
 
Contact information of reporter (Please be sure to provide in case of timely receipt):  
Reporter Email:                              Reporter Contact Number:  
Signature of reporter:                              Date of Report:  
 
Information on follow-up reports of liver function abnormalities:  
Trial No.:                                  Subject Number:  
1. 
Symptoms of liver function abnormalities such as (check if present):  
Appetite loss □, greasiness □, dyspepsia □, nausea □, vomiting □, abdominal distension □, 
abdominal pain □, diarrhea □, constipation □, clay stools □, fatigue □, weakness □, somnolence □, 
weight loss □, fluttering tremor □, altered mental status □, bleeding tendency □, fever □, other □  
 
2. 
Signs of liver function abnormalities such as (tick if present):  
Liver disease □, spider nevus □, liver palms □, ascites □, abdominal wall subcutaneous varicose 
veins □, jaundice □, body fluid yellowing □, hepatomegaly □, splenomegaly □, liver tenderness □, 
hepatic encephalopathy □, dyspnea □, lung rales □, peripheral edema □, cervical varicose veins □, 
abnormal heart sounds □, others □  
 
3. 
Medical history (check if available):  
Viral hepatitis (HBV-A □; HBV-B □; HBV-C □; HBV-D □; HBV-E □), alcoholic hepatitis □, fatty 
liver □, liver cancer □, liver metastasis □, liver cirrhosis □, liver transplantation □, blood 
transfusion □, liver enzyme elevation before the study medication □, autoimmune disease □, 
biliary disease □, cardiovascular disease □, hypotension □, diabetes □, surgery □, bone metastasis 
or bone injury □, HIV infection □, E-B virus infection □, drug toxicity □, obesity □, others □  
 
4. 
Family history of liver disease (check if available) □  
 
5. 
Concomitant medications and diet (check if yes):  


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Chemotherapy □, Chinese herbal medicine □, OTC □, dietary supplement □, drinking □, drug 
abuse □, history of exposure to chemicals □, anti-infective drugs □, paracetamol □, NSAIDS □, 
metronidazole □, others □  
 
6. 
All relevant laboratory test results (including baseline period, treatment period and post-
treatment period. If the test was performed, please check and provide the test results, unit and 
normal value):  
Hematology test □,  
Acid cell count □,  
AST □, ALT □, ALP □, GGT □,  
Total bilirubin □/Direct bilirubin □,  
Serum total protein □/albumin □/globulin □,  
Total Cholesterol □/Cholesteryl Ester □,  
Coagulation function □, such as:  
Others □, such as:  
 
7. 
Serological tests (check and provide test results if performed):  
Epstein-Barr virus (EBV) □,  
Cytomegalovirus (CMV) □,  
Herpes simplex virus (HSV) □,  
Toxoplasmosis □,  
Hepatitis (A □, B □, C □, D □, E □),  
HIV □,  
Antinuclear antibody □,  
Other antibodies □, such as:  
Others □, such as:  
  
8. 
Ancillary tests or procedures (check and provide results if performed):  
Liver ultrasound □,  
Abdominal CT □,  
Liver biopsy □,  
Liver transplant (planned or completed) □,  
Others □, such as:  
 


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Appendix 6: List of Autoimmune Diseases Present Before Inclusion  
Subjects were asked in detail whether they had acquired or congenital immunodeficiency or 
autoimmune diseases, such subjects had to be excluded from this study. The likelihood of 
autoimmune disease is very low unless the subject has a previous history of allergic disease and 
childhood joint pain. In addition, transient autoimmune manifestations due to acute infectious 
disease (e.g., Lyme arthritis) may be included if cured with antibiotics. In case of uncertain 
autoimmune diseases requiring exclusion, please contact the medical manager of the sponsor.  
Diseases associated with autoimmunity, including but not limited to:  
Acute sporadic encephalomyelitis  
IgA nephropathy  
Addison's disease  
Inflammatory bowel disease  
Alopecia universalis  
Interstitial cystitis  
Ankylosing spondylitis  
Myasthenia gravis syndrome  
Antiphospholipid 
antibody 
syndrome  
Lupus erythematosus  
Aplastic anemia  
Lyme disease - chronic  
Asthma  
Meniere's syndrome  
Autoimmune hemolytic  
Anaemia  
Corneal ulcer  
Autoimmune hepatitis  
Localized 
autoimmune 
hypophysitis  
Multiple sclerosis  
Autoimmune hypoparathyroidism  
Myasthenia gravis  
Autoimmune myocarditis  
Neuromyotonia  
Autoimmune oophoritis  
Myoclonic syndrome  
Autoimmune orchitis  
Optic neuritis  
Autoimmune 
thrombocytopenic purpura 
Ord's thyroiditis  
Behcet's disease  
Pemphigus  
Bullous pemphigoid  
Pernicious anemia  
Bran allergy  
Polyarteritis  
Chronic fatigue syndrome  
Polyarthritis  
Chronic 
Inflammation 
Demyelination  
Polyneuropathy  
Autoimmune syndrome  
Bell-Strauss syndrome  
Primary biliary cirrhosis  
Crohn's disease  
Psoriatic dermatomyositis  
Reiter's syndrome  
Type I diabetes mellitus  
Rheumatoid arthritis  
Autonomic Dysfunction  
Sarcoidosis  
Eczema  
Scleroderma  
Sjogren's syndrome  
Bullous skin lysis  
Catalepsy syndrome  
Pemphigoid in pregnancy  
Takayasu arteritis  
Giant cell arteritis  
Ulcerative colitis  
Pulmonary 
haemorrhage-
nephritis syndrome  
Vitiligo  
Graves' disease  
Vogt-Kovanagi-Harada 
disease  
Guillain-Barre syndrome  
Vulvar pain  
Hashimoto's disease  
Wegener's granulomatosis  
Kawasaki disease  
 
 
 
 


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


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 4 
Permanently discontinue 
improve, then taper with a lower rate 
- 
Once persistent clinical improvement is observed, subjects receiving 
glucocorticoids IV can start tapering the dose or switch to an 
equivalent dose of glucocorticoid PO at an earlier time (a lower 
bioavailability of oral administration should be considered) 
- 
For events that unresponsive to glucocorticoid treatment, consider a 
stronger immunosuppressants, e.g. TNF blockers (e.g. infliximab) or 
mycophenolate mofetil, after discussing with the physicians 
- 
For grade 3/4 local inflammation of lesions (such as local pain, 
irritation, and rash), IBI308 may be continued as determined by the 
investigator 


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AE Grade/Administration Adjustments 
Toxicity Management 
Pneumonitis 
Any grade 
 
- 
Monitor signs and symptoms of pneumonitis or interstitial lung 
disease (e.g. new shortness of breath, cough, chest pain or 
exacerbation of existing symptoms and signs), evaluate subjects by 
imaging, pulmonary function, and other examinations 
- 
Initial examination may include clinical evaluation, arterial oxygen 
saturation, laboratory tests, and high-resolution CT scans  
Grade 1 
No 
dose 
adjustments 
required 
However, consider interrupting the 
treatment based on clinical needs and 
during diagnostic tests for other 
causes 
For grade 1 events: 
- 
Monitor signs and symptoms and arterial oxygen saturation for 2–4 
days 
- 
Perform other laboratory tests if clinically indicated 
- 
Consider consulting a respirologist and infectious diseases specialist 


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


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 3 or 
grade 4 
Permanently discontinue 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Consider consulting a respirologist and infectious diseases specialist 
- 
Hospitalization 
- 
Supportive care (oxygen) 
- 
Begin systemic glucocorticoid treatment based on experience  
- 
If no improvement is seen within 3–5 days, consider other tests and 
stronger immunosuppressants (e.g. infliximab) 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 


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AE Grade/Administration Adjustments 
Toxicity Management 
Diarrhea 
or 
Enterocolitis 
Any grade 
 
- 
Monitor possible signs and symptoms related to diarrhea/enterocolitis 
(abdominal pain, enterospasm, changes in bowel habits, melena, 
mucous stool, bloody stool, or muscle guarding) 
- 
Subjects shall be fully evaluated to rule out any alternative causes (e.g. 
PD, infection, etc.) 
- 
If alternative causes cannot be determined, consider glucocorticoid 
treatment for low grade events to prevent from escalating to high 
grade 
- 
Use analgesics with caution (may mask the symptoms of perforation 
and peritonitis) 
Grade 1 
No dose adjustments  
required 
For grade 1 events: 
- 
Closely monitor symptom exacerbation 
- 
Consider symptomatic treatment, including fluid replacement, 
electrolyte replacement, diet modifications, and loperamide 
administration 


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


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


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


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


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


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 1 
No dose adjustments  
required 
For grade 1 events: 
- 
Consider symptomatic treatment, including oral antipruritic agents 
(e.g. diphenhydramine or hydroxyzine) and local treatment (e.g. urea 
cream or topical glucocorticoids) 
Grade 2 
No dose adjustments required 
• 
For a refractory (> 1–2 weeks) 
grade 2 event, interrupt until 
reduces  
to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2 events: 
- 
Consider symptomatic treatment including oral antipruritic agents and 
local treatment 
- 
Consider a medium-potency topical glucocorticoid 
- 
If no improvement is seen with 3–5 days, discuss with sponsor's 
medical manager and consider systemic glucocorticoid treatment 
- 
Consult a dermatologist 
- 
Consider skin biopsy if persists for > 1–2 weeks or relapses 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 3 
Interrupt 
• 
If worsens, treat as a grade 4 event 
• 
Permanently discontinue if a grade 
3 rash does not reduce to grades 0–
1 or baseline within 30 days 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Consider hospitalization 
- 
Monitor affected area (rule of nine) 
- 
Consult a dermatologist  
- 
If clinically feasible, consider skin biopsy (preferably more than once) 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
Once improved, taper glucocorticoids within 4 weeks, and consider 
prophylactic antibiotic 
Grade 4 
Permanently discontinue 


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Hypopituitarism 
All grades 
 
- 
Monitor signs and symptoms of endocrine disorders, including 
weakness, fatigue, drowsiness, nausea, emesis, chills, changes in 
bowel habits, behavioral changes, mental state changes, hypotension, 
hypoglycemia, dizziness, headache, impaired vision, low libido in 
males, irregular menstruation in females, etc. 
- 
Subjects shall be fully evaluated to rule out any alternative causes (e.g. 
PD, brain metastasis, infection, etc.) 
- 
Monitor and evaluate pituitary function: TSH, FT3, FT4, 
adrenocorticotropic hormone, cortisol, luteinizing hormone, follicle 
stimulating hormone, growth hormone, prolactin, Na+, blood glucose, 
estradiol, testosterone, and other laboratory parameters related to 
endocrine disorders. Perform functional tests when necessary 
(including adrenocorticotropic hormone (ACTH) stimulation test and 
insulin-induced hypoglycemia test) 
- 
Consider pituitary MRI 
- 
Consider consulting an endocrinologist 
- 
Consider testing for autoantibodies 


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 1 
No dose adjustments  
required 
For grade 1 events: 
- 
Monitor pituitary function 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Consider consulting an endocrinologist if clinically indicated 
Grade 2 
 
Interrupt 
• If 
worsens 
to 
grades 
3–4, 
permanently discontinue 
• If reduces to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2–4 events: 
 
Discuss with sponsor's medical manager 
 
Consult an endocrinologist 
 
Hospitalization when necessary 
 
Evaluate endocrine function, consider pituitary MRI if clinically 
indicated 
 
Begin hormone replacement therapy when necessary (cortisone 


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 3 or 
grade 4 
Permanently discontinue 
replacement therapy shall begin one week prior to levothyroxine 
treatment) 
 
Begin immunosuppressive therapy based on experience, consider 
systemic glucocorticoid treatment 
 
Once improved, taper glucocorticoids within 4 weeks (the dose of 
cortisone used for hormone replacement may be adjusted accordingly, 
but subjects whose endocrine function do not recover require long-
term treatment); consider prophylactic antibiotic during taper to 
prevent infections 


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AE Grade/Administration Adjustments 
Toxicity Management 
Adrenocortical 
Insufficiency 
Any grade 
 
- 
Monitor signs and symptoms of endocrine disorders, including 
fatigue, pigmentation, loss of appetite, hypotension, and weakness 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Monitor and evaluate adrenal function: cortisol, adrenocorticotropic 
hormone, blood sodium, blood potassium, blood glucose, and other 
endocrine laboratory parameters suspected to be related to adrenal 
function. The ACTH stimulation test shall be performed when 
necessary 
- 
Immunosuppressive therapy when necessary 
- 
Hormone replacement therapy (cortisone) when necessary 
- 
Consider consulting an endocrinologist 
- 
Consider testing for autoantibodies 
Grade 1 
No dose adjustments required 
For grade 1 events: 
 
Monitor adrenal function 
 
Consider consulting an endocrinologist if clinically indicated 


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 2 
Interrupt 
• If 
worsens 
to 
grades 
3–4, 
permanently discontinue 
• If reduces to grades 0–1 or  
baseline, continue the  
treatment at the next  
scheduled date 
For grade 2 events: 
 
Discuss with sponsor's medical manager 
 
Evaluate adrenal function, begin hormone replacement therapy when 
necessary 
Grade 3 or 


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AE Grade/Administration Adjustments 
Toxicity Management 
grade 4 
Permanently discontinue 
 
For grade 3–4 events: 
 
Discuss with sponsor's medical manager 
 
Consult an endocrinologist 
 
Consider systemic corticosteroid treatment 
 
Begin corticosteroids with mineralocorticoid activity immediately 
for adrenal crisis, severe dehydration, hypotension, or shock 
 
Once improved, taper glucocorticoids within 4 weeks (the dose of 
cortisone used for hormone replacement may be adjusted 
accordingly, but subjects whose endocrine function do not recover 
require long-term treatment); consider prophylactic antibiotic during 
taper to prevent infections 


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AE Grade/Administration Adjustments 
Toxicity Management 
Hyperthyroidism/Hyp
othyroidism 
Any grade 
 
- 
Monitor signs and symptoms of thyroid dysfunction, e.g. 
hyperthyroidism (palpitations, sweating, increased appetite and bowel 
movement, and weight loss) and hypothyroidism (general weakness, 
fatigue, cold, memory loss, and constipation) 
- 
Subjects shall be fully evaluated to rule out any alternative causes 
- 
Monitor and evaluate thyroid function 
- 
Consider consulting an endocrinologist 
- 
Consider testing for thyroid autoantibodies (antithyroglobulin 
antibodies, anti-thyroid peroxidase antibodies, and thyroid-
stimulating hormone receptor antibodies) 
Grade 1 or 
grade 2 
No dose adjustments  
required 
For grade 1–2 events: 
- 
Monitor thyroid function and thyroid autoantibodies regularly 
- 
L-thyroxine replacement therapy or anti-thyroid medications when 
necessary 


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


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 1 or 
grade 2 
No dose adjustments  
required 
For grade 1–2 events: 
 
Monitor and assess pancreas islet function 
 
Start insulin therapy when necessary 
Grade 3 
Interrupt 
 Resume treatment after blood 
glucose is under control 
For grade 3–4 events: 
 
Consult with sponsor's medical manager 
 
Monitor and assess pancreas islet function 
 
Consider consulting an endocrinologist 
 
Blood glucose control with insulin, adjust insulin dose accordingly 
 
If ketoacidosis occurs, subjects shall be hospitalized to receive 
insulin, fluid replacement, and alkali therapy 
Grade 4 
Permanently discontinue 


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AE Grade/Administration Adjustments 
Toxicity Management 
Renal 
Insufficiency 
(Creatinine Elevated) 
Any grade 
 
 
Monitor signs and symptoms closely (e.g. oliguria, dark urine, 
anemia, fatigue, and weight loss) 
 
Subjects shall be fully evaluated to rule out any alternative causes 
 
Monitor and evaluate renal function 
 
Consider consulting a nephrologist 
 
Consider kidney biopsy when necessary to distinguish between 
inflammatory and non-inflammatory causes 
Grade 1 
No dose adjustments  
required 
 
For grade 1 events: 
- 
Monitor creatinine levels Q1W 
- 
If creatinine level returns to baseline level, resume routine creatinine 
monitoring according to the study protocol 


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


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


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 4 
medications (e.g. gabapentin, duloxetine, etc) 
- 
Consider systemic corticosteroid treatment 
- 
If no improvement is seen within 3–5 days, consider other tests and 
immunosuppressants (e.g. intravenous immunoglobulin G, IVIgG) 
- 
Once stabilized, taper glucocorticoids within ≥ 4 weeks 


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Immune-related 
peripheral 
neuropathy, 
e.g. 
Guillain-Barré 
syndrome 
and 
myasthenia gravis 
Any grade 
 
- 
Monitor signs and symptoms closely (myasthenia gravis: eye or limb 
soreness and discomfort, blurred vision, fatigue, which worsens as the 
day goes on; Guillain-Barré syndrome: sudden and severe nerve pain, 
paralysis of the limbs, and prickling or burning sensation in the limbs) 
- 
Timely diagnosis of immune-related peripheral neuropathy is very 
important, as subjects may suffer from unpredictable acute 
compensation, which may lead to severe disease or death.Pay special 
attention to signs and symptoms that may indicate serious 
consequences, e.g. significant dysphagia, rapidly progressive 
weakness, respiratory insufficiency, or autonomic dysfunction 
- 
Neuroelectrophysiological tests shall be performed to rule out any 
alternative causes (e.g. PD, infection, metabolic syndrome, 
medications, etc.) It is worth noting that cancer itself and cancer 
treatment can affect neural function. The diagnosis of immune-related 
peripheral neuropathies is thus difficult. Neurological consultation 
shall be actively carried out. 
- 
Plasmapheresis or IVIgG should be considered for subjects with 


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AE Grade/Administration Adjustments 
Toxicity Management 
Guillain-Barré syndrome (glucocorticoids are generally ineffective)  
Grade 1 
No dose adjustments 
required 
For grade 1 events: 
- 
Discuss with a physician 
- 
Monitor signs and symptoms 
- 
Consider consulting a nephrologist 
Grade 2 
Interrupt 
• If reduces to grades 0–1 or 
baseline, continue the treatment 
at the next scheduled date 
• If worsens, treat as a grade 3–4 
event 
For grade 2–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Monitor signs and symptoms 
- 
Consider consulting a nephrologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain with appropriate 


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AE Grade/Administration Adjustments 
Toxicity Management 
Grade 3 or 
grade 4 
Permanently discontinue 
medications (e.g. gabapentin, duloxetine, etc.) 
      Myasthenia Gravis 
- 
Glucocorticoids may be used to treat myasthenia gravis (shall be used 
under the supervision of a neurologist since corticosteroids, especially 
high-dose, may result in initial exacerbation of symptoms) 
- 
Subjects intolerant to glucocorticoids may be treated with 
plasmapheresis or IVIgG 
- 
For 
myasthenia 
gravis-like 
neurotoxicities, 
consider 
acetylcholinesterase inhibitors in addition to glucocorticoids 
     Guillain-Barre Syndrome 
- 
Plasmapheresis or IVIgG should be considered for subjects with 
Guillain-Barré syndrome (glucocorticoids are generally ineffective)  
Table 2. Dose Modification and Toxicity Management Guidelines for Potential Other irAEs  
 
CTD Grade/Administration Adjustments 
Toxicity Management 


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


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