Conditions: Non-small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 290
Healthy volunteers: no

Brief summary:
Clinical trial results demonstrate that anti-PD-1 antibodies prolonged OS to approximately 9 months compared with 6 months in docetaxel group. Anti-PD-1 therapy in Chinese squamous NSCLC patients will be investigated in this clinical trial.

Additionally, the correlation between PD-L1 expression and the response to IBI308 treatment in Chinese squamous cell NSCLC patients as well as the role of irRECIST in immune checkpoint inhibitor treatment evaluation will also be assessed

Detailed description:

Arms:
arm 1: injection; dosage form: 10ml:100mg; frequency: 200mgQ3W; duration: randomization to the date of the first documented tumor progression per RECIST v1.1 criteria arm 2: injection; dosage form: 1ml:40mg; Frequency: 75mg/m2 Q3W; duration: randomization to the date of the first documented tumor progression per RECIST v1.1 criteria

Interventions: intervention 1: IBI308 intervention 2: Docetaxel
Intervention descriptions: intervention 1: Anti-PD-1 therapy in Chinese squamous NSCLC patients will be investigated in this clinical trial. intervention 2: As 2nd line treatment to subjects with squamous NSCLC

Protocol document:
Prot_SAP_000.pdf: 
Investigational Drug: IBI308 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized, Open-Label, Multicenter, Parallel, and Phase III 
Clinical Trial Comparing the Efficacy and Safety of IBI308 to 
Docetaxel in the Treatment of Subjects with Advanced or 
Metastatic Squamous Non-Small Cell Lung Cancer Who Have 
Failed Platinum-Based First-Line Chemotherapies(ORIENT-3) 
Protocol No.: 
CIBI308C301 
Version and Date: 
Jan. 14, 2020/Version 3.2 
Product Name: 
IBI308 
Study Phase: 
Phase III 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China 
Sponsor Contact: 
Zhou Hui  Vice President of Medical Science and Strategic 
Oncology Department 
Tel.: (+86) 21-31652896 
hui.zhou@innoventbio.com 
 
 
Confidentiality Statement 
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd. 
The content of this document shall not be disclosed to any person other than the investigators, 
research consultants or related personnel, and institutional review committee (iDMC)/independent 
EC. 
The information contained in this document must not be used for any purpose, except for the 
evaluation or conduction of this study, without the written consent of the sponsor. 
 
 


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Sponsor's Signature Page 
 
Protocol Title: A Randomized, Open-Label, Multicenter, Parallel, and Phase III Clinical Trial 
Comparing the Efficacy and Safety of IBI308 to Docetaxel in the Treatment of Subjects with 
Advanced or Metastatic Squamous Non-Small Cell Lung Cancer Who Have Failed Platinum-
Based First-Line Chemotherapies(ORIENT-3) 
 
Project No.: CIBI308C301 
 
Title 
Name (Regular Script) 
Signature 
 
Date 
Vice President of 
Medical Science and 
Strategic Oncology 
Department 
Zhou Hui 
 
 
 
 
 
 
 
 
Senior Biostatistics 
Director 
Sun Xing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Synopsis 
Protocol no. 
CIBI308C301 
Sponsor 
Innovent Biologics (Suzhou) Co., Ltd. 
Investigational drug 
Sintilimab (R&D code: IBI308) 
Active ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study title  
A Randomized, Open-Label, Multicenter, Parallel, and Phase III Clinical Trial  
Comparing the Efficacy and Safety of IBI308 to Docetaxel in the Treatment of 
Subjects with Advanced or Metastatic Squamous Non-Small Cell Lung Cancer Who 
Have Failed First-Line Platinum-Based Chemotherapies(ORIENT-3) 
Phase 
Phase III 
Study duration 
Estimated 25 months 
Study objectives 
Primary objective: 
(1) To evaluate the overall survival (OS) of subjects with advanced/metastatic 
squamous non-small cell lung cancer (sqNSCLC) who have failed first-line 
platinum-based chemotherapy treated with IBI308 versus docetaxel. 
Secondary objectives: 
(1) To evaluate the objective response rate (ORR), disease control rate (DCR), 
duration of response (DoR), and progression free survival (PFS) of subjects with 
advanced/metastatic sqNSCLC who have failed first-line platinum-based 
chemotherapy treated with IBI308 versus docetaxel; 
(2) To evaluate the safety in subjects with advanced/metastatic sqNSCLC who have 
failed first-line platinum-based chemotherapy treated with IBI308 versus 
docetaxel; 
(3) To evaluate the influence on the quality of life in subjects with 
advanced/metastatic sqNSCLC who have failed first-line platinum-based 
chemotherapy treated with IBI308 versus docetaxel. 
Exploratory objectives: 
(1) To evaluate causalities of PD-L1 expression, immunity-related gene mRNA, and 
tumor mutation burden (TMB) with efficacy in subjects with 
advanced/metastatic sqNSCLC; 
(2) To evaluate causality of dynamic PD-L1 expression on circulating tumor cell 
(CTC) surface with efficacy in the IBI308 group; 
(3) To explore the application of Immune Response Evaluation Criteria in Solid 
Tumors (iRECIST) in the evaluations of PFS, ORR, DCR, and DoR of the 
IBI308 group. 


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Study design 
This is a randomized, open-label, multicenter, parallel, and phase III clinical trial  
comparing the efficacy and safety of IBI308 to docetaxel in the treatment of subjects 
with advanced or metastatic sqNSCLC who have failed platinum-based first-line 
chemotherapies(ORIENT-3). This trial intends to enroll 290 subjects with advanced 
or metastatic sqNSCLC who have failed first-line platinum-based chemotherapies. 
The central randomization is adopted in this trial and the subjects will be stratified 
according to ECOG PS (0 or 1). 
After the subjects with advanced or metastatic sqNSCLC who have failed prior first-
line platinum-based chemotherapies sign the informed consent form (ICF) and are 
screened based on the inclusion/exclusion criteria, the eligible subjectswill be 
randomized (1:1) to receive IBI308 (200 mg, IV, Q3W) or docetaxel (75 mg/m2 IV, 
Q3W) until progressive disease (PD), death, intolerable toxicity, withdrawal of ICF, 
initiation of a new anti-tumor therapy, or treatment discontinuation due to any other 
reason specified in the protocol. 
This study will adopt RECIST v1.1 to carry out clinical tumor imaging evaluation. 
The tumor imaging evaluation, based on clinical situations of the subjects,will be 
conducted once every 6 weeks (± 7 days) ; or once every 9 weeks (±7 days) after 24 
weeks of administration until PD, initiation of a new anti-tumor therapy, withdrawal 
of ICF by the subjects, or death. For IBI308 treatment arm, subjects who develop PD 
for the first time and are clinically stable, can continue treatment with IBI308 based 
on the investigator's judgment (see details in Section 5.1.2). Subjects who discontinue 
the treatment due to causes other than PD still need to receive imaging evaluation as 
stipulated in the protocol until the occurrence of next event (initiation of a new anti-
tumor therapy, PD, withdrawal of ICF by the subjects, or death). 
After the study treatment is discontinued, 3 months of safety follow-up (30 ± 3 days 
and 90 ± 7 days after the last dosing) and survival follow-up (every 60 ± 7 days) will 
be carried out for the subjects. 
Primary efficacy endpoint in this study is OS, which is defined as the time from 
randomization to death (subjects who do not die will be censored on the date of the 
last known survival). 
An independent data monitoring committee (iDMC) is set up in this study to conduct 
an interim safety analysis for the trial. 
Inclusion criteria 
Subjects shall meet the following inclusion criteria: 
1. 
Cytologically or histologically diagnosed with sqNSCLC; 
2. 
Locally advanced, metastatic, or recurrent (i.e., ineligible for radical 


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radiochemotherapy phase IIIB, IIIC, or IV) NSCLC (as per UICC/AJCC staging 
system, version 8), including the following four situations: 
1) 
PD (RECIST v1.1) is observed during or after first-line platinum-based 
chemotherapy (including maintenance chemotherapy), and discontinuation, 
dose reduction, or replacement with any analogous drug for one of the 
medications is permitted in the first-line therapy; 
2) 
Alternative systemic treatment regimen is required due to intolerable 
toxicity of first-line platinum-based chemotherapy regimen (at least one 
complete cycle of treatment is given); 
3) 
Recurrent disease or metastasis is observed within 6 months after 
completion of platinum-based neoadjuvant/adjuvant chemotherapy (before 
or after radical surgery) or sequential/concurrent radical radiochemotherapy  
(platinum-based regimen); 
4) 
Recurrent disease or metastasis is observed over 6 months after completion 
of platinum-based neoadjuvant/adjuvant chemotherapy (before or after 
radical surgery) or sequential/concurrent radical radiochemotherapy 
(platinum-based regimen), and PD is observed after or during platinum-
based chemotherapy for the recurrent disease or metastasis; 
3. 
With at least one measurable lesion (RECIST v1.1); 
4. 
Males or females ≥ 18 and ≤ 75 years old; 
5. 
ECOG PS score is 0 or 1; 
6. 
Life expectancy ≥ 12 weeks; 
7. 
Important organ and bone marrow functions meet the following requirements 
(excluding subjects who have received any cell therapy or growth factor therapy 
within 2 weeks prior to randomization): 
1) Routine blood test: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count 
(PLT) ≥ 100 × 109/L, and hemoglobin (HGB) ≥ 90 g/L (component blood 
transfusion shall not be carried out within 1 week prior to randomization); 
2) Liver function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), 
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × 
ULN, and serum albumin (ALB) ≥ 2.8 g/dL; 
3) Renal function: serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance rate 
(CrCl) ≥ 40 mL/min (using standard Cockcroft-Gault equation): 
Female: CrCl = (140 – Age) × Weight (kg) × 0.85 
72 × Cr (mg/dL) 


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Male: CrCl = (140 – Age) × Weight (kg) × 1.00 
72 × Cr (mg/dL) 
8. 
The subjects and their sex partners should take a medically accepted 
contraceptive measure (intrauterine device (IUD), contraceptive agent or 
condom, etc.) during study treatment and within 6 months after completion of 
study treatment; 
9. 
Subjects who have signed written ICFs, and are able to comply with the follow-
up visits and relevant procedures required in the protocol. 
Exclusion criteria 
Subjects should be excluded if any of the following exclusion criteria is met: 
1. 
With known EGFR-sensitive mutation or ALK rearrangement; 
2. 
Adenosquamous Carcinoma of Lung; 
3. 
Have received anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody or docetaxel 
therapy (not including docetaxel used in systemic treatment to cure any other 
malignant cancer and with potential dose-accumulating toxicity being 
eliminated); 
4. 
Have received the following therapies: 
- 
Systemic anti-tumor therapy, such as chemotherapy, targeted therapy, and 
immunotherapy (including treatments with Chinese herbal medicine indicated 
for cancer), within 3 weeks prior to randomization; 
- 
Any investigational drugs within 4 weeks prior to randomization; 
- 
A high dose of immunosuppressant (systemic glucocorticoid therapy using 
prednisone at a dose of over 10 mg/day or the equivalent dose, excluding a 
single dose of prednisone over 10 mg/day or the quivalent does and 
glucocorticoids used as prophylactics for hypersensitivity, such as medications 
prior to CT) within 4 weeks prior to randomization; 
- 
Live attenuated vaccine within 4 weeks prior to randomization (or live 
attenuated vaccine that is planned during the study); 
- 
Major surgery (e.g., open cavity, open chest, or open abdomen operation), or 
current non-healing surgical wounds, ulcers, or fractures, within 4 weeks prior to 
randomization. 
5. 
Have received any prior anti-tumor therapy and developed adverse reaction, 
which has not recovered to CTCAE grade ≤ 1 yet (not including hair loss or 
laboratory tests of no clinical significance); 
6. 
With active autoimmune disease (inherited or acquired), such as interstitial 
pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, and 


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thyroiditis (subjects with vitiligo or childhood asthma that has completely 
resolved and does not require any intervention after adulthood can be enrolled; 
subjects with hypothyroidism necessitating hormone replacement therapy only 
or type I diabete subjects with well-controlled insulin level can also be enrolled); 
7. 
With known history of allotransplantation (except corneal transplantation) or 
allogeneic hematopoietic stem cell transplantation; 
8. 
Allergic to monoclonal antibodies or any ingredient of docetaxel preparations; 
9. 
Received chest radiotherapy over 30 Gy within 6 months prior to randomization 
or palliative radiotherapy at a dose of ≤ 30 Gy within 7 days prior to 
randomization (palliative radiotherapy for osteopathy or intracranial lesions is 
accepted); 
10. Symptomatic central nervous metastasis and/or carcinomatous meningitis. 
Subjects with asymptomatic brain metastases or with stable symptoms after 
treatment of brain metastases are allowed to participate in this study as long as 
meeting all the following criteria: presence of measurable lesions outside the 
central nervous system (CNS); absence of metastases in midbrain, pons, 
cerebellum, medulla oblongata, or spinal cord; no history of intracranial 
hemorrhage; and no glucocorticoid therapy is currently required; 
11. Afflicted with interstitial lung disease; 
12. With superior vena cava syndrome that is contraindicated for infusion; 
13. Clinically uncontrollable third space effusion, such as pleural effusion or ascites 
that cannot be controlled by drainage or other methods prior to enrollment; 
14. Afflicted with other uncontrolled severe diseases, including but not limited to: 
- 
Active or poorly controlled severe infections; 
- 
HIV infected subjects (with positive anti-HIV antibody); 
- 
Afflicted with acute or chronic active hepatitis B (HBV DNA > 1 × 103 
copies/mL or > 200 IU/mL), or acute or chronic active hepatitis C (with positive 
HCV antibody); 
- 
With active pulmonary tuberculosis, etc.; 
- 
With class III–IV congestive heart failure (based on New York Heart Association 
Classification) or poorly controlled and clinically significant arrhythmia; 
- 
Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or 
diastolic blood pressure ≥ 100 mmHg); 
- 
With any arterial thrombosis, embolism, or ischemia within 6 months prior to 
enrollment, such as myocardial infarction, unstable angina, cerebrovascular 


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accident, or transient cerebral ischemic attack, etc.; 
- 
Tumor compresses peripheral important organs (such as esophagus) with 
associated symptoms; 
- 
Uncontrolled hypercalcemia, or symptomatic hypercalcemia requiring further 
bisphosphonate therapy; 
- 
With other concurrent malignant cancers (except cured cancers, such as cervical 
carcinoma in situ and non-melanoma skin cancer). 
15. Acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that 
may lead to the following consequences: increased study drug-related risks, or 
interference with interpreting study results, and considered ineligible for 
participating in the study by the investigators; 
16. Pregnant or lactatingfemale subjects. 
Study drug, strength, 
and administration 
 
IBI308 
− 
Specification: 10 mL:100 mg 
− 
Administration: 200 mg, intravenous infusion (IV), Q3W, until PD, death, 
intolerable toxicity, withdrawal of consent, initiation of a new anti-tumor 
therapy, or treatment discontinuation due to any other protocol-specified 
reasons. 
 
Docetaxel 
- 
Specifications: 20 mg/0.5 mL, 40 mg/1 mL, or 80 mg/2 mL 
- 
Administration: 75 mg/m2, IV, Q3W, until PD, death, intolerable toxicity, 
withdrawal of consent, initiation of a new anti-tumor therapy, or treatment 
discontinuation due to any other protocol-specified reasons. 
Evaluation criteria 
Efficacy evaluation: 
 
To evaluate OS, PFS, ORR, DCR, and DoR after administration. 
Safety evaluation: 
 
Incidence and severity of all adverse events (AEs), adverse events of special 
interest (AESIs), serious adverse events (SAEs), and treatment-related adverse 
enevts (TRAEs). 
 
To evaluate changes in vital signs, physical examination, and laboratory tests 
results before, during, and after the study treatment. 
Immunogenicity evaluation (for IBI308 treatment group only): 
 
Anti-drug antibody (ADA) and neutralizing antibody (NAb). 
Biomarker evaluation: 
 
Tumor tissue samples will be collected for tumor biomarker analyses, including 


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PD-L1 expression and immune-related gene expression (e.g., expression levels 
of mRNAs of IDO1, CXCL9, CXCL10, HLA-DRA, STAT1, IFNG, etc.); 
 
Blood samples of IBI308 treatment group will be collected for biomarker study, 
including but not limited to dynamic change analysis for PD-L1. 
Quality of life: 
 
The quality of life and health status in IBI308 group and chemotherapy group 
during treatment will be evaluated based on EQ 5D-5L, EORTC QLQ-C30, and 
EORTC QLQ-LC13 scores. 
Statistical methods 
Sample size estimation: 
The primary efficacy endpoint is overall survival (OS). Assuming that  = 0.05 (two-
sided), power = 90%, IBI308-to-docetaxel survival hazard ratio HR = 0.63, endpoint 
events (death) are observed in 75% of the subjects, group assignment ratio is 1:1, the 
minimum estimated sample size is 266 cases; considering a certain dropout rate, a 
total of 290 cases are necessary for randomization, 145 cases in IBI308 group and 145 
cases in the chemotherapy group. 
Superiority hypothesis test: 
This study adopts a superiority design and the primary efficacy endpoint is OS. 
Superiority hypothesis test: 
H0: HR ≥ 1, H1: HR < 1 
Type I error rate () = 0.05 
When the P ≤  (or the upper limit of confidence interval (CI) of HR < 1) is obtained 
via between-group comparison of OS of IBI308 and docetaxel based on the stratified 
Log-rank test, IBI308 can be considered superior to chemotherapy and is able to 
prolong the OS of the subject. 
Interim analysis: 
One interim analysis is designed in this study. The objective of the analysis is to 
evaluate the safety, and the analysis indicators are the safety indicators. At the time 
point of 50, the subjects completed 4 treatment cycles (every 3 weeks for one cycle) 
without considering the adjustment of . 
Primary efficacy endpoint: 
The primary efficacy endpoint is OS. Kaplan-Meier method will be used to estimate 
median survival and its CI, 6-month, 9-month, and 12-month survival rates, and to plot 
survival curve; between-group comparison will be performed using stratified Log-Rank 
test; and stratified Cox proportional hazards model will be used to estimate HR and its 
CI. 


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Secondary efficacy endpoints: 
Survival data: The analyses of PFS and DoR are the same as that of OS. 
The analyses of ORR and DCR will adopt Fisher's exact test for between-group 
comparison. 
Safety data: 
The incidence rates and severity of AEs will be summarized on a group-by-group basis, 
and abnormal changes in laboratory test indicators, vital signs, and physical 
examination will be described. 
Immunogenicity data (for IBI308 treatment group only): 
Data of ADA- and NAb-positive rates will be summarized. 
Quality-of-life indicators: 
The quality of life and health status in IBI308 group and chemotherapy group during 
treatment will be evaluated based on EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-
LC13 scores. 
Biomarker: 
Descriptive statistics for PD-L1 expression levels and distribution as well as immune-
related gene expression results and distribution will be performed, and the potential 
correlation between the above indicators and efficacy will be explored. 
 


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Table 1. Schedule of study visits 
Stage 
Screening 
period 
Treatment period 
Safety follow-up19 
Survival 
follow-up20 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
beyond 
Visit 
1 
2 
3 
4 
5-N 
Day 
Day -28 
to -1 
1 
Day 22  
(± 3 
days) 
Day 43  
(± 3 days) 
Every 3 weeks  
(± 3 days) 
After the last dose 
Day 30  
(± 3 days) 
After the last dose 
Day 90  
(± 7 days) 
Every 
60 days 
(± 7 days) 
Standard study procedures 
 
Written ICF1 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics/medical 
history/previous medications2 
X 
 
 
 
 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
 
Weight/height4 
X 
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 
 
Routine blood test/Blood 
biochemistry/Routine urine 
test6 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test7 
X 
 
 
 
 
X 
 
 
Thyroid function8 
X 
 
X 
X 
X 
X 
 
 
Immunogenicity  
(for IBI308 group only)9 
 
X 
X 
 
X 
 
X 
 
HIV, HBV, and HCV10 
X 
 
 
 
 
 
 
 
AE evaluation11 
X 
X 
X 
X 
X 
X 
X 
 


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Stage 
Screening 
period 
Treatment period 
Safety follow-up19 
Survival 
follow-up20 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
beyond 
Visit 
1 
2 
3 
4 
5-N 
Day 
Day -28 
to -1 
1 
Day 22  
(± 3 
days) 
Day 43  
(± 3 days) 
Every 3 weeks  
(± 3 days) 
After the last dose 
Day 30  
(± 3 days) 
After the last dose 
Day 90  
(± 7 days) 
Every 
60 days 
(± 7 days) 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Survival condition 
 
 
Subsequent anti-tumor therapy 
 
 
 
 
 
X 
X 
X 
Efficacy evaluation 
 
Tumor imaging evaluation12 
X 
 
 
X 
X 
 
 
 
Randomization 
 
RAVE Balance central 
randomization13 
X 
 
 
 
 
 
 
 
Study drug infusion 
 
IBI308 group: IBI30814 
 
X 
X 
X 
X 
 
 
 
Chemotherapy group: 
docetaxel15 
 
X 
X 
X 
X 
 
 
 
Quality of life evaluation16 
 
EQ 5D-5L, EORTC QLQ-C30, 
and QLQ-LC13 scales 
 
X 
 
X 
X 
X 
 
 
Biomarker study 
 
Collection of archived or fresh 
tumor tissue samples17 
X 
 
 
 
 
 
 
 
Blood samples18 
 
X 
 
X 
X 
 
 
 


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Notes: 
1. The ICF should be signed by subjects prior to any protocol-specified procedures. 
2. Previous medications include treatment for the initial diagnosis, including chemotherapy, radiotherapy, and surgery. 
3. Vital signs include body temperature, pulse, respiratory rate, and blood pressure. 
4. Height will be measured during screening period only. Weight needs to be recorded before every planned dose during the study. If the weight fluctuation of a 
subject in docetaxel group is less than 10% compared to baseline (the day of the first dose), then the baseline weight will be used to calculate the dose. Otherwise, 
the actual dose will be calculated based on the weight of scheduled dosing days. 
5. Schedule of 12-lead ECG test: during screening, prior to study medication (except cycle 1) every 2 cycles, and at the safety visits. 
6. Routine blood tests include: red blood cell (RBC), Hemoglobin (HGB), white blood cell (WBC), Platelet (PLT), white blood cell (WBC) differentials 
[lymphocyte (LYM) and absolute neutrophil count (ANC)]. Blood biochemistry tests include: liver function [TBIL, ALT, AST, γ-glutamyltransferase (γ-GT), 
alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactate dehydrogenase (LDH)], renal function [blood urea (UREA) or urea nitrogen (BUN) , 
Cr], blood electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Routine urine tests include pH, urine albumin (UALB), urine 
protein (UPRO), urine red blood cells (URBC), and urine glucose (UGLU). Routine blood test, blood biochemistry, and Routine urine tests will be carried out 
within 7 days prior to the first dose during screening, and then within 3 days prior to each dose as well as at safety follow-up visits. Tests will be conducted at 
each study site. 
7. For female subjects of childbearing potential urine or serum pregnancy test will be performed within 3 days before the first dose and at the first safety follow-
up visit. If the urine pregnancy test is not conclusive, then blood pregnancy test should be performed. The conclusion should be based on the blood pregnancy 
test. Tests will be conducted at each study site. 
8. T3, T4, FT3, FT4, and TSH will be examined during screening; starting from cycle 2, thyroid function of IBI308 group must be examined within 3 days prior 
to dosing of study drug during each cycle and at the first safety follow-up visit. Tests will be conducted at each study site. 
9. Immunogenicity assays will be performed in IBI308 treatment group within 1 h prior to IBI308 infusion in cycles 1, 2, 4, and every 4 cycles (cycles 8, 12, 16, 
and so on) thereafter, and at the second safety follow-up visit. Tests will be conducted in the central laboratory. 
10. During screening, HIV antibody, Hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), HBV DNA, and HCV antibody will be tested. HBV 
carriers are recommended to be monitored for virus activity regularly during the study. Tests will be conducted at each study site. 
11. Safety evaluation of AEs and laboratory tests will be conducted based on NCI CTCAE v 4.03 (for the definitions, recording, causality determination, severity 
judgment, reporting time limit, and processing of AEs and SAEs, please refer to the protocol). 


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12. Tumor evaluation is based on RECIST v1.1 and iRECIST and conducted by the investigator, including the evaluation sites of neck, chest, abdomen, and pelvic 
cavity. According to the criteria in the RECIST v1.1, evaluations should be conducted at baseline (within 28 days prior to the first dose) and every 6 weeks (± 
7 days), and then every 9 weeks (± 7 days) from 24 weeks after administration until PD, initiation of a new anti-tumor therapy, withdrawal of consent by the 
subjects, or death. Subjects in the IBI308 treatment group experiencing the first PD could continue the treatment with IBI308 based on the judgment of the 
investigator if they are clinically stable (see protocol for details). Subjects who discontinue the treatment due to causes other than PD still need to receive 
imaging evaluation as stipulated in the protocol after discontinuation until the occurrence of next event (initiation of a new anti-tumor therapy, PD, withdrawal 
of consentby the subjects, or death). 
13. During screening, eligible subjects will be randomized at a ratio of 1:1 into IBI308 group or chemotherapy group. The stratification factor is ECOG score (0 or 
1). 
14. IBI308 200 mg, Q3W, until PD, death, intolerable toxicity, withdrawal of consent, initiation of a new anti-tumor therapy, or treatment discontinuation due to 
any other reason specified in the protocol. The administration on day 1 during cycle 1 must be completed within 3 working days after randomization.  
15. Docetaxel 75 mg/m2, Q3W, until PD, death, intolerable toxicity, withdrawal of consent, initiation of a new anti-tumor therapy, or treatment discontinuation due 
to any other reason specified in the protocol. The administration on day 1 during cycle 1 must be completed within 3 working days after randomization. 
16. EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 scales are adopted for evaluation of quality of life, and the evaluation will be conducted on the day of 
the first dose, at each imaging evaluation, and at the first safety follow-up visit. 
17. During screening, subjects are required to provide qualified tumor tissue samples (previous or fresh) for PD-L1 and immune-related gene mRNA tests. 
18. Subjects in the IBI308 group need to provide 10 mL of whole blood sample at each of the following time points: prior to the first dose, and at each efficacy 
evaluation during treatment before the initiation of the next treatment; the samples will be analyzed for tumor mutation burden (TMB) and circulating tumor 
cells (CTC), including but not limited to dynamic change of PD-L1. 
19. The safety follow-up will be carried out at 30 (± 3) days and 90 (± 7) days after the last dose. 
20. Survival follow-up will be carried out once every 60 (± 7) days. Telephone follow-up is allowed. 


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Table of Contents 
Protocol Synopsis .......................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 15 
List of Tables ............................................................................................................................... 20 
List of Figures .............................................................................................................................. 21 
List of Abbreviations and Definitions ....................................................................................... 22 
1 Background .............................................................................................................................. 25 
 Disease Background........................................................................................................ 25 
 Study Drug (IBI308) ....................................................................................................... 26 
 Mechanism of action .............................................................................................. 26 
 Clinical study results .............................................................................................. 27 
 Risk/Benefit Assessment ................................................................................................ 28 
2 Study Objective ........................................................................................................................ 28 
 Primary Objective ........................................................................................................... 28 
 Secondary Objectives...................................................................................................... 28 
 Exploratory Objectives ................................................................................................... 29 
3 Overall Study Design ............................................................................................................... 29 
 Overall Design ................................................................................................................ 29 
 Design Principles ............................................................................................................ 31 
 Justification for open-label study design ............................................................... 31 
 Justification for IBI308 monotherapy and dosage regimen ................................... 31 
 Justification for docetaxel as control drug ............................................................. 32 
 Rationale for treatment after progressive disease .................................................. 32 
 Independent Data Monitoring Committee ...................................................................... 32 
4 Study Population ...................................................................................................................... 32 
 Inclusion Criteria ............................................................................................................ 32 
 Exclusion Criteria ........................................................................................................... 33 
 Restrictions During the Study ......................................................................................... 35 
 Study Discontinuation/Withdrawal of Subjects .............................................................. 36 
 Discontinuation of any study drug by the subject .................................................. 36 


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 Post-discontinuation study follow-up .................................................................... 37 
 Withdrawal of consent  ......................................................................................... 37 
5 Study Drugs and Other Treatment ........................................................................................ 38 
 Treatment Regimen ......................................................................................................... 38 
 Treatment regimen ................................................................................................. 38 
 Continued treatment after progressive disease ...................................................... 39 
 Study Drug (IBI308) ....................................................................................................... 40 
 Description ............................................................................................................. 40 
 Labels ..................................................................................................................... 40 
 Storage ................................................................................................................... 40 
 Preparation and infusion ........................................................................................ 40 
 Study Drug (Docetaxel) .................................................................................................. 41 
 Description ............................................................................................................. 41 
 Pretreatment prior to administration of docetaxel ................................................. 41 
 Dose Adjustments ........................................................................................................... 41 
 General principles .................................................................................................. 41 
 IBI308 administration adjustments ........................................................................ 41 
 Docetaxel ............................................................................................................... 43 
 Principles of Managing Immune Checkpoint Inhibitor Toxicities ................................. 46 
 Concomitant Treatment .................................................................................................. 46 
 Therapies prohibited during study drug treatment ................................................. 46 
 Therapies permitted during study drug treatment .................................................. 47 
 Drug-drug interactions ........................................................................................... 47 
 Treatment Compliance .................................................................................................... 48 
 Drug Return and Destruction .......................................................................................... 48 
 Study Drug-Related Records .......................................................................................... 48 
 Complaint Handling ...................................................................................................... 48 
6 Study Evaluations and Procedures ........................................................................................ 49 
 Enrollment and Randomization ...................................................................................... 49 
 Subject enrollment and randomization procedures ................................................ 49 
 Enrollment error handling ...................................................................................... 49 


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 Study Plan and Schedule ................................................................................................. 49 
 Screening period .................................................................................................... 49 
 Baseline (prior to day 1 of cycle 1) ........................................................................ 50 
 Treatment visits ...................................................................................................... 50 
 Safety follow-up..................................................................................................... 51 
 Survival follow-up ................................................................................................. 52 
 Efficacy Evaluation ......................................................................................................... 52 
 Safety Evaluation ............................................................................................................ 53 
 Routine laboratory safety evaluation ..................................................................... 53 
 Physical examination ............................................................................................. 53 
 12-lead ECG........................................................................................................... 53 
 Vital signs .............................................................................................................. 54 
 Weight and height .................................................................................................. 54 
 Pregnancy test ........................................................................................................ 54 
 Other safety inspections ......................................................................................... 54 
 Immunogenicity .............................................................................................................. 55 
 Quality-of-Life Evaluation.............................................................................................. 55 
 Biomarker Analysis ........................................................................................................ 55 
 Storage and Destruction of Biological Samples ............................................................. 56 
7 Safety Reports and AE Management ..................................................................................... 56 
 Definition of AEs ............................................................................................................ 56 
 Definition of SAEs .......................................................................................................... 57 
 Criteria for Severity Levels of AEs ................................................................................ 57 
 Correlation Between AEs and Investigational Drug ....................................................... 58 
 Documentation of AEs .................................................................................................... 59 
 Collection and time of AEs .................................................................................... 59 
 AE follow-up ......................................................................................................... 59 
 Contents of AE documentation .............................................................................. 60 
 Expedited Reporting of SAEs and Pregnancy ................................................................ 63 
 Abnormal Hepatic Function ............................................................................................ 64 
 Management of Drug-Related Toxicities........................................................................ 64 
 Immune-related adverse event ............................................................................... 64 


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 Adverse events of special interest (AESIs) ............................................................ 65 
8 Statistics .................................................................................................................................... 65 
 Statistical Analysis Plan .................................................................................................. 65 
 Hypothesis Test ............................................................................................................... 65 
 Statistical Populations ..................................................................................................... 65 
 Statistical Analysis Methods ........................................................................................... 66 
 General method of statistical analysis.................................................................... 66 
 Analysis of the primary endpoint ........................................................................... 66 
 Analysis of the secondary endpoints...................................................................... 66 
 Analysis of quality-of-life questionnaire ............................................................... 67 
 Biomarker analysis................................................................................................. 67 
 Safety analysis ....................................................................................................... 67 
 Compliance analysis .............................................................................................. 69 
 Subjects' baseline characteristics ........................................................................... 69 
 Interim analysis ...................................................................................................... 69 
 Subgroup analysis ................................................................................................ 69 
 Multiple comparisons and adjustments ................................................................ 69 
 Eligible subject data lists ..................................................................................... 70 
 Exploratory analysis............................................................................................. 70 
 Sample Size Determination............................................................................................. 70 
 Methods for Controlling Bias ......................................................................................... 70 
 Randomization and blinding .................................................................................. 70 
 Blinding maintenance evaluation ........................................................................... 71 
 Unblinding and emergency unblinding .................................................................. 71 
9 Quality Assurance and Quality Control ................................................................................ 71 
 Clinical Monitoring ......................................................................................................... 71 
 Data Management/Coding .............................................................................................. 71 
 Quality Assurance Audit ................................................................................................. 73 
10 Ethics ....................................................................................................................................... 73 
 Ethics Committee .......................................................................................................... 73 
 Ethics Conduct of the study .......................................................................................... 74 


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 Subject Information and Informed Consent .................................................................. 74 
 Data Protection of Subjects ........................................................................................... 74 
11 Study Management ................................................................................................................ 75 
 Data Processing and Record Keeping ........................................................................... 75 
 Source Data/File Access ............................................................................................... 75 
 Protocol Revisions ........................................................................................................ 75 
 Responsibilities of the Investigator ............................................................................... 75 
 Publication of Study Data ............................................................................................. 75 
12 References ............................................................................................................................... 77 
13 Appendix ................................................................................................................................. 79 
Appendix 1: Signature Page for Investigator ........................................................................... 79 
Appendix 2: ECOG PS Scoring Criteria .................................................................................. 80 
Appendix 3: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) ... 81 
Appendix 4: Immune Response Evaluation Criteria in Solid Tumors (iRECIST) .............. 95 
Appendix 5: List of Pre-Existed Autoimmune Diseases Prior to Enrollment ..................... 101 
Appendix 6: Management for irAE......................................................................................... 102 
 
 
 


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List of Tables 
Table 1. Schedule of study visits ....................................................................................................11 
Table 2. Effective methods of contraception (one of the methods must be used) ........................ 36 
Table 3. Dosage of study drugs and treatment regimen ................................................................ 39 
Table 4. IBI308 dose adjustment protocol .................................................................................... 41 
Table 5. Docetaxel dose reduction procedure ............................................................................... 44 
Table 6. Routine laboratory safety evaluation .............................................................................. 53 
Table 7. Correlation determination between AEs and investigational drug .................................. 58 
Table 8. Liver injuries required to be reported as SAEs ............................................................... 64 
 


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List of Figures 
Figure 1. Schematic of CIBI308C301 study design and dosage regimen .................................... 30 
 


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List of Abbreviations and Definitions 
Abbreviation 
Definition 
ADA 
Anti drug antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALB 
Albumin 
ALK 
Anaplastic lymphoma kinase 
ALP  
Alkaline phosphatase 
ALT  
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AST  
Aspartate amino transferase 
CI  
Confidence Interval 
Cmax  
Maximum serum concentration of drug 
Cr 
Creatinine 
CR  
Complete Remission 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CSR 
Clinical Study Report 
CT  
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE  
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electrical Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EORTC QLQ-C30 
European organization for research and Treatment of cancer quality of life 
questionnaire C30 
EORTC QLQ-LC13 
European organization for research and treatment of cancer quality of life 
questionnaire LC13 
FAS 
Full Analysis Set 
FBG 
Fasting Blood Glucos 
FDA 
Food and Drug Administration 
FDG-PET 
Fludeoxyglucose-Positron Emission-computed Tomography 


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Abbreviation 
Definition 
FT3 
Free Triiodothyronine 
FT4 
Free Thyroxine 
GCP  
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HR 
Hazard ratio 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
iCPD 
Immune confirmed progressive disease 
ID 
identity  
IHC 
immunohistochemistry 
IDMC 
independent data monitoring committee  
IgG 
Immunoglobulin G 
irAE  
Immune-related Adverse Event 
IRR 
Infusion related reactions 
iRECIST  
Immune Response Evaluation Criteria in Solid Tumours  
iUPD 
Immune unconfirmed progressive disease 
IV  
intravenous infusion 
LDH 
lactate dehydrogenase 
LYM 
lymphocyte 
mRNA 
Messenger RNA 
MRI  
Magnetic Resonance Imaging 
NAb 
Neutralizing Antibody 
NCI  
National Cancer Institute 
NE 
Not evaluatable 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
ORR  
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive disease 
PD-1  
Programmed Cell Death 1 
PD-L1  
Programmed Cell Death Ligand 1 
PFS  
Progression Free Survival 
PK  
Pharmacokinetic 


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Abbreviation 
Definition 
PLT 
Platelet 
PR 
Partial Remission  
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
sqNSCLC 
Squamous non-small cell lung cancer 
SS 
Safety Set 
t½ 
half-life period 
T3 
triiodothyronine 
T4 
thyroxin 
TBIL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TMB 
Tumor mutation burden 
TP 
Total Protein 
TRAE 
Treatment Related Adverse Event 
TSH 
Thyroid Stimulating Hormone 
UALB 
urinary albumin 
UGLU 
urinary glucose 
ULN 
Upper limits of normal 
UPRO 
urine protein 
UREA 
Urea 
URBC 
Urinary Red Blood Cells 
WBC 
White Blood Cells 
γ-GT 
γ-glutamyltransferase 
 
 


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1 Background 
Disease Background 
With prolonged mean life expectancy and changing lifestyle of human beings, malignant tumors 
have become a major life-threatening disease and pose serious threat to the health of Chinese 
people. In particular, lung cancer tops malignant tumors in terms of incidence rate and mortality 
due to large smoker population. Statistical data in 2015 show that 733,000 people developed lung 
cancer and 600,000 people died of lung cancer in China, and both the incidence rate and the 
mortality are top of the world[1]. Advanced squamous non-small cell lung cancer (sqNSCLC) is 
lack of effective therapies. The first-line standard therapy is platinum-based chemotherapy, and 
the second-line therapy is still docetaxel-based chemotherapy[2], which is limited in therapeutic 
effect and shows a median survival of about 6 months[2], indicating the presence of extremely 
unfulfilled medical demand. Recent years, there have seen rapid advancements in  studies on 
inhibiting immune checkpoint to activate human autoimmune system which thereby exerts attack 
to tumor cells. Immune checkpoint inhibitors (PD-1/PD-L1 inhibitor) provide a new clinical 
therapy for non-small cell lung cancer (NSCLC), including sqNSCLC . 
In Jan. 2015, a phase III clinical trial of Opdivo® (nivolumab), a PD-1 inhibitor from Bristol-
Myers Squibb (BMS), in the treatment of sqNSCLC was prematurely terminated[2]. In this head-
to-head study comparing nivolumab versus docetaxel in the second-line treatment, iDMC 
assessed that nivolumab treatment group had a OS obviously superior to that in docetaxel control 
group (median OS: 9.2 vs. 6.0 months; HR: 0.59, 95%CI: 0.44–0.79; p < 0.001), a longer PFS 
(median: 3.5 vs. 2.8 months; HR: 0.62, 95%CI: 0.47–0.81; p < 0.001), and a higher ORR (20% 
vs. 9%; p = 0.008)[2]. In Mar. 2015, FDA approved the use of nivolumab in subjects with 
advanced sqNSCLC who failed first-line therapy. 
Based on the results of Keynote-010 study, PD-1 inhibitor Keytruda® (pembrolizumab) from 
Merck Sharp & Dohme (MSD) was also approved by FDA in 2015 for the use in the second-line 
treatment of PD-L1-positive NSCLC. In Keynote-010, a total of 1034 subjects were enrolled and 
randomized at a ratio of 1:1:1 to receive 2 mg/kg pembrolizumab, 10 mg/kg pembrolizumab, and 
75 mg/m2 docetaxel, respectively; the study showed that the median OS were 10.4, 12.7, and 8.5 
months, respectively, indicating significantly improved OS in two pembrolizumab treatment 
groups versus docetaxel group[3]. 
Based on the results of POPLAR study and OAK study, Roche's PD-L1 antibody Tecentriq® 
(atezolizumab) was approved by FDA in 2016 for the use in second-line treatment of NSCLC. 
Both studies are randomized controlled studies of atezolizumab versus docetaxel in second- or 
over treatment of NSCLC, and the studies showed the median OS of 12.6 vs. 9.7 months[4] and 
13.8 vs. 9.6 months[5], respectively. 


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Previous studies on causality of PD-L1 expression with prognosis of NSCLC showed 
inconsistence, which might be related to histological type and IHC PD-L1 antibody used. In the 
phase III study of nivolumab in second-line treatment of squamous non-small cell lung cancer 
(sqNSCLC), IHC staining was performed with 28-8 antibody and PD-L1 of each predetermined 
levels (1%, 5%, and 10%) showed neither prognostic effect nor predictive effect for any efficacy 
endpoint (OS, PFS, or ORR)[2]. Meanwhile, a retrospective study using 22C3 antibody also 
indicated that PD-L1 expression had no correlation with NSCLC prognosis[6]. 
Study Drug (IBI308) 
Mechanism of action 
Immune checkpoints can regulate or equilibrate intensity and extensiveness of immune response 
through mechanism of action of immunosuppression so as to prevent the body's normal cells or 
tissues from being damaged. However, tumor cells may escape from body immunosurveillance 
and avoid being eliminated utilizing the characteristics of immune checkpoints. Currently, 
multiple immune checkpoints have been found, among which CTLA-4 and PD-1/PD-L1 
inhibitors have been applicable to clinical practice. Immune checkpoint inhibitors of PD-1/PD-
L1 have good safety as well as a wide range of indications, and thus are considered having broad 
prospects for clinical application. 
PD-1 is primarily expressed on the surfaces of activated T cells and has two ligands: PD-L1 and 
PD-L2. PD-L1 is the main ligand that is expressed on activated T cells, antigen-presenting cells, 
and tumor cells[7]. The binding of PD-1 to PD-L1 plays an important role in regulating the 
activation of T cells and maintaining peripheral immune tolerance. When T cells do not express 
PD-1, they interact with antigen-presenting cells to enable the activation and proliferation of T 
cells as well as the activation of cytokine secretion, which can kill the tumor cells. The activated 
T cells begin to express PD-1. After PD-1 binds to the ligand PD-L1 expressed on the surface of 
antigen-presenting cells or tumor cells, the inhibitory signal in the downstream of PD-1 inhibits 
the proliferation of T cells and activates the secretion of cytokines, thus weakens the function of 
T cells. Most tumor cells evade the attack of immune cells through this mechanism. The activity 
and ability to kill cancer cells of T cells can be restored by blocking the PD-1/PD-L1 interaction 
with drugs[8]. 
As of the end of 2017, 5 anti-PD-1/PD-L1 monoclonal antibodies had been approved by 
regulatory authorities including FDA for marketing, and they are: nivolumab (trade name: 
OPDIVO®, from BMS), pembrolizumab (trade name: KEYTRUDA®, from MSD), atezolizumab 
(trade name: TECENTRIQ®, from Roche), avelumab (trade name: BAVENCIO®, from Merck 
Serono & Pfizer), and duralumab (trade name: IMFINZI®, from Astra Zeneca). The indications 
include multiple tumors such as advanced melanoma, advanced NSCLC, advanced classical 


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Hodgkin's lymphoma, advanced renal cell carcinoma, advanced urothelial carcinoma, advanced 
head and neck cancer, colorectal cancer, gastric cancer, and liver cancer. In addition, many 
indications have been in phase III clinical studies or have been submitted for approval. The 
approval of these drugs confirms the important role of PD-1/PD-L1 immune checkpoint 
inhibitors in cancer immunotherapy. China has no PD-1/PD-L1 immune checkpoint inhibitor 
being marketed to date. It is of very important significance to encourage the development of such 
inhibitors and thereby to provide better alternative treatment for subjects with advanced lung 
cancer in China. 
Recombinant fully human anti-PD-1 monoclonal antibody injection (R&D code: IBI308) is a 
recombinant fully human IgG4 monoclonal antibody. Multiple nonclinical in vitro tests have 
validated the effect of IBI308 in blocking PD-1 pathway, and multiple immune-functioning 
mouse tumor models also indicated the anti-tumor activity of IBI308 murine analogs (the study 
results are detailed in the Investigator's Brochure for details of the study results). The nonclinical 
study results indicated the development prospect of IBI308 in blocking the PD-1. 
Clinical study results 
A phase Ia dose escalation trial of IBI308 was initiated in Sep. 2016. About 12–24 subjects with 
advanced solid tumors who had failed standard treatment were scheduled to be enrolled in phase 
Ia and the dose escalation decision followed the standard "3 +3" design to evaluate 4 dose levels 
(1 mg/kg, 3 mg/kg, 200 mg and 10 mg/kg) of IBI308. After the completion of 1 mg/kg dose 
administration, subjects were randomized in a 1:1 ratio to either 3 mg/kg or 200 mg group for 
independent evaluations. Dose-limiting toxicity (DLT) was observed for 28 days after the first 
dose for each dose group. After completion of DLT observation, subjects were treated with 
IBI308 Q2W (1 mg/kg, 3 mg/kg, or 10 mg/kg) or Q3W (200 mg) until progressive disease (PD), 
intolerable toxicity, withdrawal of ICF, or other reasons requiring treatment discontinuation 
(whichever occurred first). 
PK evaluations on 1 mg/kg IBI308 were conducted in subjects (n = 3) with various tumors, 
among which preliminary results of a single dose showed that: The maximum body exposure 
during a single dosing was achieved right after the end of the infusion of 1 mg/kg IBI308; the 
drug rapidly completed distribution and proceeded with slow elimination (t1/2 was about 17.3 d) 
after peaking, indicating classical PK two-compartment characteristics of monoclonal antibodies 
and elimination t1/2 which was similar to the physiological t1/2 of IgG4. 
The preliminary results of pharmacodynamics (PD) study showed that: IBI308 at a dose of 1 
mg/kg could rapidly (24 h) saturate the occupancy of peripheral PD-1 (95.8 ± 2.3%) and 
maintained the PD-1 occupancy with decreasing concentrations throughout the study (28 d, 
C28d: 3.70 ± 0.15 μg/mL). Steady state was expected to be achieved after continual dosing of 1 


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mg/kg IBI308 for 84 days (Q2W, 6 doses). On the premise of no significant variation in drug 
clearance profile in the subject, the expected steady-state trough concentration was around 13 
μg/mL and the peripheral PD-1 receptor occupancy could be continuously maintained. 
As of Oct. 30, 2017, neither DLT nor unexpected AE had been observed in the completed phase 
Ia study. A total of 267 tumor subjects received IBI308 therapy, and the overall safety profile was 
similar to those of anti-PD-1 monoclonal antibodies approved overseas. 
Risk/Benefit Assessment 
Considering the mechanism of action of IBI308 and the clinical safety information of products 
with similar mechanisms, the main AEs during this clinical trial will possibly be the immune-
mediated inflammation resulted from the activation of immune system, e.g. pneumonia, colitis, 
hepatitis, renal insufficiency, and endocrine system inflammation. According to the available 
clinical data, anti-PD-1 monoclonal antibodies are well-tolerated despite of high incidence of 
adverse reactions. Treatment discontinuation due to adverse reactions only occur in a small 
number of subjects, and most events resolve after appropriate interventions. Early symptoms of 
immune related adverse events (irAEs) vary. Therefore, investigators must closely monitor early 
signs and symptoms of irAEs during the trial, make correct judgments timely, adjust the dose 
according to Section 5.4.1 in the protocol, and provide effective treatment measures to reduce risks 
to subjects. Besides, subjects with autoimmune diseases shall be excluded from the trial to avoid 
exacerbation of the original disease due to the activation of immune system. 
Pharmacological and safety data of the phase Ia clinical trial of IBI308 indicate that IBI308 has 
definite pharmacological activity and good tolerability in subjects with advanced tumor. 
The above data preliminarily demonstrate good safety and pharmacological activity of IBI308 as 
well as its significant anti-tumor activity in subjects with advanced sqNSCLC, and support 
clinical trials of IBI308 in Chinese subjects with advanced sqNSCLC. 
2 Study Objective 
Primary Objective 
(1) To evaluate OS in subjects with advanced or metastatic sqNSCLC who have failed first-line 
platinum-based chemotherapy treated with IBI308 versus docetaxel. 
Secondary Objectives 
(1) To evaluate the objective response rate (ORR), disease control rate (DCR), duration of 
response (DoR), and progression free survival (PFS) of subjects with advanced/metastatic 
sqNSCLC who have failed first-line platinum-based chemotherapy treated with IBI308 
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(2) To evaluate the safety in subjects with advanced/metastatic sqNSCLC who have failed first-
line platinum-based chemotherapy treated with IBI308 versus docetaxel; 
(3) To evaluate the influence on the quality of life in subjects with advanced/metastatic 
sqNSCLC who have failed first-line platinum-based chemotherapy treated with IBI308 
versus docetaxel. 
Exploratory Objectives 
(1) To evaluate causalities of PD-L1 expression, immunity-related gene mRNA, and tumor 
mutation burden (TMB) with efficacy in subjects with advanced/metastatic sqNSCLC; 
(2) To evaluate causality of dynamic PD-L1 expression on circulating tumor cell (CTC) surface 
with efficacy in the IBI308 group; 
(3) To explore the application of Immune Response Evaluation Criteria in Solid Tumors 
(iRECIST) in the evaluations of PFS, ORR, DCR, and DoR of the IBI308 group. 
3 Overall Study Design 
Overall Design 
This is a randomized, open-label, multicenter, parallel and phase III clinical trial comparing the 
efficacy and safety of IBI308 and docetaxel in the treatment of subjects with advanced or 
metastatic sqNSCLC who have failed first-line platinum-based chemotherapies (ORIENT-3) . 
This trial intends to enroll 290 subjects with advanced or metastatic sqNSCLC who have failed 
first-line platinum-based chemotherapies. The central randomization is adopted in this trial and 
the subjects will be stratified according to ECOG PS (0 or 1). 
After the subjects with advanced or metastatic sqNSCLC who have failed prior first-line 
platinum-based chemotherapies sign the informed consent form (ICF) and are screened based on 
the inclusion/exclusion criteria, the eligible subjects will be randomized (1:1) to receive IBI308 
(200 mg, IV, Q3W) or docetaxel (75 mg/m2 IV, Q3W) until progressive disease (PD), death, 
intolerable toxicity, withdrawal of consent, initiation of a new anti-tumor therapy, or treatment 
discontinuation due to any other reason specified in the protocol. 
This study will adopt RECIST v1.1 to carry out clinical tumor imaging evaluation. The tumor 
imaging evaluation will be conducted once every 6 weeks (± 7 days) depending on clinical 
situations of the subjects; and then once every 9 weeks (±7 days) after 24 weeks of 
administration until PD, initiation of a new anti-tumor therapy, withdrawal of consent by the 
subjects, or death. Subjects in the IBI308 treatment group experiencing the first PD could 
continue the treatment with IBI308 based on the judgment of the investigator if they are 
clinically stable (see Section 5.1.2 in the protocol for details). Subjects who discontinue the 
treatment due to causes other than PD still need to receive imaging evaluation as stipulated in the 


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protocol after discontinuation until the occurrence of next event (initiation of a new anti-tumor 
therapy, PD, withdrawal of consent by the subjects, or death). 
After the study treatment is discontinued, 3 months of safety follow-up (30 ± 3 days and 90 ± 7 
days after the last dosing) and survival follow-up (every 60 ± 7 days) will be carried out for the 
subjects. 
Primary efficacy endpoint in this study is OS, which is defined as the time from randomization to 
death (subjects who do not die will be censored on the date of the latest known survival). 
An independent data monitoring committee (IDMC) is set up in this study to conduct an interim 
safety analysis for the trial. 
 
Figure 1. Schematic of CIBI308C301 study design and dosage regimen 
 
Screening: Subjects with pathological diagnosis of 
sqNSCLC 
who have failed first-line platinum-based 
chemotherapy (n = 290) 
Randomization: 1:1 (IBI308 or docetaxel) 
Stratification: ECOG score (0 or 1) 
IBI308 group: 200 mg IV Q3W 
Docetaxel group: 75 mg/m² IV Q3W 
Safety follow-up: 1. 30 days after the last dose 
               2. 90 days after the last dose 
Survival follow-up: Every 60 days after safety follow-up 


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Design Principles 
Justification for open-label study design 
Considering that the response of the subject to the drugs may vary significantly due to the 
different mechanism of action between IBI308 and docetaxel and thereby the effective blinding 
of subjects is unachievable, this trial adopts an open-label design instead of blinding. 
IBI308 may cause autoimmune reactions involving corresponding tissues or organs of the body, 
and thus antihistamine and/or immunosuppressant (e.g., glucocorticoids) therapies are usually 
required. 
Docetaxel may cause various allergic reactions (e.g., skin rash), fluid retention, and potential 
serious impairment of bone marrow, nervous system, liver, and kidneys. In addition, concurrent 
use of CYP3A4 inhibitors would increase exposure of docetaxel, and thereby the reduction of the 
dose of docetaxel is required when the inhibitors are used concurrently to avoid serious toxic 
side effects. Potential adverse reactions to docetaxel should be handled according to related 
instructions and clinical practice. 
Justification for IBI308 monotherapy and dosage regimen 
Safety and efficacy of anti-PD-1/PD-L1 monotherapy in second-line NSCLC have been fully 
demonstrated, and anti-PD-1/PD-L1 monotherapy has been listed as second-line standard 
therapy by National Comprehensive Cancer Network (NCCN). IBI308 is an anti-PD-1 
monoclonal antibody and anti-tumor activity of IBI308 monotherapy has been validated in 
multiple immune-functioning mouse models (see Investigator's Brochure). In the phase I clinical 
study (CIBI308A101) of IBI308, the PD results showed that IBI308 had definite blocking effect 
against PD-1 receptor in the body. Therefore, this study will investigate efficacy and safety of 
IBI308 monotherapy in second-line sqNSCLC. 
This study intends to adopt administration of IBI308 at 200 mg, Q3W. The selection of this 
administration method is mainly based on the safety and exposure (concentration)-response (PD-
1 receptor occupancy) relationship data of the currently proceeding phase Ia study 
(CIBI308A101), combined with the nonclinical in vitro/in vivo PD data and relevant comparison 
data to similar drugs. On the premise that no significant variation occurs in drug clearance 
characteristics of subjects, IBI308 of 200 mg Q3W which is administered continuously for 84 
days (4 doses) can achieve steady state with steady trough concentration of about 26 μg/mL and 
can maintain peripheral and target PD-1 receptor occupancy. 


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Justification for docetaxel as control drug  
Advanced squamous non-small cell lung cancer (sqNSCLC) is lack of effective therapies and the 
first-line standard therapy is platinum-based chemotherapy. Docetaxel is one of the drugs which 
are approved for second-line treatment of NSCLC and can prolong the PFS and OS of subjects 
compared with best support care (BSC)[9] or active chemotherapy[10]. Meanwhile, docetaxel was 
used as control drug to compare with pemetrexed in a non-inferiority study, where docetaxel 
group had a median PFS of 2.9 months and median OS of about 8 months[11]. Pemetrexed was 
not approved for second-line treatment of sqNSCLC due to lack of efficacy. The studies on the 
erlotinib and gefitinib in second-line treatment of sqNSCLC were also conducted. Both of them 
showed nonuniform absorption levels in sqNSCLC subjects and thereby were not considered as 
second-line standard therapy. In summary, docetaxel is chosen as control drug in this study. 
Rationale for treatment after progressive disease 
Existing clinical data show that, a few subjects may experience "PD" (RECIST v1.1) after 
receiving PD-1 inhibitors prior to objective clinical objective response and/or stable disease 
(SD). However, continuous treatment may still bring clinical benefits[12]. The mechanism of 
action of this phenomenon may be worsening of intratumor inflammation which results increased 
tumors or even new lesions. Additionally, an anti-tumor immune response may take a certain 
time to develop. Therefore, subjects treated with IBI308 are allowed to continue study treatment 
with IBI308 after PD defined in RECIST v1.1 is preliminarily determined by the investigator, in 
case of potential clinical benefit (see Section 5.1.2 for details). 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) is set up in this study to conduct an interim 
safety analysis for the trial. The personnel composition, responsibilities, and procedures of the 
IDMC are detailed in the IDMC regulations. 
4 Study Population 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. 
Cytologically or histologically diagnosed with sqNSCLC; 
2. 
Locally advanced, metastatic, or recurrent (i.e., ineligible for radical radiochemotherapy phase IIIB, IIIC, or 
IV) NSCLC (as per UICC/AJCC staging system, version 8), including the following four situations: 
1) 
PD (RECIST v1.1) is observed during or after first-line platinum-based chemotherapy (including 
maintenance chemotherapy), and discontinuation, dose reduction, or replacement with any analogous drug 
for one of the medications is permitted in the first-line therapy; 


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2) 
Alternative systemic treatment regimen is required due to intolerable toxicity of first-line platinum-based 
chemotherapy regimen (at least one complete cycle of treatment is given); 
3) 
Recurrent disease or metastasis is observed within 6 months after completion of platinum-based 
neoadjuvant/adjuvant chemotherapy (before or after radical surgery) or sequential/concurrent radical 
radiochemotherapy  (platinum-based regimen); 
4) 
Recurrent disease or metastasis is observed over 6 months after completion of platinum-based 
neoadjuvant/adjuvant chemotherapy (before or after radical surgery) or sequential/concurrent radical 
radiochemotherapy (platinum-based regimen), and PD is observed after or during platinum-based 
chemotherapy for the recurrent disease or metastasis; 
3. 
With at least one measurable lesion (RECIST v1.1); 
4. 
Males or females ≥ 18 and ≤ 75 years old; 
5. 
ECOG PS score is 0 or 1; 
6. 
Life expectancy ≥ 12 weeks; 
7. 
Important organ and bone marrow functions meet the following requirements (excluding subjects who have 
received any cell therapy or growth factor therapy within 2 weeks prior to randomization): 
1) Routine blood test: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 100 × 109/L, and 
hemoglobin (HGB) ≥ 90 g/L (component blood transfusion shall not be carried out within 1 week prior to 
randomization); 
2) Liver function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, and serum albumin (ALB) ≥ 2.8 g/dL; 
3) Renal function: serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance rate (CrCl) ≥ 40 mL/min (using 
standard Cockcroft-Gault equation): 
Female: CrCl = (140 – Age) × Weight (kg) × 0.85 
72 × Cr (mg/dL) 
Male: CrCl = (140 – Age) × Weight (kg) × 1.00 
72 × Cr (mg/dL) 
8. 
The subjects and their sex partners should take a medically accepted contraceptive measure (intrauterine device 
(IUD), contraceptive agent or condom, etc.) during study treatment and within 6 months after completion of 
study treatment; 
9. 
Subjects who have signed written ICFs, and are able to comply with the follow-up visits and relevant 
procedures required in the protocol. 
 
Exclusion Criteria 
Subjects should be excluded if any of the following exclusion criteria is met: 


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1. 
With known EGFR-sensitive mutation or ALK rearrangement; 
2. 
Adenosquamous Carcinoma of Lung; 
3. 
Have received anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody or docetaxel therapy (not including docetaxel 
used in systemic treatment to cure any other malignant cancer and with potential dose-accumulating toxicity 
being eliminated); 
4. 
Have received the following therapies: 
- 
Systemic anti-tumor therapy, such as chemotherapy, targeted therapy, and immunotherapy (including 
treatments with Chinese herbal medicine indicated for cancer), within 3 weeks prior to randomization; 
- 
Any investigational drugs within 4 weeks prior to randomization; 
- 
A high dose of immunosuppressant (systemic glucocorticoid therapy using prednisone at a dose of over 10 
mg/day or the equivalent dose, excluding a single dose of prednisone over 10 mg/day or the quivalent does and 
glucocorticoids used as prophylactics for hypersensitivity, such as medications prior to CT) within 4 weeks 
prior to randomization; 
- 
Live attenuated vaccine within 4 weeks prior to randomization (or live attenuated vaccine that is planned 
during the study); 
- 
Major surgery (e.g., open cavity, open chest, or open abdomen operation), or current non-healing surgical 
wounds, ulcers, or fractures, within 4 weeks prior to randomization. 
5. 
Have received any prior anti-tumor therapy and developed adverse reaction, which has not recovered to 
CTCAE grade ≤ 1 yet (not including hair loss or laboratory tests of no clinical significance); 
6. 
With active autoimmune disease (inherited or acquired), such as interstitial pneumonia, uveitis, enteritis, 
hepatitis, hypophysitis, vasculitis, nephritis, and thyroiditis (subjects with vitiligo or childhood asthma that has 
completely resolved and does not require any intervention after adulthood can be enrolled; subjects with 
hypothyroidism necessitating hormone replacement therapy only or type I diabete subjects with well-controlled 
insulin level can also be enrolled); 
7. 
With known history of allotransplantation (except corneal transplantation) or allogeneic hematopoietic stem 
cell transplantation; 
8. 
Allergic to monoclonal antibodies or any ingredient of docetaxel preparations; 
9. 
Received chest radiotherapy over 30 Gy within 6 months prior to randomization or palliative radiotherapy at a 
dose of ≤ 30 Gy within 7 days prior to randomization (palliative radiotherapy for osteopathy or intracranial 
lesions is accepted); 
10. Symptomatic central nervous metastasis and/or carcinomatous meningitis. Subjects with asymptomatic brain 
metastases or with stable symptoms after treatment of brain metastases are allowed to participate in this study 
as long as meeting all the following criteria: presence of measurable lesions outside the central nervous system 
(CNS); absence of metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord; no history of 
intracranial hemorrhage; and no glucocorticoid therapy is currently required; 
11. Afflicted with interstitial lung disease; 


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12. With superior vena cava syndrome that is contraindicated for infusion; 
13. Clinically uncontrollable third space effusion, such as pleural effusion or ascites that cannot be controlled by 
drainage or other methods prior to enrollment; 
14. Afflicted with other uncontrolled severe diseases, including but not limited to: 
- 
Active or poorly controlled severe infections; 
- 
HIV infected subjects (with positive anti-HIV antibody); 
- 
Afflicted with acute or chronic active hepatitis B (HBV DNA > 1 × 103 copies/mL or > 200 IU/mL), or acute or 
chronic active hepatitis C (with positive HCV antibody); 
- 
With active pulmonary tuberculosis, etc.; 
- 
With class III–IV congestive heart failure (based on New York Heart Association Classification) or poorly 
controlled and clinically significant arrhythmia; 
- 
Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 
mmHg); 
- 
With any arterial thrombosis, embolism, or ischemia within 6 months prior to enrollment, such as myocardial 
infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack, etc.; 
- 
Tumor compresses peripheral important organs (such as esophagus) with associated symptoms; 
- 
Uncontrolled hypercalcemia, or symptomatic hypercalcemia requiring further bisphosphonate therapy; 
- 
With other concurrent malignant cancers (except cured cancers, such as cervical carcinoma in situ and non-
melanoma skin cancer). 
15. Acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that may lead to the following 
consequences: increased study drug-related risks, or interference with interpreting study results, and considered 
ineligible for participating in the study by the investigators; 
16. Pregnant or lactatingfemale subjects. 
 
Restrictions During the Study 
Female subjects of childbearing potential who are sexually active with nonsterilized male 
partners and nonsterilized male subjects who are sexually active with female partners of 
childbearing age must use at least one of the acceptable methods of effective contraception listed 
inTable 2, The contraception should be used from the beginning of the screening period to up to 
180 days after the last dose of study drug; thereafter, the subject should discuss with a physician 
in charge about discontinuation of the contraceptive measures. Periodic abstinence, calendar-
based method, and withdrawal method are not the acceptable forms of contraception. 
Female subjects of childbearing potential is defined as any female who has not undergone 
surgical sterilization (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and is not 
postmenopausal (defined as 12 months of amenorrhea without alternative medical causes). 


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Menopause is defined as 12 months of amenorrhea of a woman without any other medical 
reasons. Age requirements are as follows: 
- 
Females < 50-year old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, and luteinizing hormone and follicle stimulating 
hormone levels within the postmenopausal range, are considered menopausal. 
- 
Females ≥ 50-year old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, radiation-induced ovariectomy and the time from the last 
menorrhea > 1 year, chemotherapy-induced amenorrhea and the time from the last 
menorrhea > 1 year, or had undergone surgical sterilization (bilateral ovariectomy or 
hysterectomy), are considered menopausal. 
Table 2. Effective methods of contraception (one of the methods must be used) 
Barrier methods 
Intrauterine devices (IUDs) 
Hormonal methods 
Male condom with spermicide 
Copper-T IUD 
Implant 
Cervical cap with spermicide 
Progesterone-T IUDa 
Hormonal contraceptive injection 
Diaphragm with spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g. Mirena®)a 
Combined oral contraceptive pill 
Low-dose oral contraceptive pill 
Contraceptive patch 
aThis method is also considered as a hormonal approach 
Study Discontinuation/Withdrawal of Subjects 
Discontinuation of any study drug by the subject 
In case of any of the following situation, the subject "must" discontinue study drug: 
 
Discontinuation of study treatment required by the subject 
 
Any clinical AE, abnormal results of laboratory tests or concomitant diseases based on the 
judgment of the investigator, which indicate that subjects cannot acquire the greatest benefit 
if they continue to participate in the study 
 
Discontinuation of study required by the sponsor 
 
Discontinuation criteria specified in the study protocol 
 
Violation against the inclusion/exclusion criteria, which is likely to pose potential risk to the 
safety of subjects or affect the accuracy of study data; subjects are deemed unsuitable to 
continue participating in this study by the sponsor and the investigator;  
 
Subjects seriously violate the requirements of the study protocol, and are deemed unsuitable 
to continue participating in this study by the sponsor and the investigator; 


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 
The subject is involved in any other type of clinical trial at the same time; 
If subjects become pregnant, the investigator must report to the sponsor designee immediately. In 
most cases, the study drug will be permanently discontinued in an appropriate manner. If the 
investigator confirms the favorable benefit-to-risk ratio of further use of the study drug, then 
he/she must discuss with the sponsor designee on this issue. 
All subjects who have discontinued the study drug have to be followed up according to the 
procedure specified in Table 1, unless the subject withdraws the ICF for all study procedures 
(including post-discontinuation study follow-up). 
If a subject discontinues the study drug prior to study completion, then the reasons thereof must 
be recorded in the subject's medical record and entered on the corresponding page of Case 
Report Form (CRF). 
Post-discontinuation study follow-up 
In this study, OS is a primary endpoint. Study follow-up after completion are vital to safety of 
subjects and integrity as well as reliability of the study. All subjects who have discontinued the 
study drug must be further followed up to collect their prognoses and/or survival follow-up data 
according to the requirements specified in Table 1, until the death of subjects or the completion 
of the study. 
For subjects lost to follow-up, the study site should try the best to contact the subjects and 
ascertain the reason for loss to follow-up, and then reschedule visits if possible. Meanwhile the 
date and method of contact shall be documented in the study documents. 
Withdrawal of consent  
If a subject who requests to discontinue study drug continues the study, he/she must be further 
followed up according to the procedures specified in the study protocol. There is only one 
exception, where a subject withdraws the consent definitely and further contact with the subject 
or any person authorized previously to offer this information is impossible. Where possible, the 
subject should give the investigator a written notice on the decision to withdraw theconsent of 
future follow-up. The investigator is required to elaborate the withdrawal of consent in details in 
the medical record to specify whether the subject just decides to discontinue the drug treatment 
or to withdraw from any study procedure/follow-up after discontinuation, and the above contents 
should be entered into the corresponding pages of CRF. The evaluation of survival situation 
(survival or death of the subject), if appropriate, can be conducted only as per the corresponding 
stipulation and using public information allowed in law. 


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5 Study Drugs and Other Treatment 
Treatment Regimen 
Treatment regimen 
Study drugs in this study refer to IBI308 and docetaxel, and other medications during the study 
are non-study drugs. The treatment regimen is shown in the table below. 


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Table 3. Dosage of study drugs and treatment regimen 
Groups 
Treatment regimen 
Duration of administration 
IBI308 group 
200 mg, IV for about 1 h, Q3W 
Until PD, death, intolerable toxicity, withdrawal of consent, 
initiation of a new anti-tumor therapy, or treatment 
discontinuation due to ant other reason specified in the 
protocol (whichever occurs first); eligible subjects can 
continue the treatment with IBI308 after the first PD (see 
Section 5.1.2). 
Docetaxela 
75 mg/m2, IV for about 1 h, 
Q3W 
Until PD, death, intolerable toxicity, withdrawal of consent, 
initiation of a new anti-tumor therapy, or treatment 
discontinuation due to any other reason specified in the 
protocol (whichever occurs first). 
aThe study site will determine the actual drug dose that a subject should receive by calculating the body surface area on 
the scheduled administration day in each cycle. The maximum body surface area adopted by the protocol is 2.0 m2. For 
subjects with a body surface area > 2.0 m2, the staff of the study site will calculate the dose based on a body surface 
area of 2.0 m2. For convenience, the protocol allows for a deviation of ± 5% of the total infusion dose each time.  
Continued treatment after progressive disease 
During the treatment with IBI308, if subjects continued the treatment with IBI308 after they are 
judged to have PD for the first time as per RECIST v1.1, the following criteria must be met: 
1. 
The investigator believes that the subjects may enjoy clinical benefits from continued study 
treatment, and the disease does not show rapid progression; 
2. 
The subjects can tolerate the study drug; 
3. 
Stable ECOG PS scores; 
4. 
Will not delay the treatment of serious complications requiring urgent intervention (such as 
metastasis in the CNS); 
5. 
Before continuing treatment with IBI308, the subjects must be fully informed and the 
investigator must elucidate all foreseeable risks or discomforts and alternative treatments. 
If the above criteria are met, the investigator and sponsor's medical manager will decide whether 
the subjects shall continue the treatment after PD, and record it in the study records. 
Data from subjects who continue IBI308 treatment after initial PD shall be collected. Refer to 
Table 1 for collection of data variables. The treatment will continue until no clinical benefit, 
death, intolerable toxicity, withdrawal of consent, or initiation of a new anti-tumor therapy 
(whichever occurs first) based on the judgment of the investigator. 
For subjects who continue IBI308 treatment after initial PD, treatment shall be discontinued if 
clinical symptoms worsen with the absence of imaging evidence of further PD, and the subjects 


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should be recorded as "deterioration of clinical symptoms". In this case, the investigator should 
continue imaging evaluation as described in Section 6.3. 
Study Drug (IBI308) 
Description 
The study drug is a recombinant fully human anti-PD-1 monoclonal antibody injection 
(hereinafter referred to as IBI308). 
The main active ingredient of IBI308 is the recombinant fully human anti-PD-1 monoclonal 
antibody. The strength of IBI308 drug product is 10 mL: 100 mg. IBI308 does not contain any 
preservatives. The concentration is 10 mg/mL, with excipients including 140 mmol/L mannitol, 
25 mmol/L histidine, 20 mmol/L dihydrate sodium citrate, 50 mmol/L sodium chloride, 0.02 
mmol/L disodium edetate (ethylenediaminetetraacetic acid disodium), and 0.2 mg/mL 
polysorbate 80, at a pH of 6.0. 
IBI308 is a clear, colorless liquid and is free of foreign matters, flocs, and precipitation. 
IBI308 is manufactured by Innovent Biologics (Suzhou) Co., Ltd. 
Labels 
The smallest packaging unit is one box. Each box contains 2 vials of IBI308 injection. The 
IBI308's package contains the drug name, drug number, dosage form, strengths, drug code, batch 
number, shelf life, storage conditions, dosage and administration, precautions, and sponsor's 
information. The label on the vial contains the same information as the outer package except for 
dosage form and precautions. Both package and vial shall be labeled " for clinical study only".  
Storage 
To be stored at 2–8 °C protected from light. The shelf life is 24 months. If any quality problems 
such as turbidity and precipitation are observed in the injection, the vialshould be sealed 
immediately and notify the sponsor. 
Preparation and infusion 
The preparation and infusion of IBI308 are as follows: 
1. 
Completely withdraw the contents of two vials of IBI308 injection and transfer them into a 
100 mL IV infusion bag containing 0.9% (w/v) sterile normal saline, then document the 
start time of the preparation. 
2. 
The IV bag is gently inverted to mix the solution, ensuring  uniformity of the contents. No 
vigorous shaking is allowed to avoid foam. 
3. 
Administer with a 0.2–1.2 μm in-line filter the infusion time is recommended to be 


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controlled within 30–60 min). Document the start and stop time of infusion. 
Note: Before preparation, make sure that the IBI308 injection is clear without any quality issues 
such as turbidity or precipitation; make sure that the time from withdrawing IBI308 from the first 
vial to the end of infusion is no more than 24 h (storage conditions for the prepared solution is 2–
8 °C in the fridge); avoid mixing with other drugs; do not administer as an IV push. 
Study Drug (Docetaxel) 
Description 
Docetaxel is an approved anti-tumor drug and will be provided by the sponsor after re-labeling. 
The study site should store, prepare, and administer these drugs according to the approved 
prescribing information. Strengths: 20 mg/0.5 mL, 40 mg/1 mL, or 80 mg/2 mL. 
Pretreatment prior to administration of docetaxel 
Dexamethasone (8 mg, Bid, Po) should be administered one day prior to chemotherapy, on the 
day of chemotherapy, and the next day after chemotherapy. Alternatively, dexamethasone could 
be administered according to the study site's standard directions for dexamethasone. 
Dose Adjustments 
General principles 
• 
On the first dosing day of study drug, the subject's hematologic, hepatic, and renal 
function pre-dose must meet the requirements, and all other toxicities must resolve to 
NCI CTCAE v4.03 grade 0–1 or baseline levels (excluding alopecia and fatigue). 
• 
All the dose adjustments should be documented, including the reasons and actions 
taken. 
IBI308 administration adjustments 
Dose adjustments of IBI308 are not permitted throughout the trial. The IBI308 administration 
adjustment protocol (only for AEs related to IBI308 as determined by the investigator) is shown 
in Table below. 
Table 4. IBI308 dose adjustment protocol 
AE 
Severity level 
Dose adjustments 
Pneumonia 
Grade 2 pneumonia 
Interruptiona 
Grade 3 or 4 pneumonia 
Permanent 
discontinuation 


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AE 
Severity level 
Dose adjustments 
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 
Hepatitis 
Grade 2 AST, ALT, or TBIL elevation for subjects with 
normal AST, ALT, or TBIL at baseline; AST, ALT, or TBIL 
elevation by ≥ 50% (meeting the criteria for grade 2) lasting 
for < 7 days for subjects with AST, ALT, or TBIL > ULN at 
baseline 
Interruptiona 
Grade 3 or 4 AST, ALT, or TBIL elevation for subjects with 
normal AST, ALT or TBIL at baseline; AST, ALT, or TBIL 
elevation of ≥ 50% (reaching the requirements of grade 3 or 
4) for ≥ 7 days for subjects with AST, ALT, or TBIL > ULN 
at baseline 
Permanent 
discontinuation 
Hypophysitis 
Grade 2 hypophysitis 
Interruptionb 
Grade 3 or 4 hypophysitis 
Permanent 
discontinuation 
Adrenocortical 
insufficiency 
Grade 2 adrenocortical insufficiency 
Interruptionb 
Grade 3 or 4 adrenocortical insufficiency 
Permanent 
discontinuation 
Hyperthyroidism 
Grade 3 or 4 hyperthyroidism 
Permanent 
discontinuation 
Type I diabetes 
Grade 3 hyperglycemia 
Interruptionb 
Grade 4 hyperglycemia 
Permanent 
discontinuation 
Renal insufficiency 
Grade 2 or 3 Cr elevation 
Interruptiona 


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AE 
Severity level 
Dose adjustments 
Grade 4 Cr elevation 
Permanent 
discontinuation 
Neurotoxicity 
Grade 2 neurotoxicity 
Interruptiona 
Grade 3 or 4 neurotoxicity 
Permanent 
discontinuation 
Infusion reactions 
Grade 3 or 4 infusion reaction 
Permanent 
discontinuation 
a: Resume the administration after symptoms improve to grade 0–1 or baseline levels. 
b: Resume administration of the study drug if hypophysitis, adrenocortical insufficiency, or type I diabetes is 
adequately controlled and require only physiological hormone replacement. 
Study drug is allowed to be interrupted for up to 6 weeks. If the symptoms do not resolve to the 
level, at which the treatment can be resumed, within 6 weeks, the subject must permanently 
discontinue IBI308 treatment and enter the follow-up phase of the study, except for the following 
two cases: 
 IBI308 interruption > 6 weeks due to dose reduction of glucocorticoid that is used to 
treat irAEs. Consult the sponsor's medical manager prior to resuming IBI308. Tumor 
imaging evaluation for efficacy shall not be affected by treatment interruption and 
should be performed as scheduled. 
 IBI308 interruption > 6 weeks due to AEs possibly related or unrelated to IBI308. 
Consult the sponsor's medical manager prior to resuming IBI308. Tumor imaging 
evaluation for efficacy shall not be affected by treatment interruption and should be 
performed as scheduled. 
Docetaxel 
5.4.3.1 Dose delay 
Administration of docetaxel should be delayed in case of the following circumstances: 
 
Any grade ≥ 2 non-skin drug-related AE, except the following events: 
- 
Grade 2 drug-related fatigues or abnormal results of laboratory tests does not require 
treatment delay 
 
Any grade 3 drug-associated skin AE 
 
Any grade ≥ 3 drug-related abnormal results of laboratory tests, excluding the following 


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circumstances of lymphocytopenia, neutrophil count, AST, ALT or TBIL: 
- 
Grade 3 lymphocytopenia does not require administration delay 
- 
No dose should be administered in case of neutrophil count < 1500 cells/mm3 
- 
No dose should be administered in case of TBIL > ULN, or AST and/or ALT > 1.5 × 
ULN with ALP > 2.5 × ULN 
 
Any AE, abnormal result of laboratory tests, or concurrent disease, which require delay of 
the study drug, based on the judgment of the investigator. 
Subsequent doses may be reduced according to Section 5.4.3.2. 
Subjects who are treated with docetaxel may need to use growth factors (including G-CSF and 
erythropoietin). The specific administration is decided by the investigator. 
5.4.3.2 Dose reduction 
Dose reduction may be required for docetaxel, and the actual practice will be carried out 
according to the table below. 
Table 5. Docetaxel dose reduction procedure 
Dose 
Docetaxel 
Starting dose 
75 mg/m² 
The first dose reduction 
55 mg/m² 
The second dose reduction 
37.5 mg/m² 
The third dose reduction 
Discontinuation of docetaxel 
Does adjustments of docetaxel are required for subjects who experience the following 
circumstances during docetaxel treatment: neutropenia with fever, neutrophil count < 500 
cells/mm³ for over 1 week despite of support care with growth factors, severe or cumulative skin 
reaction, or grade 3/4 non-hematological toxicity. Subjects should delay the treatment as per 
Section 5.4.3.1 and then resume administration at a dose reduced by one level (55 mg/m²). If 
such AEs occur after the first dose reduction, then another reduction to 37.5 mg/m² is permitted. 
If the third dose reduction is required, then the subject should discontinue docetaxel treatment 
and proceed to follow-up stage. 
Subjects who experience grade ≥ 3 peripheral neuropathy or meet other criteria described in 
Section 5.4.3.4 should discontinue docetaxel treatment and proceed to follow-up stage. 
5.4.3.3 Criteria for resumption of docetaxel treatment 
After drug-related AE resolves to grade ≤ 1 or baseline level, the subject could resume docetaxel 
treatment, except for the following circumstances: 


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 
Subjects with grade 2 fatigue could resume the treatment; 
 
Subjects with the absence of grade 3 drug-associated skin AE while the presence of grade 2 
skin toxicity could resume the treatment; 
 
Subjects with decreased neutrophil count or increased TBIL, AST or ALT must meet the 
criteria for resumption of treatment established according to the black box warning in the 
prescribing information of docetaxel; 
 
Subjects who meet discontinuation criteria (Section 5.4.3.4) as determined based on values 
of grade 2 elevations in AST/ALT and TBIL should permanently discontinue the study drug; 
If treatment delays for a period > 6 weeks, then the subject must permanently discontinue the 
study treatment, except for the situations specified in Section 5.4.3.4. 
The resumption of docetaxel treatment should follow the dose reduction recommendation 
described in Section 5.4.3.2. 
5.4.3.4 Criteria for discontinuation of docetaxel 
Administration of docetaxel should be permanently discontinued in case of the following 
circumstances: 
 
Any grade ≥ 3 peripheral neuropathy; 
 
Any grade ≥ 3 non-skin drug-related AE lasting for > 7 days, except the following abnormal 
results of laboratory tests: 
- 
Grade 3 drug-related abnormal results of laboratory tests does not require treatment 
delay, except for the following situations: 
 
Grade 3 drug-related thrombocytopenia with hemorrhage requiring discontinuation; 
 
Any drug-related abnormal results of liver function test (LFT) which meet the 
following criteria requires discontinuation: 
 
ALT or AST > 5 × ULN lasting for > 2 weeks 
 
AST or ALT > 10 × ULN 
 
TBIL > 5 × ULN 
 
AST or ALT > 3× ULN with TBIL > 2 × ULN 
 
Any grade 4 drug-related AE or abnormal results of laboratory tests, except the following 
events that do not require discontinuation: 
- 
Grade 4 neutropenia lasting for ≤ 7 days 


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- 
Grade 4 lymphocytopenia or leukopenia 
- 
Solitary grade 4 electrolyte imbalance/abnormality which has no clinical sequela and 
can be corrected by using corresponding supplementary therapy/pertinent handling 
within 72 h after onset. 
 
Dose delay for a period > 6 weeks, except the following circumstances: 
- 
The dose lay for > 6 weeks is allowed if the reason thereof is unrelated with the drug 
and the approval is obtained from the sponsor's medical manager. The subjects who 
experience dose delay for > 6 weeks must consult with the sponsor's medical manager 
prior to resumption of the treatment. Tumor evaluation should continue according to the 
study protocol despite of the dose delay. 
 
Continued docetaxel treatment may cause any AE, abnormal results of laboratory tests, or 
concurrent disease, which will pose considerable clinical risk to the subject, based on the 
judgment of the investigator. 
Principles of Managing Immune Checkpoint Inhibitor Toxicities 
The mechanism of action of IBI308 is to stimulate T-cell activation and proliferation, which 
could result in immune hyperfunction and thereby lead to autoimmune disease involving 
multiple systems. Autoimmune AEs such as immune-related pneumonitis, diarrhea/enterocolitis, 
renal insufficiency, skin rash, hepatitis, endocrine disorders, and peripheral or central neuritis 
have been observed in the clinical application of other immune checkpoint inhibitors such as 
ipilimumab, nivolumab, pembrolizumab, and atezolizumab. Once subjects developed the above 
AEs in this study, monitoring on signs and symptoms as well as relevant examinations should be 
performed to identify the cause. If an alternative cause is not found (such as PD, concomitant 
medications, or infection) and glucocorticoids and/or other immunosuppressants are required 
(endocrine events such as hyperthyroidism/hypothyroidism, hypophysitis, type I diabetes, and 
adrenal insufficiency which may not require immunosuppressants are still considered related to 
immune hyperfunction caused by IBI308), then any AE described above is considered related to 
immune hyperfunction caused by IBI308 and should be diagnosed as an irAE. 
Management for irAE is shown in Appendix 6. 
Concomitant Treatment 
Therapies prohibited during study drug treatment 
 
Other therapies to treat tumors such as chemotherapy, immunotherapy, targeted therapy, 
and traditional Chinese medicine with anti-tumor potency. 
 
Immunomodulators and high-dose glucocorticoids (except for those to treat subjects 


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with AEs). 
 
Immunoglobulins. 
 
Live attenuated vaccine. 
Therapies permitted during study drug treatment 
 
Medications that meet the protocol requirements, as determined by the investigator (e.g. 
concomitant medication used for disease-related symptoms and treatment-related AEs). 
 
Subjects who need medications for a long time due to pre-existing diseases, such as 
hypertensive and diabetes mellitus, can continue the use of drug. 
 
Locoregional surgery or radiotherapy (the radiotherapy field does not cover lungs) used 
for isolated lesions (excluding target lesions) during the study treatment. 
 
Supportive care for relieving tumor-related symptoms, such as bisphosphonate 
treatment for bone metastases. 
 
Use of locoregional corticosteroids, such as dermal, ocular, nasal, and inhaled 
corticosteroids. 
 
Prophylactic use of anti-emetics, glucocorticoids, or other therapies indicating toxicities 
for chemotherapy group. 
 
Use of colony-stimulating factors according to relevant guidelines for chemotherapy 
group. 
Drug-drug interactions 
 
IBI308: no available data on drug interactions at present. 
 
Docetaxel: Subjects in docetaxel group should avoid being given potent CYP3A4 
inhibitors (see details in the package insert of docetaxel) during the study. These drugs 
include (but are not limited to): 
- 
Ketoconazole 
- 
Itraconazole 
- 
Clarithromycin 
- 
Atazanavir 
- 
Indinavir 
- 
Nefazodone 
- 
Nelfinavir 


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- 
Ritonavir 
- 
Saquinavir 
- 
Telithromycin 
- 
Voriconazole 
Excessive grapefruits, lime and its products and juice made from these fruits are not encouraged 
for subjects in docetaxel group. 
Treatment Compliance  
Study treatment will be given at the study sites. Treatment compliance will be monitored by 
medication dispensing and return records, medical records, and eCRFs. 
Drug Return and Destruction 
After confirmation by clinical research associate (CRA), the containers, vials, infusion bags, and 
syringes of used and partially used study drugs can be destroyed on-site or recycled according to 
the appropriate guidelines and operating procedures established by study sites and local agencies. 
Upon the completion or discontinuation of the study, all unused or expired study drugs must be 
returned to the sponsor for destruction. Arrangements for the return of IBI308 will be made by 
the CRA designated by the sponsor. 
Study Drug Records 
The designee of local study site should make timely records of receipt, dispensing, using, storing, 
destroying, returning, and damaging the study drugs in accordance with the relevant regulations 
and guidelines as well as the requirements of operation processes of this study. 
Complaint Handling  
To ensure the safety and proper monitoring of the subjects, and facilitate the improvement of trial 
process and drug product, the sponsor will collect complaints related to the study drugs. 
Complaints regarding concomitant medications will be directed to the manufacturer according to 
the prescribing information of the drugs. 
The investigator or designee should complete the following procedures for product complaints in 
accordance with applicable requirements of the study: 
 
A drug complaint form specific for clinical trials will be used to document product 
complaints and relevant description completely. 
 
The completed product complaint form will be submitted to the sponsor or designee by 
fax within 24 h. 


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If the investigator is asked to return the product for further investigation, the investigator should 
return the product along with a copy of the complaint form. 
6 Study Evaluations and Procedures 
Enrollment and Randomization 
Subject enrollment and randomization procedures 
The investigator will enroll the subjects by the following steps: 
1. Obtain the ICF signed by the subjects prior to any study-related procedures. 
2. Confirm the subjects' eligibility by the principal investigator or trained designee after 
reviewing the inclusion/exclusion criteria. 
3. Randomize the subjects by central randomization and with stratification factor of 
ECOG score (0 or 1). 
Subjects who have failed to meet the criteria (screen failures) can be re-screened. If re-screening 
is considered, the investigator must contact the sponsor's medical manager. Each subject can be 
re-screened once. The subjects must sign the ICF again and receive a new identification number 
when they are re-screened. 
Enrollment error handling 
The inclusion and exclusion criteria must be strictly followed. If an ineligible subject is enrolled, 
the sponsor's medical manager and the investigator will discuss whether to allow the subject to 
continue in the study and whether to use the study drug. If as determined by the investigator, 
allowing the subject to continue with the study is appropriate medically, which is also agreed 
with by the sponsor's medical manager, the subject will continue participating in the study and 
receive the study drug; if as determined by the investigator, allowing the subject to continue with 
the study is appropriate medically, which is not agreed with by the sponsor's medical manager, 
the subject shall not continue participating in the study (regardless of receiving the study drug or 
not). The investigator will not allow the subject to continue with the study until receive the 
written approval from the sponsor. 
Study Plan and Schedule 
Screening period 
The following procedures must be completed during the screening (day –28 to –1) to ensure 
subject eligibility: 
 
Signing of ICF 
 
Confirming the inclusion/exclusion criteria 


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 
Recording the demographics, medical history, and previous medications 
 
Recording vital signs, height, and body weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead ECG 
 
Routine blood test/blood chemistry/urinalysis (within 7 days prior to the first dose) 
 
Pregnancy test (within 3 days prior to the first dose) 
 
Thyroid function 
 
HIV antibody, hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), HBV 
DNA, and HCV antibody 
 
AE evaluation 
 
Concomitant medications 
 
Tumor imaging evaluation 
 
Archived or fresh tumor tissue sample 
 
RAVE Balance randomization 
Refer to Sections 6.3 and 6.4 for details regarding tumor imaging evaluation and safety 
evaluation. 
Baseline (prior to day 1 of cycle 1) 
 
Recording the vital signs 
 
Body weight 
 
ECOG PS score 
 
Immunogenicity 
 
AE evaluation 
 
Concomitant medications 
 
EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 scales 
 
Blood sampling for biomarkers 
Treatment visits 
 
Recording of vital signs and body weight; if the weight fluctuation is less than 10% 


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compared to baseline (the day of the first dose) in the docetaxel group, the baseline 
weight will be used to calculate the dose. Otherwise, the actual dose will be calculated 
based on the weight of scheduled dosing days. 
 
Physical examination 
 
ECOG PS score 
 
12-lead ECG 
 
Routine blood test/blood biochemistry/Rutine urine test 
 
Thyroid function 
 
Immunogenicity (for IBI308 group only) 
 
AE evaluation 
 
Concomitant medications 
 
Tumor imaging evaluation 
 
Administration of investigational drug 
 
EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 scales 
 
Blood sampling for biomarkers 
 
Survival condition 
The schedule of visits is shown in Table 1. 
Refer to Sections 6.3, 6.4, and 6.5 for details of tumor imaging evaluation, safety evaluation, and 
blood sampling for immunogenicity. 
Safety follow-up 
Two safety follow-ups will be carried out. The first visit will be conducted 30 (± 3) days after the 
last dose, and the second visit will be conducted 90 (± 7) days after the last dose. The following 
contents should be included: 
 
Recording the vital signs 
 
Body weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead ECG 
 
Routine blood test/blood biochemistry/Routine urine test 


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 
Thyroid function 
 
Pregnancy test (at the first visit only) 
 
Immunogenicity (in IBI308 group at the second visit only) 
 
AE evaluation 
 
Concomitant medications 
 
Subsequent anti-tumor therapy (if applicable) 
 
Survival condition 
 
EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 scales 
Subjects terminating treatment prematurely need to complete the above safety follow-ups, too. 
Tests related to premature treatment termination should be carried out on D21–D30 after the last 
dose, and their results can be documented as the results of the first safety follow-up. 
Prior to initialization of therapy with other anti-tumor drugs, the above safety follow-ups have to 
be done first. If therapy with other anti-tumor drugs starts within 90 days after the last dose, then 
the second safety follow-up 90 days after the last dose is not required. The investigator may 
conduct the second safety follow-up because of reasons including AEs of special interest. 
Survival follow-up 
After completing the safety follow-up, the subject shall be contacted every 60 (± 7) days 
(telephone visits are acceptable) to obtain the survival information, any subsequent systemic 
anti-tumor therapy, and PD information (for subjects with no imaging PD). Long-term follow-up 
should be continued until death or end of study. 
Efficacy Evaluation 
The method for evaluation of tumor burden during each subsequent follow-up should be the 
same as the one used at the baseline (CT/MRI). Sites to be evaluated in each subject include 
neck, chest, abdomen, and pelvic cavity, and based on symptoms and signs of each subject, other 
involving sites (e.g., brain) will be examined. Baseline evaluation is conducted within 28 days 
prior to the first dose of the study treatment. The investigator can evaluate the imaging results 
within 28 days prior to the enrollment. 
Once every 6 weeks (± 7 days) after the first dose of investigational drug, tumor imaging 
evaluation will be carried out; 24 weeks after the first dose of investigational drug, tumor 
imaging evaluation can be conducted once every 9 weeks (± 7 days), until PD, initiation of a new 
anti-tumor therapy, withdrawal of the informed consent forms (ICFs) by the subjects, or death. 
Subjects in IBI308 treatment group whose imaging PD is initially documented will be evaluated 


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once, and part of the subjects meeting particular requirements are permitted to continue receiving 
the treatment with the investigational drug after PD (refer to Section 5.1.2). For subjects who 
discontinue the treatment for reasons other than imaging PD, an imaging evaluation should be 
carried out at the end of the treatment as per the protocol, until the occurrence of any of the 
following events: initiation of a new anti-tumor therapy, PD, withdrawal of consent by subjects, 
and death. 
The subject may continue the treatment if PD cannot be confirmed by the investigator, especially 
for non-target lesions and new lesions, until the occurrence of clinical symptoms or the next 
scheduled evaluation time point when the imaging evaluation will be performed again. If 
repeated scans confirm PD, then the PD should be recorded using the date of the initial scan. 
In this study, the tumor evaluations, as the primary analysis, are performed based on RECIST 
v1.1 at the study site. Refer to Appendix 3 for the evaluation methods. 
Safety Evaluation 
Routine laboratory safety evaluation 
Table 6. Routine laboratory safety evaluation 
Routine blood test 
RBC, HGB, WBC, PLT, LYM, and ANC 
Blood 
biochemistry 
TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, UREA/BUN, Cr, Na, K, Cl, Mg, Ca, P, 
amylase, and FBG 
Routine urine test 
PH, UALB, UPRO, URBC, and UGLU 
Physical examination 
A complete physical examination includes: evaluations of general conditions, respiratory tract, 
cardiovascular system, abdomen, skin, head and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, musculoskeletal system (including spine and limbs), genitalia/anus, and 
nervous system. 
Refer to the schedule of visits (Table 1) for the time of examination. Refer to Appendix 2 for 
ECOG PS scoring criteria. 
12-lead ECG 
A resting 12-lead ECG will be performed at the local laboratory in accordance with the schedule 
of visits (Table 1).  
The subjects are required to rest in supine position for at least 5 minutes prior to 12-lead ECG. 
All 12-lead ECGs should be performed while the subjects are resting in the supine position. 
Further ECG is performed if clinically indicated, such as a cardiac AE. The investigator should 
review the ECG on the day it is performed, and document the results on the ECG. The same 


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method of evaluation is used throughout the study. 
Investigator should evaluate all ECGs based on the types of abnormalities with or without 
clinical significance. For a clinically significant abnormality, investigator should record the result 
as an AE in eCRF. 
Vital signs 
Vital signs will be performed in accordance with the schedule of visits (Table 1). Vital signs 
include body temperature, pulse, respiratory rate, and blood pressure. 
Additional monitoring of vital signs is allowed based on standard clinical practice or clinical needs. 
Additional records for vital signs may be collected in medical record when an AE/SAE occurs (if 
applicable). The time and date of collection and measurement should be recorded in an 
appropriate section of the eCRF 
6.4.4.1 Pulse and blood pressure 
Pulse and blood pressure should be measured prior to the administration of investigational drug. 
6.4.4.2 Body temperature and respiratory rate 
The body temperature and respiratory rate should be collected prior to the infusion on the 
scheduled administration day. 
Weight and height 
Height will be measured only during screening. 
Weight needs to be recorded before every planned dose during the study. If the weight 
fluctuation of a subject in docetaxel group is less than 10% compared to baseline (the day of the 
first dose), then the baseline weight will be used to calculate the dose. Otherwise, the actual dose 
will be calculated based on the weight of scheduled dosing days. 
Pregnancy test 
Urine or serum human chorionic gonadotropin (hCG) pregnancy test will be performed in female 
subejects  of childbearing age (for the definition, refer to Section 4.3) within 3 days prior to the 
first dose of investigational drug. For the result of urine hCG of positive or inconclusive, a serum 
β-hCG pregnancy test is performed. Result of the serum pregnancy test is determinative. For the 
serum β-hCG result of positive, the subject is not eligible or discontinued participating in the 
study. A repeated test is performed for the suspected pregnancy during the study. 
Other safety inspections 
• 
HIV antibody 


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• 
Hepatitis B: hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb) and 
HBV DNA. 
• 
Hepatitis C: HCV antibody. 
• 
Thyroid function: T3, T4, TSH, FT3, and FT4. 
Immunogenicity 
Immunogenicity assays will be performed in IBI308 treatment group only, within 1 h prior to 
IBI308 infusion in cycles 1, 2, 4, and every 4 cycles (cycles 8, 12, 16, and so on) thereafter, and 
during the second safety follow-up. Tests will be conducted in the central laboratory. 
ADA titer should be tested for each subject in IBI308 treatment group, and ADA-positive serum 
samples should be further tested for neutralizing antibodies (NAbs). 
For ADA and NAb assays, 4 mL of whole blood is collected using vacutainers with clot 
activator. Serum is then separated, dispensed in aliquots, and frozen. 
Refer to the "Laboratory Manual" provided by the sponsor-designated central laboratory for 
sampling methods, sample storage, transport, and analysis. 
Quality of Life Evaluation 
Quality of life evaluation will be performed on the day of the first dose, during each imaging 
evaluation, and at the first safety follow-up using EQ 5D-5L, EORTC QLQ-C30, and EORTC 
QLQ-LC13 scales. 
EQ-5D-5L is a standardized tool used for subjects to self-report their health status. Subjects will 
fill out a questionnaire that consists of 5 levels (no problems, slight problems, moderate 
problems, severe problems, and extreme problems) and 5 dimensions (mobility, self-care, daily 
activities, pain/discomfort, and anxiety/depression). A single EQ-5D health status is defined after 
combining the different levels of all 5 dimensions. In addition, subjects will mark on a visual 
analog scale (VAS) for their health status, which ranges from 0 (the imaginable worse state) to 
100 (the best imaginable state). 
The EORTC QLQ-C30 is a core questionnaire for subjects with cancer consisting of 30 items 
which are divided into 15 dimensions : 5 functional dimensions  (physical, role, cognitive, 
emotional, and social), 3 symptom dimensions  (fatigue, pain, and nausea and vomiting), 1 
global health status/quality-of-life scale, and 6 single items. 
Biomarker Analysis  
When permitted by the EC, subjects who meet the inclusion criteria are required to provide 
diagnosed tumor tissues at the baseline. For the acceptable tumor tissues, including the archived 
tumor tissues or those newly collected and prepared during the screening period, at least 8 


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unstained sections of 4–5 microns will be required for PD-L1 assay and expression level assay of 
immune-related mRNA (including but not limited to expression levels of messenger RNA of 
IDO1, CXCL9, CXCL10, HLA-DRA, STAT1, and IFNG). 
Subjects in the IBI308 group need to provide 10 mL of whole blood sample at each of the 
following time points: prior to the first dose, and at each efficacy evaluation during treatment 
before the initiation of the next treatment; the samples will be analyzed for tumor mutation burden 
(TMB) and circulating tumor cells (CTC), including but not limited to dynamic change of PD-L1. 
Storage and Destruction of Biological Samples 
Samples will be disposed or destroyed, pooled and anonymized. Additional analyses of pooled 
and anonymized samples may be performed to further evaluate and validate the analytical 
method. Results of these analyses may be published separately from the CSR. 
Reproducibility (if performed) will be assessed simultaneously with the biological analysis of the 
samples. The results of these evaluations will not be published in the clinical study report, but 
will be presented separately in a biological analysis report. 
7 Safety Reports and AE Management 
Definition of AEs 
An adverse event (AE) is defined as any adverse medical event that is observed in the period 
from the signing of the ICF to 90 days after the last dose of the investigational drug, regardless 
of whether or not considered as related to the investigational drug. Not all laboratory test 
abnormalities/vital sign abnormalities should be reported as AEs, and only the laboratory test 
abnormalities/vitals sign abnormalities meeting any of the followings can be reported as AEs: for 
AEs, including but not limited to the followings: 
(1) Worsening of pre-existing (prior to enrollment) medical conditions/diseases 
(including symptoms, signs, and laboratory test abnormalities); 
(2) Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
(3) Abnormal laboratory test results/vital sign abnormalities (including infusion-related 
reactions) accompanied with clinical symptoms or resulting in change of 
investigational drug (e.g., temporary or permanent discontinuation); 
(4) Abnormal laboratory test results requiring medical intervention or change of both 
treatment; 
(5) Other clinically significant laboratory abnormalities judged by the investigator. 


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Definition of SAEs 
An SAE refers to an AE meeting at least one of the followings: 
(1) Death, except for the cases caused by PD. 
(2) Life-threatening (a life-threatening event is defined as an AE when the subject is at 
immediate risk of death at the time, but does not include the case that may lead to 
death only when the event worsens). 
(3) Requires hospitalization or prolonged hospitalization, excluding the followings: 
- 
Hospitalization at a rehabilitation institution 
- 
Hospitalization at a sanatorium 
- 
General emergency admission 
- 
Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
- 
Hospitalizations or prolonged hospitalizations unrelated to worsening of an AE are 
not considered as SAEs. Hospitalization due to pre-existing disease, without new 
AEs or exacerbation of pre-existing disease (e.g., hospitalization to examine 
laboratory abnormalities that have been persistent before the study); hospitalization 
for administrative reasons (e.g., annual routine physical examinations); 
hospitalizations during the study as specified in the protocol (e.g., hospitalization 
performed in accordance study protocol); elective hospitalization unrelated to 
worsening of AEs (e.g., elective surgery); scheduled treatment or surgical 
procedures, which should be documented in the entire study protocol and/or 
individual subject's baseline information; and hospitalization merely due to the use 
of blood products. 
(4) Resulting in permanent or severe disability/incapacity. 
(5) Resulting in congenital abnormalities/birth defects. 
(6) Other important medical events: These events are defined as events that may 
jeopardize the subjects and require medical or surgical interventions to prevent one of 
the other outcomes listed in the definition above. 
Criteria for Severity Levels of AEs 
The severity level of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03. 
AEs not included in CTCAE v4.03 are graded in accordance with the following CTCAE 
principles: 


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(1) Grade 1 mild; asymptomatic or mild signs; clinical or diagnostic observations only; 
medical intervention not indicated. 
(2) Grade 2 moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (e.g., cooking, shopping, using 
telephone and managing money). 
(3) Grade 3 severe or clinically significant but not immediately life-threatening; 
hospitalization or prolonged hospitalization indicated; disabling; limiting self-care 
activities of daily life (e.g., bathing, dressing and undressing, feeding self, using toilet, 
and taking medications), but not bedridden. 
(4) Grade 4 life-threatening consequences; urgent intervention indicated. 
(5) Grade 5 death related to AE. 
Correlation Between AEs and Investigational Drug 
The relationship between the investigational drug and AEs can be determined by the 
classification and the criteria in the followings: 
Table 7. Correlation determination between AEs and investigational drug 
Correlation 
Criteria 
Definitely 
related 
- 
The AE occurrence has a reasonable time relationship with administration time; 
- 
The investigational drug can more reasonably explain the AE than the other causes (such as 
concurrent disease, environment, toxicity, or other treatment received); 
- 
The AE resolves or is alleviated after treatment interruption or dose reduction; 
- 
The event meets the recognized pharmacological AE type; 
- 
The AE is observed again after re-administration. 
Possibly 
related 
- 
The AE occurrence has a reasonable time relationship with administration time; 
- 
The investigational drug provides same reasonable explanations on the AE as the other 
causes (such as concurrent disease, environment, toxicity, or other treatment received); 
- 
The AE resolves or is alleviated after treatment interruption or dose reduction (if applicable); 
Possibly not 
related 
- 
Other causes provide more reasonable explanations on the AE than the investigational drug 
(such as concurrent disease, environment, toxicity, or other treatment received); 
- 
The AE does not resolve or be alleviated after treatment interruption or dose reduction (if 
applicable), or the situation is unclear; 
- 
The AE is not observed again after re-administration or the situation is unclear. 
Definitely 
not related 
- 
The AE occurrence has no reasonable time relationship with administration time, or 
- 
other causes provide evident explanations (such as concurrent disease, environmental, 
toxicity, or other treatment received by the subject). 


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Correlation 
Criteria 
Cannot be 
determined 
- 
The above information is unclear and cannot be determined based on the available 
information. Further follow-up information is not accessible to the investigator. 
Documentation of AEs 
The investigator should document AEs or SAEs using medical terms/concepts. Avoid 
colloquialisms/abbreviations. All the AEs (including SAEs) should be documented in the AE 
form of the eCRF. 
If any clinically significant laboratory test abnormality or vital sign abnormality is manifestation 
of a disease or syndrome (e.g., cholecystitis-induced elevations in ALP and bilirubin exceeding 5 
times ULN), then such diagnosis (i.e., cholecystitis) will be documented in the AE form of the 
eCRF only. Otherwise, such laboratory test abnormalities or vital sign abnormalities should be 
documented in the AE form of the eCRF, and any laboratory value being higher or lower than 
normal reference range should be indicated (e.g., "serum potassium increased" rather than 
"serum potassium abnormality" should be documented). If there is a standard clinical term 
corresponding to such laboratory test abnormality or vital sign abnormality, then the clinical term 
(e.g., "anemia" rather than "hemoglobin decreased") should be documented in the eCRF. The 
same laboratory test abnormality or vital sign abnormality with clinical significance is found in 
multiple follow-ups, unless change in severity or etiology, should not be repeatedly documented 
as an AE or SAE in the eCRF. 
Collection and time of AEs 
The investigator should learn about AEs by asking the subjects non-leading questions. 
All the AEs, including SAEs, that occur from the signing of the ICF to 90 days after the last dose 
are collected, regardless of whether they are observed by the investigator or self-reported by the 
subject. If the subject initiates a therapy with other anti-tumor drugs within 90 days after the last 
dose of the investigational drug, then only AEs considered related to the drug are required to be 
collected. 
After 90 days since the last dose, the investigator should report any SAEs that are considered 
related to the investigational drug or study procedures. 
AE follow-up 
The AE should be followed until the event returns to the baseline or grade 0–1, or until the 
investigator believes that no further follow-up is required for reasonable reasons (e.g., the event 
cannot be resolved or has already been improved). If the event cannot be resolved, a reasonable 
explanation should be documented in the eCRF. The outcome of an AE/SAE and date should be 
documented in the eCRF and medical record, regardless of whether the event is related to the 


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investigational drug. 
Contents of AE documentation 
Investigator should document all the AEs, including the diagnosis (document signs and 
symptoms including the laboratory abnormalities if there is no diagnosis), time and date of 
occurrence (if applicable), CTCAE grade of severity and changes in severity (events ≥ grade 3), 
whether it is an SAE, whether it is an AE of special interest (AESI), measures taken for the 
investigational drug, treatment for the AE and outcome of the event, and relationship between the 
event and investigational drug. 
For an SAE, the investigator should also provide the date when the AE meets the criteria for an 
SAE, the date when the investigator is informed of the SAE, the reason of being an SAE, date of 
hospitalization, date of hospital discharge, possible cause of death, date of death, whether an 
autopsy has been performed, causality assessment of the study procedures, causality assessment 
of other drugs, and other possible causes of the SAE. The investigator should provide the 
rationales of the causality and a description of the SAE. In the SAE description, the following 
information should also be included: the subject number, age, gender, height, and weight; 
indications for receiving the investigational drug, cancer staging and overall condition; SAE 
occurrence, development, outcome, and result; laboratory results related to the SAE (the time of 
the test, unit, and normal ranges must be provided); medical history, onset and duration of 
concurrent diseases related to the SAE; medication history and initiation, duration, and dosage of 
concomitant medications related to the SAE; initiation, duration, and dosage of the 
investigational drug. 
Descriptions of the AE are as follows: 
Diagnosis, symptoms, and signs 
Document the definite diagnosis, if there is one, rather than just listing the independent signs and 
symptoms (e.g., hepatic failure rather than jaundice, elevated transaminase, and asterixis). Signs 
and symptoms should be reported as separate AEs/SAEs if cannot be attributed to the diagnosis. 
If it is determined that the signs and symptoms are caused by the diagnosis, then only the 
diagnosis shall be reported, including the signs and symptoms. The record of signs and 
symptoms should then be deleted. A follow-up SAE report should be submitted. 
AEs secondary to other events 
Generally, AEs secondary to other events (such as result of another event or clinical sequelae) 
should be documented as the primary event, unless the event is severe or an SAE. However, 
clinically significant secondary events should be recorded as independent AEs in the eCRFs if 
they occur at different time than the primary event. If the relationship between events is unclear, 


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document them as separate events in the eCRFs. 
Ongoing or recurrent AEs 
An ongoing AE refers to an event that does not resolve and is ongoing between two evaluation 
time points. These AEs should only be documented once in the eCRFs. The initial severity level 
should be documented, and the information should be updated if the event exacerbates. 
Recurrent AEs refer to AEs that have resolved between the two time points of evaluation but 
subsequently occur again. These events should be independently documented in the eCRFs. 
Laboratory test abnormalities 
All clinically significant laboratory test abnormalities are reported as AEs. The investigator has 
responsibilities for reviewing all the laboratory test abnormalities and determining whether the 
abnormalities should be reported as AEs. 
Death 
During the entire course of the study, all the deaths that occur within 90 days after the last dose 
are documented in the "Death Report Form" in the eCRFs and reported to the sponsor promptly, 
regardless of the causality with the investigational drug. 
When documenting death events, for the death with a known cause, the cause of death should be 
documented as an AE and the outcome of the AE should be death, and the event should also be 
reported as an SAE (death caused by tumor progression will not be documented and reported as 
an AE/SAE, but the investigator should document the death in the "Death Report Form" of the 
eCRF and inform the sponsor promptly). For the death with an unknown cause, the AE should be 
documented as "death with an unknown cause" in the AE form of the eCRF, and reported as an 
SAE. Further investigation should be performed next to identify the exact cause of death. 
If the death is definitely caused by tumor progression, then it should not be documented and 
reported as an AE/SAE; nonetheless, the investigator should document the death in the "Death 
Report Form" of the eCRF and inform the sponsor promptly. 
Pre-existing medical conditions 
Symptoms/signs presenting during the screening period will be recorded and reported as AEs 
only if the severity level, frequency, or property becomes aggravated (except for worsening of 
the studied disease). The relative change from previous conditions should be documented, such 
as "increased frequency of headaches". 
Progressive disease 
A progressive disease is defined as the worsening of subject condition caused by the primary 
tumor that the investigational drug is targeting, the appearance of new lesions, or the progression 


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of the primary lesion. PD will not be reported as an AE. Any deaths, life-threatening events, 
hospitalizations or prolonged hospitalizations, permanent or significant disability/incapacity, 
congenital anomaly/birth defects, or other important medical events caused by PD will not be 
reported as SAEs. 
Overdose 
A dose exceeding the dose specified in the study protocol is called overdose. In the event of 
overdose accompanied with an AE, the AE should be documented. When overdose is 
accompanied with an SAE, the SAE should be reported quickly in accordance with SAE 
procedures. 


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Expedited Reporting of SAEs and Pregnancy 
SAE reporting: 
SAEs that occur from the signing of ICF within 90 days (inclusive) since the last dose must be 
reported. The investigator must fill out the "SAE Report Form" from NMPA, regardless of 
whether it is an initial report or a follow-up report, and sign and date the form. The investigator 
must report the SAE to the sponsor, NMPA, and EC within 24 hours of noticing the event. 
For SAEs occurring outside of the above-mentioned period, those considered related to the 
investigational drug should also be reported to the sponsor. 
The investigator must submit the completed SAE report form to the sponsor within 24 hours of 
noticing the event. The investigator should urgently perform visit on missing information and 
provide a complete SAE report for events that result in death or are life-threatening. 
When submitting the SAE report by mail, it is recommended for the investigator to encrypt the 
report file and send the report file and password in different emails. 
The investigator should also report the event to the NMPA, health administration department, 
and EC in accordance with the regulations. 
Pregnancy 
The risk of embryotoxicity exists for the similar kind of drugs. All the subjects with childbearing 
potential must take effective contraceptive measures. 
During the study, if a female subject becomes pregnant, she must be excluded in the study. The 
investigator must report to the sponsor within 24 hours of noticing the event and submit the 
"Innovent Clinical Study Pregnancy Report/Follow-Up Form". 
During the study, if a female partner of a male subject becomes pregnant, the subject will 
continue in the study. The investigator must report to the sponsor within 24 hours of noticing the 
event and submit the "Innovent Clinical Study Pregnancy Report/Follow-Up Form". 
The investigator must conduct visits on the outcome of the pregnancy until 8 weeks after the 
subject gives birth. The outcome should be reported to the sponsor. 
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any 
congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the 
event is required to be reported in accordance with SAE procedures and time limits. 
If the subject also experiences an SAE during the pregnancy, the "SAE Report Form" from 
NMPA should also be filled out and reported in accordance with SAE procedures. 


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Abnormal Hepatic Function 
Drug-induced liver injury is considered if abnormal AST and/or ALT levels are accompanied 
with abnormal elevation of TBIL, and the following conditions are met without other possible 
causes. Such cases should always be considered as important medical events. 
Table 8. Liver injuries required to be reported as SAEs 
Baseline 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment period 
ALT or AST ≥ 3 × ULN  
with total TBIL ≥ 2 × ULN 
and ALP ≤ 2 × ULN 
and no hemolysis 
ALT or AST ≥ 8 × ULN 
with TBIL increased by ≥ 1 × ULN or TBIL ≥ 
3 × ULN 
Once being notified with the abnormalities, the subject must return to the study site promptly 
(ideally within 48 hours) and receive an assessment. The evaluation should include laboratory 
tests, detailed medical history, and physical assessment, and the possibility of hepatic tumor 
(primary or secondary) should be considered. 
Other than repeated AST and ALT tests, albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamine transferase, prothrombin time (PT)/international normalized 
ratio (INR), and alkaline phosphatase should also be tested. Detailed medical history should 
include history of alcohol, acetaminophen, soft drugs, various supplements, family diseases, 
occupational exposure, sexual behavior, travel, contact with a patient with jaundice, surgery, 
blood transfusion, hepatic diseases, or allergic diseases. Further tests may also include detection 
of acute hepatitis A, B, C, and E and hepatic imaging (such as biliary tract). If a retest shows 
consistency with the criteria outlined in Table 8 and there are no other possible causes, the 
possibility of drug-induced liver injury should be considered before all the results of etiological 
tests are accessible. These potentially drug-induced liver injury should be reported as SAEs. 
Management of Drug-Related Toxicities 
During the course of the trial, the sponsor will conduct regular safety review. Detailed 
information regarding the frequency of review and type of data to be reviewed will be presented 
in a separate safety review plan. 
Immune-related adverse event 
Since the mechanism of action of IBI308 involves T-cell activation and proliferation, immune 
related adverse events (irAEs) are likely to be observed during this study, the definition of irAE 
is shown in Section 5.5. Signs and symptoms of irAEs should be monitored. 
Refer to Section 5.4.2 for dose adjustments of IBI308 and principles of AE management and 
Appendix 6 for management for irAE. 


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Adverse events of special interest (AESIs) 
AESIs refer to events that require close monitoring in order to enhance the understanding of the 
safety of the investigational drug. AESI can be non-serious events. 
AESIs for this study include the following: 
• 
Grade 3 or greater infusion reactions 
• 
Grade 2 or greater diarrhea, colitis, uveitis, and interstitial pneumonia 
• 
Other grade 3 or greater immune-related adverse events 
8 Statistics 
Statistical Analysis Plan 
The final analysis was planned to be performed when 75% of the subjects had an endpoint event 
(death), or 18 months after the last subject was enrolled. 
The drafting of a detailed statistics analysis plan (SAP) will be started after the enrollment of the 
first subject, and the final draft will be determined before database locking. All analyses and the 
expression methods for the results will be detailed in the SAP. 
 Hypothesis Test 
This study is a superiority design to compare IBI308 and chemotherapeutic drugs. The 
superiority hypothesis test is adopted: 
H0:HR ≥ 1; H1:HR < 1 
Type I error rate  = 0.05 (bilateral). The stratified log-rank test is used to compare the OS of 
IBI308 and docetaxel groups: 
If the P value is ≤ , (or the upper limit of confidence interval of HR < 1), then it can be 
considered that the superiority of IBI308 over docetaxel is valid. 
Statistical Populations 
The analysis sets include the safety set (SS), full analysis set (FAS), and per-protocol set (PPS): 
1) 
SS: subjects who receive at least one dose of the investigational drug. 
2) 
Full analysis population: randomized subjects. 
3) 
PPS: a subset of the FAS, including subjects with good compliance and no serious protocol 
violations or prohibited medications. 


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Statistical Analysis Methods 
General method of statistical analysis 
Variable data will be summarized using the mean, standard deviation, median, maximum, and 
minimum; attributes data will be described using frequency and percentage. 
All statistical analyses will be carried out using SAS 9.2 or above. 
The significance level of the comparison between groups:  = 0.05 (bilateral). If the P value ≤ 
0.05, the difference between groups can be considered statistically significant. 
Analysis of the primary endpoint 
OS: the time from randomization to the death of the subject. If the subject is still alive at the end 
of the study, the known "last date of subject survival" will be used as the censoring date. 
In OS analysis, Kaplan-Meier will be used to estimate the median overall survival (mOS) and its 
confidence interval, and the survival graph will be plotted. A stratified log-rank test will be used 
to compare the PFS between groups. Stratified Cox proportional hazards model will be used for 
HR estimation, with randomization stratification factors added into the model. In OS analysis, 
RMST will also be used to compare inter-group differences in case of the inconformity between 
the potential HR and constant HR. 
Survival rates at 6, 9, and 12 months are estimated by Kaplan-Meier. 
Analysis of the secondary endpoints 
All efficacy endpoints are evaluated based on the RECIST v1.1: 
(1) Progression free survival (PFS) 
PFS: The time from randomization to first PD (imaging). For subjects died of any cause before 
PD, the PFS is the time from randomization to death. Subjects who do not have PD or die will be 
censored on the date of their last imaging evaluation. Subjects who do not receive any imaging 
evaluation after baseline will be censored on the date of randomization. 
In PFS analysis, Kaplan-Meier will be used to estimate the median progression free survival 
(mPFS) and its 95% CI, and the survival graph will be plotted. A stratified log-rank test will be 
used to compare the PFS between groups. 
(2) Overall response rate (ORR) 


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%
100
*
subjects
 
of
 
number
 
Total
PR
 
 with
subjects
 
of
 
Number

CR
ORR
 Binomial distribution will be used to 
calculate the 95% CI, inter-group difference and the 95% CI of the inter-group difference. 
Fisher's exact probability test will be used for comparison between groups. 
(3) Disease control rate (DCR) 
%
100
*
subjects
 
of
 
number
 
Total
SD
 
 with
subjects
 
of
 
Number



PR
CR
DCR
Binomial distribution will be used 
to calculate the 95% CI, inter-group difference and the 95% CI of the inter-group difference. 
Fisher's exact probability test will be used for comparison between groups. 
(4) Duration of response (DoR) 
For subjects achieved CR or PR, DoR: the time from the date of the first response to PD or 
death. For subjects without PD or death, the censoring date is the date when the last imaging 
evaluation is done. 
Kaplan-Meier will be used to estimate median duration of remission (mDoR) and its 95%CI, and 
the survival graph will be plotted. A stratified log-rank test will be used to compare the PFS 
between groups. 
Analysis of quality-of-life questionnaire 
The quality of life and health status in IBI308 group and chemotherapy group during treatment 
will be evaluated based on EQ 5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 scores. 
Biomarker analysis 
 
Tumor tissue samples are collected for tumor biomarker analysis, including but not 
limited to the expression level of PD-L1 and immune-related genes in tumor samples 
(including but not limited to the expression levels of mRNAs of IDO1, CXCL9, 
CXCL10, HLA-DRA, STAT1 and IFNG), to analyze the relationship between the 
above biomarkers and efficacy. 
 
Blood samples of the IBI308 group are collected for circulating tumor cell (CTC) 
analysis, including but not limited to the dynamic changes of PD-L1 and the efficacy 
levels at different expression levels of PD-L1. 
Safety analysis 
The safety analysis will be performed based on SS. Safety parameters include AEs, laboratory 
tests, vital signs, ECG, and immunogenicity. 


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8.4.6.1 Drug exposure 
The drug exposure, duration of treatment (number of treatment cycles) of the subjects will be 
summarized. 
8.4.6.2 Adverse event 
All the AEs will be coded according to MedDRA. 
The incidence rate of AEs, TEAEs, ADRs, immune-related adverse events (irAE), adverse events 
of special interest (AESI), SAEs, and AEs leading to study termination are summarized 
respectively (frequency). The distributions of severity levels of TEAE, ADR, irAE, and AESI are 
summarized by SOC and PT in MedDRA coding according to NCI CTCAE v4.03. 
Subjects who discontinue the treatment due to AEs, develop SAEs, or die will be listed 
(including at least the followings: start date and end date of the AEs, severity levels, relationship 
with investigational drug, measures taken, and outcome). 
8.4.6.3 Laboratory test 
Measurements and changes before and after treatment in routine blood test and blood chemistry 
parameters will be described using mean ± SD, maximum, minimum, and median. Normal and 
abnormal changes after treatment will be described using a cross-classification table. 
Urinalysis: A cross-classification table will be used to describe normal and abnormal changes 
after treatment. 
The proportion of subjects with "clinically significant abnormalities" will be presented. The 
clinical significance should be determined by the investigator. 
Subjects with abnormal changes (whether clinically significant or not) after treatment will be 
listed out. 
8.4.6.4 ECG 
Descriptive statistics will be performed on ECG parameters and changes from baseline. A cross-
classification table will be used to describe normal and abnormal changes after treatment and 
data lists will be provided. 
8.4.6.5 Vital signs, physical examination and other safety-related examinations 
Descriptive statistics of vital signs and relative changes from baseline will be shown. 
Abnormal changes from baseline in physical examination will be tabulated 
8.4.6.6 Immunogenicity indicators 
The positive rates of ADA and NAb will be calculated. Subjects' antibody titer will be tabulated. 


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Compliance analysis 
The frequency and proportion of subjects who violate the expected dosing regimen will be 
summarized. 
The proportion of subjects who are given 80–120% of the dose of the investigational drug 
specified in the protocol will be summarized. 
The proportions of the subjects who complete the study and who complete different treatment 
cycles will also be summarized. 
Subjects' baseline characteristics 
Subjects' demographic characteristics (gender and age), tumor diagnosis information 
(pathological diagnosis, tumor staging, previous therapy), baseline tumor evaluation (target 
lesion, number of non-target lesions, sites, total diameter, etc.), and other baseline information 
(height and weight (BMI, BSA), vital signs, laboratory tests, previous/concomitant medications) 
will be analyzed using descriptive statistics. 
Interim analysis 
One interim analysis is designed in this study. The objective of the analysis is to evaluate the 
safety, and the analysis parameters are the safety parameters. At the time point of 50, the subjects 
completed 4 treatment cycles without considering the adjustment of . 
Subgroup analysis 
An efficacy analysis of PD-L1 positive subjects; 
A subgroup analysis based on random stratification factors and other prognostic factors (PS 
score). 
A subgroup analysis based on baseline characteristics of subjects and other potential factors with 
clinical significance. 
The subgroup analysis to be carried out will be defined in detail in the statistical analysis plan. 
Multiple comparisons and adjustments 
This study is a phase III clinical study, and the interim analysis is a safety analysis. As efficacy 
endpoints are not involved, no  adjustment will be performed. 
All the secondary efficacy endpoints are analyzed only once in this study, and the comparison of 
the secondary endpoints is controlled by step-down method for : If the P value of the OS inter-
group comparison ≤ , the comparison of the PFS between groups is conducted. If the P value of 
PFS inter-group comparison is ≤ , the comparison of the ORR between groups is conducted. If 


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the P value of ORR inter-group comparison is ≤ , the comparison of the DCR between groups 
is conducted. If the P value of the inter-group comparison of any endpoint is > , the subsequent 
endpoint is compared nominally between groups. 
Eligible subject data lists 
In addition to subjects' data list, tumor evaluation (date of evaluation, lesion status, evaluation 
results) and efficacy endpoints of subjects who have achieved CR and PR will be listed 
separately. 
PFS, OS and other data of all subjects at the end of the study (PD date, date of death, PFS, OS) 
Exploratory analysis 
Relationship between different expression levels of PD-L1 and efficacy. 
The parameters of the clinical benefit evaluation are based on the iRECIST, including ORR, 
DoR, PFS and DCR. 
The relationship between the level of each biomarker and the efficacy endpoints. 
Sample Size Determination 
The primary efficacy endpoint is overall survival (OS). Assuming that  = 0.05 (bilateral), power 
= 90%, IBI308-to-docetaxel survival hazard ratio HR = 0.63, endpoint event (death) is observed 
in 75% of the subjects, group assignment ratio is 1:1, and the minimum estimated sample size is 
266 cases; considering a certain dropout rate, a total of 290 cases are required for enrollment, 
145 cases in IBI308 group and 145 cases in the chemotherapy group. The deadline for final data 
will be determined in advance based on the OS incidence in all subjects observed during the 
study before the preset number of events is reached. 
Methods for Controlling Bias 
Randomization and blinding 
In this study, subjects are randomized into groups using RAVE Balance, and the random 
stratification factor is ECOG PS score (0 or 1). The investigator or qualified designee will log 
into the system via their respective password. The system will assign each subject a unique 
random code and also obtain the name of the investigational drug to be received by the subject 
through RAVE Balance. The independent statistician in charge of randomization will generate a 
randomization table of subjects (subject random code) based on a 1:1 ratio of IBI308 and 
docetaxel, and the subject random code will be submitted to the randomization system in the 
form of an electronic document. 
This is an open-label, unblinded study. 


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Blinding maintenance evaluation 
The investigational drug is not blind in this study. 
IDMC will be used in the interim analysis of the primary efficacy endpoint (OS) and safety. 
Unblinding and emergency unblinding 
N/A 
9 Quality Assurance and Quality Control 
According to the GCP guidelines,  sponsor is responsible for implementing and maintaining the 
study quality and quality control system in accordance with the corresponding standard operation 
procedures to ensure that the implementation of the clinical trials, the authenticity of data and 
that the collection, recording and reporting of clinical trial data comply with requirements in the 
protocol, GCP and corresponding regulations. 
Clinical Monitoring 
The sponsor or its authorized contract research organization (CRO) will conduct clinical 
monitoring of this study. The CRA should perform the monitoring in accordance with the 
standard operation procedures provided by the sponsor or CRO, and has the same rights and 
responsibilities as the sponsor's medical monitor. The monitor must maintain regular 
communication with the investigator, authorized research personnel, and sponsor. 
Before the start of the study, the CRA will assess the qualifications of each study site, and report 
issues related to facilities, technical equipment, or medical staff to the sponsor. During the study, 
the CRA is responsible for the monitoring of whether the written ICFs from all subjects have 
been obtained and whether the data records are correct and complete. Also, the CRA will 
compare the data entered into the eCRFs with the source data, and inform the investigator of any 
error or omission. The CRA will also control study center's adherence to with the protocol and 
study procedures, arrange for the supply of the investigational drug and clinical trials, and ensure 
that the drug is kept under prescribed conditions. 
The monitoring visit will be conducted in accordance with applicable statutes and regulations. 
Each site receives regular monitoring visits from the time the subjects are enrolled. After each 
visit to the study site, the CRA should submit a written report to the sponsor. 
Data Management/Coding 
This study will use an electronic data acquisition (EDC) system, and the study data will be 
recorded in the eCRFs by the investigator or its authorized personnel. Before the initiation of the 
study site or data entry, the investigator and authorized personnel will be properly trained and 
appropriate security measures will be taken for the computers and other equipment. 


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Data entry into the eCRFs should be completed as soon as possible during or after the visit. The 
eCRFs should be updated at any time to ensure that they reflect the latest developments of the 
subjects. To avoid the differences in outcome evaluations by different evaluators, the baseline 
and all the subsequent efficacy and safety evaluations of a given subject shall be performed by 
the same individual. The investigator shall review the data to ensure the accuracy and correctness 
of all data entered into the eCRFs. During the study, the investigator should document any 
evaluations that are not conducted, or any information that is not available, applicable, or known. 
The investigator needs to sign all verified data electronically. 
The CRA will review the eCRFs, and assess the completeness and consistency. The CRA will 
also compare the eCRFs with the source documents to ensure the consistency of critical data. All 
data entry, correction and modification will be performed by the investigator or the designee. The 
data in the eCRFs are submitted to the data server and any modification to the data should be 
recorded in the audit trail, including reasons, operator names, time and dates of modifications. 
The roles and permission levels of the personnel responsible for data entry will be determined in 
advance. The CRA or data manager will submit data queries in the EDC system, and study 
personnel shall respond to the queries. The EDC system will record the audit trail of each query, 
including the name of the investigator, as well as the time and date. 
Unless otherwise specified, the eCRF should be considered simply as a form for data collection 
and not a source document. The source documents are all records used by the investigator or 
hospital, which are related to the subjects and are able to demonstrate the presence, 
inclusion/exclusion criteria, and participation of the subjects, including laboratory records, ECG 
results, pharmaceutical records, and subject folders. 
The investigator should be responsible for maintaining all source documents and offering the 
documents to the CRA for review during each visit. In addition, the investigator must submit a 
complete eCRF for each enrolled subject, regardless of the duration of participation. The 
protocol numbers and subject numbers of all supporting documents (such as laboratory records 
or hospital records) submitted with the eCRFs should be carefully verified. All the personal 
privacy information (including the subjects' names) should be deleted or made illegible to protect 
the privacy of the subjects. The investigator should verify that the record has been reviewed and 
that the data are accurate with an electronic signature. The electronic signature is completed with 
the investigator's user ID and password. The system automatically attaches the date and time of 
the signature. The investigator shall not share the user ID and password with other personnel. If 
data in the eCRF need to be modified, the procedures defined by the EDC system have to be 
followed. All modifications and reasons for the changes are recorded in the audit trail. 
AEs, and concurrent diseases/medical history will be coded. The medical dictionary used for 
coding will be described in the "Clinical Study Report" (CSR). 


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


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Ethics Conduct of the study 
The process of study and informed consent are subject to the Declaration of Helsinki, relevant GCP 
requirements, as well as laws and regulations related to the protection of drug and data in China. 
The GCP is an international ethical and scientific specification for designing, conducting, 
recording and reporting clinical trials that involve the participation of human subjects. This study 
will be conducted in accordance with the GCP and relevant national regulations and in 
accordance with the relevant ethical principles of the Declaration of Helsinki to protect the 
rights, safety, and health of the subjects. 
The investigator is required to follow the procedures specified in this protocol and must not 
change the procedures without the permission from the sponsor. Any protocol violation must be 
reported to the EC, sponsor, or regulatory authorities. 
Subject Information and Informed Consent 
Prior to undergoing any study procedure, the ICF should be used to explain to potential 
participants the potential risks and benefits of this study. The informed consent form should be in 
a language that is simple and be easy to understand. The ICF statement should clarify that ICF is 
voluntarily signed and the risks and benefits of participating in this study should be clearly 
outlined. The subject may withdraw from the study at any time. The investigator may only enroll 
a subject after fully explaining the details of the study, answering questions to the subject's 
satisfaction, giving the subject sufficient time for consideration, and obtaining written ICF from 
the subject or his/her legal representative. All signed ICFs must be kept in the investigator's files 
or in the subject's folder. 
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF 
signed and dated by the subject or his/her legal representative prior to starting the study. The 
investigator should provide the subject with a copy of the signed ICF. The investigator must 
document the informed consent process in the source document of the trial. 
Data Protection of Subjects 
An ICF shall include (or in some cases, use separate files together) information on data and 
privacy protection. 
Take precautions to ensure the confidentiality of the documents and prevent the disclosure of 
information that can determine the identity of the subject. However, under special circumstances, 
some personnel may be permitted to see the genetic data and personal identification number of a 
subject. For example, in the event of a medical emergency, the sponsor, designated physician, or 
investigator will have access to the subject identification code and the subject's genetic data. In 
addition, relevant regulatory authorities require access to relevant documents. 


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11 Study Management 
Data Processing and Record Keeping 
Records from the clinical trial (such as protocol and protocol revision, completed eCRFs, and 
signed ICFs) are to be kept and managed in accordance with the GCP. The study sites should 
keep these documents for 5 years after the end of the study. 
The study documents should be retained properly for future access or data traceability. Safety 
and environmental risks should be considered when retaining documents. 
The documents associated with the study may only be destroyed with the written consent of the 
sponsor and the investigator. The investigator/study site may transfer the study documents to 
other parties that comply with the record-keeping requirements or to another location that meet 
record-keeping requirements only after notifying the sponsor and obtaining the written consent. 
Source Data/File Access 
The investigator agrees that the sponsor, CRO, and relevant authorized regulatory agencies shall 
have direct access to all the study-related documents, including medical records of the subjects. 
Protocol Revisions 
Any possible revision to the protocol during the course of the study will be communicated 
between and agreed by the sponsor and the investigator. The sponsor shall ensure that the 
protocol revision is submitted to the regulatory authority in a timely manner. 
All revisions to the protocol shall be kept as supplements to the protocol. Any change to the 
protocol must be submitted to the EC for approval or filing in accordance with the EC's 
regulations. If necessary, it should also be submitted to regulatory authorities for approval and 
only implemented after being approved by the EC and regulatory authorities (if applicable) (with 
changes to the protocol that eliminate direct hazards to the trial subjects as exception). 
Responsibilities of the Investigator 
The investigator shall adhere to the protocol, ethical principles of the Declaration of Helsinki, 
Chinese GCP and requirements of the corresponding regulations for this study. 
The detailed responsibilities of the relevant investigators are listed in Chapter 5 (Responsibilities 
of the Investigator) of the Chinese GCP (Order No. 3). 
Publication of Study Data 
All data generated from this study are the confidential information of the sponsor. The sponsor 
has the right to publish the study results. Information on the publishing policies of the sponsor 
and investigator will be described in the clinical trial agreement. 


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All the information on this trial (not limited to the protocol and "Investigator's Brochure") must 
be kept strictly confidential. The investigator must recognize that the scientific or medical 
information derived from this trial may be of commercial value to the sponsor. The investigator 
shall keep the information and data related to this study confidential. The sponsor must be 
consulted in advance and written consent must be obtained prior to publishing of any study-
related information or conclusions. In order to protect the rights and interests, the sponsor may 
request the investigator not to publish information on this trial before the investigational drug is 
approved for marketing. 
The sponsor has the right to announce or publish information or data related to the trial or to 
report it to the drug administration. If the Sponsor needs to display the name of the investigator 
in a publication or advertisement, the consent of the investigator should be obtained. 
Financing and Insurance 
The sponsor will purchase insurance for subjects participanting in this study in accordance with 
local regulations and the minimum requirements. Insurance-related terms will be saved in the study 
folder. 
 
 


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12 References 
[1]. http://globocan.iarc.fr/Default.aspx. 
[2]. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. 
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N 
Engl J Med 2015,373:123-135. 
[3]. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab 
versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung 
cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016,387:1540-1550. 
[4]. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. 
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung 
cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 
2016,387:1837-1846. 
[5]. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. 
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung 
cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 
2017,389:255-265. 
[6]. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab 
for the treatment of non-small-cell lung cancer. N Engl J Med 2015,372:2018-2028. 
[7]. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 2008,8:467-477. 
[8]. 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. 
[9]. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective 
randomized trial of docetaxel versus best supportive care in patients with non-small-cell 
lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 
2000,18:2095-2103. 
[10]. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized 
phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-
small-cell lung cancer previously treated with platinum-containing chemotherapy 
regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 
2000,18:2354-2362. 


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[11]. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. 
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell 
lung cancer previously treated with chemotherapy. J Clin Oncol 2004,22:1589-1597. 
[12]. 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. 
[13]. NCCN Guidelines Version 8.2017 Non-Small Cell Lung Cancer. 
 
 


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13 Appendix 
Appendix 1: Signature Page for Investigator 
Protocol Title: 
A Randomized, Open-Label, Multicenter, Parallel, and Phase III Clinical Trial (ORIENT-3) 
Comparing the Efficacy and Safety of IBI308 and Docetaxel in the Treatment of Subjects with 
Advanced or Metastatic Squamous Non-Small Cell Lung Cancer Who Have Failed Platinum-
Based First-Line Chemotherapies 
 
Protocol No.: CIBI308C301 
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and 
fully understood this protocol, and agree to conduct this study in accordance with the 
requirements specified in this protocol and the "Good Clinical Practice" (GCP), and in 
compliance with relevant laws and regulations and the Declaration of Helsinki. Also, I promise 
not to reveal any confidential information to a third-party without the written consent from 
Innovent Biologics (Suzhou) Co., Ltd. 
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job 
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd. 
 
I have read the entire contents of this study protocol and shall perform the study as required: 
Signature of Investigator: _____________ Date: _____________ 
Name (Print): ___________________________ 
Job Title: _______________________________ 
Name/Address of Study Site: ___________________________ 
 
___________________________ 
 
___________________________ 


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Appendix 2: ECOG PS Scoring Criteria 
Score 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or wheelchair 
5 
Death 
 
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 the baseline level, tumor lesions/lymph nodes will be categorized into measurable and non-
measurable ones according to the following definitions: 
1.1.1 
Measurable lesion 
Tumor lesion: At least one diameter line that can be accurately measured (recorded as the 
maximum diameter), and its minimum length is as follows: 
 
10 mm by CT scan (with a slice thickness of no more than 5 mm) 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in minimum diameter when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm). At baseline and follow-up, only the 
minimum diameter will be measured and followed up. 
1.1.2 Non-measurable lesion 
All other lesions, including small lesions (with the maximum diameter of < 10 mm or the 
minimum diameter of a pathological lymph of ≥ 10 mm to < 15 mm) and non-measurable 
lesions. Non-measurable lesions include: meningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast cancer, cancerous lymphangiitis of the skin/lung, abdominal 
masses that cannot be diagnosed and followed up by imaging, and cystic lesions. 
1.1.3 Special considerations for lesion measurement 
Bone lesions, cystic lesions, and lesions with prior locoregional treatment must be specified: 
Bone lesions: 
 
Bone scan, PET scan, or plain film are not suitable for measuring bone lesions, but can be 
used to confirm the presence or disappearance of bone lesions; 


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 
In case of osteolytic lesions or mixed osteolytic/osteogenic lesions that have a definite soft 
tissue composition with the soft tissue composition meeting the above measurability 
definition, these lesions can be considered as measurable lesions provided that they can be 
evaluated using tomographic imaging techniques such as CT and MRI; 
 
Osteogenic lesions are non-measurable lesions. 
Cystic lesions: 
 
A lesion that meets the definition criteria for simple cysts in radiography should not be 
considered as a malignant lesion because it is a simple cyst by definition, which should be 
neither a measurable lesion nor a non-measurable lesion; 
 
If such lesion is cystic metastatic and meets the above measurability definition, it can be 
regarded as a measurable lesion. However, if noncystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional treatment, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. The conditions under which these lesions are 
measurable should be detailed in the study protocol. 
1.2 Description of Measurement Method 
1.2.1 Measurement of lesions 
When performing clinical evaluation, all tumor measurements should be recorded in metric 
notation. All baseline assessments of tumor lesion size should be possibly completed within 28 
days (4 weeks) before the start of treatment. 
1.2.2 Assessment method 
The same technique and method should be used for baseline assessment and subsequent 
measurement of lesions. Except for lesions that cannot be evaluated by imaging, while the 
clinical examination is applicable only, other lesions must be evaluated by imaging. 
Clinical lesions: Clinical lesions can only be considered as measurable lesions (such as skin 
nodules) when they are on the surface and have a measured diameter of ≥ 10 mm. For subjects 
with skin lesions, it is recommended to use color photos containing the size of the lesion 
measured by ruler as an archive. When the lesion can be evaluated by both imaging and clinical 
examination, imaging evaluation should be used whenever possible since it is more objective and 
may also be reviewed at the end of the study. 


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Chest X-ray: Chest CT is preferred over chest X-ray when progression is an important endpoint, 
particularly in identifying new lesions. Chest X-ray examination is only applicable when the 
boundary of the measured lesion is clear and the lungs are well ventilated. 
CT and MRI: CT is the best currently available and repeatable method for efficacy evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is.≤ 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
Ultrasound: Ultrasound should not be used as a measurement method to measure the lesion size. 
Ultrasonic examination can not be repeated after the measurement due to its operational 
dependency, and cannot guarantee 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 trial, 
CT or MRI should be used for confirmation. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
Endoscopy and laparoscopy: These techniques are not recommended for objective evaluation of 
tumors, but they can be used to confirm the CR results when biopsy specimens are obtained, or 
to confirm the relapse in trials where the endpoint is defined as a relapse or surgical resection 
after CR. 
Tumor markers: Tumor markers cannot be used alone to evaluate objective tumor response. 
However, if the marker level exceeds the ULN at baseline, it must be returned to normal when 
used to evaluate a CR. Since the tumor markers are varied from diseases, it needs to be 
considered when writing measurement criteria in the protocol. Specific criteria for CA-125 
response (recurrent ovarian cancer) and PSA (recurrent prostate cancer) response have been 
published. In addition, the International Gynecologic Cancer Society (IGCS) has prepared the 
criteria for CA-125 progression, which will soon be added to the objective evaluation criteria for 
tumors in the first-line treatment of ovarian cancer. 
Cytological/histological technologies: Under certain circumstances specified in the protocol, 
these technologies can be used to identify PR and CR (e.g., residual benign tumor tissue is often 
present in the lesions of germ cell tumors). When exudation may be a potential side effect of a 
certain therapy (such as treatment with a taxane compound or an angiogenesis inhibitor), and the 
tumor can be measured meeting the criteria for response or disease stabilization, the occurrence 
of tumor-related exudation during treatment or aggravation can be confirmed by cytological 
technologies to distinguish response (or SD) and PD. 


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2 
ASSESSMENT OF TUMOR REMISSION 
2.1 Assessment of All Tumors and Measurable Lesions 
In order to evaluate the objective response or possible future progress, it is necessary to perform 
a baseline assessment of the total tumor burden of all tumor lesions, which then should be used 
as the references for the subsequent measurement results. In clinical protocols with objective 
response as the primary treatment endpoint, only subjects with measurable lesions at baseline can 
be enrolled. Measurable lesion is defined by the presence of at least one measurable lesion. For 
trials with PD (time of PD or degree of progression on a fixed date) as the primary endpoint of 
treatment, the inclusion criteria for subjects with or without measurable lesions must be specified 
in the protocol. 
2.2 Baseline Documentation of Target and Non-Target Lesions 
When there are more than one measurable lesions in the baseline assessment, all lesions should 
be recorded and measured, and the total number should not exceed 5 (not more than 2 per organ), 
since the target lesion represents all involved organs (i.e., for subjects with 1 or 2 involved 
organs only, at most 2 or 4 target lesions can be selected for baseline measurement). 
Target lesions must be selected based on size (the maximum diameter), and can represent all 
involved organs, and measurements must have well repeatability. Sometimes when the largest 
lesion cannot be measured repeatedly, the lesion with the maximum diameter may be selected 
again. 
Special attention should be paid to the lymph nodes defined as normal tissues that can be 
identified by imaging, even if there is no signs of tumor metastasis. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the following criteria: 
the minimum diameter by CT scan of ≥ 15 mm. Only the minimum diameter should be measured 
at the baseline. Usually, radiologists will use the minimum diameter of a nodule to determine 
whether the nodule has metastasized. The nodule size is generally expressed in 2-D data of 
imaging (either an axial plane in CT or one of the axial, sagittal, or coronal plane in MRI). The 
minimum value is the minimum diameter. For example, a 20 mm × 30 mm abdominal nodule 
with a minimum diameter of 20 mm can be considered as a malignant, measurable nodule. In this 
example, 20 mm is the measured value of the nodule. Nodules with a diameter of ≥ 10 but < 15 
mm should not be considered as target lesions. Nodules with a diameter of < 10 mm should be 
not classified as pathological nodules, requiring no further records or observations. 
The sum of the calculated diameters of all target lesions (including the maximum and the 
minimum diameters of non-nodular lesions) will be reported as the sum of the diameters at the 
baseline. If the lymph node diameter is included, as mentioned above, only the minimum 


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diameter is counted. The sum of the baseline diameters will be used as a reference value for the 
disease at the baseline. 
All the remaining lesions, including pathological lymph nodes, can be considered as non-target 
lesions and no measurement is required, but such lesions should be recorded during baseline 
assessment. For example, such lesions can be recorded as "presence", "absence", or "definitive 
progression" in rare cases. Extensive target lesions can be recorded with target organs (such as 
massively enlarged pelvic lymph nodes or large-scale liver metastases). 
2.3 Response Criteria 
2.3.1 Assessment of target lesions 
Complete response (CR): All target lesions should be disappeared, with the minimum diameter 
of all pathological lymph nodes (including target and non-target nodules) reducing to < 10 mm. 
Partial response (PR): The sum of target lesion diameters is reduced by at least 30% compared to 
the baseline level. 
PD: The minimum value of the sum of all measured target lesion diameters throughout the study 
should be used as a reference, with increases in the diameter of at least 20% compared to the 
baseline level (if the baseline measurement is the minimum value, it should be used as a 
reference); otherwise, the absolute value of the sum of the diameter must be increased by 5 mm 
(the appearance of one or more new lesions is also considered to be PD). 
SD: Due to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, the minimum sum of diameters can be taken as reference in this study. 
2.3.2 Considerations for non-target lesion assessment 
Lymph nodes: Even if the lymph nodes are identified as target lesions of a decrease of less than 
10 mm, the actual minimum diameter value corresponding to the baseline must be recorded for 
each measurement (consistent with the anatomical plane at baseline measurement). In other 
words, if the lymph node is a target lesion, even if the criteria for CR are reached, a CR cannot 
be determined due to the definition of < 10 mm of the minimum diameter of a normal lymph 
node. Target lymph node lesions that need to be specifically recorded in specific locations in the 
eCRF by other recording methods: For CR, the minimum diameter of all lymph nodes must be < 
10 mm; for PR, SD, and PD, the actual measured minimum diameter of the target lymph node 
will be included in the sum of the target lesion diameters. 
Target lesions that are too small to be measured: In clinical studies, all lesions (nodules or non-
nodules) recorded at baseline should be recorded again in subsequent assessments, even if these 
lesions are very small (as small as 2 mm, for example). However, in some cases, the lesion may 
be too small so that the CT scan image is very blurry, and it is difficult for the radiologist to 


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define the measurement value. Therefore, such lesion may be reported as "too small to be 
measured". In this case, it is very important to record a value on the eCRF. If it is the opinion of 
the radiologist that the lesion has probably disappeared, the measurement value should be 
recorded as 0 mm. If the lesion does exist but with a blurry image so that an exact measurement 
value cannot be obtained, the default recording should be 5 mm. (Note: This is unlikely to occur 
in lymph nodes, because a lymph node normally has a measurable size, or it is often surrounded 
by fat tissues as in the retroperitoneal cavity; but if the measurement value of such node cannot 
be obtained, the default recording should also be 5 mm). The default value of 5 mm is 
determined by the cutting thickness of the CT scan (which will not change due to different 
cutting thickness values of CTs). Since the same measurement value is hardly possible to occur 
twice, providing the aforesaid default value can reduce the risk of erroneous assessment. But it 
needs to be reiterated that if the radiologist can provide the exact measured size of the lesion, the 
actual value must be recorded, even if the diameter of the lesion is less than 5 mm. 
Separated or combined lesions: When a non-nodular lesion is presented in parts, the maximum 
diameter of each separated part is added to calculate the sum of the lesion diameters. Similarly, 
for combined lesions, they can be distinguished by the plane between the combined parts, and 
then calculate the maximum diameter of each. However, if the combination is inseparable, the 
maximum diameter should be taken as the maximum diameter of the entire combined lesion. 
2.3.3 Assessment of non-target lesions 
This section defines the response criteria for non-target lesions. While some non-target lesions 
may actually be measurable but without measurement requirements, such lesions should be 
assessed only qualitatively at time points specified in the protocol. 
CR: All non-target lesions are disappeared and the levels of tumor markers are recovered to 
normal. All lymph nodes must be non-pathological in size (with the minimum diameter of < 
10 mm). 
Incomplete response/non-progressive disease: At least 1 non-target lesion is found with/without 
persistent tumor marker levels that exceed normal levels. 
PD: Definitive progression of existing non-target lesions. Note: A PD will be considered if at 
least 1 new lesion is found. 
2.3.4 Special considerations regarding the assessment of non-target lesion progression 
The supplementary explanation for the non-target lesion progression is as follows: When the 
subject has measurable non-target lesions, if a clear definition of progress is to be made on the 
basis of the non-target lesions, the overall non-target lesions must have deteriorated to the extent 
that the treatment must be terminated even if the target lesions are evaluated as stable or PR. 


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However, the general increase in the size of one or more non-target lesions is often insufficient to 
meet the criteria for PDs. Therefore, when the target lesion reachs stable or PR, it is very rare 
that the change of non-target lesions alone can define the overall tumor progression. 
When all of the subject's non-target lesions are not measurable: This is applicable to some phase 
Ⅲ trials provided that the presence of a measurable lesion is required in the inclusion criteria. 
However, the overall assessment is also based on the aforesaid requirements since no 
measurement value can be obtained for the lesion. The assessment of the exacerbation of non-
target lesions is a major challenge (by definition: all non-target lesions must not be measurable), 
and thus when the changes in non-target lesions lead to an increase in the overall disease load 
equivalent to the PD of target lesions, an effective test method should be established for 
assessment according to the definitive progressions of non-target lesions. For example, the lesion 
can be described as an increase in tumor burden equivalent to an additional 73% increase in 
volume (equivalent to a 20% increase in the diameter of a measurable lesion); or a peritoneal 
effusion from "minor" to "major"; or a lymphatic lesion from "local" to "extensive"; or in the 
protocol as "sufficient to cause changes in the therapy". Other examples include a pleural 
effusion from "trace" to "major", lymphatic involvement spreading from the primary site to a 
distant site, or lesions described in the protocol as "requiring changes in the treatment". If a 
definitive progression has been found, the subject should be generally considered as having PD 
at the time point of the finding. It is best to have objective criteria applicable to the assessment of 
non-measurable lesions. Notably, the additional criteria must be reliable. 
2.3.5 New lesions 
The appearance of new malignant lesions can be an indication for the progression of the disease. 
Therefore, it is critical to perform a certain assessment for such new lesions. Currently, there is 
no specific criteria for imaging tests of these lesions, while the findings for new lesions should 
be definitive. For example, the progression cannot be attributed to differences in imaging 
technologies, changes in imaging morphology, or other lesions except tumors (such as some 
"new bone lesions" that are simply the cure or the recurrence of the underlying lesions). This is 
of great importance when the patient is partially or completely responded to the treatment for 
his/her lesions at baseline. Specifically, a necrosis of a liver lesion may be defined as a new 
cystic lesion in the CT report, but it is not. 
Lesions that have been detected during follow-up but not found at baseline will be considered as 
new lesions, and will be an indication for a PD. For example, for a subject who is found to have 
visceral lesions during the baseline examination, and then metastases by a head CT or MRI, the 
subject's intracranial metastatic lesion will be considered as the rationale for the determination of 
PD, even if no cranial examination is performed at baseline. 


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If a new lesion is not definitive due to its small size or other reasons, further treatment and 
follow-up evaluation are required to confirm whether it is a new lesion. If the lesion is confirmed 
to be a new one by repeated examinations, the time of the initial finding should be counted as the 
start of the PD. 
Generally, the FDG-PET assessment of lesions requires additional tests for supplemental 
confirmation, and it is reasonable to combine the results from FDG-PET tests and those from CT 
tests (especially for new suspicious diseases). New lesions can be identified by FDG-PET tests 
based on the following procedures: 
In case of negative FDG-PET test results at baseline in combination with positive results from 
subsequent follow-up FDG-PET tests, a PD is indicated. 
In case of no FDG-PET tests at baseline in combination with positive results from subsequent 
FDG-PET tests: 
A PD can be proved if new lesions determined by the subsequent FDG-PET test results which 
are positive are consistent with those determined by CT test results. 
Otherwise, the CT tests should be performed again for confirmation of new lesions with positive 
test results of FDG-PET found in follow-ups (if confirmed, the time of abnormality found by 
previous FDG-PET tests should be counted as the start of the PD). 
And no progression should be determined in case of consistency between the subsequent FDG-
PET test results which are positive and those of existing lesions determined by CT tests. 
2.4 Evaluation of Optimal Overall Efficacy 
The evaluation of the best overall response refers to the best response recording from the start to 
the end of the study, while any necessary conditions must also be taken into account for 
confirmation. Sometimes, the therapeutic response will appear after the end of treatment. As a 
result, it should be clearly specified in the protocol that whether the efficacy evaluation after the 
treatment is counted in the evaluation of the best overall response. Also in the protocol, it must 
be specified that how any new therapy before progression affects the best response. The best 
response from the subjects mainly depends on the results of target and non-target lesions and the 
manifestations of new lesions. In addition, the response depends on the nature of the study, as 
well as the requirements and measurement criteria in the protocol. Specifically, the response 
from the subjects is the primary endpoint in non-randomized studies where the confirmation of 
PR or CR is required for the evaluation of the best overall response. 


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2.4.1 Time point response 
It is assumed that there will be an efficacy evaluation at each time point defined in the protocol. 
Table 1 summarizes the overall efficacy evaluation at each time point for subjects with 
measurable lesions at baseline. 
If no measurable lesions (no target lesions) are found in subjects, see Table 2 for the 
corresponding evaluation. 
2.4.2 Description of missing evaluations and non-evaluable cases 
If the imaging or measurement of the lesions of a subject cannot be performed at a specific time 
point, the subject should then be determined non-evaluable at that time point. If only part of the 
lesions of a subject can be evaluated in an evaluation, the case should then be determined as non-
evaluable at that time point, unless there is evidence to prove that the missing lesions will not 
affect the efficacy evaluation at the specified time point. In addition, such case may be an 
indication for a PD. For example, a subject has 3 lesions with a sum of diameters of 50 mm at the 
baseline level, but only 2 are subsequently determined evaluable, with a sum of diameters of 80 
mm, and then the subject will be evaluated as having a PD, regardless of the effects of the 
missing lesion. 
2.4.3 Optimal overall response: at all time points 
Once all data of the subjects are available, their optimal overall response can be determined. 
Evaluation of the optimal overall response when the confirmation of complete or partial response 
(CR/PR) is not required in the study: The best response in the study refers to the optimal 
response at all time points (for example, SD is the efficacy evaluation for the subjects in cycle 1, 
PR for cycle 2, and PD for the last cycle. However, the optimal overall response should be 
evaluated as PR). When the optimal overall response is evaluated as SD, the minimum time from 
the baseline level specified in the protocol must be met. If not, the SD result will not be accepted 
and the optimal overall response from the subjects will depend on the subsequent evaluations. 
For example, if the response from the subjects is evaluated as SD in cycle 1 and PD in cycle 2, 
but the minimum time requirement of SD is not met, the optimal overall response will be 
evaluated as PD. Similarly, if the response from the subjects is evaluated as SD in cycle 1, 
followed by a loss to follow-up, the subjects will be considered non-evaluable. 
Evaluation of the optimal overall response when the confirmation of CR/PR is required in the 
study: The complete or partial response can be determined only if the CR/PR criteria required by 
the study are met by each subject, and at a subsequent time point (usually 4 weeks later) 
specifically mentioned in the protocol, the efficacy is confirmed again. In this case, the optimal 
overall response can be found in the description of Table 3. 


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2.4.4 Special notes on efficacy evaluation 
When nodular lesions are included in the overall target lesion assessment and the diameters of 
such lesions are reduced to the "normal" level (< 10 mm), a scan report of the lesion size will 
still be provided. In order to avoid overestimating the condition indicated by the increase in 
nodule size, the measurement result will still be recorded even if the size is normal. As 
mentioned above, this suggests that the measurement results from subjects who are evaluated as 
CR will not be recorded as 0 in the eCRF. 
If the efficacy confirmation is required during the study, the optimal overall response will be 
more difficult to be evaluated at the repeated "non-measurable" time points. For these missing 
data/evaluations, it must be stated in the analysis plan of the study that they can be explained 
clearly when determining efficacy. In most studies, for example, the response from a subject in 
PR-NE-PR can be considered as the efficacy confirmation. 
When a subject experiences a overall deterioration of the health status requiring discontinuation 
of the treatment, but no objective evidences are obtained, it should be reported as a symptomatic 
progression. In addition, the cases with objective progression should be possibly assessed even 
after the treatment is terminated. Symptomatic deterioration is not an assessment description of 
objective response, but the reason for the discontinuation of the treatment. In this case, the 
objective response will be assessed by the target and non-target lesions shown in Tables 1 to 3. 
The assessment should be based on the early progression as required by the definition, but early 
deaths or non-evaluable cases are defined as special cases for studies, which should be 
specifically described in each of the study protocol (depending on the treatment intervals and 
cycles). 
Sometimes, it may be difficult to distinguish local lesions from normal tissues. When such 
definition is the basis for the assessment of CR, we recommend a biopsy before evaluating the 
efficacy by CR of local lesions. When the abnormal imaging results of the local lesions in some 
subjects are considered as indications for lesion fibrosis or scarring, the FDG-PET should be 
taken as criteria similar to biopsy, in order to confirm the efficacy by CR. In this case, the 
application of FDG-PET should be prospectively described in the protocol, and supported by the 
report of the specialty medical literatures. However, it must be realized that false positive results 
can be obtained in the CR assessment due to the limitations of FDG-PET and biopsy themselves 
(including the resolution and sensitivity). 


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Table 1. Time point efficacy: subjects with target lesions (including or excluding non-
target lesions) 
Target lesion 
Non-target lesion 
New Lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-progressive or 
not completely 
evaluable 
No 
PR 
SD 
Non-progressive or 
not completely 
evaluable 
No 
SD 
Not completely 
evaluable 
Non-progressive 
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 = 
non-measurable 
Table 2. Time point efficacy: subjects with non-target lesions only 
Non-target lesion 
New lesion 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not completely evaluable 
No 
NE 
PD that cannot be determined 
Yes or no 
PD 
Any 
Yes 
PD 
Note: "Non-CR/non-PD" is preferred over SD for non-target disease. Since SD is increasingly used as an endpoint 
for efficacy evaluation, the efficacy by non-CR/non-PD is determined for cases without specified measurable 
lesions.  
For indefinite progression findings (such as very small and uncertain new lesions; and cystic or necrotic changes in 
the underlying lesions), the treatment can be continued until the next assessment. If a PD is confirmed in the next 
assessment, the date when a suspected progression is found previously will be taken as the date of the progression. 


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Table 3. Optimal overall responses required to be confirmed for efficacy by CR and PR 
Overall response at 
the first time point 
Overall response at the 
subsequent time points 
Optimal overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
If SD meets the minimum time requirement, it should be the 
result otherwise PD 
CR 
PD 
If SD meets the minimum time requirement, it should be the 
result otherwise PD 
CR 
NE 
If SD meets the minimum time requirement, it should be the 
result otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
If SD meets the minimum time requirement, it should be the 
result otherwise PD 
PR 
NE 
If SD meets the minimum time requirement, it should be the 
result otherwise NE 
NE 
NE 
NE 
Note: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = non-
evaluable. SUP. "a": If CR is definitely confirmed at the first time point, for subjects who are found to have any 
disease at the subsequent time points, the evaluation results at the subsequent time points should still be PD (due to 
the recurrence of the disease after CR) even if the PR criteria are met according to the efficacy from the baseline. 
The optimal response will be determined by whether SD is observed at the minimum treatment interval. The first 
evaluation result may be CR in some cases, while small lesions are indicated by scanning at the subsequent time 
points. Consequently, the efficacy in the subjects at the first time point should actually be PR rather than CR. In this 
case, the initial CR result should be changed to PR, for which the optimal response will be PR. 
2.5. Frequency of Tumor Re-Evaluation 
The frequency of the tumor re-evaluation during the treatment will be determined according to 
the treatment regimen while being consistent with the type and schedule of the treatment. For the 
phase III trial, it is rational to perform a follow-up every 6–9 weeks (the time is designed at the 
end of a cycle), for which the time interval may be adjusted depending on special protocols or 
circumstances. In the protocol, it must be specified that which tissue sites are assessed at the 
baseline level (usually those that are most likely to be closely related to the metastatic lesion of 
the studied tumor type), along with the frequency to repeat the evaluation. Normally, both the 
target and non-target lesions should be evaluated in each assessment, while some non-target 
lesions may be less frequently evaluated under optional circumstances, such as bone scans that 
are only required when the evaluation of the efficacy by the target disease is confirmed as CR or 
when a progressive bone disease is suspected. 


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After treatment, the tumor re-evaluation will be determined by whether the response rate or the 
time to an event (progression/death) is used as the endpoint of the clinical trial. If the time to an 
event (such as TTP/DFS1/PFS) is used as the endpoint, the routine re-evaluation should be 
performed as required by the protocol. Especially in randomized comparison studies, pre-defined 
evaluations should be included in the schedule (e.g., 6–8 weeks during treatment, or 3–4 months 
after treatment) and not be affected by other factors, such as delayed treatment, dosing intervals, 
and any other events that may bring imbalanced treatment arms in the timing of disease 
evaluation. 
2.6. Confirmation of Efficacy Evaluation/Response Period 
2.6.1. Confirmation 
For non-randomized clinical studies with efficacy as the primary endpoint, the efficacy by PR 
and CR must be confirmed to ensure that the efficacy results are not obtained from inaccurate 
evaluations. This allows reasonable explanations for the results when the historical data are 
available, but the efficacy results based on the historical data should also be confirmed. In all 
other cases, such as randomized trials (phase Ⅱ or Ⅲ) or studies with either SD or PD as the 
primary endpoint, there are no more requirements for an efficacy confirmation since it is a 
valueless practice when explaining the trial results. Nevertheless, eliminating the requirement for 
efficacy confirmation will make the review at the study site even more important in preventing 
deviations, especially for unblinded studies. 
In the case of SD, the measurement that meets the SD criteria specified in the protocol must be 
obtained at least once in the shortest time interval (generally no shorter than 6–8 weeks) after the 
start of the study. 
2.6.2 Overall response period 
The overall response period refers to the time from the first measurement consistent with the 
criteria for CR or PR (whichever is obtained first) to the time when the recurrence or progression 
of the disease is firstly recorded (the minimum measurement recorded in the study is used as a 
reference for determination of PD). The overall response duration refers to the time from the first 
measurement consistent with the criteria for CR to the time when the recurrence or progression 
of the disease is firstly recorded. 
2.6.3 Stable disease period 
The stable disease period refers to the time from the start of the treatment to the occurrence of a 
PD (which should be started from the time of randomization in randomized trials) while using 
the minimum sum in the study as a reference (if the baseline sum is the minimum value, it is 
used as a reference for PD calculation). The clinical association of SD period varies with 


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different studies and diseases. For a specific trial using the proportion of subjects with SD for a 
minimum period of time as an endpoint, it should be specified in the protocol that the minimal 
time interval between two measurements defined by SD. 
Note: The DOR and SD as well as the progression-free survival (PFS) are influenced by the 
frequency of the follow-up after baseline evaluation. It is not in the scope of the guidelines to 
define a standard follow-up frequency. A number of factors should be considered for the follow-
up frequency, such as the type and staging of the disease, treatment cycles, criteria, and 
specifications. When a comparison across studies is required, the accuracy limitations of the 
corresponding measurement endpoints should also be considered. 
2.7. PFS/TTP 
2.7.1. Phase II clinical trial 
This guideline is mainly about using objective response as a study endpoint in phase II clinical 
trial. In some cases, the response rate may not be preferred when evaluating the potential anti-
cancer activities of new drugs/new regimens. In such cases, PFS/PPF results at the cut-off time 
points can be considered as suitable alternative indicators for being the signal source to identify 
the biological activity of the new drug. However, such evaluations obviously are questionable in 
an uncontrolled trial given that the seemingly valuable observations may be related to the patient 
screening and other biological factors rather than the effect of drug intervention. Therefore, it is 
preferable to have a randomized control designed for the phase II clinical trials using the 
objective response as endpoint. However, for certain tumors with consistent clinical 
manifestations (usually in persistent and poor conditions), it is also acceptable to have non-
randomized trials. Yet in such cases without a positive control, close attention should be paid to 
recording for efficacy evidences when assessing the expected PFS or PPF results. 


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Appendix 4: Immune Response Evaluation Criteria in Solid Tumors 
(iRECIST) 
iRECIST: Efficacy Evaluation Guidelines for Immunotherapy in Clinical Trials (Appendix) 
(Excerpt) 
1. iRECTIST EFFICACY EVALUATION 
Immunotherapy may promote the infiltration of immune cells, resulting in a transient increase in 
tumor volume or enabling falsely undetectable lesions. A large degree of consistency can be 
found between this version and RECIST v1.1; however, the evaluation of cases that may not 
reflect the true progression of the tumor, such as increased tumor load or the appearance of new 
lesions, has been adjusted. 
The key differences are explained below. All efficacy indicators evaluated using iRECIST will be 
prefixed with "i". The efficacy of iRECIST at each time point and the best overall response will 
be recorded separately. 
1.1. Confirmation of Progression 
Unlike RECIST v1.1, iRECIST requires confirmation of PD and introduces iUPD (unconfirmed 
progression) and iCPD (confirmed progression) standards. Scans to confirm progression can be 
performed as early as 4 weeks after iUPD and no later than 8 weeks after iUPD. 
If the tumor load still increases compared with the last measurement result, it is judged as iCPD. 
For specific evidences, refer to one or more of the following: 
• 
On the basis of PD (compared to the lowest point) of target lesions, non-target lesions or 
new lesions that meet the definition of RECIST v1.1, the tumor load continues to 
increase 
 Target lesion deterioration, manifested by an increase in the absolute value of the 
sum of the measured values by at least 5 mm 
 The progression of non-target lesions is definitive, manifested by increased tumor 
load 
 The increase of previously discovered new lesions (the absolute value of the sum of 
the measured values of new target lesions increases by at least 5 mm) or other new 
lesions are discovered 
• 
Other lesions (target lesions, non-target lesions, or new lesions) with no previous tumor 
progression are found to meet the RECIST v1.1 progression criteria, including the 
discovery of other new lesions 


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If iUPD is not confirmed in the next evaluation, the corresponding efficacy evaluation result will 
be recorded (if iUPD still meets and does not deteriorate, it will be recorded as iUPD, if it meets 
the criteria of iSD, iPR or iCR compared to the baseline, it will be recorded as the corresponding 
result). As shown in Table 2, in the case where iUPD's next efficacy evaluation does not reach 
iCPD, the previous iUPD does not affect the recording of iCR, iPR, or iSD at a later evaluation 
time point or at the time of the best overall response. 
1.2. New Lesion 
New lesions shall be measured and evaluated according to the RECIST v1.1 (up to 5 lesions, no 
more than 2 per organ, with a longest diameter of at least 10 mm [lymph node lesion with a 
minimum diameter of at least 15 mm]), and clearly marked as a new ones from previous ones. 
New lesions should meet the definition of new target lesions or non-target lesions, and be 
recorded as iUPD (or iCPD). The measurement of such target lesions should not be calculated as 
the sum of the measured values of target lesions defined at baseline. The measurement results of 
these new target lesions should be recorded in a separate CRF. 
PD can be confirmed based on the following conditions: An imaging evaluation performed at 
least 4 weeks (not more than 8 weeks) after iUPD found that the absolute value of the sum of the 
measured values of the new target lesion increased by at least 5 mm or the new non-target lesion 
increase in volume (no explicit increase required) or other new lesions appear. 
All subjects will define the immune best overall response (iBOR) from the beginning of 
treatment to the end of treatment according to Table 3. 
2. TIME TO RESPONSE AND STABLE DISEASE (RECIST V1.1 and iRECIST) 
The time to response will be calculated from the time that the CR/PR or iCR/iPR is met 
(whichever occurs first) until relapse or a PD is found, and the minimum measurement value 
(including baseline) during the study period is also recorded as a reference. 
The time to SD will be calculated from the time that the SD/PR or iCR/iPR is met (whichever 
occurs first) until a PD is found, and the minimum measurement value (including baseline) 
during the study period is also recorded as a reference. 
Table 1. RECIST v1.1 and iRECIST 
 
RECIST v1.1 
iRECIST 
Definitions for 
measurable and non-
measurable lesions; 
number and location 
of target lesions 
The lesion with the maximum diameter 
longer than or equal to 10 mm should be 
defined as a measurable lesion (15 mm 
for lymph node lesions); up to 5 lesions 
(2 per organ); other lesions for non-target 
lesions (the minimum diameter of a 
lymph node lesion should be ≥ 10 mm) 
No change; but the new lesion will be 
recorded separately in the CRF according to 
the RECIST v1.1 (the sum of the measured 
values of the target lesion at baseline is not 
counted) 


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RECIST v1.1 
iRECIST 
CR, PR, or SD 
Unrecordable PD before CR, PR, or SD 
IUPD (one or more) before iCR, iPR or 
iSD, but no iCPD 
Confirmation of CR 
or PR 
For non-randomized trials only 
Same as RECIST v1.1 
Confirmation of SD 
Not necessary 
Same as RECIST v1.1 
New lesion 
Evaluated as PD while no measurement 
required 
Evaluated as iUPD while recorded as iCPD 
for the next evaluation if conditions are met 
• 
Occurrence of other new lesion or 
• 
increased volume of new lesions (the 
sum of the measured values of new 
target lesions increased by ≥ 5 mm or 
any new non-target lesion increased) 
New lesions that have never been recorded 
before can also be confirmed as iCPD 
Independent blind 
review and central 
image acquisition 
Recommended in some cases 
Recommended in all cases (without 
independent review) 
Confirmation of PD 
Not required (unless indefinitive) 
Required 
Consider the patient's 
clinical status 
Not in the evaluation 
Continue the medication after iUPD based 
on the stability of the patient's clinical status 
(see definition) 
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; iCR: immune complete 
response; iPR: immune partial response; iSD: immune stable disease; iUPD: immune unconfirmed progressive 
disease; iCPD: immune confirmed progressive disease. 
Table 2. iRECIST efficacy records at different evaluation time points 
Efficacy evaluation at this time 
Target lesion* 
Non-target lesion* 
New 
lesion* 
Efficacy evaluation result 
Without 
previous iUPD** 
With previous 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 


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Efficacy evaluation at this time 
Target lesion* 
Non-target lesion* 
New 
lesion* 
Efficacy evaluation result 
Without 
previous iUPD** 
With previous iUPD**, *** 
iUPD is 
unchanged or 
reduced from 
the last 
evaluation 
iUPD is unchanged 
or reduced from the 
last evaluation 
Yes 
NA 
In case of a new lesion which has 
been diagnosed before or observed 
with increase (an increase in SOM of 
≥ 5 mm or new increase in non-target 
lesion), it can be confirmed as an 
iCPD. In case of no changes in a new 
lesion compared to the lase evaluation 
(volume or quantity), the new lesion 
should also be recorded as iUPD 
iSD, iPR, iCR 
iUPD 
No 
iUPD 
The increase in the volume of non-
target lesions (no definitive PD in 
accordance with RECIST v1.1 is 
required) can be confirmed as iCPD, 
otherwise it is still iUPD 
iUPD 
Non-iCR/Non-iUPD; 
iCR 
No 
iUPD 
In case of meeting the following 
conditions, then it is confirmed to be 
iCPD, otherwise iUPD: 
• 
Except for a target lesion with 
an increase in SOM ≥ 5 mm, the 
target lesion should also be 
recorded as iUPD 
iUPD 
iUPD 
No 
iUPD 
In case of meeting the following 
conditions, then it is confirmed to be 
iCPD, otherwise iUPD: 
• 
A previous target lesion of iUPD 
with an increase in SOM of ≥ 
5 mm and/or 
• 
an increase in non-target lesion 
of iUPD (previous evaluation — 
without definitive PD) 
iUPD 
iUPD 
Yes 
iUPD 
In case of meeting the following 
conditions, then it is confirmed to be 
iCPD, otherwise iUPD: 
• 
A previous target lesion of iUPD 
with an increase in SOM of ≥ 
5 mm and/or 
 


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Efficacy evaluation at this time 
Target lesion* 
Non-target lesion* 
New 
lesion* 
Efficacy evaluation result 
Without 
previous iUPD** 
With previous iUPD**, *** 
• 
The non-target lesion of iUPD 
with an increase in size 
(definitive PD is not required) 
and/or 
• 
an increase in volume or 
quantity of a new lesion with 
history 
Non-iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
In case of meeting the following 
conditions, then it is confirmed to be 
iCPD, otherwise iUPD: 
• 
an increase in volume or 
quantity of a new lesion with 
history 
*Refer to the principles in RECIST v1.1. In case of no false progression, the regulations on CR, PR, and SD in 
RECIST v1.1 are consistent those in iRECIST .** For any type of lesion.*** Found in the most recent assessment 
before this one. 
iCR: immune complete response; iPR: immune partial response; iSD: immune stable disease; iUPD: immune 
unconfirmed progressive disease; iCPD: immune confirmed progressive disease; SOM: sum of measured values; 
NA: not applicable: NE: non-evaluable 


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Table 3. Best overall response by iRECIST 
Best overall response 
Evaluation 1 
Evaluation 2 
Evaluation 3 
Evaluation 4 
Evaluation 5 
Immune 
best overall 
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 — May be multiple cases following the same principle 
• 
This table is assumed to be following a randomization study design without confirmation of CR or PR 
• 
For subjects with only non-target lesions at baseline, the evaluation at each time point is only recorded as iCR 
or non-CR/non-PD, but it is not reflected in the table for convenience 
iCR: immune complete response; iPR: immune partial response; iSD: immune stable disease; iUPD: immune 
unconfirmed progressive disease; iCPD: immune confirmed progressive disease; SOM: sum of measured values; 
NA: not applicable: NE: non-evaluable


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Appendix 5: List of Pre-Existed Autoimmune Diseases Prior to Enrollment 
Ask whether the subject has acquired or congenital immunodeficiency or autoimmune diseases. 
These subjects are excluded from the study. Unless the subject has a history of allergic reactions 
and juvenile arthritis, the likelihood of suspected autoimmune disease is very low. In addition, 
subjects with transient autoimmune manifestations due to acute infections (such as Lyme 
arthritis) can enroll if have been treated with antibiotics. If an autoimmune disease cannot be 
confirmed, please contact the sponsor's medical manager. 
 
Autoimmune diseases include but are not limited to: 
Acute sporadic encephalomyelitis 
IgA nephropathy 
Addison's disease 
Inflammatory bowel disease 
Alopecia 
Interstitial cystitis 
Ankylosing spondylitis 
Myasthenia gravis 
Antiphospholipid antibody syndrome 
Lupus 
Aplastic anemia 
Lyme disease (chronic) 
Asthma 
Meniere's syndrome 
Autoimmune hemolytic 
Anemia 
Corneal ulcer 
Autoimmune hepatitis 
Localized autoimmune hypophysitis 
Multiple sclerosis 
Autoimmune hypoparathyroidism 
Myasthenia gravis 
Autoimmune myocarditis 
Neuromuscular ankylosis 
Autoimmune ovaritis 
Myoclonus syndrome 
Autoimmune orchitis 
Optic neuritis 
Autoimmune thrombocytopenia 
purpura 
Ord's thyroiditis 
Bechet disease 
Pemphigus 
Bullous pemphigoid 
Pernicious anemia 
Celiac disease 
Multiple arteritis 
Chronic fatigue syndrome 
Polyarthritis 
Chronic inflammation demyelinating 
Polyneuropathy 
Autoimmune syndrome 
Churg-Strauss syndrome 
Primary biliary cirrhosis 
Crohn's disease 
Psoriasis dermatomyositis 
Rett syndrome 
Type I Diabetes 
Rheumatoid arthritis 
Autonomic dysfunction 
Sarcoidosis 
Eczema 
Scleroderma 
Sjogren syndrome 
Bullous dermolysis 
Stiff-person syndrome 
Pemphigus during pregnancy 
Takayasu arteritis 
Giant cell arteritis 
Ulcerative colitis 
Pulmonary hemorrhage-
glomerulonephritis syndrome 
Vitiligo 
Graves’ disease 
Vogt-Kovanagi-Harada 
disease 
Guillain-Barre syndrome 
Vulvodynia 
Hashimoto's disease 
Wegener's granulomatosis 
Kawasaki disease 


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Appendix 6: Management for irAE 
Table 1. Dose adjustments and toxicity management of major potential irAEs 
 
AE Grade/Dose Adjustments 
Toxicity Management 
General principles 
AEs are graded according to NCI 
CTCAE v4.03 
It is recommended to manage irAEs according 
to the guideline in this table. 
- 
Subjects should be fully evaluated to rule 
out any alternative causes (e.g., PD, 
concomitant medication, infection) 
- 
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 should be increased 
until symptoms are stabilized or 
improved, then tapering 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 
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 the treatment 
Grade 4 
Permanent discontinuation 


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AE Grade/Dose Adjustments 
Toxicity Management 
Pneumonia 
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 
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 the sponsor's medical 
manager, and 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 antibiotics 
- 
Consider consulting a respirologist and 
infectious diseases specialist 
 
 
 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 3 
or 
Grade 4 
Permanent discontinuation 
For grade 3–4 events: 
- 
Discuss with the 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 antibiotics 
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 should be fully evaluated to rule 
out any alternative causes (e.g., PD and 
infection) 
- 
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 
Grade 2 
or 3 
Interrupt 
• If worsens, treat as a 
For grade 2–3 events: 
- 
Consider symptomatic treatment, 
including fluid replacement, electrolyte 
replacement, diet modifications, and 


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AE Grade/Dose Adjustments 
Toxicity Management 
grade 3/4 event 
• If reduces to grades 0–1 
or baseline, continue the 
treatment at the next 
scheduled date 
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 ≤ 1 within 3–4 
days, discuss with the sponsor's medical 
manager 
- 
Once improved, taper glucocorticoids 
within ≥ 4 weeks, and consider 
prophylactic antibiotics 
 
Grade 4 
Permanent discontinuation 
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 antibiotics 


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AE Grade/Dose Adjustments 
Toxicity Management 
Hepatitis (ALT, 
AST, or TBIL 
increased) 
Any 
grade 
 
 
Closely monitor hepatitis-related signs 
and symptoms (e.g., jaundice, tea-
colored urine, nausea, emesis, loss of 
appetite, hepatalgia, and hemorrhagic 
tendency) 
 
Monitor and evaluate hepatic function 
 
Evaluate alternative causes (e.g. viral 
hepatitis, PD, concomitant medication) 
 
The dose adjustments and toxicity 
management in this table are 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 
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 ≤ 1 within 3–4 
days, discuss with the 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) 


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AE Grade/Dose Adjustments 
Toxicity Management 
 
- 
Once improved, taper steroids within ≥ 4 
weeks, and consider prophylactic 
antibiotics 
Grade 3 
or 4 
Permanent discontinuation 
 
 
For grade 3–4 events: 
- 
Discuss with the 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 antibiotics 
Dermatitis 
Any 
grade 
 
- 
Monitor signs and symptoms or 
dermatitis, e.g. rash, exudation, 
hypopigmentation, photaesthesia, and 
pruritus 
- 
If there is formation of bullae, contact the 
sponsor's medical manager 
- 
Consult a dermatologist 
- 
Perform skin biopsy when necessary 
Grade 1 
No dose adjustments 
required 
For grade 1 events: 
- 
Consider symptomatic treatment, 
including oral antipruritic agents (e.g. 
diphenhydramine or hydroxyzine) and 
local treatment (e.g. urea cream or topical 
glucocorticoids) 
Grade 2 
No dose adjustments 
required 
• For a refractory (> 1–2 
weeks) grade 2 event, 
For grade 2 events: 
- 
Consider symptomatic treatment 
including oral antipruritic agents and 


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AE Grade/Dose Adjustments 
Toxicity Management 
interrupt until reduces to 
grades 0–1 or baseline, 
continue the treatment at 
the next scheduled date 
local treatment 
- 
Consider a medium-potency topical 
glucocorticoid 
- 
If no improvement or deterioration is seen 
with 3–5 days, discuss with the 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 antibiotics 
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 the 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 antibiotics 
Grade 4 
Permanent discontinuation 
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 
- 
Subjects should be fully evaluated to rule 
out any alternative causes (e.g., PD, brain 


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AE Grade/Dose Adjustments 
Toxicity Management 
metastasis, and infection) 
- 
Monitor and evaluate pituitary function: 
TSH, FT3, FT4, adrenocorticotropic 
hormone, cortisol, luteinizing hormone, 
follicle stimulating hormone, growth 
hormone, prolactin, Na+, blood glucose, 
estradiol, testosterone, and other 
laboratory parameters related to 
endocrine disorders. Perform functional 
tests when necessary (including 
adrenocorticotropic hormone [ACTH] 
stimulation test and insulin-induced 
hypoglycemia test) 
- 
Consider pituitary MRI 
- 
Consider consulting an endocrinologist 
- 
Consider testing for autoantibodies 
Grade 1 
No dose adjustments 
required 
For grade 1 events: 
- 
Monitor pituitary function 
- 
Subjects should be fully evaluated to rule 
out any alternative causes 
- 
Consider consulting an endocrinologist 
based on clinical indications 
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 the sponsor's medical manager 
 
Consult an endocrinologist 
 
Hospitalization when necessary 
 
Evaluate endocrine function, consider 
pituitary MRI if clinically indicated 
 
Begin hormone replacement therapy when 
necessary (cortisone replacement therapy 
should 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 
Grade 3 
or 4 
Permanent discontinuation 


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AE Grade/Dose Adjustments 
Toxicity Management 
long-term treatment); consider 
prophylactic antibiotics when tapering to 
prevent opportunistic infections 
Adrenal 
insufficiency 
Any 
grade 
 
- 
Monitor signs and symptoms of 
endocrine disorders, including fatigue, 
pigmentation, loss of appetite, 
hypotension, and weakness 
- 
Subjects should 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 
indexes suspected to be related to adrenal 
function. The ACTH stimulation test 
should 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 
based on clinical indications 
Grade 2 
Interrupt 
• If worsens to grade 3 or 
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 the sponsor's medical 
manager 
 
Evaluate adrenal function, begin hormone 
replacement therapy when necessary 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 3 
or 
Grade 4 
permanent discontinuation 
 
For grade 3–4 events: 
 
Discuss with the 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 antibiotics when tapering to 
prevent opportunistic infections 
Hyperthyroidism/ 
hypothyroidism 
Any 
grade 
 
- 
Monitor signs and symptoms of thyroid 
dysfunction, e.g. hyperthyroidism 
(palpitations, sweating, increased appetite 
and bowel movement, and weight loss) 
and hypothyroidism (general weakness, 
fatigue, cold, memory loss, and 
constipation) 
- 
Subjects should 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 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/Dose Adjustments 
Toxicity Management 
Grade 3 
or 4 
Hyperthyroidism 
• Permanent 
discontinuation 
Hypothyroidism 
• No dose adjustments 
required 
For grade 3–4 events: 
 
Discuss with the 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 should be fully evaluated to rule 
out any alternative causes 
- 
Monitor and assess pancreas islet 
function: blood glucose, insulin, c-
peptide, β-cell autoantibodies, blood 
ketones, and other endocrine laboratory 
parameters related to type I diabetes 
Grade 1 
or 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 the 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 should 
be hospitalized to receive insulin, fluid 
replacement, and alkali therapy 
Grade 4 
Permanent discontinuation 


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AE Grade/Dose 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 should 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 
Grade 2 
or 
3 
Interrupt 
• If reduces to grades 0–1, 
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 the 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 puncture biopsy 
- 
Consult a nephrologist 
Grade 4 
Permanent discontinuation 
For grade 4 events: 
- 
Discuss with the 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 puncture biopsy 


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AE Grade/Dose Adjustments 
Toxicity Management 
Immune-related 
neurotoxicities 
(except for 
myasthenia gravis 
and Guillain-Barre 
syndrome) 
 
Any 
grade 
 
- 
Monitor the subject's systemic symptoms 
(headache, nausea, dizziness, behavioral 
changes, or weakness) 
- 
Subjects should be fully evaluated to rule 
out any alternative causes (e.g., PD, 
infection, metabolic syndrome, and 
medications) 
- 
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 
Interruption 
• If reduces to grades 0–1, 
continue the treatment at 
the next scheduled date 
• If worsens, treat as a 
grade 3 event 
For grade 2–4 events: 
- 
Discuss with the sponsor's medical 
manager 
- 
Consider consulting a neurologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain 
with appropriate medications (e.g. 
gabapentin, duloxetine, etc) 
- 
Consider systemic corticosteroid 
treatment 
- 
If no improvement is seen within 3–5 
days, consider other tests and 
immunosuppressants (e.g., intravenous 
immunoglobulin G, IVIgG) 
- 
Once stabilized, taper glucocorticoids 
within ≥ 4 weeks 
Grade 3 
Grade 4 
Permanent discontinuation 
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, 


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AE Grade/Dose Adjustments 
Toxicity Management 
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 should be 
performed to rule out any alternative 
causes (e.g., PD, infection, metabolic 
syndrome, and medications). 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 should be 
actively carried out 
- 
Plasmapheresis or IVIgG should be 
considered for subjects with 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 neurologist 
Grade 2 
Interruption 
• If reduces to grades 0–1, 
continue the treatment at 
the next scheduled date 
• If worsens, treat as a 
grade 3–4 event 
For grade 2–4 events: 
- 
Discuss with the sponsor's medical 
manager 
- 
Monitor signs and symptoms 
- 
Consult a neurologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain 
with appropriate medications (e.g., 
gabapentin and duloxetine) 
Myasthenia gravis 
- 
Glucocorticoids may be used to treat 
myasthenia gravis (should be used under 
the supervision of a neurologist since 
corticosteroids, especially high-dose, may 
Grade 3 
or 4 
Permanent discontinuation 


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AE Grade/Dose Adjustments 
Toxicity Management 
result in initial deterioration 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 adjustments and toxicity management of other potential irAEs 
 
CTD grade/dose adjustments 
Toxicity 
Management 
Any grade 
Dose adjustments are not required for AEs unrelated to study treatment 
or laboratory abnormalities that are not clinically significant (events 
caused by underlying disease) 
Manage based on local 
clinical practice 
Grade 1 
No dose adjustments required 
Grade 2 
Consider interruption until reduces to grade 0–1 or baseline 
Grade 3 
• First occurrence: interrupt until reduces to grade 0–1 or baseline 
• Second occurrence of the same grade 3 AE: 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 
Permanent discontinuation* 
*Note: For laboratory abnormalities, the event should be determined based on clinical signs/symptoms and 
the clinical judgment of the investigator 


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Table 3. Dose adjustments and toxicity management of infusion reactions 
CTD Grade 
Dose 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, and 
rash) and allergic reactions (e.g., systemic urticaria, 
angioedema, asthma, hypotension, and tachycardia) 
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 
Permanent discontinuation 
For grade 3–4 events: 
- 
Manage severe infusion-related reactions according 
to local clinical practice (e.g. administration of 
epinephrine, diphenhydramine, ranitidine, and 
glucocorticoids)