Clinical trial NCT02937116
Conditions: Cancer, Solid Tumor
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2016-10-19; Completion date: 2020-09-30
Enrollment: 233 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability and efficacy of IBI308 monotherapy or in combination with chemotherapy in patients with certain types of advanced solid tumors. Another purpose is to determine the pharmacokinetics, pharmacodynamics and immunogenicity of IBI308.

Detailed description:
This is a study which consists of phase 1a study (dose escalation stage) and phase 1b study (expansion stage). Phase 1a study will adopt the classical 3+3 dose escalation design, exploring safety and tolerance of 4 dose cohorts (1mg/kg, 3mg/kg, 200mg and 10mg/kg) and determining the recommended dose for phase 1b study. Phase 1b is expansion study of 8 cohorts which will evaluate anti-tumor efficacy and safety of eight IBI308 monotherapy or in combination with chemotherapy. Cohort A is IBI308 monotherapy for advanced melanoma. Cohort B is IBI308 monotherapy for advanced digestive system carcinoma or neuroendocrine neoplasm after failure or intolerance of first line standard therapy. Cohort C is IBI308 monotherapy for advanced non-small cell lung cancer (NSCLC) after failure or intolerance of first line standard therapy. Cohort D is IBI308 in combination with cisplatin and pemetrexed for treatment naïve locally advanced, recurrent or metastatic non-squamous NSCLC. Cohort E is IBI308 in combination with gemcitabine and cisplatin for treatment-naïve locally advanced, recurrent or metastatic squamous NSCLC. Cohort F is IBI308 in combination with oxaliplatin and capecitabine for treatment naïve locally advanced gastric or gastroesophageal junction adenocarcinoma. Cohort G is IBI308 in combination with etoposide and cisplatin for treatment naïve locally advanced, recurrent or metastatic high grade(G3) neuroendocrine tumor. Cohort H is IBI308 in combination with irinotecan and 5-FU for advanced high grade(G3) neuroendocrine tumor after failure of first line standard therapy. Phase 1a and 1b consist of screening period (28 days before enrollment), treatment period and follow up period (every 3 months until death or the end of study). In phase 1a, dose limiting toxicity (DLT) will be recorded for up to 28 days after the 1st dose of IBI308. Efficacy will be evaluated by RECIST v1.1. Adverse events will be monitored throughout the study. Further exploration of pharmacokinetic/pharmacodynamics and immunogenicity information will be assessed throughout the trial.

Arms: arm 1: Participants will receive IBI308 1mg/kg, 3mg/kg or 10mg/kg intravenous every 2 weeks, or 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity.

Drug: IBI308 arm 2: Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308 arm 3: Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308 arm 4: Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308 arm 5: Participants will receive IBI308 200mg in combination with cisplatin 75mg/m2 and pemetrexed 500mg/m2 intravenously every 3 weeks for upto 4 cycles, and those who haven't progressed will receive maintenance treatment of IBI308 200mg in combination with pemetrexed 500mg/m2 intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308/Cisplatinum/Pemetrexed arm 6: Participants will receive IBI308 200mg and cisplatin 75mg/m2 intravenously every 3 weeks in combination with gemcitabine 1250mg/m2 intravenously day 1 and 8 of every 3 weeks for upto 6 cycles, and those those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308\\gemcitabine\\cisplatin arm 7: Participants will receive IBI308 200mg and oxaliplatin 130mg/m2 intravenously every 3 weeks in combination with capecitabine 1000mg/m2 orally day 1 to 14 of every 3 weeks for upto 6 cycles, and those those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308\\oxaliplatin\\capecitabine arm 8: Participants will receive IBI308 200mg in combination with cisplatin 75mg/m2 intravenously and etoposide 100mg/m2 intravenously day 1 to 3 of every 3 weeks for upto 6 cycles. Those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308\\etoposide\\cisplatin arm 9: Participants will receive IBI308 200mg in combination with irinotecan 125mg/m2 intravenously day 1and 8 and 5-FU 1000mg/m2 intravenously day 1 to 3 of every 3 weeks for upto 6 cycles.Those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment.

Drug: IBI308\\irinotecan\\5-FU
Interventions: intervention 1: IBI308 intervention 2: IBI308\Cisplatinum\Pemetrexed intervention 3: IBI308\cisplatin\gemcitabine intervention 4: IBI308\oxaliplatin\capecitabine intervention 5: IBI308\etoposide\cisplatin intervention 6: IBI308\irinotecan\5-FU
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Study Title: 
An Open-Label, Multi-Center, and Phase Ia/Ib Study Evaluating 
the Monotherapy or Combination Chemotherapy of IBI308 in the 
Treatment of Chinese Subjects with Advanced Malignant Tumors 
Protocol Number: 
CIBI308A101 
Version and Date: 
Jan. 31, 2019/Version 3.0 
Product Name: 
Sintilimab (IBI308) 
Study Phase: 
Phase Ia/Ib 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China 
Sponsor Contact: 
Zhou Hui Senior Medical Director 
+ 86 021-31652896 
hui.zhou@innoventbio.com 
 
 
Confidentiality Statement 
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd. 
The content of this document shall not be disclosed to any person other than the investigators, 
research consultants or related personnel, and institutional review board/independent 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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Protocol Synopsis 
Protocol no. 
CIBI308A101 
Sponsor 
Innovent Biologics (Suzhou) Co., Ltd. 
Investigational 
drug 
Sintilimab (IBI308) 
Active 
ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study title  
An Open-Label, Multi-Center, and Phase Ia/Ib Study Evaluating the Monotherapy or 
Combination Chemotherapy of IBI308 in the Treatment of Chinese Subjects with Advanced 
Malignant Tumors 
Study phase 
Phase I 
Expected study 
duration  
Phase Ia: approximately 12 months; 
Phase Ib: approximately 36 months. 
Study objectives 
Primary study endpoints: 
• 
To evaluate the safety and tolerability of the monotherapy or combination 
chemotherapy of IBI308 in subjects with advanced solid tumors; 
• 
To evaluate the anti-tumor activity of the monotherapy or combination chemotherapy 
of IBI308 in subjects with advanced solid tumors. 
Secondary study endpoints: 
• 
To evaluate the pharmacokinetic (PK) characteristics of single- and 
repeated-administration of IBI308 in subjects with advanced solid tumors; 
• 
To evaluate the immunogenicity of IBI308 in subjects with advanced solid tumors; 
• 
To evaluate the pharmacodynamic (PD) parameters of IBI308 in subjects with 
advanced solid tumors. 
Exploratory objectives: 
• 
To explore the use of "immunerelated Response Evaluation Criteria in Solid Tumors" 
(irRECIST) to assess the efficacy of IBI308 in subjects with advanced solid tumors; 
• 
To explore the potential biomarkers in tumor tissues that can predict the efficacy of 
IBI308: including but not limited to immunohistochemistry assay of PD-L1 expression 
in tumor samples, whole exome sequencing to detect tumor mutation burden (TMB), 
multicolor immunohistochemistry, and PD-L1 and CD8 double staining assay. 


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Study design 
This is a multi-center, open-label, phase Ia/Ib study of IBI308 monotherapy or combination 
chemotherapy in the treatment of Chinese subjects with advanced malignant tumors. 
Phase Ia study: This is designed to investigate tolerability, safety, and PK of IBI308. Around 
12–24 patients with advanced solid tumors that failed standard treatment will be enrolled. The 
dose escalation strategy is established using the standard "3 + 3" design. Four dose levels (1 
mg/kg, 3 mg/kg, 200 mg, and 10 mg/kg) will be evaluated in this section. After the completion 
of 1 mg/kg dose administration, subjects are randomized in a 1:1 ratio to either 3 mg/kg or 200 
mg dose group for independent evaluations. Dose limiting toxicity (DLT) is observed for 28 
days after the first dose for each dose group. After completion of DLT observation, subjects are 
treated with IBI308 Q2W (1 mg/kg, 3 mg/kg, or 10 mg/kg) or Q3W (200 mg) until PD, 
intolerable toxicity, withdrawal of informed consent, or other reasons requiring treatment 
discontinuation (whichever occurs first). The specific study visit arrangement is shown in Table 
1 and Table 2. 
Phase Ib study: This is designed to preliminarily assess the safety and anti-tumor activity of 
IBI308 in the following cohorts. 
• 
Cohort A: Melanoma study, enrolling approximately 10–20 subjects with advanced 
melanoma. They will receive 200 mg IV Q3W of IBI308 until PD, intolerable 
toxicity, withdrawal of informed consent, 24 months of treatment, or other reasons 
for discontinuation of the study treatment (whichever occurs first). After enrollment 
of up to 20 subjects, the sponsor can decide whether to expand the enrollment based 
on PK, preliminary efficacy, and safety data. The specific study visit arrangement is 
shown in Table 3 and Table 6. 
• 
Cohort B: Study on malignant tumors of the digestive system or neuroendocrine 
tumors, enrolling approximately 50–100 subjects with such tumors who failed or 
became intolerable to first-line systemic standard treatment. They will receive 200 
mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of informed 
consent, 24 months of treatment, or other reasons for discontinuation of the study 
treatment (whichever occurs first). After enrollment of 50 subjects, the sponsor will 
terminate the enrollment of subjects based on the progress of clinical development 
and preliminary efficacy and safety data of IBI308. The specific study visit 
arrangement is shown in Table 3 and Table 6. 
• 
Cohort C: Lung cancer study, enrolling approximately 10–20 subjects of advanced 
NSCLC who failed or became intolerant to first-line systemic standard treatment. 
They will receive 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). The specific study 
visit arrangement is shown in Table 3 and Table 6. 
• 
Cohort D: Study on the safety and preliminary efficacy evaluation of first-line 
treatment of advanced non-squamous non-small cell lung cancer (nsNSCLC) using 
IBI308 in combination with chemotherapy, enrolling approximately 20 subjects. 
Each treatment cycle contains 3 weeks. And 200 mg IV of IBI308, 500 mg/m2 IV of 
pemetrexed, and 75 mg/m2 IV of cisplatin are given on D1 of each cycle. Up to 4 


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cycles of triple drug combination therapy are given. Subsequently, the subjects 
experiencing no PD can receive a maintenance treatment of 200 mg IV Q3W of 
IBI308 and 500 mg/m2 IV Q3W of pemetrexed until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). The specific study 
visit arrangement is shown in Table 4 and Table 6. 
• 
Cohort E: Study on the safety and preliminary efficacy evaluation of first-line 
treatment of advanced squamous cell non-small cell lung cancer (scNSCLC) using 
IBI308 in combination with chemotherapy, enrolling approximately 20 subjects. 
Each treatment cycle contains 3 weeks. The dosing regimen is IBI308 200 mg IV D1 
+ gemcitabine 1250 mg/m2 IV D1, D8 + cisplatin 75 mg/m2 IV D1. Up to 6 cycles of 
triple drug combination therapy are given. Subsequently, the subjects experiencing 
no PD can receive a maintenance treatment of 200 mg IV Q3W of IBI308 until PD, 
intolerable toxicity, withdrawal of informed consent, 24 months of treatment, or other 
reasons for discontinuation of the study treatment (whichever occurs first). The 
specific study visit arrangement is shown in Table 4 and Table 6. 
• 
Cohort F: Study on the safety and preliminary efficacy evaluation of first-line 
treatment of inoperable locally progressing, recurrent/metastatic gastric or 
gastroesophageal junction adenocarcinoma using IBI308 in combination with 
oxaliplatin/capecitabine (XELOX), enrolling approximately 20 subjects. Each 
treatment cycle contains 3 weeks. And 200 mg IV of IBI308 and 130 mg/m2 IV of 
oxaliplatin are given on D1 of each cycle, while 2000 mg/m2/d of capecitabine is 
given orally bid on D1–14. Up to 6 cycles of triple drug combination therapy are 
given. Subsequently, the subjects experiencing no PD can receive a maintenance 
treatment of 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of 
informed consent, 24 months of treatment, or other reasons for discontinuation of the 
study treatment (whichever occurs first). The specific study visit arrangement is 
shown in Table 4 and Table 6. 
• 
Cohort G: Study on the safety and efficacy evaluation of first-line treatment of 
inoperable locally progressing, recurrent/metastatic high-grade (G3) neuroendocrine 
tumors using IBI308 in combination with chemotherapy, enrolling approximately 15 
subjects. Each treatment cycle contains 3 weeks. The dosing regimen is IBI308 200 
mg IV D1 + etoposide 100 mg/m2 IV D1–3 + cisplatin 75 mg/m2 IV D1. Up to 6 
cycles of triple drug combination therapy are given. Subsequently, the subjects 
experiencing no PD can receive a maintenance treatment of 200 mg IV Q3W of 
IBI308 until PD, intolerable toxicity, withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation of the study treatment (whichever 
occurs first). The specific study visit arrangement is shown in Table 5. 
• 
Cohort H: Study on the safety and efficacy of IBI308 in combination with 
chemotherapy in the treatment of subjects with advanced high-grade (G3) 
neuroendocrine tumors who failed first-line systemic standard treatment, enrolling 
approximately 15 subjects. Each treatment cycle contains 3 weeks. The dosing 
regimen is IBI308 200 mg IV D1 + irinotecan 125 mg/m2 IV D1, D8 + 5-fluorouracil 


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(5-FU) 1000 mg/m2 IV D1–3. Up to 6 cycles of triple drug combination therapy are 
given. Subsequently, the subjects experiencing no PD can receive a maintenance 
treatment of 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of 
informed consent, 24 months of treatment, or other reasons for discontinuation of the 
study treatment (whichever occurs first). The specific study visit arrangement is 
shown in Table 5. 
• 
Cohorts G and H of the phase Ib study are newly added for the protocol 3.0. Study 
sites who don't participate in studies in these two cohorts will be closed after the end 
of clinical studies in cohorts A–F. 
Dose-limiting 
toxicity 
According to the National Cancer Institute "Common Terminology Criteria for Adverse Events" 
(NCI CTCAE) version 4.03, DLT is defined as any of the following IBI308-related adverse 
events (AEs) that occur within the first treatment cycle (Days 1–28) in the phase Ia 
dose-escalation study: 
1. Hematological toxicity: 
• 
Grade 4 hematological toxicity lasting > 7 days. 
• 
Grade 3 thrombocytopenia with bleeding tendency or requiring platelet transfusion. 
• 
Grade 3 neutropenic fever with bacteremia or sepsis. 
2. Non-hematological toxicity: 
• 
Any grade 4 immune related adverse event (irAE); 
• 
Grade 3 pneumonia. 
• 
Grade 2 pneumonia that does not recover to ≤ grade 1 within 14 days after 
intervention. 
• 
Other grade 3 irAEs that do not recover to ≤ grade 2 within 3 days after intervention 
or ≤ grade 1 within 14 days after intervention (except for asymptomatic grade 3 
thyroid, adrenal gland, or pituitary insufficiency, and grade 3 inflammatory responses 
at the tumor site). 
• 
Other grade 3 or 4 non-hematological toxicity [excluding: grade 3 electrolyte 
abnormalities, grade 3 or 4 infusion-related reactions (IRRs), manageable grade 3 
hypertension, grade 3 infusion site extravasation, grade 3 arthralgia/myalgia, grade 3 
asthenia/fatigue, manageable grade 3 vomiting, grade 3 or 4 liver transaminase 
elevation lasting < 7 days]. 
3. Any grade 5 AE. 
Note: Grade 3 or 4 IRR is not a DLT. However, if a grade 3 or 4 IRR occurs, subject needs to 
discontinue treatment and be replaced by a new subject. If ≥ 2 subjects experience a grade 3 or 
4 IRR in any treatment group, then enrollment must be suspended. The sponsor needs to review 
the safety data to determine whether to continue enrolling subjects. 


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Inclusion 
criteria 
1. 
Subjects with advanced solid tumors, including: 
1) 
Phase Ia: Patients with locally advanced, recrrent, or metastatic solid tumors that failed 
standard treatment; 
2) 
Phase Ib: 
Cohort A: 
• 
Patients with locally advanced, recurrent or metastatic melanoma confirmed by 
cytology or histology. 
Cohort B: 
• 
Patients with locally advanced, recurrent or metastatic esophageal squamous cell 
carcinoma confirmed by cytology or histology who failed or became intolerant to 
first-line systemic standard treatment; 
• 
Patients with locally advanced, recurrent or metastatic gastric adenocarcinoma 
(including gastroesophageal junction adenocarcinoma) confirmed by cytology or 
histology who failed or became intolerant to first-line systemic standard 
treatment; 
• 
Patients with locally advanced, recurrent or metastatic hepatocellular cell 
carcinoma (HCC) confirmed by cytology or histology who were not suitable for 
locoregional treatment or failed locoregional treatment and failed or became 
intolerant to first-line systemic standard treatment; 
• 
Patients with other advanced malignant tumors of the digestive system who failed 
or became intolerant to standard therapy; 
• 
Patients with advanced neuroendocrine tumors who failed, became intolerant, or 
refused to receive standard therapy. Metastatic neuroendocrine tumors confirmed 
by histopathology, including well differentiated neuroendocrine tumors and 
poorly differentiated neuroendocrine carcinomas; with imaging-confirmed tumor 
PD within 12 months before the first dose; for poorly differentiated 
neuroendocrine carcinomas, they should experience progression after being 
treated with platinum-based regimens; for well-differentiated neuroendocrine 
tumors, they should have received at least one systemic treatment, including 
somatostatin analogs, mTOR inhibitors, anti-angiogenic drugs, and 
chemotherapy; patients with neuroendocrine tumors or neuroendocrine 
carcinomas who cannot tolerate or refuse to receive the above treatment can also 
be enrolled. 
Cohort C: 
• 
Patients with locally advanced, recurrent or metastatic NSCLC confirmed by 
cytology or histology who failed or became intolerant to first-line systemic 
standard treatment, excluding patients with known epidermal growth factor 
receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) 
rearrangement. 
 


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Cohort D: 
• 
Patients with inoperable locally advanced (stage IIIB), recurrent or metastatic 
(stage IV) nsNSCLC (staged according to the 7th edition of "Staging Manual in 
Thoracic Oncology" published by the International Association for the Study of 
Lung Cancer) confirmed by histology or cytology who didn't received first-line 
treatment, excluding patients with EGFR mutations and ALK rearrangement. 
• 
For patients with stage IIIB nsNSCLC who previously received platinum-based 
adjuvant or neoadjuvant chemotherapy or radical chemoradiotherapy, if local 
recurrence or distant metastasis occurred within 6 months after the treatment was 
completed, the previous platinum-based treatment will be considered to be a 
first-line treatment and hence the patients cannot be enrolled into the cohort. 
Cohort E: 
• 
Previously untreated patients with inoperable locally advanced (stage IIIB), 
recurrent or metastatic (stage IV) scNSCLC (staged according to the 7th edition 
of "TNM Staging of Thoracic Tumor" published by the International Association 
for the Study of Lung Cancer) who previously not received first-line treatment, 
excluding patients with EGFR mutations and ALK rearrangement. 
• 
For patients with stage IIIB scNSCLC who previously received platinum-based 
adjuvant or neoadjuvant chemotherapy or radical chemoradiotherapy, if local 
recurrence or distant metastasis occurred within 6 months after the treatment was 
completed, the previous platinum-based treatment will be considered to be a 
first-line treatment and hence the patients cannot be enrolled into the cohort. 
Cohort F: 
• 
Patients with inoperable locally advanced, recurrent or metastatic gastric or 
gastroesophageal junction adenocarcinoma confirmed by histopathology; 
• 
Excluding patients with known HER2 gene amplification or overexpression. 
• 
Not previously treated by chemotherapy for advanced diseases, or with 
progression occurring more than 6 months after the end of systemic adjuvant 
therapy. 
Cohort G: 
• 
Previously untreated patients with inoperable locally progressive, recurrent or 
metastatic high-grade (G3) neuroendocrine tumors confirmed by histology or 
cytology. 
• 
Patients must have high-grade (G3) neuroendocrine tumors with a Ki-67 index 
of > 20%. 
• 
Not previously treated by chemotherapy for advanced diseases, or with 
progression occurring more than 6 months after the end of systemic adjuvant 
therapy. 
 
 


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Cohort H: 
• 
Patients with advanced high-grade (G3) neuroendocrine tumors confirmed by 
histology or cytology who failed or became intolerant to first-line systemic 
standard treatment. 
• 
Patients must have high-grade (G3) neuroendocrine tumors with a Ki-67 index 
of > 20%. 
• 
For patients who received adjuvant or neoadjuvant chemotherapy for 
neuroendocrine tumors, if local recurrence or distant metastasis occurred within 6 
months after this treatment was completed, this treatment will be considered to be 
a first-line treatment and hence the patients can be enrolled into the cohort. 
2. 
Patients who have signed ICF, and are able to complete follow-up visits and relevant 
procedures required in the protocol. 
3. 
Ages ≥ 18 and ≤ 70 years. 
4. 
Estimated survival ≥ 12 weeks. 
5. 
Patients with at least one measurable or evaluable lesion according to "Response 
Evaluation Criteria in Solid Tumors" version 1.1 (RECIST V1.1). 
6. 
An Eastern Cooperative Oncology Group Performance Status (hereinafter referred to as 
the ECOG PS score) score of 0 or 1. 
7. 
Patients (female patients of childbearing age or male patients whose partners are of 
childbearing age) must take effective contraceptive measures during the entire course of 
the trial and 6 months after the treatment (see Table 24 in Section 5.7.2). 
8. 
Sufficient organ and bone marrow functions, as defined below: 
1) 
Routine blood test: absolute neutrophil count (ANC) ≥ 1.5 × 109/L; platelets (PLTs) ≥ 
100 × 109/L; hemoglobin (HGB) ≥ 9.0 g/dL. 
2) 
Hepatic function: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); TBIL ≤ 3 × 
ULN for patients with HCC, liver metastasis, or a history/suspected history of Gilbert 
syndrome (persistent or recurrent hyperbilirubinemia, mainly manifested as high 
unconjugated bilirubin, with no evidence of hemolysis or liver disease); alanine 
aminotransferase (ALT) and aspartate transferase (AST) ≤ 2.5 × ULN for patients without 
HCC and liver metastases; ALT or AST ≤ 5 × ULN for patients with HCC or liver 
metastases. 
3) 
Renal function: Serum creatinine (SCr) ≤ 1.5 × ULN or clearance of creatinine (CCr) ≥ 50 
mL/min; urinalysis results showing urine protein < 2+; for patients whose baseline 
urinalysis results showing urine protein ≥ 2+, they should undergo 24-h urine collection 
and the protein content in the collected urine should be < 1 g. 
4) 
Coagulation function: activated partial thromboplastin time (APTT) and international 
normalized ratio (INR) ≤ 1.5 × ULN. 
5) 
Thyroid stimulating hormone (TSH) or free thyroxine (FT4) are within the normal range. 


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Exclusion 
criteria 
1. 
Previous exposure to any anti-PD-1 or anti-PD-L1 antibody. 
2. 
Experienced any ≥ grade 3 irAE (based on NCI CTCAE V4.03) while receiving any 
immunotherapy drugs in the past. Patients who were treated with ipilimumab are not 
enrolled unless all of the following criteria are met: 
• The ipilimumab-related irAE has completely recovered, and the treatment of irAE 
have ended 4 weeks before the first dose of IBI308; 
• There was at least a 12-week interval between the first dose of ipilimumab and the first 
dose of IBI308 and a 6-week interval between the last dose of ipilimumab and the first 
dose of IBI308; 
• The use of ipilimumab did not result in grade 4 irAEs or grade 3 irAEs requiring > 4 
weeks of treatment; 
• A clear PD was observed after the last dose of ipilimumab. 
3. 
Enrolled in another interventional clinical study, unless only involved in an observational 
study (non-interventional) or in the follow-up phase of an interventional study. 
4. 
Received any investigational drug within 4 weeks prior to the first dose of IBI308. 
5. 
Received the last dose of anti-tumor therapy (chemotherapy, endocrine therapy, targeted 
therapy, immunotherapy, tumor embolization) within 3 weeks before the first dose of 
IBI308; received the last dose of biologics, nitrosourea or mitomycin C within 6 weeks 
before the first dose of IBI308 (if the biological product received was for antitumor 
endocrine therapy, refer to the requirement of "received the last dose within 3 weeks 
before the first dose of IBI308"). 
6. 
Received immunosuppressants within 4 weeks before the first dose of IBI308, excluding 
locoregional glucocorticoids administered by nasal, inhaled, or other routes, or systemic 
glucocorticoids of physiological doses (no more than 10 mg/day of prednisone or 
equivalents). Glucocorticoid administration for pretreatment or special examinations is 
allowed. 
7. 
Received a live attenuated vaccine within 4 weeks prior to the first dose of IBI308, or plan 
to receive this vaccine during the study period. 
8. 
Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to 
the first dose of IBI308, or has unhealed wounds, ulcers, or fractures. 
9. 
Antitumor therapy-induced toxicity (excluding alopecia) that has not yet resolved to NCI 
CTCAE V4.03 grade 0 or 1 prior to the first dose of IBI308. 
10. Previously received whole pelvic radiotherapy. 
11. Patients with known leptomeningeal metastasis; patients with other known CNS 
metastases that have not been effectively controlled by treatment or remain untreated. 
Excluding patients who were treated, are now stable, and stopped glucocorticoids and 
anticonvulsants ≥ 4 weeks prior to receiving the first dose of IBI308. 
 
 


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12. Known active autoimmune disease (see Appendix 5) or a history of such disease within the 
past 2 years (patients with vitiligo, psoriasis, alopecia, or Graves' disease not requiring 
systemic treatment within the next 2 years, or those with hypothyroidism only requiring 
thyroid hormone replacement therapy, and type I diabetes only requiring insulin 
replacement therapy within the past 2 years may be enrolled). For patients with positive 
autoimmune antibodies only, they should be evaluated by the investigator to determine 
whether they have an autoimmune disease. 
13. Known history of primary immunodeficiency diseases. 
14. Known history of pulmonary tuberculosis. 
15. Known history of allotransplantation or allogeneic hematopoietic stem cell transplantation. 
16. Known allergy to any ingredients in IBI308; previously severe allergic reactions to other 
monoclonal antibodies; for Cohort D of the Phase Ib study, patients who were previously 
allergic to pemetrexed or cisplatin, or patients who were unable or unwilling to receive 
folic acid and/or vitamin B12 treatment; for Cohort E of the Phase Ib study, patients who 
were previously allergic to cisplatin or gemcitabine; for Cohort F of the Phase Ib study, 
patients who were previously allergic to capecitabine or oxaliplatin; for Cohort G of the 
Phase Ib study, patients who were previously allergic to etoposide or cisplatin; for Cohort 
H of the Phase Ib study, patients who were previously allergic to irinotecan or 5-FU. 
17. Uncontrolled concurrent diseases including but not limited to: 
• 
Those infected with HIV (positive for HIV1/2 antibody). 
• 
Active or poorly clinically controlled serious infections. 
• 
Symptomatic congestive cardiac failure (New York Heart Association (NYHA) 
Class II–IV) or symptomatic or poorly controlled arrhythmia. 
• 
Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic 
blood pressure ≥ 100 mmHg) despite of standard treatment. 
• 
Any arterial thromboembolic events occurred within 6 months prior to enrollment, 
including myocardial infarction, unstable angina, cerebrovascular accident, or 
transient cerebral ischemic attack. 
• 
Patients with esophageal or gastric varices requiring immediate intervention (such 
as variceal ligation or sclerotherapy) or those considered to have a high bleeding 
risk by the investigator, gastroenterologist, or hepatologist. Patients with signs of 
portal hypertension (including splenomegaly confirmed by medical imaging) or a 
history of variceal bleeding are required to undergo endoscopy within 3 months 
prior to enrollment. 
• 
Life-threatening hemorrhagic events or grade 3 or 4 gastrointestinal/variceal 
hemorrhage requiring blood transfusion, endoscopy, or surgical treatment within 3 
months prior to enrollment. 
• 
History of deep venous thrombosis, pulmonary embolism, or other serious 
thromboembolic events within 3 months prior to enrollment (implantable port or 
catheter-related thrombosis, or superficial venous thrombosis are not considered 


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as "serious" thromboembolisms). 
• 
Uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or 
cancer-related secondary diseases that may lead to high medical risks and/or 
uncertainty in survival evaluation. 
• 
Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh 
Class B or C (See Appendix 7 for Child-Pugh grading). 
• 
Bowel obstruction or history of the following diseases: inflammatory bowel 
disease or extensive bowel resection (partial colectomy or extensive small bowel 
resection accompanied with chronic diarrhea), Crohn's disease, ulcerative colitis, 
or chronic diarrhea. 
• 
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. 
18. Patients with acute or chronic active hepatitis B or hepatitis C infection (for patients 
treated with IBI308 monotherapy, they will be enrolled if their HBsAg is positive but their 
HBV DNA copy number is 1 × 104/mL; for patients treated with IBI308 in combination 
with chemotherapy, they will be enrolled only if their HBsAg is positive and their HBV 
DNA copy number is below the LLD. For the prevention and treatment requirements, refer 
to the 2015 edition of "Prevention and Treatment Guide for Chronic Hepatitis"; patients 
with inactive Hepatitis C are allowed for enrollment). 
19. History of GI perforation and/or fistula within 6 months prior to the enrollment. 
20. Interstitial lung diseases (including previous and current history, refer to Appendix 6). 
21. Clinically uncontrollable third space effusion, such as pleural effusion and ascites that 
cannot be controlled by drainage or other methods prior to enrollment. 
22. History of other primary malignant tumors, excluding: 
• 
History of radical treatment for malignant tumors with no evidence of tumor 
recurrence for more than 5 years prior to enrollment and with a very low risk of 
recurrence; 
• 
Adequately treated nonmelanoma skin cancer or lentigo maligna with no signs of 
disease recurrence; 
• 
Adequately treated carcinoma in situ with no signs of disease recurrence. 
23. Pregnant or breastfeeding female patients. 
Study drug, 
strengths, and 
administration 
1. 
IBI308: 10 mL:100 mg, IV infusion. 
2. 
Pemetrexed: 100 mg/vial or 500 mg/vial, IV infusion. 
3. 
Cisplatin: 10 mg/vial, 20 mg/vial, or 30 mg/vial, IV infusion. 
4. 
Gemcitabine: 200 mg/vial or 1 g/vial, IV infusion. 
5. 
Capecitabine: 500 mg/tablet, oral administration. 


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6. 
Oxaliplatin: 50 mg/vial or 100 mg/vial, IV infusion. 
7. 
Etoposide: 50 mg/vial or 100 mg/vial, IV infusion. 
8. 
Irinotecan: 40 mg/vial, 100 mg/vial, or 300 mg/vial, IV infusion. 
9. 
5-FU: 10 mL: 250 mg, IV infusion. 
Evaluation 
criteria 
Safety evaluation: 
• 
Incidence, relationship with investigational drug, and severity level of all adverse 
events (AEs), treatment emergent adverse events (TEAEs), adverse events of special 
interest (AESIs), and serious adverse events (SAEs) will be evaluated. 
• 
Changes in vital signs, physical examination, and laboratory tests results before, 
during, and after the study treatment will be evaluated. 
• 
Immunogenicity assessment: Anti-drug antibody (ADA) assay will be conducted for 
subjects, and ADA-positive samples will be further tested to determine whether the 
ADA is a neutralizing antibody (NAb). 
Efficacy evaluation: 
• 
Efficacy evaluation is based on RECIST V1.1. Objective response rate (ORR), time 
to response (TTR), duration of response (DOR), progression free survival (PFS), 
6-month and 1-year PFS rates, disease control rate (DCR), overall survival (OS), and 
6-month and 1-year survival rates after drug administration are evaluated. 
• 
The irRECIST-based evaluation of irORR, irDCR, irPFS, and irDOR is explored. 
PK/PD evaluation: 
• 
The PK characteristics of single or multiple doses of IBI308 in the human body are 
described, and the main PK parameters, including but not limited to area under curve 
(AUC), Cmax, CL, V, and t1/2, are determined. 
• 
Blood samples are collected to analyze PD parameters, including but not limited to 
PD-1 receptor saturation. 
• 
PK/PD evaluation is required only for Cohorts A–F of phase Ia and Ib studies. 
Biomarker evaluation: 
• 
Tumor tissue samples are collected for tumor biomarker analysis, including but not 
limited to the expression of PD-L1 in tumor specimens, whole exome sequencing to 
detect tumor mutation burden (TMB) in tumor tissues, multicolor 
immunohistochemistry, and PD-L1 and CD8 double staining assay. 
• 
Biomarkers are evaluated only in Cohorts A–F of phase Ia and Ib studies and not 
evaluated in Cohorts G and H of the phase Ib study. 


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Statistical 
methods 
Sample size: 
Phase Ia: Four dose levels are assessed. The dose escalation strategy is established using the 
standard "3 + 3" design. Around 12–24 patients with advanced solid tumors that failed standard 
treatment need to be enrolled. 
Phase Ib: It is planned to enroll 10–20 subjects in Cohort A, 50–100 ones in Cohort B, 10–20 
ones in Cohort C, 20 ones in each of Cohorts D, E, and F, and 15 ones in each of Cohorts G 
and H. 
Statistical analysis methods: 
The analysis method is descriptive statistics. In principle, no between-group comparison will be 
carried out. Continuous variables will be described using number of cases, mean, standard 
deviation(SD), median, minimum, and maximum. Categorical variables will use frequencies 
and percentages. 
The safety parameters (AE, laboratory tests, vital signs), PK/PD parameters, immunogenicity, 
and anti-tumor activity of IBI308 monotherapy or combination therapy in subjects of advanced 
solid tumors are summarized by tumor stages, cohorts, and types of tumor. 
The ORR, DCR and their 95% confidence intervals (CIs) are calculated under different dosing 
regimens. The median progression free survival (mPFS), median overall survival (mOS), and 
6-month and 1-year PFS rates and survival rates are estimated using Kaplan-Meier. For subjects 
achieving objective response, DOR, TTR, and maintained response rate at the data cut-off date 
of analysis are calculated. 
Exploratory analyses: 
A subgroup analysis of anti-tumor activity (ORR) is carried out based on factors that are 
clinically considered to affect prognosis, such as gender, age, and ECOG PS score. 
The level of PD-L1 expression and its relationship with anti-tumor activity (ORR, DOR). 
The relationship between AUC and anti-tumor activity (ORR, DOR). 


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Table 1. Schedule of study visits in the phase Ia study 
Stage 
Screening 
period 
Treatment period 
End-of-treatment 
visit/safety 
follow-up18 
Survival follow-up19 
Cycle 1 (28 days) 
Cycle 2 and 
beyond 
Visit 
1 
2 
3 
4 
5 
6 
7 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
22 
Day 1 (± 2 days) 
End of treatment 
(EOT), 90 days  
(± 7 days) after EOT 
Every 90 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 
 
Weight/height4 
X 
X 
 
 
 
 
 
X 
 
 
Physical examination 
X 
 
 
 
 
X 
 
X 
X 
 
ECOG PS score 
X 
X 
 
 
 
 
 
X 
X 
 
12-Lead ECG5 
X 
X 
 
 
 
 
 
X 
X 
 
Routine blood test/blood 
chemistry/urinalysis6 
X 
 
 
 
 
X 
 
X 
X 
 
Coagulation function7 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
Thyroid function9 
X 
 
 
 
 
 
 
X 
X 
 
Autoantibody10 
X 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADA, 
NAb)11 
 
X 
 
 
 
 
 
X 
X 
 
HIV, HBV, and HCV12 
X 
 
 
 
 
 
 
 
 
 
PK13 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Stage 
Screening 
period 
Treatment period 
End-of-treatment 
visit/safety 
follow-up18 
Survival follow-up19 
Cycle 1 (28 days) 
Cycle 2 and 
beyond 
Visit 
1 
2 
3 
4 
5 
6 
7 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
22 
Day 1 (± 2 days) 
End of treatment 
(EOT), 90 days  
(± 7 days) after EOT 
Every 90 days  
(± 7 days) 
PD13 
 
X 
X 
 
X 
 
 
X 
X 
 
AE evaluation14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival condition 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-tumor therapy 
 
 
 
 
 
 
 
 
X 
X 
Efficacy evaluation 
 
 
 
 
 
 
 
 
 
 
Tumor imaging evaluation15 
X 
 
 
 
 
 
 
X 
X 
 
Study drug infusion 
 
 
 
 
 
 
 
 
 
 
IBI30816 
 
X 
 
 
 
 
 
X 
 
 
Biomarker study 
 
 
 
 
 
 
 
 
 
 
Archived or fresh tumor tissue 
sample17 
X 
 
 
 
 
 
 
 
 
 
Note: 
1. Informed consent form (ICF) should be signed by subjects prior to any procedures outlined in the protocol. 
2. Previous medications include treatment for the initial diagnosis, chemotherapy, radiotherapy, and surgery. The time of the last anti-tumor treatment must be 
recorded. 
3. Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. Refer to 6.4.4.1 for specific requirements for pulse and blood pressure 
monitoring. 
4. Height is measured during screening period only. Weight must be measured before every planned dose during the study. If the weight fluctuation is less than 
10% compared to baseline (date of 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. 


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5. Time of 12-lead ECG examinations: during the screening period, within 60 min after the end of IBI308 infusion in each cycle, and during safety follow-ups. 
6. Routine blood test involves red blood cell (RBC), HGB, hematocrit value (HCT), white blood cell (WBC), platelet (PLT), WBC differential count 
[lymphocyte count (LYM), ANC, monocyte count (MONO), eosinophil count (EOS), and basophil cell count (BASO)]. Blood chemistry includes hepatic 
function [TBIL, ALT, AST, γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactate dehydrogenase (LDH)], 
renal function [(blood urea and Cr)], electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Routine urinalysis includes pH, 
urinary WBC (UWBC), urine protein (UPRO), urine red blood cell (URBC), and urine glucose (UGLU). Subjects who showed urine protein of ≥ 2+ during 
the urinalysis in the screening period should undergo a 24-h urine protein quantitation test. The routine blood test, blood chemistry, and urinalysis are 
performed during screening, within 7 days prior to each dose of IBI308, on day 15 of Cycle 1, and during safety follow-up. Tests will be conducted at each 
study site. 
7. Coagulation function test includes thrombin time (TT), PT, APTT, and INR. The test will be conducted within 7 days prior to the first dose and during the 
safety follow-up. Tests will be conducted at each study site. 
8. Women of childbearing age should undergo a urine or blood pregnancy test within 3 days before the first dose. 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. 
9. Thyroid function test includes triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), FT4, and TSH. The test is conducted during screening, 
within 7 days prior to each dose of IBI308 after Cycle 1, and during safety follow-up. Tests will be conducted at each study site. 
10. Autoantibodies include: anti-nuclear antibodies (ANA), anti-dsDNA antibodies, and anti-thyroglobulin antibodies. The test is conducted during screening, 
and afterwards retest will be done only if deemed necessary by the investigator. Tests will be conducted at each study site. 
11. Immunogenicity assays will be performed within 1 h prior to IBI308 infusion in Cycles 1, 2 and then every 2 cycles thereafter (Cycles 4, 6, 8, and so on), 
and during safety follow-up visits. If an infusion-related reaction occurs during IBI308 infusion, blood samples should be taken near the start and end of this 
event and around 30 days after the reaction and used for comparative analysis of immunogenicity. Tests will be conducted in the central laboratory. 
12. Including tests for HCV and HIV antibodies, as well as HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb. HBV-DNA should be further tested for subjects 
positive for HBsAg and/or HBcAb. The test is conducted during screening, and afterwards retest will be done only if deemed necessary by the investigator. 
Tests will be conducted at each study site. 
13. Refer to PK/PD sampling schedule (Table 2). Tests will be conducted in the central laboratory. 
14. AEs and laboratory safety assessments will be performed based on NCI CTCAE V4.03. Refer to Section 7 for definitions, recording, causality determination, 
severity level, reporting deadlines, and treatment of AEs and SAEs. 
15. Tumor evaluations are based on RECIST V1.1 and irRECIST. There is no central imaging evaluation in this study. Tumor imaging examinations usually 
include contrast-enhanced CT or MRI of the chest, abdomen, and pelvic cavity. The same subject should receive the same type of imaging examination 
during the study. Baseline evaluation will be conducted within 28 days prior to enrollment. The investigators can evaluate imaging results within 28 days 
prior to enrollment. Tumor imaging evaluation should be carried out every 9 weeks (± 7 days) after first dose of the study drug. For subjects with initial 


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response (complete response (CR) or partial response (PR)), tumor imaging examination should be performed 4 weeks (± 7 days) later for confirmation. 
Subsequently, this evaluation should be performed every 12 weeks (± 7 days) until PD is suggested in the image. For subjects who are recorded as imaging 
PD for the first time, an imaging evaluation should be carried out 4 weeks (± 7 days) later for confirmation. If these subjects continue to receive the study 
drug after this confirmation, imaging evaluation will be carried out once every 9 weeks (± 7 days) until the second PD, which is defined as an increase of 
more than 10% in the sum of the longest diameter (mm) of target lesions compared with the first imaging PD or the occurrence of new measurable lesions. 
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 and 
every 9 weeks (± 7 days) after treatment discontinuation until start of a new anti-tumor therapy, PD, ICF withdrawal by subjects, or death. 
16. The Cycle 1 for every dose group is the period of DLT observation (28 days) and the drug is only administered on day 1. Since the Cycle 2, IBI308 is 
intravenously infused once every 2 weeks in the 1 mg/kg, 3 mg/kg, and 10 mg/kg groups and once every 3 weeks in the 200 mg group. Some subjects who 
meet particular requirements are allowed to continue receiving treatment after PD ("Section 5.1.2 Continued treatment after progressive disease" of the study 
protocol). 
17. Subjects are required to provide archived or fresh tumor tissue samples meeting test requirements during screening. 
18. Treatment follow-up is performed after the end of treatment. Safety follow-up is performed 90 ± 7 days after the last dose. The study drug-related AEs need 
to be followed up until resolved to grade 0 or 1, stable, or withdrawal of ICF (whichever occurs first). Refer to 6.2.3 for details. 
19. Survival follow-up: once every 90 days (± 7 days) after the end of treatment. Telephone follow-up is allowed. 
 
 


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Table 2. PK/PD sampling schedule in the phase Ia study 
Stage 
Screening 
period 
Treatment period 
Safety 
follow-up5 
Cycle 1 (28-day period of DLT observation)2 
Cycle 2 and thereafter3,4 
Day 
−28 to −1 
1 
2 
3 
8 
15 
22 
Day 1 (± 2 days) 
90 days  
(± 7 days) 
Sampling time1 
 
−1 h 
During 
infusion 
Immediately 
at the end of 
infusion 
1 h after 
the end of 
infusion 
6 h after the 
start of 
infusion 
24h 
48h 
168h 
336h 
504h 
-1h 
During 
infusion 
Immediately 
at the end of 
infusion 
 
Time window 
of blood 
sampling 
 
 
 
+5min 
±5min 
±15min 
±1h 
±2h 
±8h 
±12h 
±24h 
 
 
+5min 
 
IBI308 
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 3 
X 3 
X 5 
PD 
X 
X 
X 
X 4 
X 5 
Note: 
1. Samples should be collected from the opposite arm of the infusion site. 
2. If the dosing on Day 1 of Cycle 2 is delayed due to an AE or other reasons, additional sampling is required at 672 ± 24 h (Day 29) in Cycle 1. 
3. From Cycle 2, PK blood sampling is performed every 2 cycles (Cycles 2, 4, 6, and so on). Except for cycle 4, the blood sampling time points are within 1 h 
before the start of the infusion and immediately after the end of the infusion (+ 5 min). In Cycle 4 (dense sampling), for the 200 mg cohort, blood is sampled 
within 1 h before the start of infusion, at 0 h (+ 5 min) and 1 h ± 5 min after the end of infusion, and at 6 h ± 15 min, 24 ± 1 h, 48 ± 2 h, 168 ± 8 h (Day 8), 
336 ± 12 h (Day 15), and 504 ± 24 h (Day 22) after the start of infusion; and for 1 mg/kg, 3 mg/kg, and 10 mg/kg cohorts, blood is sampled within 1 h before 
the start of infusion, at 0 h (+ 5 min) and 1 h ± 5 min after the end of infusion, and at 6 h ± 15 min, 24 ± 1 h, 48 ± 2 h, 168 ± 8 h (Day 8), and 336 ± 12 h 
(Day 15) after the start of infusion. 
4. From Cycle 2, PD samples are collected every 4 cycles (Cycles 6, 10, 14, and so on). 
5. Both PK and PD sampling are required during safety follow-ups, but not required during survival follow-ups. 
 
 


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Table 3. Visit schedule for Cohorts A/B/C in the Phase Ib study 
Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-treatment 
visit18 
Safety 
follow-up19 
Survival 
follow-up20 
Cycle 1 
Cycle 2 and 
beyond 
Visit 
1 
2 
3 
4 
5 
6 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
Day 1 (± 2 
days) 
Within 7 days 
after the end of 
treatment is 
confirmed 
90 days (± 7 
days) after 
the end of 
treatment 
Every 90 
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 
 
Weight/height4 
X 
X 
 
 
 
 
X 
X 
X 
 
Physical examination 
X 
 
 
 
 
 
X 
X 
X 
 
ECOG PS score 
X 
X 
 
 
 
 
X 
X 
X 
 
12-Lead ECG5 
X 
X 
 
 
 
 
X 
X 
X 
 
Routine blood test/blood 
chemistry/urinalysis6 
X 
 
 
 
 
 
X 
X 
X 
 
Coagulation function7 
X 
 
 
 
 
 
 
X 
X 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
Thyroid function9 
X 
 
 
 
 
 
X 
X 
X 
 
Autoantibody10 
X 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADA, NAb)11 
 
X 
 
 
 
 
X 
 
X 
 
HIV, HBV, and HCV12 
X 
 
 
 
 
 
 
 
 
 
PK13 
 
X 
X 
X 
X 
X 
X 
 
X 
 


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Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-treatment 
visit18 
Safety 
follow-up19 
Survival 
follow-up20 
Cycle 1 
Cycle 2 and 
beyond 
Visit 
1 
2 
3 
4 
5 
6 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
Day 1 (± 2 
days) 
Within 7 days 
after the end of 
treatment is 
confirmed 
90 days (± 7 
days) after 
the end of 
treatment 
Every 90 
days (± 7 
days) 
PD13 
 
X 
X 
 
X 
 
X 
 
X 
 
AE evaluation14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival condition 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-tumor therapy 
 
 
 
 
 
 
 
 
X 
X 
Efficacy evaluation 
 
 
 
 
 
 
 
 
 
 
Tumor imaging evaluation15 
X 
 
 
 
 
 
X 
X 
X 
 
Study drug infusion 
 
 
 
 
 
 
 
 
 
 
IBI30816 
 
X 
 
 
 
 
X 
 
 
 
Biomarker study 
 
 
 
 
 
 
 
 
 
 
Archived or fresh tumor tissue 
sample17 
X 
 
 
 
 
 
 
 
 
 
Note: 
1. The ICF should be signed by subjects prior to any procedures outlined in the protocol. 
2. Previous medications include: treatment for the initial diagnosis, including chemotherapy, radiotherapy, and surgery. The time of the last anti-tumor 
treatment must be recorded. 
3. Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. Weight must be measured before every planned dose during the study. 
4. Height is measured during screening period only. Weight must be measured before every planned dose during the study. 
5. Time of 12-lead ECG examinations: during the screening period, within 60 min after the end of IBI308 infusion in each cycle, and during safety follow-ups. 
6. Routine blood test include: RBC, HGB, HCT, WBC, PLT, and white blood cell differential (LYM, ANC, MONO, EOS, BASO). Blood chemistry include: 
hepatic function (TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH), renal function (Urea, Cr), blood electrolytes (Na, K, Cl, Mg, Ca, P), amylase, and FBG. 


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Urinalysis include: PH, UWBC, UPRO, URBC, and UGLU. Subjects who showed urine protein of ≥ 2+ during the urinalysis in the screening period should 
undergo a 24-h urine protein quantitation test. Routine blood test, blood chemistry test, and urinalysis are carried out during the screening period, within 7 
days before each administration of IBI308, during the end-of-treatment visit, and during the safety follow-ups. Tests will be conducted at each study site. 
7. Coagulation function tests include: TT, PT, APTT, and INR. They are tested within 7 days before the first dose of IBI308, during the end-of-treatment visit, 
and during the safety follow-ups. Tests will be conducted at each study site. 
8. Women of childbearing age should undergo a urine or blood pregnancy test within 3 days before the first dose. 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. 
9. Carried out during the screening period, within 3 days before each administration of IBI308 since Cycle 2, during the end-of-treatment visit, and during the 
safety follow-ups. T3, T4, FT3, FT4, and TSH are examined during the screening period. Starting from Cycle 2, only TSH is examined. If there are 
abnormalities, the examination of other thyroid function parameters will be considered. Tests will be conducted at each study site. 
10. Autoantibodies include: anti-nuclear antibodies, anti-dsDNA antibodies, and anti-thyroglobulin antibodies. The test is conducted during screening, and 
afterwards retest will be done only if deemed necessary by the investigator. Tests will be conducted at each study site. 
11. Immunogenicity examinations are carried out within 1 h before the infusion of IBI308 in Cycle 1, Cycle 2, and every 2 cycles thereafter (Cycles 4, 6, 8, and 
so on), and during safety follow-ups. If an infusion-related reaction occurs during IBI308 infusion, blood samples should be taken near the start and end of 
this event and around 30 days after the reaction and used for comparative analysis of immunogenicity. Tests will be conducted in the central laboratory. 
12. Including tests for HCV and HIV antibodies, as well as HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb. HBV-DNA should be further tested for subjects 
positive for HBsAg and/or HBcAb. The tests will be carried out at each study site during the screening period, and afterwards retest will be done only if 
deemed necessary by the investigator based on the clinical indications. 
13. See the PK/PD sampling schedule (Table 6) for the time of PK and PD assays. For Cohort B, after the PK/PD blood samples of 20 subjects who meet the 
requirements of assay and analysis are collected, subsequent subjects are not required to undergo PK/PD assays. Tests will be conducted in the central 
laboratory. 
14. AEs and laboratory safety assessments will be performed based on NCI CTCAE V4.03. Refer to Section 7 for definitions, recording, causality 
determination, severity level, reporting deadlines, and treatment of AEs and SAEs. 
15. Tumor evaluations are based on RECIST V1.1 and irRECIST. There is no central imaging evaluation in this study. Tumor imaging examinations usually 
include contrast-enhanced CT or MRI of the chest, abdomen, and pelvic cavity. The same subject should receive the same type of imaging examination 
during the study. Baseline evaluation will be conducted within 28 days prior to enrollment. The investigators can evaluate imaging results within 28 days 
prior to enrollment. Tumor imaging evaluation should be carried out every 9 weeks (± 7 days) after first dose of the study drug. For subjects with initial 
response (CR or PR), an imaging evaluation is carried out 4 weeks (± 7 days) later to confirm the response, and the imaging evaluation is carried out every 9 
weeks (± 7 days) thereafter until imaging PD is recorded. For subjects who are first recorded as imaging PD that is confirmed related to immunity by the 
imaging evaluation carried out 4 weeks later, if they continue to receive the study drug, imaging evaluations should be carried out every 9 weeks (± 7 days) 
until the recurrence of PD. The recurrence of PD is defined as the increase in the sum of the longest diameter of the tumor target lesions by > 10% on the 


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basis of the first imaging PD or the occurrence of a new measurable lesion. For subjects with first imaging PD but an unstable clinical situation or rapid 
progression who are deemed as not suitable for continued drug treatment, it is not necessary for them to undergo further imaging examinations to confirm 
PD. 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 
and every 9 weeks (± 7 days) after treatment discontinuation until start of a new anti-tumor therapy, PD, ICF withdrawal by subjects, or death. 
16. IBI308 200 mg, intravenous infusion, once every 3 weeks. Some subjects who meet particular requirements are allowed to continue receiving treatment after 
PD ("Section 5.1.2 Continued treatment after progressive disease" of the study protocol). The treatment by IBI308 lasts for up to 24 months. 
17. Subjects are required to provide archived or fresh tumor tissue samples meeting test requirements during screening. 
18. The end-of-treatment visit is carried out within 7 days after the end of treatment is confirmed, as detailed in 6.2.3 of the protocol. 
19. A safety follow-up should be carried out within 90 ± 7 days after the last dose or before the start of a new anti-tumor treatment (whichever occurs first). The 
study drug-related AEs need to be followed up until resolved to grade 0 or 1, stable, or withdrawal of ICF (whichever occurs first). Refer to 6.2.3 for details. 
20. Survival follow-up: once every 90 days (± 7 days) after the drug treatment is stopped. Telephone follow-up is allowed. 
 
 


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Table 4. Visit schedule for Cohorts D/E/F in the Phase Ib study 
Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-trea
tment 
visit21 
Safety 
follow-up22 
Survival 
follow-up2
3 
Combination therapy 
Combination or 
maintenance 
treatment 
Cycle 1 
Cycle 2 Cycle 3 Cycle 4 Cycle 5/720 and 
thereafter 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
Day 1 (± 2 days) 
Within 7 
days after 
the end of 
treatment is 
confirmed 
90 days (± 7 
days) after 
the end of 
treatment 
Every 90 
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 
X 
 
Weight/height4 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
ECOG PS score 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG5 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Routine blood test/blood 
chemistry/urinalysis6 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Coagulation function7 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function9 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 


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Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-trea
tment 
visit21 
Safety 
follow-up22 
Survival 
follow-up2
3 
Combination therapy 
Combination or 
maintenance 
treatment 
Cycle 1 
Cycle 2 Cycle 3 Cycle 4 Cycle 5/720 and 
thereafter 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
Day 1 (± 2 days) 
Within 7 
days after 
the end of 
treatment is 
confirmed 
90 days (± 7 
days) after 
the end of 
treatment 
Every 90 
days (± 7 
days) 
Autoantibody10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADA, 
NAb)11 
 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
 
HIV, HBV, and HCV12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PD13 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
AE evaluation14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival condition 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-tumor 
therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Efficacy evaluation 
Tumor imaging 
evaluation15 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Study drug administration in Cohort D16 
IBI308 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Pemetrexed 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 


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Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-trea
tment 
visit21 
Safety 
follow-up22 
Survival 
follow-up2
3 
Combination therapy 
Combination or 
maintenance 
treatment 
Cycle 1 
Cycle 2 Cycle 3 Cycle 4 Cycle 5/720 and 
thereafter 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
N 
Day 
−28 to −1 
1 
2 
3 
8 
15 
Day 1 (± 2 days) 
Within 7 
days after 
the end of 
treatment is 
confirmed 
90 days (± 7 
days) after 
the end of 
treatment 
Every 90 
days (± 7 
days) 
Cisplatin 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
Study drug administration in Cohort E17 
IBI308 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Gemcitabine 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
Cisplatin 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
Study drug administration in Cohort F18 
IBI308 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Capecitabine 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Oxaliplatin 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
Biomarker study 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived or fresh tumor 
tissue sample19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Note: 
1. The ICF should be signed by subjects prior to any procedures outlined in the protocol. 
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. 


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4. Height is measured during screening period only. Weight must be measured before every planned dose during the study. If the weight fluctuation of a subject 
is less than 10% compared to the baseline (the day when the first dose of IBI308 is given), 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. Time of 12-lead ECG examinations: during the screening period, within 60 min after the end of IBI308 infusion in each cycle, and during the 
end-of-treatment visit and safety follow-ups. 
6. Routine blood test include: RBC, HGB, HCT, WBC, PLT, and white blood cell differential [LYM, ANC, MONO, EOS, BASO]. Blood chemistry include: 
hepatic function [TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH], renal function [BUN, Cr], blood electrolytes (Na, K, Cl, Mg, Ca, P), lipase, amylase, and 
FBG. Urinalysis include: PH, UALB, UPRO, URBC, and UGLU. Any subject with urine protein ≥ 2+ from urinalysis dipstick in routine urinalysis at 
screening needs to undergo a 24-h urine protein test. The tests will be conducted during screening, within 7 days before the first dose of the study drug, 
within 3 days before each administration of the study drug starting from Cycle 2, during the end-of-treatment visit, and during the safety follow-ups. Tests 
will be conducted at each study site. 
7. Coagulation function tests include: TT, PT, APTT, and INR. They are tested within 3 days before the first dose of IBI308, during the end-of-treatment visit, 
and during the safety follow-ups. Tests will be conducted at each study site. 
8. Women of childbearing age should undergo a urine or blood pregnancy test within 3 days before the first dose. 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. 
9. They are tested during screening, within 3 days before each administration of the study drug starting from Cycle 2, during the end-of-treatment visit, and 
during the safety follow-ups. T3, T4, FT3, FT4, and TSH are examined during the screening period. Starting from Cycle 2, only TSH is examined. If there 
are abnormalities, the examination of other thyroid function parameters will be considered. Tests will be conducted at each study site. 
10. Autoantibodies include: anti-nuclear antibodies, anti-dsDNA antibodies, and anti-thyroglobulin antibodies. The test is conducted during screening, and 
afterwards retest will be done only if deemed necessary by the investigator. Tests will be conducted at each study site. 
11. Immunogenicity examinations will be carried out within 1 h before the start of IBI308 infusion in Cycle 1, Cycle 2, and every 2 cycles thereafter (Cycles 4, 6, 
8, and so on), and during safety follow-ups. If an infusion-related reaction occurs during IBI308 infusion, blood samples should be taken near the start and 
end of this event and around 30 days after the reaction and used for comparative analysis of immunogenicity. Tests will be conducted in the central 
laboratory. 
12. Including tests for HCV and HIV antibodies, as well as HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb. They are tested during screening. Tests will be 
conducted at each study site. 
13. Refer to PK/PD sampling schedule (Table 6). Tests will be conducted in the central laboratory. 
14. AEs and laboratory safety assessments will be performed based on NCI CTCAE V4.03. Refer to Section 7 for definitions, recording, causality determination, 
severity level, reporting deadlines, and treatment of AEs and SAEs. 


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15. Tumor evaluations are based on RECIST V1.1 and irRECIST. There is no central imaging evaluation in this study. Tumor imaging examinations usually 
include contrast-enhanced CT or MRI of the chest, abdomen, and pelvic cavity. The same subject should receive the same type of imaging examination 
during the study. Baseline evaluation is conducted within 28 days prior to enrollment. The investigators can evaluate imaging results within 28 days prior to 
enrollment. Tumor imaging evaluation should be carried out every 9 weeks (± 7 days) after first dose of the study drug. For subjects with initial response (CR 
or PR), an imaging evaluation is carried out 4 weeks (± 7 days) later to confirm the response, and the imaging evaluation is carried out every 9 weeks (± 7 
days) thereafter until imaging PD is recorded. For subjects who are first recorded as imaging PD, an imaging evaluation should be carried out 4 weeks (± 7 
days) later for confirmation. For subjects with first imaging PD but an unstable clinical situation or rapid progression who are deemed as not suitable for 
continued drug treatment, it is not necessary for them to undergo further imaging examinations to confirm PD. 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 and every 9 weeks (± 7 days) after treatment 
discontinuation until start of a new anti-tumor therapy, PD, ICF withdrawal by subjects, or death. 
16. For Cohort D, 200 mg of IBI308 is given via intravenous infusion every 3 weeks. Pemetrexed + cisplatin, intravenous infusion, administered once every 3 
weeks. Up to 4 cycles of treatment with IBI308 in combination with pemetrexed + cisplatin are given before the subjects enter the maintenance treatment 
phase of IBI308 in combination with pemetrexed until PD, intolerable toxicity, withdrawal of ICF, a total of 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). The treatment by IBI308 lasts for up to 24 months. 
17. For Cohort E, each treatment cycle contains 3 weeks. The dosing regimen is IBI308 200 mg IV D1 + gemcitabine 1250 mg/m2 IV D1, D8 + cisplatin 75 
mg/m2 IV D1. Up to 6 cycles of triple drug combination therapy are given. Subsequently, the subjects experiencing no PD can receive a maintenance 
treatment with 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of ICF, 24 months of treatment, or other reasons for discontinuation of 
the study treatment (whichever occurs first). The treatment by IBI308 lasts for up to 24 months. 
18. For Cohort F, 200 mg of IBI308 is given via intravenous infusion every 3 weeks. Each treatment cylce contains 3 weeks. The dosing regime is capecitabine 
1000 mg/m2 PO bid D1–14 + oxaliplatin 130 mg/m2 IV D1 (XELOX regimen). After up to 6 cycles of treatment with IBI308 in combination with XELOX, 
the subjects experiencing no PD can receive a maintenance treatment with 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of ICF, 24 
months of treatment, or other reasons for discontinuation of the study treatment (whichever occurs first). The treatment by IBI308 lasts for up to 24 months. 
19. Subjects are required to provide archived or fresh tumor tissue samples meeting test requirements during screening. 
20. For Cohort D, up to 4 cycles of triple drug combination therapy are given; for Cohorts E and F, up to 6 cycles of triple drug combination therapy are given. 
21. The end-of-treatment visit is carried out within 7 days after the end of treatment is confirmed, as detailed in 6.2.3 of the protocol. 
22. A safety follow-up should be carried out within 90 ± 7 days after the last dose or before the start of a new anti-tumor treatment (whichever occurs first). The 
study drug-related AEs need to be followed up until resolved to grade 0 or 1, stable, or withdrawal of ICF (whichever occurs first). Refer to 6.2.3 for details. 
23. Survival follow-up: once every 3 months (± 7 days) after treatment discontinuation. Telephone follow-up is allowed. 
 
 


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Table 5. Visit schedule for Cohorts G/H in the Phase Ib study 
Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-treatment 
visit16 
Safety 
follow-up17 
Survival 
follow-up18 
Combination therapy 
Maintenance 
therapy 
Cycle 1 
Cycles 2–6 
Cycle 7 and 
beyond 
Visit 
1 
2 
3–7 
N 
Day 
−28 to −1 
D1 
2 
3 
Day 1  
(± 2 days) 
2 
3 
Day 1  
(± 2 days) 
Within 7 days 
after the end of 
treatment is 
confirmed 
90 days (± 7 
days) after the 
end of 
treatment 
Every 90 
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 
 
Weight/height4 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Physical examination 
X 
 
 
 
X 
 
 
X 
X 
X 
 
ECOG PS score 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
12-Lead ECG5 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Routine blood test/blood 
chemistry/urinalysis6 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Coagulation function7 
X 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
Thyroid function9 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Autoantibody10 
X 
 
 
 
 
 
 
 
 
 
 


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Stage 
Screening 
period 
Treatment period (21 days per cycle) 
End-of-treatment 
visit16 
Safety 
follow-up17 
Survival 
follow-up18 
Combination therapy 
Maintenance 
therapy 
Cycle 1 
Cycles 2–6 
Cycle 7 and 
beyond 
Visit 
1 
2 
3–7 
N 
Day 
−28 to −1 
D1 
2 
3 
Day 1  
(± 2 days) 
2 
3 
Day 1  
(± 2 days) 
Within 7 days 
after the end of 
treatment is 
confirmed 
90 days (± 7 
days) after the 
end of 
treatment 
Every 90 
days (± 7 
days) 
HIV, HBV, and HCV11 
X 
 
 
 
 
 
 
 
 
 
 
AE evaluation12 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Survival condition 
 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-tumor 
therapy 
 
 
 
 
 
 
 
 
 
X 
X 
Efficacy evaluation 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging evaluation13 
X 
 
 
 
 
 
 
X 
 
X 
 
Study drug administration in Cohort G 14 
IBI308 
 
X 
 
 
X 
 
 
X 
 
 
 
Etoposide 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cisplatin 
 
X 
 
 
X 
 
 
 
 
 
 
Study drug administration in Cohort H 15 
IBI308 
 
X 
 
 
X 
 
 
X 
 
 
 
Irinotecan 
 
X 
 
 
X 
 
 
 
 
 
 
5-FU 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Note: 
1. 
The ICF should be signed by subjects prior to any procedures outlined in the protocol. 


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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 is measured during screening period only. Weight must be measured before every planned dose during the study. If the weight fluctuation of a subject 
is less than 10% compared to the baseline (the day when the first dose of IBI308 is given), 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. 
Time of 12-lead ECG examinations: during the screening period, within 60 min after the end of IBI308 infusion in each cycle, and during the 
end-of-treatment visit and safety follow-ups. 
6. 
Routine blood test include: RBC, HGB, HCT, WBC, PLT, and white blood cell differential (LYM, ANC, MONO, EOS, BASO). Blood chemistry include: 
hepatic function (TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH), renal function (BUN, Cr), blood electrolytes (Na, K, Cl, Mg, Ca, P), lipase, amylase, and 
FBG. Urinalysis include: PH, UALB, UPRO, URBC, and UGLU. Any subject with urine protein ≥ 2+ from urinalysis dipstick in routine urinalysis at 
screening needs to undergo a 24-h urine protein test. The tests will be conducted during screening, within 7 days before the first dose of the study drug, 
within 3 days before each administration of the study drug starting from Cycle 2, during the end-of-treatment visit, and during the safety follow-ups. Tests 
will be conducted at each study site. 
7. 
Coagulation function tests include: TT, PT, APTT, and INR. They are tested within 7 days before the first dose of IBI308, during the end-of-treatment visit, 
and during the safety follow-ups. Tests will be conducted at each study site. 
8. 
Women of childbearing age should undergo a urine or blood pregnancy test within 3 days before the first dose. 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. 
9. 
They are tested during screening, within 7 days before each administration of the study drug starting from Cycle 2, during the end-of-treatment visit, and 
during the safety follow-ups. T3, T4, FT3, FT4, and TSH are examined during the screening period. Starting from Cycle 2, only TSH is examined. If there 
are abnormalities, the examination of other thyroid function parameters will be considered. Tests will be conducted at each study site. 
10. Autoantibodies include: anti-nuclear antibodies, anti-dsDNA antibodies, and anti-thyroglobulin antibodies. The test is conducted during screening, and 
afterwards retest will be done only if deemed necessary by the investigator. Tests will be conducted at each study site. 
11. Including tests for  HCV and HIV antibodies, as well as HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb. They are tested during screening. Tests will be 
conducted at each study site. 
12. AEs and laboratory safety assessments will be performed based on NCI CTCAE V4.03. Refer to Section 7 for definitions, recording, causality determination, 
severity level, reporting deadlines, and treatment of AEs and SAEs. 
13. Tumor evaluations are based on RECIST V1.1 and irRECIST. There is no central imaging evaluation in this study. Tumor imaging examinations usually 
include contrast-enhanced CT or MRI of the chest, abdomen, and pelvic cavity. Additional examination sites are determined based on sites involved by 
tumors. The same subject should receive the same type of imaging examination during the study. Baseline evaluation is conducted within 28 days prior to 
enrollment. The investigators can evaluate imaging results within 28 days prior to enrollment. Tumor imaging evaluation should be carried out every 9 


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weeks (± 7 days) after first dose of the study drug. For subjects with initial response (CR or PR), an imaging evaluation is carried out 4–6 weeks later to 
confirm the response and every 9 weeks (± 7 days) thereafter until imaging PD is recorded. For subjects who are first recorded as imaging PD, an imaging 
evaluation should be carried out 4 weeks (± 7 days) later for confirmation. For subjects with first imaging PD but an unstable clinical situation or rapid 
progression who are deemed as not suitable for continued drug treatment, it is not necessary for them to undergo further imaging examinations to confirm 
PD. 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 
and every 9 weeks (± 7 days) after treatment discontinuation until start of a new anti-tumor therapy, PD, ICF withdrawal by subjects, or death. 
14. Combination therapy regimen for Cohort G: Each treatment cycle contains 3 weeks. The dosing regime is IBI308 200 mg IV D1 + etoposide 100 mg/m2 IV 
D1–3 + cisplatin 75 mg/m2 IV D1. Up to 6 cycles of combination therapy are given. Subsequently, the subjects experiencing no PD can receive a 
maintenance treatment with 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of ICF, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). 
15. Combination therapy regimen for Cohort H: Each treatment cycle contains 3 weeks. The dosing regime is IBI308 200 mg IV D1 + irinotecan 125 mg/m2 IV 
D1, D8 + 5-FU 1000 mg/m2 IV D1–3. Up to 6 cycles of combination therapy are given. Subsequently, the subjects experiencing no PD can receive a 
maintenance treatment with 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of ICF, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). 
16. The end-of-treatment visit is carried out within 7 days after the end of treatment is confirmed, as detailed in 6.2.3 of the protocol. 
17. A safety follow-up should be carried out within 90 ± 7 days after the last dose or before the start of a new anti-tumor treatment (whichever occurs first). The 
study drug-related AEs need to be followed up until resolved to grade 0 or 1, stable, or withdrawal of ICF (whichever occurs first). Refer to 6.2.3 for details. 
18. Survival follow-up: once every 3 months (± 7 days) after treatment discontinuation. Telephone follow-up is allowed. 
 
 


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Table 6. PK/PD sampling schedule of Cohorts A/B/C/D/E/F in the Phase Ib study 
Stage 
Screening 
period 
Treatment period (21 days per cycle) 
Safety 
follow-up5 
Cycle 12 
Cycle 2 and thereafter3,4 
Day 
-28~-1 
1 
2 
3 
8 
15 
Day 1 (± 2 days) 
90 days  
(± 7 days) 
Sampling 
time1 
 
-1h 
During 
infusion 
Immediately 
at the end of 
infusion 
1 h after 
the end of 
infusion 
6 h after the 
start of 
infusion 
24h 
48h 
168h 
336h 
-1h 2 
During 
infusion 
Immediately 
at the end of 
infusion 
 
Time 
window of 
blood 
sampling 
 
 
 
+5min 
±5min 
±15min 
±1h 
±2h 
±8h 
±12h 
 
 
+5min 
 
IBI308 
 
X 
 
 
 
 
 
 
 
X 
 
 
PK6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 3 
X 3 
X 5 
PD6 
X 
 
X 
X 
X 4 
 
X 5 
Note: 
1. 
Samples should be collected from the opposite arm of the infusion site. 
2. 
If the dosing on Day 1 of Cycle 2 is delayed due to an AE or other reasons, additional sampling is required at 504 ± 24 h (Day 22) in Cycle 1. 
3. 
Since Cycle 2, PK samples are collected every 2 cycles (Cycles 2, 4, 6, and so on). 
4. 
Since Cycle 2, PD samples are collected every 4 cycles (Cycles 6, 10, 14, and so on). 
5. 
Both PK and PD samples are collected during safety follow-ups, but not collected during survival follow-ups. 
6. 
For Cohort B, after the PK/PD blood samples of 20 subjects who meet the requirements of assay and analysis are collected, subsequent subjects are not 
required to undergo PK/PD assays. 


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TABLE OF CONTENTS 
Protocol Synopsis .......................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 34 
List of Tables ............................................................................................................................... 40 
List of Figures .............................................................................................................................. 41 
List of Abbreviations and Definitions ....................................................................................... 42 
1. 
BACKGROUND ................................................................................................................. 45 
1.1. 
Introduction ................................................................................................................ 45 
1.2. 
Disease Background ................................................................................................... 46 
1.2.1. 
Melanoma ........................................................................................................ 46 
1.2.2. 
Esophageal cancer and gastric cancer ............................................................. 46 
1.2.3. 
Liver cancer ..................................................................................................... 47 
1.2.4. 
Neuroendocrine neoplasm ............................................................................... 47 
1.2.5. 
Lung cancer ..................................................................................................... 48 
1.3. 
Immune Checkpoint Therapy ..................................................................................... 48 
1.4. 
Study Drug (IBI308) .................................................................................................. 49 
1.4.1. 
Nonclinical pharmacodynamic studies of IBI308 ........................................... 49 
1.4.2. 
Nonclinical pharmacokinetic studies of IBI308 .............................................. 50 
1.4.3. 
Nonclinical toxicological studies of IBI308 .................................................... 52 
1.5. 
Risk and Benefit Assessment ..................................................................................... 53 
2. 
STUDY OBJECTIVES ....................................................................................................... 54 
2.1. 
Primary Study Endpoints ........................................................................................... 54 
2.2. 
Secondary Study Endpoints ....................................................................................... 54 
2.3. 
Exploratory Objectives ............................................................................................... 54 
3. 
Overall Study Design .......................................................................................................... 54 
3.1. 
Design Principles ....................................................................................................... 66 
3.1.1. 
IBI308 dose selection principles ..................................................................... 66 
3.1.2. 
Rationale for selecting melanoma, gastrointestinal tumors, neuroendocrine 
neoplasms, and lung cancer for the phase Ib study ......................................... 66 


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3.1.3. 
The principle of giving combined treatment of IBI308 and  
chemotherapy to patients with lung cancer ..................................................... 67 
3.1.4. 
The principle of giving combined treatment of IBI308 and  
chemotherapy to patients with previously untreated gastric  
or gastroesophageal junction adenocarcinoma ................................................ 68 
3.1.5. 
Rationale for exploring PD-L1 as a biomarker ............................................... 69 
3.1.6. 
Rationale for treatment after progressive disease ........................................... 69 
3.2. 
Phase Ia Study ............................................................................................................ 70 
3.2.1. 
Dose-limiting toxicity (DLT) .......................................................................... 70 
3.2.2. 
Maximal tolerated dose (MTD) ....................................................................... 71 
3.2.3. 
Dose escalation method ................................................................................... 71 
3.2.4. 
Subjects evaluable for DLT ............................................................................. 71 
3.3. 
Phase Ib Study ............................................................................................................ 72 
3.3.1. 
Treatment regimen selection for the phase Ib study........................................ 72 
4. 
STUDY POPULATION ..................................................................................................... 72 
4.1. 
Inclusion Criteria ........................................................................................................ 72 
4.2. 
Exclusion Criteria ....................................................................................................... 75 
4.3. 
Restrictions During the Study .................................................................................... 78 
4.4. 
Study Discontinuation/Withdrawal of Subjects ......................................................... 79 
5. 
STUDY DRUGS AND OTHER TREATMENTS ............................................................ 80 
5.1. 
Treatment Regimen .................................................................................................... 80 
5.1.1. 
Treatment regimen for the phase Ia/Ib study .................................................. 80 
5.1.2. 
Continued treatment after progressive disease ................................................ 81 
5.2. 
IBI308 ........................................................................................................................ 83 
5.2.1. 
Description ...................................................................................................... 83 
5.2.2. 
Labels .............................................................................................................. 83 
5.2.3. 
Storage ............................................................................................................. 83 
5.2.4. 
Preparation and infusion .................................................................................. 83 
5.3. 
Chemotherapeutics ..................................................................................................... 84 
5.3.1. 
Pemetrexed ...................................................................................................... 84 
5.3.2. 
Cisplatin .......................................................................................................... 85 
5.3.3. 
Gemcitabine .................................................................................................... 85 


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5.3.4. 
Capecitabine .................................................................................................... 86 
5.3.5. 
Oxaliplatin ....................................................................................................... 86 
5.3.6. 
Etoposide ......................................................................................................... 87 
5.3.7. 
Irinotecan ......................................................................................................... 87 
5.3.8. 
5-FU ................................................................................................................ 87 
5.4. 
Dose Adjustments ...................................................................................................... 87 
5.4.1. 
General principles ........................................................................................... 87 
5.4.2. 
IBI308 administration adjustments ................................................................. 88 
5.4.3. 
Dose adjustments of pemetrexed and cisplatin ............................................... 90 
5.4.4. 
Dose adjustments of gemcitabine and cisplatin .............................................. 91 
5.4.5. 
Dose adjustments for oxaliplatin and capecitabine ......................................... 93 
5.4.6. 
Dose adjustments of etoposide ........................................................................ 95 
5.4.7. 
Dose adjustments of irinotecan ....................................................................... 97 
5.4.8. 
Dose adjustments of 5-FU ............................................................................... 97 
5.5. 
Principles of Managing Immune Checkpoint Inhibitor Toxicities ............................ 98 
5.6. 
Concomitant Treatment .............................................................................................. 99 
5.6.1. 
Prohibited treatments ....................................................................................... 99 
5.6.2. 
Permitted treatments ........................................................................................ 99 
5.6.3. 
Drug-drug interactions .................................................................................... 99 
5.7. 
Dosing During Pregnancy, Childbearing Age and Lactation ................................... 103 
5.7.1. 
Pregnancy ...................................................................................................... 103 
5.7.2. 
Childbearing age ........................................................................................... 103 
5.7.3. 
During Lactation ........................................................................................... 104 
5.8. 
Treatment Compliance ............................................................................................. 104 
5.9. 
Drug Return and Destruction ................................................................................... 104 
5.10. Study Drug-related Records ..................................................................................... 104 
5.11. Complaint Handling ................................................................................................. 104 
6. 
STUDY EVALUATIONS AND RELEVANT PROCEDURES ................................... 105 
6.1. 
Enrollment and Randomization ................................................................................ 105 
6.1.1. 
Subject enrollment ......................................................................................... 105 
6.1.2. 
Enrollment error handling ............................................................................. 105 
6.1.3. 
Randomization and blinding ......................................................................... 106 


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6.2. 
Study Plan and Schedule .......................................................................................... 106 
6.2.1. 
Screening period ............................................................................................ 106 
6.2.2. 
Treatment visits ............................................................................................. 107 
6.2.3. 
End-of-treatment visit/safety follow-up ........................................................ 109 
6.2.4. 
Survival follow-up ......................................................................................... 110 
6.3. 
Efficacy Evaluation .................................................................................................. 110 
6.3.1. 
RECISIT 1.1 efficacy evaluation .................................................................. 111 
6.3.2. 
Efficacy evaluation by immune-related remission standard (irRECIST) ..... 111 
6.4. 
Safety Evaluation ..................................................................................................... 112 
6.4.1. 
Routine laboratory safety evaluation ............................................................. 112 
6.4.2. 
Physical examination ..................................................................................... 113 
6.4.3. 
12-lead electrocardiogram (ECG) ................................................................. 113 
6.4.4. 
Vital signs ...................................................................................................... 113 
6.4.5. 
Weight and height ......................................................................................... 114 
6.4.6. 
Pregnancy test ............................................................................................... 114 
6.4.7. 
Autoantibody ................................................................................................. 114 
6.4.8. 
Other safety inspections include the followings: .......................................... 114 
6.4.9. 
Safety Review Committee ............................................................................. 115 
6.5. 
Pharmacokinetics: .................................................................................................... 115 
6.5.1. 
Collection of specimens ................................................................................ 115 
6.5.2. 
Measurement of drug concentration .............................................................. 116 
6.6. 
Pharmacodynamics .................................................................................................. 116 
6.6.1. 
Phase Ia study ................................................................................................ 116 
6.6.2. 
Phase Ib study ................................................................................................ 116 
6.7. 
Immunogenicity ....................................................................................................... 117 
6.8. 
Biomarker Analysis .................................................................................................. 117 
6.9. 
Storage and Destruction of Biological Samples ....................................................... 118 
7. 
SAFETY REPORTS AND AE MANAGEMENT ......................................................... 119 
7.1. 
Definition of AEs ..................................................................................................... 119 
7.2. 
Definition of SAEs ................................................................................................... 119 
7.3. 
Criteria for Severity Levels of AEs .......................................................................... 120 
7.4. 
Correlation Between AEs and Study Drug .............................................................. 120 


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7.5. 
Documentation of AEs ............................................................................................. 121 
7.5.1. 
Collection and Time of AEs .......................................................................... 121 
7.5.2. 
AE follow-up ................................................................................................. 121 
7.5.3. 
Contents of AE documentation ..................................................................... 122 
7.6. 
Expedited Reporting of SAEs and Pregnancy ......................................................... 124 
7.7. 
Abnormal Hepatic Function ..................................................................................... 125 
7.8. 
Management of Drug-Related Toxicities ................................................................. 126 
7.8.1. 
Immune related adverse events ..................................................................... 126 
7.8.2. 
Adverse events of special interest (AESIs) ................................................... 126 
8. 
STATISTICS ..................................................................................................................... 127 
8.1. 
Statistics Analysis Plan ............................................................................................ 127 
8.2. 
Hypothesis Test ........................................................................................................ 127 
8.3. 
Statistical Populations .............................................................................................. 127 
8.4. 
Statistical Analysis Methods .................................................................................... 127 
8.4.1. 
General statistical analysis ............................................................................ 127 
8.4.2. 
Analysis of the primary endpoint .................................................................. 128 
8.4.3. 
Analysis of secondary endpoints ................................................................... 129 
8.4.4. 
Safety analysis ............................................................................................... 129 
8.4.5. 
Compliance analysis ...................................................................................... 131 
8.4.6. 
Subjects' baseline characteristics ................................................................... 131 
8.4.7. 
Interim analysis ............................................................................................. 131 
8.4.8. 
Subgroup analysis ......................................................................................... 131 
8.4.9. 
Multiple comparisons and adjustments ......................................................... 131 
8.4.10. 
Eligible subject data lists ............................................................................... 131 
8.4.11. 
Exploratory analysis ...................................................................................... 131 
8.5. 
Sample Size Determination ...................................................................................... 132 
8.6. 
Methods for Controlling Bias ................................................................................... 132 
8.6.1. 
Randomization and blinding ......................................................................... 132 
8.6.2. 
Blinding maintenance evaluation .................................................................. 132 
8.6.3. 
Unblinding and emergency unblinding ......................................................... 132 
8.7. 
Statistical Analysis and Clinical Study Report ........................................................ 132 


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9. 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................. 133 
9.1. 
Clinical Monitoring .................................................................................................. 133 
9.2. 
Data Management/Coding ....................................................................................... 133 
9.3. 
Quality Assurance Audits ........................................................................................ 135 
10. ETHICS ............................................................................................................................. 135 
10.1. Ethics Committee ..................................................................................................... 135 
10.2. Ethics ........................................................................................................................ 136 
10.3. Subject Information and Informed Consent ............................................................. 136 
10.4. Data Protection of Subjects ...................................................................................... 136 
11. STUDY MANAGEMENT ................................................................................................ 137 
11.1. Data Processing and Record Keeping ...................................................................... 137 
11.2. Source Data/File Access .......................................................................................... 137 
11.3. Protocol Revisions ................................................................................................... 137 
11.4. Responsibilities of the Investigator .......................................................................... 137 
11.5. Publishing Policy ..................................................................................................... 138 
11.6. Financing and Insurance .......................................................................................... 138 
REFERENCES .......................................................................................................................... 139 
APPENDIX ................................................................................................................................ 142 
Appendix 1: Signature Page for Investigator ......................................................................... 143 
Appendix 2: ECOG PS Scoring Criteria ................................................................................ 144 
Appendix 3: Response Evaluation Criteria in Solid Tumors Version 1.1  
(RECIST V1.1) .................................................................................................... 145 
Appendix 4: Abnormal Hepatic Function Monitoring and Follow-Up Report .................. 159 
Appendix 5: List of Pre-Existed Autoimmune Diseases Prior to Enrollment ..................... 162 
Appendix 6: Definition and Main Pathological Types of Interstitial Lung Disease ........... 163 
Appendix 7: Child-Pugh Grading and Evaluation System ................................................... 164 
Appendix 8: Dose Adjustments and Toxicity Management of IBI308................................. 165 
 


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List of Tables 
Table 1. Schedule of study visits in the phase Ia study ................................................................ 15 
Table 2. PK/PD sampling schedule in the phase Ia study............................................................. 19 
Table 3. Visit schedule for Cohorts A/B/C in the Phase Ib study ................................................. 20 
Table 4. Visit schedule for Cohorts D/E/F in the Phase Ib study ................................................. 24 
Table 5. Visit schedule for Cohorts G/H in the Phase Ib study .................................................... 29 
Table 6. PK/PD sampling schedule of Cohorts A/B/C/D/E/F in the Phase Ib study .................... 33 
Table 7. Dose escalation method .................................................................................................. 71 
Table 8. Dose and treatment protocol ........................................................................................... 80 
Table 9. Calculation formulas for volume of IBI308 required ..................................................... 84 
Table 10. Dose adjustments of IBI308 ......................................................................................... 88 
Table 11. Dose adjustments of pemetrexed and cisplatin due to hematological toxicity ............. 90 
Table 12. Dose adjustments of pemetrexed and cisplatin due to other  
non-hematological toxicity ........................................................................................... 90 
Table 13. Dose adjustments of gemcitabine and cisplatin ............................................................ 91 
Table 14. Dose adjustments of gemcitabine and cisplatin due to hematological toxicity ............ 92 
Table 15. Dose adjustments of gemcitabine and cisplatin due to non-hematological toxicity ..... 92 
Table 16. Dose adjustments of oxaliplatin and capecitabine ........................................................ 93 
Table 17. Dose adjustments of capecitabine and oxaliplatin due to non-hematological  
toxicity .......................................................................................................................... 94 
Table 18. Dose adjustments of etoposide due to hematological toxicity ...................................... 96 
Table 19. Dose adjustments of etoposide due to nephrotoxicity .................................................. 96 
Table 20. Dose adjustments of etoposide due to other non-hematological toxicity ..................... 96 
Table 21. Dose adjustments of irinotecan ..................................................................................... 97 
Table 22. Dose adjustments of 5-FU due to hematological toxicity............................................. 98 
Table 23. Dose adjustments of 5-FU due to non-hematological toxicity ..................................... 98 
Table 24. Effective methods of contraception (one of the followings must be used) ................ 103 
Table 25. Routine laboratory safety evaluation .......................................................................... 112 
Table 26. Correlation determination between AEs and study drug ............................................ 120 
Table 27. SAE report contacts .................................................................................................... 124 
Table 28. Liver injuries required to be reported as SAEs ........................................................... 125 
Table 29. Schedule of clinical study reports ............................................................................... 132 


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List of Figures 
Figure 1. Schematic of phase Ia study design and dosing regimen .............................................. 58 
Figure 2. Schematic of phase Ib study design............................................................................... 59 
Figure 3. Schematic of dosing regimen for cohorts A/B/C in the phase Ib study ........................ 60 
Figure 4. Schematic of dosing regimen for cohort D in the phase Ib study ................................. 61 
Figure 5. Schematic of dosing regimen for cohort E in the phase Ib study .................................. 62 
Figure 6. Schematic of dosing regimen for cohort F in the phase Ib study .................................. 63 
Figure 7. Schematic of dosing regimen for cohort G in the phase Ib study ................................. 64 
Figure 8. Schematic of dosing regimen for cohort H in the phase Ib study ................................. 65 
 
 


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List of Abbreviations and Definitions 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALB 
Albumin 
ALK  
Anaplastic lymphoma kinase 
ALP  
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST  
Aspartate amino transferase 
AUC 
Area under the curve 
BASO 
Basophil count 
BUN 
Blood urea nitrogen 
CCr 
Clearance of creatinine 
CHO 
Chinese hamster ovary cell 
CI  
Confidence interval 
Cmax  
Maximum observed concentration 
Cr 
Serum creatinine 
CR  
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
CT  
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTLA-4  
Cytotoxic T-lymphocyte antigen 4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
ECG  
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EGFR  
Epidermal growth factor receptor 
EOS 
Eosinophil count 
FAS 
Full analysis set 
FBG 
Fasting blood glucose 
FFPE  
Formalin fixed paraffin-embedded 
FT3 
Free triiodothyronine 


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FT4 
Free thyroxine 
GCP  
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCC  
Hepatocellular carcinoma 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference for Harmonization 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 
irAE  
Immune related adverse events 
IRR 
Infusion-related reaction 
irRECIST  
Immune-related Response Evaluation Criteria in Solid Tumors 
IV  
Intravenous infusion 
LDH 
Lactate dehydrogenase 
LYM 
Lymphocyte count 
MedDRA  
Medical Dictionary for Regulatory Activities 
MONO 
Monocyte count 
mOS 
Median overall survival 
mPFS 
Median progression free survival 
MRI  
Magnetic resonance imaging 
MTD 
Maximal tolerated dose 
NAb 
Neutralizing antibody 
NEC 
Neuroendocrine carcinoma 
NCI  
National Cancer Institute 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect level 
NSCLC  
Non-small cell lung cancer 
nsNSCLC 
Non-squamous non-small cell lung cancer 
ORR  
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamics 
PD-1  
Programmed cell death receptor 1 
PD-L1  
Programmed cell death ligand 1 
PFS  
Progression free survival 


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PH 
Potential of hydrogen 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PLT 
Platelet 
PR 
Partial response 
PVC 
Polyvinyl chloride 
Q2W 
Once every 2 weeks 
Q3W 
Once every 3 weeks 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistics analysis plan 
scNSCLC 
Squamous-cell non-small cell lung cancer 
SD 
Stable disease 
SS 
Safety analysis set 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBIL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
TP 
Total protein 
TSH 
Thyroid stimulating hormone 
TT 
Thrombin time 
TTR 
Time to response 
UALB 
Urinary white blood cell 
UGLU 
Urine glucose 
ULN 
Upper limit of normal 
UPRO 
Urine protein 
URBC 
Urine red blood cell 
WBC 
White blood cell 
WHO 
World Health Organization 
γ-GT 
γ-glutamyltransferase 
 
 


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1. BACKGROUND 
1.1. Introduction 
Due to prolonged life expectancy and lifestyle changes of humans, malignant tumors have 
become an important serious health threat and also the most life-threatening disease for humans. 
As estimated, there were 14.1 million new cancer cases and 8.2 million new cancer deaths 
worldwide in 2012[1]. In 2009, the total cancer incidence in China was 285.9/100,000 and the 
total mortality was 180.5/100,000[2]. Among all cancer deaths, the leading cause of death is lung 
cancer (25.2%), successively followed by liver cancer (14.4%), stomach cancer (14.3%), and 
esophageal cancer (9.3%). These 4 cancers have poor prognosis and cause 63.2% of all cancer 
deaths[2]. The incidence of melanoma in Chinese population is about 20,000 new cases per year, 
but the incidence has increased quickly in recent years. In China, the 5-year survival is less than 
5% due to poor treatment effects of advanced melanoma. Great medical needs related to 
advanced melanoma and esophageal, stomach, liver, and lung cancers have not been met in 
China. 
In recent years, tumor treatment via immune checkpoints has gradually become a research 
hotspot, and tremendous breakthroughs have been made in this field. Unlike cytotoxic drugs, 
monoclonal antibodies or small molecule tyrosine kinase inhibitors that target oncogenes, 
immune checkpoint therapy of tumors does not directly target tumor cells, but rather improve the 
function of T cells, remove the tolerance of the immune system to tumor cells, and improve the 
effective recognition and killing of tumor cells by T cells via blocking the inhibitory signals 
against T cell proliferation and activation. Currently, the immune checkpoint targets showing 
significant clinical efficacy in tumor treatment include cytotoxic T lymphocyte-associated 
antigen-4 (CTLA-4) and programmed cell death receptor 1/ligand 1 (PD-1/PD-L1)[3]. 
Recombinant fully human anti-PD-1 monoclonal antibody injection (Sintilimab, R&D code: 
IBI308) is a Category 1 new drug independently developed by Innovent Biologics (Suzhou) Co., 
Ltd. When the study protocol 3.0 is being revised, IBI308 has been approved for marketing by 
the National Medical Products Administration on Dec. 24, 2018 in China. IBI308 is an anti-IgG4 
(immunoglobin G4) monoclonal antibody. It can specifically bind to PD-1 molecules on the 
surface of T lymphocytes, thereby blocking the PD-1/PD-L1 pathway which causes immune 
tolerance to tumors and reactivating the anti-tumor activity of T lymphocytes so as to treat the 
tumors. IBI308 shares the same target as two marketed anti-PD-1 monocolonal antibodies 
(nivolumab and pembrolizumab), but its amino acid sequence is different from that of the two 
marketed antibodies. The existing study results have showed IBI308 has a clear structure and its 
stability, activity, PK/PD in animals, and safety are comparable or superior to those of similar 
drugs from foreign countries. With reference to the approved indications and clinical study data 
of similar drugs developed overseas, the sponsor applies for clinical studies to explore the 


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PK/PD characteristics of IBI308 in humans as well as the efficacy and safety of IBI308 in the 
treatment of various solid tumors, especially melanoma, esophageal carcinoma, gastric cancer, 
hepatocellular carcinoma, and NSCLC, based on the urgent clinical needs and the 
epidemiological characteristics of tumors in China. 
This study is the first-in-human clinical study of IBI308. The phase Ia dose escalation study is 
mainly designed to evaluate the safety, tolerability, and PK/PD of IBI308 in the treatment of 
subjects with advanced solid tumors who failed standard treatment. The objective of phase Ib 
study is to evaluate the safety and preliminary anti-tumor activity of the monotherapy or 
combination chemotherapy of IBI308 in the treatment of specific types of advanced cancers 
(melanoma, malignant neoplasms of the digestive system, NSCLC, and neuroendocrine 
neoplasms). In addition, other data planned to be evaluated include immunogenicity of IBI308 
and related biomarkers. 
1.2. Disease Background 
1.2.1. Melanoma 
In the Chinese population, the incidence of melanoma is lower (about 20,000 cases per year) 
than that in the European and American population, but melanoma cases have obviously 
increased in recent years. For Chinese patients with advanced melanoma, the current standard 
therapy is dacarbazine chemotherapy or high-dose interleukin-2 (IL-2) therapy, but the 5-year 
survival rate is less than 5% due to low response rate and limited survival benefits[4]. 
Breakthroughs in drug therapy for advanced melanoma have been achieved in recent years. For 
metastatic or unresectable BRAF-mutant melanoma, tyrosine kinase inhibitors (TKIs) targeting 
BRAF mutations (vemurafenib and dabrafenib) has been approved by FDA to be used alone or in 
combination with MEK inhibitors (trametinib and cobimetinib) as the first-line therapy; for 
metastatic or unresectable BRAF wild-type melanoma, two types of immune checkpoint 
inhibitors (anti-CTLA-4 monoclonal antibody ipilimumab and anti-PD-1 monoclonal antibody 
nivolumab/pembrolizumab) can be used alone or combined as the first-line therapy[5]. However, 
these drugs have not been marketed in China. 
1.2.2. Esophageal cancer and gastric cancer 
Most of the esophageal and gastric cancer cases are staged at the initial diagnosis to be advanced 
and have been incurable. A large proportion of patients undergoing surgery for early-stage 
esophageal or gastric cancer experience recurrence and distant metastasis or die of this cancer or 
related complications. The 5-year survival rate is less than 10% in advanced cases. Patients with 
advanced esophageal and gastric cancers are treated mainly with systemic therapy. Active drugs 
for these two cancers include chemotherapeutics and targeted agents. Such chemotherapeutics 
for clinical use include fluorouracil or its derivatives (capecitabine, and tegafur, gimeracil, and 


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oteracil porassium capsules), platinum-based drugs (cisplatin and oxaliplatin), taxanes (paclitaxel 
and docetaxel), and epirubicin. Some of such patients can be treated with targeted agents. For 
examples, trastuzumab can be combined with the first-line chemotherapy in patients with 
HER2-positive gastroesophageal junction adenocarcinoma and gastric adenocarcinoma, and 
apatinib, an anti-vascular tyrosine kinase inhibitor, can be used in gastric cancer patients who 
have failed second-line chemotherapy. Overall, systemic therapy delivers limited efficacy against 
advanced esophageal and gastric cancers, and the median survival for patients with esophageal 
and gastric cancers is demonstrated in multiple large-scale clinical studies to be about 1 year[6, 7]. 
1.2.3. Liver cancer 
Hepatocellular carcinoma (HCC) is the main pathological type (more than 90%) of primary liver 
cancer. In China, HCC is mainly caused by chronic hepatitis B infection and often complicated 
with chronic hepatitis or cirrhosis, resulting in poor tolerance of some patients to liver cancer 
therapy. Most of HCC cases are staged at the initial diagnosis to be in the middle or advanced 
stage due to insidious onset and rapid progression. A large proportion of patients undergoing 
surgery for early-stage HCC still experience a relapse, indicating extremely poor prognosis. 
Effective systemic drugs for advanced HCC are limited. The common ones used in China include 
fluorouracil, oxaliplatin, and sorafenib. Generally, the mean survival is only about six months for 
patients with advanced HCC[8]. 
1.2.4. Neuroendocrine neoplasm 
Neuroendocrine neoplasms are malignant solid neoplasms that arise from diffuse neuroendocrine 
cells. These cells are distributed across the body, so these neoplasms may occur at any site of the 
body. The most common ones are neuroendocrine neoplasms of the digestive system (stomach, 
intestine, pancreas), about 2/3 of all of this type of neoplasms. According to the WHO 2010 
nomenclature for neuroendocrine neoplasms, "neuroendocrine neoplasm (NEN)" refers to all 
tumors arising from neuroendocrine cells, and moderately- and highly- differentiated ones are 
named "neuroendocrine tumor (NET)" while poorly-differentiated ones are named 
"neuroendocrine carcinoma (NEC)". 
Drugs for neuroendocrine neoplasms are used to control symptoms resulting from excessive 
secretion of functional neuroendocrine neoplasm hormones as well as tumor growth. Biologic 
and targeted therapies are the main drug therapies for highly-differentiated neuroendocrine 
neoplasms. The existing biotherapeutic agents for neuroendocrine neoplasms are somatostatin 
analogs including octreotide and lanreotide; targeted drugs include everolimus (a mammalian 
target of rapamycin protein inhibitor) and sunitinib (a tyrosine kinase inhibitor ). Conventional 
cytotoxic chemotherapeutics still serve as the first-line therapy for poorly differentiated 
neuroendocrine carcinoma, but the OS is about 10 months due to rapid PD. 


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1.2.5. Lung cancer 
About 80–85% of lung cancer cases are NSCLC ones. Approximately 70% of NSCLC patients 
are judged at the initial diagnosis to be locally advanced or metastatic and unsuitable for surgical 
resection. Besides, a large proportion of NSCLC patients undergoing surgery for early-stage 
NSCLC experience recurrence or distant metastasis, or even die due to progression. About 60% 
of Chinese NSCLC cases are nsNSCLC. Patients with advanced nsNSCLC are treated mainly 
with chemotherapy, and some of them are suitable for targeted therapy. The EGFR mutation rate 
is about 40% in Chinese nsNSCLC cases. EGFR inhibitors (gefitinib, erlotinib, or icotinib) are 
recommended as the first-line therapy for patients with EGFR-mutated advanced NSCLC. The 
incidence of ALK rearrangement is about 3% in China. The first-line therapy with crizotinib (an 
ALK inhibitor) is recommended for patients with ALK-rearranged advanced NSCLC. For 
nsNSCLC and scNSCLC patients without EGFR mutation and ALK rearrangement, the 
platinum-based doublet chemotherapy is the first-line standard therapy, and the survival 
following failed first-line chemotherapy is 6–9 months only[9]. 
1.3. Immune Checkpoint Therapy 
Immune checkpoints are a type of immune inhibitory molecules, whose physiological function is 
to regulate the breadth and magnitude of the immune response, avoiding the damage and 
destruction of normal tissues. Cancer cells often use these immune checkpoints to avoid being 
attacked by immune cells. Currently, immune checkpoints CTLA-4 and PD-1/PD-L1 have been 
validated clinically. Immune checkpoint inhibitors that target PD-1/PD-L1 have better prospects 
for clinical applications due to better safety and a broader range of indications[10-11]. 
PD-1 is primarily expressed on activated T-cells and has two ligands: PD-L1 and PD-L2. PD-L1 
is the main ligand that is expressed on activated T-cells, antigen-presenting cells, and tumor 
cells[12-15]. PD-L1 expression is upregulated in a variety of solid tumors. The expression of 
PD-L1 is closely related to the shortened survival and poor prognosis of various tumors[16-23] 
such as lung caner, hepatic cancer, gastric cancer, esophageal carcinoma, urothelial carcinoma, 
renal carcinoma, pancreatic cancer, and ovarian cancer. The binding of PD-1 with PD-L1 plays 
an important role in regulating the activation of T cells and maintaining peripheral immune 
tolerance. When T cells do not express PD-1, they interact with antigen-presenting cells to enable 
the activation and proliferation of T cells as well as the activation of cytokine secretion, which 
can kill the tumor cells. The activated T cells begin to express PD-1. After PD-1 binds to the 
ligand PD-L1 expressed on the surface of antigen-presenting cells or tumor cells, the inhibitory 
signal transmitted by PD-1 inhibits the proliferation of T cells and activates the secretion of 
cytokines, thus weakens the function of T cells. Most tumor cells evade the attack of immune 
cells through this mechanism. The activity and ability to kill cancer cells of T cells can be 
restored by blocking the PD-1/PD-L1 interaction with drugs[24]. 


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A total of 6 PD-1/PD-L1 products have been approved by US FDA for marketing. They are 
nivolumab (anti-PD-1 mAb, trade name: OPDIVO) by BMS, pembrolizumab (anti-PD-1 mAb, 
trade name: KEYTRUDA) by Merck, atezolizumab (anti-PD-1 mAb, trade name: Tecentriq) by 
Roche, avelumab (anti-PD-L1 mAb, trade name: Bavencio) by Pfizer/Merck Drugs & 
Biotechnology, durvalumab (anti-PD-L1 mAb, trade name: Imfinzi) by AstraZeneca, and 
cemiplimab (anti-PD-1 mAb, trade name: Libtayo) by Regeneron/Sanofi. These products are 
indicated for advanced melanoma, advanced NSCLC, advanced small cell lung cancer (SCLC), 
advanced head and neck squamous cell carcinoma, advanced classical Hodgkin's lymphoma, 
primary mediastinal large B-cell lymphoma, advanced renal cell carcinoma, advanced urothelial 
carcinoma, microsatellite instability-high tumors, advanced gastric cancer, advanced cervical 
cancer, advanced HCC, metastatic or locally advanced cutaneous squamous cell carcinoma 
(CSCC), etc.[25-27] In addition, many indications have been under 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. It is of great significance 
to actively develop such inhibitors to provide better treatment options for domestic patients with 
advanced cancers. 
1.4. Study Drug (IBI308) 
IBI308 is a recombinant fully human IgG4 monoclonal antibody consisting of 1,322 amino acids, 
including two light chains (LCs) and two heavy chains (HCs), which are connected by 4 pairs of 
inter-chain disulfide bonds and 12 pairs of intra-chain ones to a "Y" structure. Each LC consists 
of 214 amino acids, while each HC consists of 447 amino acids. The intact molecular weight of 
IBI308 is about 146.4 kDa. For IBI308 containing no oligosaccharide, the theoretical molecular 
weight of the light chain is 143,788.4 Da, and the measured molecular weight is 143,502 Da. The 
theoretical molecular weight of HC containing no oligosaccharide is 48,811.4 Da, and the 
measured molecular weight is 48,668.2 Da. The theoretical molecular weight of the light chain is 
23,098.9 Da, and the measured molecular weight is 23,099.5 Da. 
The completed nonclinical studies on PD, PK in animals, and toxicology have shown IBI308 is 
characterized by clear targets, reliable source of cell lines, and good stability and activity. 
IBI308-related study conclusions are briefly described below. Refer to "Investigator's Brochure" 
for detailed study results. 
1.4.1. Nonclinical pharmacodynamic studies of IBI308 
The completed in vitro PD studies showed IBI308 has marked species specificity and target 
specificity. 
IBI308 has very high affinity to recombinant human PD-1 and cynomolgus monkey PD-1, weak 
affinity to recombinant rabbit PD-1, and no affinity to recombinant rat PD-1 and mouse PD-1 as 


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well as recombinant human CTLA-4 and CD28. The affinity specificity of IBI308 is consistent 
with that of nivolumab, but IBI308's affinity to recombinant human PD-1 and cynomolgus 
monkey PD-1 is higher than that of nivolumab. 
The in vitro cytological study demonstrated that, IBI308 has very high affinity to Chinese 
hamster ovary (CHO) cells expressing human PD-1 while competitively inhibiting binding of 
human PD-L1 or human PD-L2 to human PD-1-expressing CHO cells. The above effects of 
IBI308 are basically the same as those of nivolumab. 
The in vitro studies have also found that IBI308 can dose-dependently promote the release of 
interleukin-2 (IL-2) and interferon-γ (IFN-γ) by T cells, and this effect is similar to that of 
nivolumab. In addition, the direct action of IBI308 and nivolumab on human peripheral blood 
mononuclear cells (PBMCs) does not affect the release of cytokines, and the effects of IBI308 
and nivolumab are similar. 
The in vivo PD study on drug antitumor efficacy demonstrated that the murine substitute (11430) 
of IBI308 is able to significantly inhibit tumor growth in MC38 tumor-bearing C57bl/6 mouse 
models, with a tumor growth inhibition (TGI) of more than 60%, and is more efficacious than the 
positive reference standard RMP1-14. 
In the NSG mouse model (SCID-Winn model) inoculated with a mixture of NCI-H292 and 
human PBMCs, IBI308 was able to significantly inhibit tumor cell growth in an evident 
dose-dependent manner, and did not influence body weights of mice. IBI308 is more efficacious 
than the positive reference standard nivolumab. 
The above results suggest that IBI308 has clear target, clear mechanism of action, and significant 
immunity-enhancing and anti-tumor effects. 
1.4.2. Nonclinical pharmacokinetic studies of IBI308 
IBI308 binds specifically to the surface antigens in normal human lymph nodes, spleen, and 
tonsil membrane. It can specifically bind to the surface antigens in normal intestinal 
mucosa-related lymphoid tissues, mesenteric lymph nodes, spleen and tonsil membrane in 
cynomolgus monkeys, and has no specific binding to other tissues. The tissue cross-reactivity 
characteristics of IBI308 are basically the same as those of commercially available analogous 
drug nivolumab. These suggest IBI308 has specific binding to major immune tissues or organs 
where immune cell distribution density is high. 
Cynomolgus monkeys received a single IV infusion of 1 mg/kg, 6 mg/kg and 30 mg/kg IBI308 
and 6 mg/kg nivolumab. For female and male animals, the concentration-time curves obtained 
were quite similar without gender difference and indicated a linear PK profile. The metabolic 
characteristics of nivolumab were basically the same as those of IBI308 at the same dose. 


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After intravenous infusion of IBI308 at 6 mg/kg once a week for 4 consecutive times in 
cynomolgus monkeys, the drug concentration-time curves at Week 4 in male ones were similar to 
those at Week 1, but those in female ones showed a certain difference from those at Week 1 
possibly due to the presence of anti-drug antibodies (ADAs). There was no drug accumulation. 
This suggested IBI308 has a good linear PK profile and a low risk of accumulation following 
multiple doses. 
The single-dose pharmacodynamic study was performed in parallel with single-dose PK study. 
At 24 h after a single intravenous infusion of different doses of IBI308 (1 mg/kg, 6 mg/kg, and 
30 mg/kg) in cynomolgus monkeys, the results of CD3 + T cells in the body showed that the 
ratio of PD-1 not binding to IBI308 dropped to zero in all groups. In the 1 mg/kg dose group, the 
ratio of the PD-1 not binding to IBI308 increased again on Day 14 after administration. Almost 
no PD-1 did bind to IBI308 on Day 42 after administration. In the 6 mg/kg and 30 mg/kg groups, 
the PD-1 not binding to IBI308 started to appear again in the animals at Day 28 after 
administration, and the ratio of such PD-1 in the 6 mg/kg group was higher than that in the 30 
mg/kg group. On Day 42 after administration, the ratio of non-binding PD-1 in the 6 mg/kg 
group was 74.06%, higher than that (62.55%) in the 30 mg/kg group. The results showed that, 
after a single intravenous infusion of IBI308 in cynomolgus monkeys, the changes over time in 
the ratio of the PD-1 not binding to IBI308 correlate with the changes in serum drug 
concentration, which can accurately reflect the occupancy of PD-1 by IBI308 on the surface of 
CD3 + T cells. However, the changes over time in the ratio of IBI308-bound PD-1 showed poor 
correlation with the changes in serum drug concentration, which may be due to the interference 
generated by the assay and serum drug concentration. These suggested that, after a single 
intravenous infusion of IBI308, the changes over time in the ratio of the PD-1 not binding to 
IBI308 highly correlate with those in the serum drug concentration, so PD-1 can be used as a 
pharmacodynamic biomarker. 
IBI308 (6 mg/kg, 40 mg/kg, and 200 mg/kg) was intravenously infused to cynomolgus monkeys 
once a week for 5 consecutive doses, Cmax and AUC0-t increased proportionally with the 
increasing dose after the first administration, but did not change significantly after dose 
normalization. The values of Cmax and AUC0-t increased with the increasing dose after the fourth 
dose. At the dose of 6 mg/kg, dose-normalized Cmax and AUC0-t were slightly lower than those 
obtained at 40 mg/kg and 200 mg/kg. Such differences may be due to the higher incidence and 
titer of ADAs. There were no gender differences between male and female animals, and no 
significant drug accumulation after multiple administrations. These suggested IBI308 has no 
accumulation following multiple doses but is immunogenic to some extent, to which attention 
should be paid. 


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After a single intravenous infusion of 125I-IBI308 in cynomolgus monkeys, the AUC ranking of 
the total radioactive drug equivalent was similar to the radioactivity ranking of precipitated 
fraction of trichloroacetic acid (TCA), and the recovery of radioactivity from the precipitated 
fraction of TCA was high in most tissues. The drug in its original form, was mainly distributed in 
the blood circulation system, followed by organs having high blood supply, such as lungs, 
gonads, liver, heart and spleen (an immune-related organ). A certain distribution was also found 
in excretory organs and body fluids such as bladder, kidneys, and urine. The drug was less 
distributed in tissues such as eyeballs, fat, pancreas, bone marrow, muscle, and brain. In most 
tissues and organs, the trend of changes over time in the radioactive drug equivalent was 
consistent with the trend in the serum drug concentration-time curves after intravenous infusion 
of the drug. The drug was mainly excreted into the urine of cynomolgus monkeys, while a very 
small amount was excreted in the feces. The cumulative excretion rate exceeded 80% at 408 h 
after a single dose, indicating that the drug clearance was basically completed. As suggested 
above, IBI308 is distributed, mainly in its original form, in circulation systems; its distribution in 
tissues is affected by local blood flow and target antigen distribution; it is metabolized into small 
molecules and excreted in urine. 
1.4.3. Nonclinical toxicological studies of IBI308 
Cynomolgus monkeys were divided into IBI308 6, 40, and 200 mg/kg groups. Corresponding 
doses were given through intravenous infusion. There was no significant effect on CNS, 
cardiovascular system, and respiratory system. A single intravenous injection of up to 400 mg/kg 
IBI308 was given to cynomolgus monkeys. No reactions associated with IBI308 were observed 
in the animals within 14 days after administration. After IBI308 was intravenously injected to 
cynomolgus monkeys at doses of 6 mg/kg, 40 mg/kg and 200 mg/kg once weekly for 5 
consecutive doses, followed by 4-week observation after the drug was discontinued, no adverse 
change was observed in animals in clinical observation, administration site observation, body 
weight, food intake, body temperature, blood pressure, ECG, respiration, ophthalmologic 
examination, hematology, coagulation, blood chemistry, urinalysis, organ weight, gross 
anatomical observation, and histopathological observation. A few animals in the 40 mg/kg group 
and the animals in the 200 mg/kg group showed an increase in globulin (immunoglobulin IgG), 
which may be caused by the fact that IBI308 itself is an IgG monoclonal antibody. The abnormal 
globulin results basically returned to normal at the end of the recovery period. In addition, at the 
above doses, IBI308 showed no effect on the numbers of CD3 + CD4 + cells and CD3 + CD8 + 
cells, or on the ratio between these two types of cells. The NOAEL of IBI308 was 200 mg/kg in 
multi-dose cases. 
As shown by the immunogenicity study results, in the single-/multi-dose PK and toxicokinetic 
studies of IBI308 intravenously infused in cynomolgus monkeys, the production of ADAs was 


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initiated at all doses of IBI308, and some ADAs were NAbs. The result of in vitro hemolysis 
experiment showed that IBI308 did not cause hemolysis at the intended clinical concentrations. 
As suggested above, IBI308 has good safety and tolerability and is suitable for multiple 
intravenous infusions, but it is immunogenic to some extent, to which attention should be paid. 
1.5. Risk and Benefit Assessment 
Risks/benefits were assessed based on nonclinical study results of PK, PD, and toxicology. The 
dose range for this study is proposed to be 1–10 mg/kg. 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. 
The in vivo PD study on drug antitumor efficacy demonstrated that the murine substitute (11430) 
of IBI308 is able to significantly inhibit tumor growth in MC38 tumor-bearing C57bl/6 mouse 
models. In the NSG mouse model (SCID-Winn model) inoculated with a mixture of NCI-H292 
and human PBMCs, IBI308 was able to significantly inhibit tumor cell growth in a evident 
dose-dependent manner, and did not influence body weights of mice. The commercially available 
anti-PD-1/PD-L1 monoclonal antibodies have been widely applied and shown significant 
efficacy in the treatment of advanced melanoma, advanced NSCLC, advanced SCLC, advanced 
head and neck squamous cell carcinoma, advanced classical Hodgkin's lymphoma, primary 
mediastinal diffuse large B-cell lymphoma, advanced renal cell carcinoma, advanced urothelial 
carcinoma, microsatellite instability-high tumors, advanced gastric cancer, advanced cervical 
cancer, advanced HCC, metastatic or locally advanced CSCC. The above data indicate anti-PD-1 
monoclonal antibodies have controllable safety and anti-tumor activity against multiple advanced 
solid tumors, supporting clinical studies in patients with advanced solid tumors. 


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2. STUDY OBJECTIVES 
2.1. Primary Study Endpoints 
• 
To assess the safety and tolerability of IBI308 alone or in combination with 
chemotherapy in subjects with advanced solid tumors; 
• 
To evaluate the anti-tumor activity of the monotherapy or combination chemotherapy of 
IBI308 Treatment in subjects with advanced solid tumors. 
2.2. Secondary Study Endpoints 
• 
To evaluate the PK characteristics of single-dose or multi-dose IBI308 in subjects with 
advanced solid tumors; 
• 
To evaluate the immunogenicity of IBI308 in subjects with advanced solid tumors; 
• 
To evaluate the PD parameters of IBI308 in subjects with advanced solid tumors. 
2.3. Exploratory Objectives 
• 
To explore the use of irRECIST in evaluating the efficacy of IBI308 in subjects with 
advanced solid tumors; 
• 
To explore the potential biomarkers in tumor tissues that can predict the efficacy of 
IBI308: including but not limited to immunohistochemistry assay of PD-L1 expression 
in tumor samples, whole exome sequencing to detect tumor mutation burden (TMB), 
multicolor immunohistochemistry, and PD-L1 and CD8 double staining assay. 
3. Overall Study Design 
This is a multicenter, open-label, phase Ia/Ib study of monotherapy or combination 
chemotherapy of IBI308 in the treatment of advanced malignant tumors in China. 
Phase Ia study: This is designed to investigate tolerability, safety, and PK of IBI308. Around 12–
24 patients with advanced solid tumors that failed standard treatment will be enrolled. The dose 
escalation strategy is established using the standard "3 + 3" design. Four dose levels (1 mg/kg, 3 
mg/kg, 200 mg, and 10 mg/kg) will be evaluated in this section. After the completion of 1 mg/kg 
dose administration, subjects are randomized in a 1:1 ratio to either 3 mg/kg or 200 mg dose 
group for independent evaluations. DLT is observed for 28 days after the first dose for each dose 
group. After completion of DLT observation, subjects are treated with IBI308 Q2W (1 mg/kg, 3 
mg/kg, or 10 mg/kg) or Q3W (200 mg) until PD, intolerable toxicity, withdrawal of ICF, or other 
reasons requiring treatment discontinuation (whichever occurs first). The specific study visit 
arrangement is shown in Table 1 and Table 2. 


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Phase Ib study: This is designed to preliminarily assess the safety and anti-tumor activity of 
IBI308 in the following cohorts. 
• 
Cohort A: Melanoma study, enrolling approximately 10–20 subjects with advanced 
melanoma. They will receive 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). After enrollment of up 
to 20 subjects, the sponsor can decide whether to expand the enrollment based on PK, 
preliminary efficacy, and safety data. The specific study visit arrangement is shown in 
Table 3 and Table 6. 
• 
Cohort B: Study on malignant tumors of the digestive system or neuroendocrine tumors, 
enrolling approximately 50–100 subjects with such tumors who failed or became 
intolerable to first-line systemic standard treatment. They will receive 200 mg IV Q3W 
of IBI308 until PD, intolerable toxicity, withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation of the study treatment (whichever occurs 
first). After enrollment of 50 subjects, the sponsor will terminate the enrollment of 
subjects based on the progress of clinical development and preliminary efficacy and 
safety data of IBI308. The specific study visit arrangement is shown in Table 3 and 
Table 6. 
• 
Cohort C: Lung cancer study, enrolling approximately 10–20 subjects of advanced 
NSCLC who failed or became intolerant to first-line systemic standard treatment. They 
will receive 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of 
informed consent, 24 months of treatment, or other reasons for discontinuation of the 
study treatment (whichever occurs first). The specific study visit arrangement is shown 
in Table 3 and Table 6. 
• 
Cohort D: Study on the safety and preliminary efficacy evaluation of first-line treatment 
of advanced nsNSCLC using IBI308 in combination with chemotherapy, enrolling 
approximately 20 subjects. Each treatment cycle contains 3 weeks. And 200 mg IV of 
IBI308, 500 mg/m2 IV of pemetrexed, and 75 mg2 IV of cisplatin are given on D1 of 
each cycle. Up to 4 cycles of triple drug combination therapy are given. Subsequently, 
the subjects experiencing no PD can receive a maintenance treatment of 200 mg IV 
Q3W of IBI308 and 500 mg/m2 IV Q3W of pemetrexed until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). The specific study visit 
arrangement is shown in Table 4 and Table 6. 


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• 
Cohort E: Study on the safety and preliminary efficacy evaluation of first-line treatment 
of scNSCLC using IBI308 in combination with chemotherapy, enrolling approximately 
20 subjects. Each treatment cycle contains 3 weeks. The dosing regimen is IBI308 200 
mg IV D1 + gemcitabine 1250 mg/m2 IV D1, D8 + cisplatin 75 mg/m2 IV D1. Up to 6 
cycles of triple drug combination therapy are given. Subsequently, the subjects 
experiencing no PD can receive a maintenance treatment of 200 mg IV Q3W of IBI308 
until PD, intolerable toxicity, withdrawal of informed consent, 24 months of treatment, 
or other reasons for discontinuation of the study treatment (whichever occurs first). The 
specific study visit arrangement is shown in Table 4 and Table 6. 
• 
Cohort F: Study on the safety and preliminary efficacy evaluation of first-line treatment 
of inoperable locally progressing, recurrent/metastatic gastric or gastroesophageal 
junction adenocarcinoma using IBI308 in combination with oxaliplatin/capecitabine 
(XELOX), enrolling approximately 20 subjects. Each treatment cycle contains 3 weeks. 
And 200 mg IV of IBI308 and 130 mg/m2 IV of oxaliplatin are given on D1, while 1000 
mg/m2 of capecitabine is given orally bid on D1–14. Up to 6 cycles of triple drug 
combination therapy are given. Subsequently, the subjects experiencing no PD can 
receive a maintenance treatment of 200 mg IV Q3W of IBI308 until PD, intolerable 
toxicity, withdrawal of informed consent, 24 months of treatment, or other reasons for 
discontinuation of the study treatment (whichever occurs first). The specific study visit 
arrangement is shown in Table 4 and Table 6. 
• 
Cohort G: Study on the safety and efficacy evaluation of first-line treatment of 
inoperable locally progressing, recurrent/metastatic high-grade (G3) neuroendocrine 
tumors using IBI308 in combination with chemotherapy, enrolling approximately 15 
subjects. Each treatment cycle contains 3 weeks. The dosing regimen is IBI308 200 mg 
IV D1 + etoposide 100 mg/m2 IV D1–3 + cisplatin 75 mg/m2 IV D1. Up to 6 cycles of 
triple drug combination therapy are given. Subsequently, the subjects experiencing no 
PD can receive a maintenance treatment of 200 mg IV Q3W of IBI308 until PD, 
intolerable toxicity, withdrawal of informed consent, 24 months of treatment, or other 
reasons for discontinuation of the study treatment (whichever occurs first). The specific 
study visit arrangement is shown in Table 5. 
• 
Cohort H: Study on the safety and efficacy of IBI308 in combination with 
chemotherapy in the treatment of subjects with advanced high-grade (G3) 
neuroendocrine tumors who failed first-line systemic standard treatment, enrolling 
approximately 15 subjects. Each treatment cycle contains 3 weeks. The dosing regimen 
is IBI308 200 mg IV D1 + irinotecan 125 mg/m2 IV D1, D8 + 5-FU 1000 mg/m2 IV 
D1–3. Up to 6 cycles of triple drug combination therapy are given. Subsequently, the 


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subjects experiencing no PD can receive a maintenance treatment of 200 mg IV Q3W of 
IBI308 until PD, intolerable toxicity, withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation of the study treatment (whichever occurs 
first). The specific study visit arrangement is shown in Table 5. 
During the treatment with IBI308 in phase Ia and Ib studies, the subjects in Cohorts A, B, and C 
are allowed to continue receiving IBI308 after they are judged to have PD for the first time 
according to the RECIST V1.1 criteria. For the detailed criteria, refer to Section 5.1.2 of the 
protocol. 
After the study treatment is terminated, an end-of-treatment visit is required within 7 days after 
the termination of the study treatment is confirmed and before the subject receive a new 
anti-tumor treatment. A safety follow-up should be carried out within 90 days ± 7 days after the 
last dose or before the start of a new anti-tumor treatment (whichever occurs first). The survival 
follow-up is carried out every 3 months (± 7 days) after the safety follow-up (telephone 
follow-up is acceptable). 
Cohorts G and H of the phase Ib study are newly added for the protocol 3.0. Study sites who 
don't participate in studies in these two cohorts will be closed after the end of clinical studies in 
cohorts A–F. 


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Figure 1. Schematic of phase Ia study design and dosing regimen 
 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PDa 
Cycle 1 
(DLT observation window) 
1 mg/kg, 3 mg/kg, and 10 mg/kg IV. Cycle 1 is the period of DLT observation (28 days), with administration on day 1 only. In cycle 2 and thereafter, subjects are 
administered once every 2 weeks X 200 mg IV. Cycle 1 is the period of DLT observation (28 days), with administration on day 1 only. In cycle 2 and thereafter, 
subjects are administered once every 3 weeks 
Phase Ia dose escalation studya 
Subjects with advanced solid 
tumors 
(N=12-24) 
Randomization in 
a 1:1 ratio 
a Cycle 1 is the period of DLT observation (28 days), with administration on day 1 only. In cycle 2 and thereafter, subjects in the 200 mg dose group are 
administered once every 3 weeks and those in other dose groups are dosed once every 2 weeks. 


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Figure 2. Schematic of phase Ib study design 
 
 
Cohort A 
Cohort B 
Cohort C 
Cohort D 
Cohort E 
Cohort F 
Subjects with advanced melanoma 
IBI308, 200 mg IV Q3W 
IBI308, 200 mg IV Q3W 
IBI308, 200 mg IV Q3W 
IBI308, 200 mg IV D1 Q3W 
Pemetrexed, 500 mg/m2 IV D1 Q3W 
Cisplatin, 75 mg/m2 IV D1 Q3W 
IBI308, 200 mg IV D1 Q3W 
Gemcitabine, 1250 mg/m2 IV D1, D8 Q3W 
Cisplatin, 75 mg/m2 IV D1 Q3W 
IBI308, 200 mg IV D1 Q3W 
Oxaliplatin, 130 mg/m2 IV D1 Q3W 
Capecitabine, 1000 mg/m2 PO BID D1–14 Q3W 
IBI308, 200 mg IV D1 Q3W 
Etoposide, 1000 mg/m2 IV D1–3 Q3W 
Cisplatin, 75 mg/m2 IV D1 Q3W 
IBI308, 200 mg IV D1 Q3W 
Irinotecan, 125 mg/m2 IV D1, D8 Q3W 
Cohort G 
Cohort H 
Subjects with advanced digestive system 
malignancy or neuroendocrine tumors 
Subjects with advanced NSCLC who failed 
first-line therapy 
(N=10~20)b 
Treatment-naive subjects with advanced 
scNSCLC 
(N=20)c 
Treatment-naive subjects with advanced 
nsNSCLC 
(N=20)d 
Treatment-naive subjects with advanced gastric or 
gastroesophageal junction adenocarcinoma 
(N=20)e 
Treatment-naive subjects with advanced 
neuroendocrine tumors 
(N=15)f 
Subjects with advanced neuroendocrine tumors 
who failed first-line therapy 
(N=15)g 
a. After the completion of enrollment in the melanoma cohort, whether to expand the enrollment will be decided based on PK, preliminary 
efficacy, and safety 
b. During the treatment with IBI308 alone, subjects meeting protocol requirements and achieving PD can continue receiving IBI308. 
c. IBI308 in combination with pemetrexed and cisplatin is given for up to 4 cycles, followed by maintenance treatment with IBI308 in 
combination with pemetrexed. 
d. IBI308 in combination with gemcitabine and cisplatin is given for up to 6 cycles, followed by maintenance treatment with IBI308. 
e. IBI308 in combination with oxaliplatin and capecitabine is given for up to 6 cycles, followed by maintenance treatment with IBI308. 
f. IBI308 in combination with etoposide and cisplatin is given for up to 6 cycles, followed by maintenance treatment with IBI308. 
g. IBI308 in combination with irinotecan and 5-FU is given for up to 6 cycles, followed by maintenance treatment with IBI308. 


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Figure 3. Schematic of dosing regimen for cohorts A/B/C in the phase Ib study 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PDa 
X  IBI308, 200 mg IV D1 Q3W 
a  
Some subjects judged to be eligible by the 
investigator can continue to use the drug after 
treatment for PD 


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Figure 4. Schematic of dosing regimen for cohort D in the phase Ib study 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PD 
X IBI308, 200 mg IV D1 Q3W 
& Pemetrexed, 500 mg/m2 IV D1 Q3W 
* Cisplatin, 75 mg/m2 IV D1 Q3W 


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Figure 5. Schematic of dosing regimen for cohort E in the phase Ib study 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PD 
X IBI308, 200 mg IV D1 Q3W 
& Gemcitabine, 1250 mg/m2 IV D1, D8 Q3W 
* Cisplatin, 75 mg/m2 IV D1 Q3W 


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Figure 6. Schematic of dosing regimen for cohort F in the phase Ib study 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PD 
X IBI308, 200 mg IV D1 Q3W 
& Capecitabine, 2000 mg/m2 PO BID D1–14 Q3W 
* Oxaliplatin, 130 mg/m2 IV D1 Q3W 


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Figure 7. Schematic of dosing regimen for cohort G in the phase Ib study 
 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PD 
X IBI308, 200 mg IV D1 Q3W 
& Etoposide, 100 mg/m2 IV D1–3 Q3W 
* Cisplatin, 75 mg/m2 IV D1 Q3W 


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Figure 8. Schematic of dosing regimen for cohort H in the phase Ib study 
 
Screening period 
Treatment period 
Follow-up period 
Day −28 
PD 
X IBI308, 200 mg IV D1 Q3W 
& Irinotecan, 125 mg/m2 IV D1, D8 Q3W 
* 5-FU, 1000 mg/m2 IV D1–3 Q3W 


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3.1. Design Principles 
3.1.1. IBI308 dose selection principles 
In the first-in-human study of IBI308, the recommended starting dose is 1 mg/kg. 
The starting dose of 1 mg/kg is designed based on multiple evidence data from in vitro activity 
studies, nonclinical PK/PD studies, nonclinical efficacy studies in disease models, and 
comparability studies of IBI308 vs. marketed drugs with the same mechanism of action. This 
recommended starting dose of 1 mg/kg is expected to (a) obtain the PK and immunogenicity 
characteristics of IBI308 in the target population for the first time and (b) to determine the 
IBI308 exposure (about 10 μg/mL, determined based on nonclinical data and clinical data of 
drugs of the same class) delivering the maximum anti-tumor activity in animal models, while 
ensuring the safety of subjects. 
The dose range of this study is proposed, based on PK/PD data and toxicology data from 
completed studies, to be 1–10 mg/kg. The proposed maximum dose of 10 mg/kg is 
approximately 1/6 of NOAEL in cynomolgus monkeys and 1/13 of NOEL in cynomolgus 
monkeys. 
Based on the above analyses and PK/PD characteristics, the dose is proposed to be escalated via 
semi-logarithmic increment including 1 mg/kg, 3 mg/kg, 200 mg, and 10 mg/kg. 
3.1.2. Rationale for selecting melanoma, gastrointestinal tumors, neuroendocrine 
neoplasms, and lung cancer for the phase Ib study 
Lung cancer and malignant gastrointestinal tumors (mainly including esophageal carcinoma, 
gastric cancer, and hepatic cancer) rank the top four causes of cancer-related deaths in China, and 
there is a large unmet medical demand. Although the incidence of melanoma and neuroendocrine 
neoplasms among Chinese is low, it has increased rapidly in recent years. Currently, nivolumab 
and pembrolizumab have been approved for the treatment of advanced melanoma and lung 
cancer. At present, anti-PD-1/PD-L1 treatment has shown some positive clinical study results in 
the treatment of esophageal carcinoma, gastric cancer, and hepatic cancer, but the current 
standard treatment for neuroendocrine neoplasms is poorly efficacious, especially in the 
treatment of G3 type neuroendocrine tumors. Therefore, the efficacy of anti-PD-1 monoclonal 
antibody in neuroendocrine tumors is worth further exploration. 
In a phase Ib clinical study (KEYNOTE-028) of pembrolizumab in advanced esophageal 
carcinoma that failed or became intolerant to at least first-line systemic treatment[28], the ORR 
was 30% (95% CI: 13–53). In a phase Ib study of averumab monotherapy in treating 
unresectable advanced gastric and gastroesophageal junction carcinoma, the patients who failed 
first-line treatment or received a maintenance treatment after first-line chemotherapy were 


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enrolled, and their ORR was 9.7% and 9.0%, respectively, while their DCR was 29.0% and 
57.3%, respectively. In the PD-L1 positive (≥ 1%) population, the ORR was 18.2% (95% CI: 
2.3–51.8) and 10.0% (95% CI: 1.2–31.7), respectively[29]. The CheckMate-032 study was a 
Phase I/II study evaluating the use of nivolumab alone or in combination with anti-CTLA-4 
antibody ipilimumab in the treatment of patients with malignant tumors of the stomach, 
esophagus, and gastroesophageal junction who failed standard chemotherapy, and the ORR 
judged by the investigator was 12% (nivolumab 3 mg/kg), 24% (nivolumab 1 mg/kg in 
combination with ipilimumab 3 mg/kg), and 8% (nivolumab 3 mg/kg in combination with 
ipilimumab 1 mg/kg), respectively, while the ORR in the PD-L1 positive (≥ 1%) population was 
19%, 40%, and 23%, respectively[30]. Currently, a number of clinical studies for registration are 
ongoing to test anti-PD-1/PD-L1 monoclonal antibody products in the treatment of advanced 
esophageal carcinoma and gastric cancer. 
In a phase I/II clinical study (CheckMate-040) evaluating the efficacy of nivolumab in subjects 
with advanced hepatic cancer[31], the ORR in the dose-escalation stage and dose-expansion stage 
was 15% (95% CI: 6–28) and 20% (95% CI: 15–26), respectively, and the 9-month OS rates 
were 66% (95% CI: 51–78) and 74% (95% CI: 67–79), respectively. Currently, a phase III 
clinical study comparing the efficacy of nivolumab and sorafenib in the first-line treatment of 
advanced hepatic cancer is ongoing (CheckMate-459)[32]. 
Nivolumab and pembrolizumab have good efficacy and safety in the second-line treatment of 
NSCLC, and both have been approved by the US FDA[25,26]. Compared with docetaxel, 
nivolumab prolonged the survival of unselected nsNSCLC and scNSCLC without EGFR 
mutation or ALK rearrangement by 3.2 months and 2.8 months, respectively, with significant 
statistical differences[25]. Compared with docetaxel, pembrolizumab shows significant survival 
benefits in NSCLC of weakly positive PD-L1 expression that has failed first-line treatments[26]. 
3.1.3. The principle of giving combined treatment of IBI308 and chemotherapy to patients 
with lung cancer 
Nivolumab and pembrolizumab have good efficacy and safety in the second-line treatment of 
NSCLC, and both have been approved by the US FDA. However, the ORR of their monotherapy 
is only about 20%[25,26], and most subjects cannot benefit from the drugs. Currently, many 
clinical studies evaluating the efficacy of anti-PD-1/PD-L1 monoclonal antibody products in 
combination with chemotherapy, anti-vascular therapy, targeted therapy, and other 
immunomodulatory target drugs in lung cancer treatment are ongoing. In the KEYNOTE-021 
study, the efficacy of pembrolizumab in combination with platinum-based chemotherapy as the 
first-line treatment of advanced NSCLC without EGFR mutation or ALK rearrangement was 
evaluated. The ORR reached 48% (pembrolizumab in combination with carboplatin and 
paclitaxel, for all histological types), 56% (pembrolizumab in combination with carboplatin, 


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paclitaxel, and bevacizumab for nsNSCLC), and 75% (pembrolizumab in combination with 
carboplatin and pemetrexed for nsNSCLC), respectively, while the median PFS reached 10.3 
months (95% CI: 6.1–14.6), 7.1 months (95% CI: 4.2–14.3), and 10.2 months (95% CI: 6.5–
13.9), respectively[33]. In a phase I clinical trial evaluating the safety and efficacy of nivolumab 
in combination with different platinum-based doublet chemotherapies as the first-line dual-drug 
treatment of NSCLC, the combination therapy was well tolerated. The ORR of nivolumab in 
combination with pemetrexed + cisplatin was 47%, while the ORR of nivolumab in combination 
with cisplatin + gemcitabine was 33%. The PFS rates after 24 weeks of treatment were 51% and 
71%, respectively, while the 2-year survival rates were 25% and 33%, respectively[34]. The 
KEYNOTE-189 study was a phase III, randomized, and double-blind study comparing 
pembrolizumab or placebo in combination with pemetrexed and platinum-based chemotherapy 
for the first-line treatment of metastatic nsNSCLC without EGFR mutation or ALK 
rearrangement. The 12-month OS rates of pembrolizumab vs. placebo were 69.2% and 49.4% 
(HR 0.49; 95% CI, 0.38–0.64; P < 0.001), respectively, and the benefit in OS was present in all 
subgroups with various levels of PD-L1 expression. The ORR of the two groups was 47.6% (95% 
CI: 42.6–52.5) and 18.9% (95% CI: 13.8–25.0) (P < 0.001), respectively[35]. 
3.1.4. The principle of giving combined treatment of IBI308 and chemotherapy to patients 
with previously untreated gastric or gastroesophageal junction adenocarcinoma 
For advanced gastric cancer, several studies have shown that compared with the best supportive 
care, chemotherapy can give subjects a significant survival benefit. Based on the ML17032 study, 
5-FU in combination with cisplatin or capecitabine is one of the recognized first-line treatment 
options for advanced gastric cancer[36]. The REAL-2 study further proved that capecitabine was 
not inferior to 5-fluorouracil, and oxaliplatin was not inferior to cisplatin[37]. In the TOGA study, 
the combination of trastuzumab with chemotherapy can significantly prolong the survival of 
patients of gastric or gastroesophageal junction adenocarcinoma with HER2 gene amplification 
or high HER2 protein expression[38]. The KEYNOTE-012 study enrolled PD-L1 positive patients 
with recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. The ORR of 
pembrolizumab monotherapy (judged by central imaging) was 22.2% (95% CI, 10–39); the 
median DOR was 40 weeks; and the median OS was 11.4 months (95% CI, 5.7–NR)[39]. In a 
phase Ib study of averumab monotherapy in treating unresectable advanced gastric and 
gastroesophageal junction carcinoma, the patients who failed first-line treatment or received a 
maintenance treatment after first-line chemotherapy had ORR of 9.7% and 9.0%, respectively, 
while their DCR was 29.0% and 57.3%, respectively. In the PD-L1 positive (≥ 1%) population, 
the ORR was 18.2% (95% CI, 2.3–51.8) and 10.0% (95% CI, 1.2–31.7), respectively[29]. 
However, in a phase III randomized and open-label study (JAVELIN Gastric 300) of avelumab 
versus chemotherapy for third-line treatment of advanced gastric or gastroesophageal junction 


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carcinoma, the primary endpoint OS and secondary endpoints PFS and ORR were not 
reached[40]. 
Based on the preliminary study results of anti-PD-1/PD-L1 antibody in advanced gastric cancer, 
a number of phase II/III clinical studies are underway to evaluate the survival benefit of immune 
checkpoint drugs in the first-line treatment of gastric or gastroesophageal junction carcinoma, 
including CheckMate-649[41] (comparing nivolumab in combination with ipilimumab vs. 
nivolumab in combination with chemotherapy vs. chemotherapy alone, NCT02872116), 
ATTRACTION-4 (comparing nivolumab in combination with chemotherapy vs. placebo in 
combination with chemotherapy, NCT02746796), KEYNOTE-062[42] (comparing 
pembrolizumab alone or in combination with chemotherapy vs. chemotherapy alone for the 
treatment of PD-L1 positive patients, NCT02494583), and JAVELIN Gastric 100 (comparing 
avelumab monotherapy or maintenance chemotherapy for the treatment of patients achieving SD 
after first-line treatment with platinum-based chemotherapy, NCT02625610). Among them, the 
interim analysis of part 1 of the ATTRACTION-4 study[43] obtained an ORR of 68.4% and a 
DCR of 86.6%. 
3.1.5. Rationale for exploring PD-L1 as a biomarker 
PD-L1 expression is upregulated in a variety of solid tumors. The expression of PD-L1 is closely 
related to the shortened survival and poor prognosis of various tumors[16-23] such as lung caner, 
hepatic cancer, gastric cancer, esophageal carcinoma, urothelial carcinoma, renal carcinoma, 
pancreatic cancer, and ovarian cancer. In in vitro studies, tumor cells expressing PD-L1 could 
promote the apoptosis of activated tumor-specific T cells, while tumor cells could avoid being 
killed by effector T cells[44,45]. The PD-L1 expression level in tumor tissue was shown in multiple 
clinical studies of nivolumab and pembrolizumab to be positively correlated with the 
efficacy[46,47]. Based on the above evidence, the PD-L1 expression level in tumor tissue may be 
associated with the efficacy of IBI308, so preliminary biomarker exploration is necessary. 
3.1.6. Rationale for treatment after progressive disease 
Clinical data from approved products showed that a small number of subjects receiving 
immunotherapy may benefit clinically despite of preliminary evidence of PD (based on routine 
response criteria) prior to achieving objective response and/or SD. This phenomenon may be 
explained by two reasons. First, aggravated inflammation in tumors may lead to increase of 
tumor volume, manifested as an increased measurable lesion size and emergence of new, visible, 
non-measurable lesions. Over time, the malignant and inflammatory parts of the mass may 
shrink, resulting in significant imaging response and improvement in clinical signs. Second, in 
some patients, the initiation of anti-tumor immune response is slow, and tumor inhibition in the 
early stages is less than the tumor growth. Over time, anti-tumor activity will dominate, giving 
rise to imaging response and improvement in clinical signs. Therefore, study treatment continued 


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for subjects treated with IBI308 if they benefited clinically from and were tolerant to the study 
drug despite of preliminary evidence of PD defined by RECIST V1.1, as assessed by the 
investigators (see Section 5.1.2). Subjects must discontinue the study treatment if there is further 
evidence of PD. 
3.2. Phase Ia Study 
3.2.1. Dose-limiting toxicity (DLT) 
Based on the toxicity evaluation criteria from NCI CTCAE V4.03, DLT refers to any of the 
following IBI308-related AE that is observed during the Cycle 1 (Days 1–28) in the phase Ia 
dose-escalation study: 
1. Hematological toxicity: 
• 
Grade 4 hematological toxicity lasting > 7 days. 
• 
Grade 3 thrombocytopenia with bleeding tendency or requiring platelet transfusion. 
• 
Grade 3 neutropenic fever with bacteremia or sepsis. 
2. Non-hematological toxicity: 
• 
Any grade 4 irAE. 
• 
Grade 3 pneumonia. 
• 
Grade 2 pneumonia that does not recover to ≤ grade 1 within 14 days after intervention. 
• 
Other grade 3 irAEs that do not recover to ≤ grade 2 within 3 days after intervention or 
≤ grade 1 within 14 days after intervention (except for asymptomatic grade 3 thyroid, 
adrenal gland, or pituitary insufficiency, and grade 3 inflammatory responses at the 
tumor site). 
• 
Other grade 3 or 4 non-hematological toxicity (excluding: grade 3 electrolyte 
abnormalities, grade 3 or 4 IRRs, manageable grade 3 hypertension, grade 3 infusion 
site extravasation, grade 3 arthralgia/myalgia, grade 3 asthenia/fatigue, manageable 
grade 3 vomiting, grade 3 or 4 liver transaminase elevation lasting < 7 days). 
3. Any grade 5 AE. 
Note: Grade 3 or 4 IRR is not a DLT. However, if a grade 3 or 4 IRR occurs, subject needs to 
discontinue treatment and be replaced by a new subject. If ≥ 2 subjects experience a grade 3 or 4 
IRR in any treatment group, then enrollment must be suspended. The sponsor needs to review the 
safety data to determine whether to continue enrolling subjects. 


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3.2.2. Maximal tolerated dose (MTD) 
MTD often refers to the highest dose that causes DLT in ≤ 1/6 of subjects in Cycle 1 of treatment 
(Days 1–28). If DLT is observed in > 1/6 of subjects in one dose group, the previous lower dose 
level will be regarded as the MTD. 
3.2.3. Dose escalation method 
The dose escalation in this study is based on the standard "3 + 3" design. 
The initial daily dose is 1 mg/kg and is proposed to escalated to 3 mg/kg and 200 mg 
(randomized at 1:1 and studied simultaneously) and then to 10 mg/kg. The Safety Assessment 
Committee will determine, based on the safety of the previous dose, whether the next dose will 
be studied. If no DLT is observed in the first three subjects enrolled in one dose group, the trial 
will be initiated in the next dose group. If DLT is observed in one (1/3) of the first three subjects 
enrolled in one dose group, three new subjects will be enrolled in this dose group (thus 6 in total 
in this dose group). The trial will be carried out in the next dose group if no DLT is observed in 
the three new subjects. If DLT is observed in one or more of the three new subjects or in 2 or 
more of all 6 subjects, the dose escalation won't be allowed. Meanwhile, another 3 subjects need 
to be enrolled into the previous dose group (and so on) until determination of MTD. Therefore, 
the MTD dose group requires at least 6 subject for confirmation. The dose escalation is detailed 
in Table 7. 
Table 7. Dose escalation method 
Dose 
group 
Dose 
Route of administration 
Number of 
subjects 
1 
1 mg/kg 
IV, Day 1 of Cycle 1 
3–6 
2 
3 mg/kg or 200 mg (randomized at 1:1 and studied 
simultaneously) 
IV, Day 1 of Cycle 1 
3–6 per group 
3 
10 mg/kg 
IV, Day 1 of Cycle 1 
3–6 
3.2.4. Subjects evaluable for DLT 
Subjects evaluable for DLT need to meet any of the following criteria: 
1. DLT is observed in the DLT observation window (Cycle 1, Days 1–28). 
2. DLT observation is completed within the specified time window. 
When one subject does not meet one of the above criteria, a new subject will be enrolled. 


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3.3. Phase Ib Study 
3.3.1. Treatment regimen selection for the phase Ib study 
Based on animal experimental results and published data of products of the same class, the 200 
mg IV Q3W is selected as the primary treatment regime for the phase Ib study. 
4. STUDY POPULATION 
4.1. Inclusion Criteria 
1. Subjects with advanced solid tumors, including: 
1) Phase Ia: Patients with locally advanced, recurrent, or metastatic solid tumors that failed 
standard treatment; 
2) Phase Ib: 
Cohort A: 
• 
Patients with locally advanced, recurrent or metastatic melanoma confirmed by 
cytology or histology. 
Cohort B: 
• 
Patients with locally advanced, recurrent or metastatic esophageal squamous cell 
carcinoma confirmed by cytology or histology who failed or became intolerant to 
first-line systemic standard treatment; 
• 
Patients with locally advanced, recurrent or metastatic gastric adenocarcinoma 
(including gastroesophageal junction adenocarcinoma) confirmed by cytology or 
histology who failed or became intolerant to first-line systemic standard treatment; 
• 
Patients with locally advanced, recurrent or metastatic HCC confirmed by cytology 
or histology who were not suitable for locoregional treatment or failed locoregional 
treatment and failed or became intolerant to first-line systemic standard treatment; 
• 
Patients with other advanced malignant tumors of the digestive system who failed or 
became intolerant to standard therapy; 
• 
Patients with advanced neuroendocrine neoplasms who failed, became intolerant, or 
refused to receive standard therapy: 
- 
Metastatic neuroendocrine neoplasms confirmed by histopathology, including 
well differentiated neuroendocrine tumors and poorly differentiated 
neuroendocrine carcinomas; 
- 
With imaging-confirmed tumor PD within 12 months before the first dose; 


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- 
For poorly differentiated neuroendocrine carcinoma, they should show 
progression after being treated with platinum-based regimens; for 
well-differentiated neuroendocrine tumors, they should have received at least 
one systemic treatment, including somatostatin analogs, mTOR inhibitors, 
anti-angiogenic drugs, and chemotherapy; 
- 
Patients with neuroendocrine tumors or neuroendocrine carcinomas who cannot 
tolerate or refuse to receive the above treatment can also be enrolled; 
Cohort C: 
• 
Patients with locally advanced, recurrent or metastatic NSCLC confirmed by 
cytology or histology who failed or became intolerant to first-line systemic standard 
treatment; 
• 
Excluding patients with EGFR mutations and ALK rearrangements. 
Cohort D: 
• 
Patients with inoperable locally advanced (stage IIIB), recurrent or metastatic (stage 
IV) nsNSCLC (staged according to the 7th edition of "Staging Manual in Thoracic 
Oncology" published by the International Association for the Study of Lung Cancer) 
confirmed by histology or cytology who previously not received first-line treatment; 
• 
Excluding patients with EGFR mutations and ALK rearrangements; 
• 
For patients with stage IIIB nsNSCLC who previously received platinum-based 
adjuvant, neoadjuvant, or radical chemoradiotherapy, if local recurrence or distant 
metastasis occurred within 6 months after the treatment was completed, the previous 
platinum-based treatment will be considered to be a first-line treatment and hence the 
patients cannot be enrolled into the cohort. 
Cohort E: 
• 
Patients with inoperable locally advanced (stage IIIB), recurrent or metastatic (stage 
IV) scNSCLC (staged according to the 7th edition of "Staging Manual in Thoracic 
Oncology" published by the International Association for the Study of Lung Cancer) 
confirmed by histology or cytology who previously not received first-line treatment; 
• 
Excluding patients with EGFR mutations and ALK rearrangements. 
• 
For patients with stage IIIB scNSCLC who previously received platinum-based 
adjuvant or neoadjuvant chemotherapy or radical chemoradiotherapy, if local 
recurrence or distant metastasis occurred within 6 months after the treatment was 
completed, the previous platinum-based treatment will be considered to be a 
first-line treatment and hence the patients cannot be enrolled into the cohort. 


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Cohort F: 
• 
Patients with inoperable locally advanced, recurrent or metastatic gastric or 
gastroesophageal junction adenocarcinoma confirmed by histopathology; 
• 
Excluding patients with known HER2 gene amplification or overexpression. 
• 
Not previously treated by chemotherapy for advanced diseases, or with progression 
occurring more than 6 months after the end of systemic adjuvant therapy; 
Cohort G: 
• 
Previously untreated patients with inoperable locally progressive, recurrent or 
metastatic high-grade (G3) neuroendocrine tumors confirmed by histology or 
cytology. 
• 
Patients must have high-grade (G3) neuroendocrine tumors with a Ki-67 index of > 
20%. 
• 
Not previously treated by chemotherapy for advanced diseases, or with progression 
occurring more than 6 months after the end of systemic adjuvant therapy. 
Cohort H: 
• 
Patients with advanced high-grade (G3) neuroendocrine neoplasms confirmed by 
histology or cytology who failed first-line systemic standard treatment. 
• 
Patients must have high-grade (G3) neuroendocrine tumors with a Ki-67 index of > 
20%. 
• 
For patients who received adjuvant or neoadjuvant chemotherapy for neuroendocrine 
tumors, if local recurrence or distant metastasis occurred within 6 months after this 
treatment was completed, this treatment will be considered to be a first-line treatment 
and hence the patients can be enrolled into the cohort. 
2. Patients who have signed ICF, and are able to complete follow-up visits and relevant 
procedures required in the protocol. 
3. Ages ≥ 18 and ≤ 70 years. 
4. Estimated survival ≥ 12 weeks. 
5. Patients with at least one measurable or evaluable lesion according to "Response Evaluation 
Criteria in Solid Tumors" version 1.1 (RECIST V1.1). 
6. An Eastern Cooperative Oncology Group Performance Status (ECOG PS score) score of 0 
or 1. 


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7. Patients (female patients of childbearing age or male patients whose sexual partners are of 
childbearing age) must take effective contraceptive measures during the entire course of the 
trial and 6 months after the treatment (see Table 22 in Section 5.7.2) 
8. Sufficient organ and bone marrow functions, as defined below: 
1) Routine blood test: ANC ≥ 1.5 × 109/L, PLT ≥ 100 × 109/L, HGB ≥ 9.0 g/dL. 
2) 
Hepatic function: TBIL ≤ 1.5 × ULN; for patients with HCC, liver metastases, or 
suspected/history of Gilbert syndrome (persistent or recurrent hyperbilirubinemia, mainly 
unconjugated bilirubin, no evidence of hemolysis or liver disease), TBIL≤ 3 × ULN; for 
patients without HCC or liver metastases, ALT and AST ≤ 2.5 × ULN; for patients with 
HCC or liver metastases, ALT and AST ≤ 5 × ULN. 
3) Renal function: Cr ≤ 1.5 × ULN or CCr ≥ 50 mL/min; urinalysis results showing urine 
protein < 2+; for patients whose baseline urinalysis results showed urine protein ≥ 2+, 24-h 
urine collection should be required and the protein content in the collected urine should be < 
1 g. 
4) Coagulation: APTT and INR ≤ 1.5 × ULN. 
5) TSH or FT4 is within the normal range. 
4.2. Exclusion Criteria 
1. Previous exposure to any anti-PD-1 or anti-PD-L1 antibody. 
2. Experienced any ≥ grade 3 irAE (based on NCI CTCAE V4.03) while receiving any 
immunotherapy drugs in the past. Patients who were treated with ipilimumab are not 
enrolled unless all of the following criteria are met: 
• 
The ipilimumab-related irAE has completely recovered, and the treatment of irAE have 
ended 4 weeks before the first dose of IBI308; 
• 
There was at least a 12-week interval between the first dose of ipilimumab and the first 
dose of IBI308 and a 6-week interval between the last dose of ipilimumab and the first 
dose of IBI308; 
• 
The use of ipilimumab did not result in grade 4 irAEs or grade 3 irAEs requiring > 4 
weeks of treatment; 
• 
A clear PD was observed after the last dose of ipilimumab. 
3. Enrolled in another interventional clinical study, unless only involved in an observational 
study (non-interventional) or in the follow-up phase of an interventional study. 
4. Received any investigational drug within 4 weeks prior to the first dose of IBI308. 


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5. Received the last dose of anti-tumor therapy (chemotherapy, endocrine therapy, targeted 
therapy, immunotherapy, tumor embolization) within 3 weeks before the first dose of IBI308; 
received the last dose of biologics, nitrosourea or mitomycin C within 6 weeks before the 
first dose of IBI308 (if the biological product received was for antitumor endocrine therapy, 
refer to the requirement of "received the last dose within 3 weeks before the first dose of 
IBI308"). 
6. Received immunosuppressants within 4 weeks before the first dose of IBI308, excluding 
locoregional glucocorticoids administered by nasal, inhaled, or other routes, or systemic 
glucocorticoids of physiological doses (no more than 10 mg/day of prednisone or 
equivalents). Glucocorticoid administration for pretreatment or special examinations is 
allowed. 
7. Received a live attenuated vaccine within 4 weeks prior to the first dose of IBI308, or plan 
to receive this vaccine during the study period. 
8. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to 
the first dose of IBI308, or has unhealed wounds, ulcers, or fractures. 
9. Antitumor therapy-induced toxicity (excluding alopecia) that has not yet resolved to NCI 
CTCAE V4.03 grade 0 or 1 prior to the first dose of IBI308. 
10. Previously received whole pelvic radiotherapy. 
11. Subjects with known leptomeningeal metastasis; subjects with untreated or treated but 
uncontrolled CNS metastasis, excluding those who were treated, are now stable, and stopped 
glucocorticoids and anticonvulsants ≥ 4 weeks prior to receiving the first dose of IBI308. 
12. Known active autoimmune disease (see Appendix 5) or a history of such disease within the 
past 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring 
systemic treatment within the next 2 years, or those with hypothyroidism only requiring 
thyroid hormone replacement, or those with type I diabetes only requiring insulin 
replacement may be enrolled). For patients with positive autoimmune antibodies only, they 
should be evaluated by the investigator to determine whether they have an autoimmune 
disease. 
13. Known history of primary immunodeficiency diseases. 
14. Known history of pulmonary tuberculosis. 
15. Known history of allotransplantation or allogeneic hematopoietic stem cell transplantation. 


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16. Known allergy to any ingredients in IBI308; or previous severe allergic reactions to other 
monoclonal antibodies; for Cohort D of the phase Ib study, patients who were previously 
allergic to pemetrexed or cisplatin, or patients who were unable or unwilling to receive folic 
acid and/or vitamin B12 treatment; for Cohort E of the phase Ib study, patients who were 
previously allergic to cisplatin or gemcitabine. For Cohort F of the phase Ib study, patients 
who were previously allergic to capecitabine or oxaliplatin; for Cohort G of the phase Ib 
study, patients who were previously allergic to etoposide or cisplatin; for Cohort H of the 
phase Ib study, patients who were previously allergic to irinotecan or 5-FU. 
17. Uncontrolled concurrent diseases including but not limited to: 
• 
Those infected with HIV (positive for HIV1/2 antibody). 
• 
Active or poorly clinically controlled serious infections. 
• 
Symptomatic congestive cardiac failure (New York Heart Association (NYHA) Class 
II–IV) or symptomatic or poorly controlled arrhythmia. 
• 
Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) despite of standard treatment. 
• 
Any arterial thromboembolic events occurred within 6 months prior to enrollment, 
including myocardial infarction, unstable angina, cerebrovascular accident, or transient 
cerebral ischemic attack. 
• 
Patients with esophageal or gastric varices requiring immediate intervention (such as 
variceal ligation or sclerotherapy) or those considered to have a high bleeding risk by 
the investigator, gastroenterologist, or hepatologist. Patients with signs of portal 
hypertension (including splenomegaly confirmed by medical imaging) or a history of 
variceal bleeding are required to undergo endoscopy within 3 months prior to 
enrollment. 
• 
Life-threatening hemorrhagic events or grade 3 or 4 gastrointestinal/variceal 
hemorrhage requiring blood transfusion, endoscopy, or surgical treatment within 3 
months prior to enrollment. 
• 
History of deep venous thrombosis, pulmonary embolism, or other serious 
thromboembolic events within 3 months prior to enrollment (implantable port or 
catheter-related thrombosis, or superficial venous thrombosis are not considered as 
"serious" thromboembolisms). 
• 
Uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or 
cancer-related secondary diseases that may lead to high medical risks and/or 
uncertainty in survival evaluation. 


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• 
Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B 
or C (see Appendix 7 for Child-Pugh grading). 
• 
Bowel obstruction or history of the following diseases: inflammatory bowel disease or 
extensive bowel resection (partial colectomy or extensive small bowel resection 
accompanied with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic 
diarrhea. 
• 
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. 
18. Patients with acute or chronic active hepatitis B or hepatitis C infection (for patients treated 
with IBI308 monotherapy, they will be enrolled if their HBsAg is positive but their HBV 
DNA copy number is 1 × 104/mL; for patients treated with IBI308 in combination with 
chemotherapy, they will be enrolled only if their HBsAg is positive and their HBV DNA 
copy number is below the LLD. For the prevention and treatment requirements, refer to "The 
Guideline of Prevention and Treatment for Chronic Hepatitis B: A 2015 Update"; patients 
with inactive Hepatitis C are allowed for enrollment). 
19. History of GI perforation and/or fistula within 6 months prior to the enrollment. 
20. Interstitial lung diseases (including previous and current history, refer to Appendix 6). 
21. Clinically uncontrollable third space effusion, such as pleural effusion and ascites that 
cannot be controlled by drainage or other methods prior to enrollment. 
22. History of other primary malignant tumors, excluding: 
• 
History of radical treatment for malignant tumors with no evidence of tumor recurrence 
for more than 5 years prior to enrollment and with a very low risk of recurrence; 
• 
Adequately treated nonmelanoma skin cancer or lentigo maligna with no signs of 
disease recurrence; 
• 
Adequately treated carcinoma in situ with no signs of disease recurrence. 
23. Pregnant or breastfeeding female patients. 
4.3. Restrictions During the Study 
• 
Subjects should not donate blood during the study or within 12 weeks after the end of 
the last dose. 


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• 
See Section 5.7 for medications in pregnant or lactating females and females of 
childbearing age. 
4.4. Study Discontinuation/Withdrawal of Subjects 
Subjects should discontinue/withdraw from the study in any of the following circumstances: 
1. Subjects do not meet the inclusion/exclusion criteria, and are deemed unsuitable to 
continue participating in this study by the sponsor and investigator; 
2. Subjects are enrolled in any other clinical trial of study drugs or in another clinical trial 
that is considered scientifically or medically incompatible with this study. 
3. Subjects seriously violate the study protocol, and are deemed unsuitable to continue this 
study by the sponsor and investigator. 
4. Subjects are lost to follow-up (study site personnel shall regain contact with the subjects 
to determine the cause of loss to follow-up and reschedule study visits if possible. The 
date and method of contact shall be documented in the study documents). 
5. Decided by the investigator 
• 
Based on the safety and benefits of the subjects, the investigator believes that the 
subjects should terminate the treatment and withdraw from the study. 
• 
If the subjects require treatment with another drug for any reason, and the drug has 
been demonstrated to be effective for the indication of this study, then the subject 
shall withdraw from this study prior to starting the new drug. 
• 
Subjects receiving IBI308 monotherapy develop PD, and the investigator believes it is 
inappropriate for them to continue the study treatment (IBI308 therapy can be 
continued after PD in the circumstances specified in "Section 5.1.2" of the study 
protocol). 
• 
Grade 3–4 IRRs occur and cannot be attributed to one study drug in the opinion of the 
investigator (considered to be likely related to at least one study drug). 
• 
Any treatment-related event that is considered to be life-threatening occurs, regardless 
of the severity level of the event. 
• 
The study drug shall be discontinued due to toxicities (see Section 5.4.1 and 5.4.2). 
• 
The investigator believes that the concurrent disease during the treatment or any 
change in the subject's condition renders the subject unsuitable for subsequent 
treatment. 


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6. Subjects or their representatives (such as parents or legal guardians) request withdrawal 
from the study or discontinuation of the study drug (subjects may be eligible for 
long-term follow-up if they withdraw ICF for treatment but not for follow-up). 
7. The sponsor may discontinue the study or discontinue subject participation in the study 
due to medical, safety, regulatory, or other reasons related to the applicable laws, 
regulations, and "Good Clinical Practice" (GCP). 
The reasons and dates of discontinuation for all the subjects shall be documented. Subjects who 
have been randomized but have discontinued the treatment shall undergo related study 
procedures as specified in the study visit schedule regardless of whether they have received the 
study drugs. 
5. STUDY DRUGS AND OTHER TREATMENTS 
5.1. Treatment Regimen 
5.1.1. Treatment regimen for the phase Ia/Ib study 
In phase Ia an Ib studies, the study drug of Cohorts A, B, and C is IBI308. In the phase Ib study, 
the study drugs of Cohort D are IBI308, pemetrexed, and cisplatin; those of Cohort E are IBI308, 
gemcitabine, and cisplatin; those of Cohort F are IBI308, oxaliplatin, and capecitabine; those of 
Cohort G are IBI308, etoposide, and cisplatin; those of Cohort H are IBI308, irinotecan, and 
5-FU. Other drugs used in the study are non-study drugs. The treatment regimen is shown in 
Table 8. Refer to Section 5.3 of the protocol for chemotherapy pretreatment. Subjects in Cohorts 
D, E, and F are given chemotherapy after 1 h of observation following the end of the 
administration of IBI308 in the first 2 cycles; if there are no infusion related adverse reactions, 
this observation can be omitted in Cycle 3 and subsequent cycles. 
Table 8. Dose and treatment protocol 
Study phase 
Drug 
Dose, route of 
administration, and cycle 
Duration of administration 
Phase Ia 
IBI308 
1 mg/kg, 3 mg/kg, and 10 
mg/kg IV Q2W, 200 mg IV 
Q3W 
Until PD (refer to Section 5.1.2 in the 
protocol for continued treatment after PD), 
intolerable toxicity, withdrawal of informed 
consent, up to 24 months of treatment, or 
other reasons for discontinuation of the study 
treatment (whichever occurs first). 
Cohorts A–C of 
the phase Ib 
study 
IBI308 
200 mg IV Q3W 
Cohort D of the 
phase Ib study 
IBI308 
200 mg IV D1 Q3W  
Up to 4 cycles of triple drug combination 
therapy are given. Subsequently, the subjects 
receive the maintenance treatment with 
IBI308 in combination with pemetrexed until 
PD, intolerable toxicity, withdrawal of 
informed consent, 24 months of treatment, or 
other reasons for discontinuation of the study 
Pemetrexeda 
500 mg/m2 IV D1 Q3W 
Cisplatina 
75 mg/m2 IV D1 Q3W 


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Study phase 
Drug 
Dose, route of 
administration, and cycle 
Duration of administration 
treatment (whichever occurs first). 
Cohort E of the 
phase Ib study 
IBI308 
200 mg IV D1 Q3W 
Up to 6 cycles of triple drug combination 
therapy are given. Subsequently, the subjects 
experiencing no PD can receive a 
maintenance treatment with IBI308 until PD, 
intolerable toxicity, withdrawal of informed 
consent, 24 months of treatment, or other 
reasons for discontinuation of the study 
treatment (whichever occurs first). 
Gemcitabinea 
1250 mg/m2 IV D1,D8 Q3W 
Cisplatina 
75 mg/m2 IV D1 Q3W 
Cohort F of the 
phase Ib study 
IBI308 
200 mg IV Q3W 
Up to 6 cycles of triple drug combination 
therapy are given. Subsequently, the subjects 
experiencing no PD can receive a 
maintenance treatment of 200 mg IV Q3W of 
IBI308 until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation 
of the study treatment (whichever occurs 
first). 
Capecitabinea 
2000 mg/m2/day PO BID 
D1–14, Q3W 
Oxaliplatina 
130 mg/m2 IV Q3W 
Cohort G of the 
phase Ib study 
IBI308 
200 mg IV D1 Q3W 
Up to 6 cycles of triple drug combination 
therapy are given. Subsequently, the subjects 
experiencing no PD can receive a 
maintenance treatment of 200 mg IV Q3W of 
IBI308 until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation 
of the study treatment (whichever occurs 
first). 
Etoposidea 
100 mg/m2 IV D1-3 Q3W 
Cisplatina 
75 mg/m2 IV D1 Q3W 
Cohort H of the 
phase Ib study 
IBI308 
200 mg IV D1 Q3W 
Up to 6 cycles of triple drug combination 
therapy are given. Subsequently, the subjects 
experiencing no PD can receive a 
maintenance treatment of 200 mg IV Q3W of 
IBI308 until PD, intolerable toxicity, 
withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation 
of the study treatment (whichever occurs 
first). 
Irinotecana 
125 mg/m2 IV D1,D8 Q3W 
5-FUa 
1000 mg/m2 IV D1-3 Q3W 
a The study site determines the actual dose that one subject should receive by calculating his/her body surface area 
on the scheduled administration day in each cycle (the body surface area is calculated in accordance with routine 
method of the study site). The maximum body surface area adopted by the protocol is 2.0 m2. For subjects with a 
body surface area of > 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. 
5.1.2. Continued treatment after progressive disease 
During the treatment with IBI308 alone (Cohorts A–C in both phase Ia and Ib studies), subjects 
are allowed to continue receiving IBI308 after they are judged to experience PD for the first time 
(first PD) according to the RECIST V1.1 criteria. The IBI308 treatment can be continued if all 
the following criteria are met: 


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1. The investigator believes that the subject may enjoy clinical benefits from continued 
study treatment, and the disease does not show rapid progression (rapid progression is 
defined as the occurrence of PD during the first imaging evaluation); 
2. The subject can tolerate the study drug (no ≥ grade 2 adverse reactions or serious 
adverse reactions related to the study drug); 
3. No clinically significant symptoms and signs suggesting PD (including worsenin 
laboratory test values); 
4. An ECOG PS score of 0–1; 
5. Will not delay the treatment of serious complications requiring urgent intervention (such 
as metastasis in the CNS or spinal cord compression); 
6. Before continuing treatment with IBI308, subjects must be fully informed and the 
investigator must elucidate the 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 or 3 for collection of data variables. 
For subjects who are first recorded to have imaging PD that is confirmed related to immunity by 
the imaging evaluation carried out 4 weeks later, if they can continue receiving the treatment 
with the study drug, an imaging evaluation should be carried out every 9 weeks (± 7 days) until 
the recurrence of PD. The second PD is defined as an increase of more than 10% in the sum of 
the longest diameter of tumor target lesions and/or the presence of a new measurable lesion. 
Subjects with the recurrent PD will terminate the IBI308 treatment. The main criteria for the 
judgment of "deterioration of clinical symptoms" are: 
• 
Clinically significant signs and symptoms suggesting PD (including worsening 
laboratory test values); 
• 
Continued increase in ECOG PS or  > 2 ; 
• 
The appearance of serious complications requiring urgent intervention (such as 
metastasis in the CNS or spinal cord compression) 
In this case, the investigator shall continue imaging evaluation as described in the "Section 6.3" 
of the study protocol. 
For Cohorts D–H of the phase Ib study, the IBI308 therapy is not allowed to be continued after 
PD is confirmed. 


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5.2. IBI308 
5.2.1. 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 sodium citrate (dihydrate), 50 mmol/L sodium chloride, 0.02 
mmol/L disodium edetate, 0.2 mg/mL polysorbate 80, citric acid (monohydrate), and water for 
injection, at a pH of 6.0. 
This product is a clear to slightly opalescent, colorless to light yellow liquid, free of flocs and 
precipitation. 
IBI308 is manufactured by Innovent Biologics (Suzhou) Co., Ltd. 
5.2.2. Labels 
The smallest packaging unit is one box. Each box contains one vial 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 "use for clinical study 
only". 
5.2.3. Storage 
Stored at 2–8 °C away from light. The shelf life is 24 months. If quality issues such as turbidity 
and precipitation are observed in the injection, seal the vial immediately and notify the sponsor. 
5.2.4. Preparation and infusion 
5.2.4.1 Preparation before infusion 
Eligible subjects selected during screening will be approved to be admitted to the study site's 
wards 24 h before dosing. All baseline safety evaluation results must be obtained pre-dose. 
On dosing days, vital signs are observed, and dosing is initiated after blood sampling as per visit 
requirements. 


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5.2.4.2 
Preparation and infusion 
The preparation and infusion of IBI308 are as follows: 
1. The volume of IBI308 to be extracted should be calculated using the formula in Table 9. 
Table 9. Calculation formulas for volume of IBI308 required 
Group 
Volume of IBI308 added into the IV infusion bag (mL) 
1 mg/kg group 
1 mg/kg × weight (kg)a  ÷ IBI308 concentration (rated: 10 mg/mL) 
3 mg/kg group 
3 mg/kg × weight (kg)a  ÷ IBI308 concentration (rated: 10 mg/mL) 
10 mg/kg group 
10 mg/kg × weight (kg)a  ÷ IBI308 concentration (rated: 10 mg/mL) 
200 mg group 
200 mg ÷ IBI308 concentration (rated: 10 mg/mL) 
a The dose is calculated based on baseline weight, but if a change from baseline weight by ≥ 10% is found, the 
actual dose will be calculated based on the weight of scheduled dosing days. 
2. An appropriate volume of IBI308 is taken and added into 100 mL of sterile normal 
saline containing 0.9% (w/v) sodium chloride. The start time of preparation is 
documented. 
3. The IV bag is gently inverted to mix the solution, ensuring the uniformity of the 
contents. No vigorous shaking is allowed to avoid foam. 
4. IBI308 is administered with an IV infusion pump equipped with a 0.2–1.2 μm in-line 
filter (suggested infusion time is 30–60 min). The start and end time of infusion are 
documented. 
Note: IBI308 should be infused before dosing of chemotherapeutics. Different batches of IBI308 
cannot be mixed for a single infusion. 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. 
5.3. Chemotherapeutics 
Pemetrexed, cisplatin, gemcitabine, capecitabine, oxaliplatin, etoposide, irinotecan, and 5-FU 
have been approved as anti-tumor drugs. They 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. The following information is for reference. 
5.3.1. Pemetrexed  
Pemetrexed for injection is provided as sterile lyophilized powder for IV injection in 100 mg or 
500 mg vials. The active ingredient of lyophilized drug product is pemetrexed which is present 
as pemetrexed disodium. The drug product is white to pale yellow or yellow green lyophilized 


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solid. The actual amount of pemetrexed in each vial is more than the labeled amount to ensure 
extraction of the labeled amount of pemetrexed.  
100 mg or 500 mg of pemetrexed is reconstituted with 0.9% sodium chloride solution to get a 
clear solution. The solution is colorless to yellow or yellow green (refer to the reconstitution 
volume requirement described in the prescribing information). The content in the vial should be 
visually inspected pre-dose to determine whether there are sub-visible particles and discoloration. 
If the content contains sub-visible particles or is dark green, dosing will not be allowed.  
For clinical use, the reconstituted content will be diluted in 0.9% sodium chloride injection (refer 
to the reconstitution volume requirement described in the prescribing information). The dilution 
for infusion can keep stable for up to 24 h in a fridge or at room temperature. 
Pemetrexed is compatible with dosing devices and IV infusion bags made from polyvinyl 
chloride and polyolefin. No antibacterial preservative is contained in both reconstituted 
pemetrexed and dilution for infusion. The unused pemetrexed in the open vial should be 
discarded. Pemetrexed is incompatible with calcium-containing diluents including sodium lactate 
ringer's injection and ringer's injection, so it should not be diluted with these diluents. 
5.3.2. Cisplatin 
Cisplatin is a solution or lyophilized powder. It is provided in 10 mg, 20 mg, or 30 mg vials and 
diluted with sterile normal saline. Before cisplatin therapy, hydration should be made according 
to clinical practice of each study site. Intravenous drip infusion of 2000 mL of isotonic glucose 
solution is recommended before 12 h prior to cisplatin therapy, and infusion of 3000–3500 mL of 
isotonic saline or glucose solution on the cisplatin dosing day. Besides, potassium chloride, 
mannitol, and furosemide are administered to maintain a daily urine volume of 2000–3000 mL. 
During treatment, attention is paid to changes in blood potassium and blood magnesium. Low 
levels of potassium and magnesium will be corrected if necessary. 
5.3.3. 
Gemcitabine 
Gemcitabine hydrochloride for injection is provided as lyophilized powder for injection in 200 
mg or 1 g vial. The preservative-free 0.9% sodium chloride solution is recommended as the only 
solvent to dissolve lyophilized gemcitabine hydrochloride powder for injection. For dilution, at 
least 5 mL of 0.9% sodium chloride solution should be added into a 200 mg vial; at least 25 mL 
of this solution should be added into a 1000 mg vial. The vial is shaken for complete dissolution, 
followed by dilution with 0.9% sodium chloride solution. The post-dilution concentration should 
not be higher than 40 mg/mL, avoiding incomplete dilution due to a too high concentration. The 
prepared gemcitabine solution keeps stable for 24 h at room temperature. 


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5.3.4. Capecitabine 
Capecitabine is provided as a 500 mg tablet. The starting dose is 1000 mg/2 bid PO for 14 
consecutive days every 3 weeks. Capecitabine is orally taken, with 200 mL of water (not juice) , 
within 30 minutes after a meal (breakfast or dinner) twice (12-h interval) a day. 
Each capecitabine dose will be based on the subject's body surface area (mg/m2, calculated based 
on height and weight) at baseline. Subjects are recommended to receive a standard therapy of 
capecitabine 1500 mg (morning) + 2000 mg (evening). The dose to each subject can be adjusted 
by the investigator based on the actual body surface area of the subject, but the total dose should 
not be more than 4000 mg/day. 
5.3.5. Oxaliplatin 
Oxaliplatin is lyophilized powder in a 100 mg or 50 mg vial. The preparation is completed with 5% 
glucose solution (do not prepare or dilute the product with saline solution). One 50 g vial of 
oxaliplatin is prepared with 10 mL of 5% glucose solution to 5.0 mg/mL; one 100 mg vial of 
oxaliplatin is prepared with 20 mL of 5% glucose solution to 5.0 mg/mL. The prepared solution 
is taken out of the vial and immediately diluted with 250–500 mL of 5% glucose solution to 
more than 0.2 mg/mL (normally, the physicochemical properties of solution remain stable at 2–
8 °C for 24 h). Oxaliplatin is infused into peripheral veins or central veins within 2–6 h (if acute 
laryngospasm occurs when administration of oxaliplatin is completed within 2 h, extend the 
infusion duration to 6 h for subsequent administration). 
Special precautions: 
Do not use injection equipment containing aluminum; 
• 
Do not use without dilution; 
• 
Do not prepare or dilute the product with saline solution; 
• 
Do not mix or administer simultaneously with other drugs through the same infusion line; 
The infusion line should be flushed after the oxaliplatin infusion is completed; 
• 
The infusion line should be flushed prior to oxaliplatin infusion; 
• 
Only the recommended solvent (5% glucose solution) can be used; 
• 
Do not use the prepared solution if any precipitation appears, and the prepared solution 
should be destroyed according to regulations regarding the disposal of hazardous articles. 


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5.3.6. 
Etoposide 
Preparation is completed with 0.9% sodium chloride solution. Etoposide should be administered, 
after administration of cisplatin, via IV drip for no less than 60 minutes. Rapid IV push is not 
allowed. The prophylactic use of antiemetic drugs is recommended, and such drugs are used 
according to the routine practice of each study site. 
5.3.7. Irinotecan 
Preparation is completed with 0.9% sodium chloride solution. Irinotecan should be administered 
via IV drip for about 90 minutes. The prophylactic use of antiemetic drugs is recommended, and 
such drugs are used according to the routine practice of each study site. If subjects develop early 
diarrhea (any grade) or other cholinergic syndromes, prophylactic administration of atropine 
(0.25–1 mg) in the subsequent treatment cycles will be considered unless this is clinically 
contraindicated. In case of delayed diarrhea (any grade), loperamide will be considered for 
treatment. 
5.3.8. 5-FU 
Preparation is completed with 0.9% sodium chloride solution. 5-FU is intravenously infused with 
a micro infusion pump for 72 h. The prophylactic use of antiemetic drugs is recommended, and 
such drugs are used according to the routine practice of each study site. 
5.4. Dose Adjustments 
5.4.1. General principles 
• 
On the first dosing day of study drug, the subject's hematologic, hepatic, and renal 
function pre-dose must meet the requirements (ANC ≥ 1.5 × 109/L, PLT ≥ 75 × 109/L, 
Hb ≥ 80 g/L, and hepatic and renal function: CTCAE V4.03 grade 0–1 or baseline level). 
All other toxicities must resolve to NCI CTCAE V4.03 grade 0–1 or baseline levels 
(excluding alopecia, fatigue, and other cases which are judged by the investigator to be 
of no clinical significance). 
• 
The dose of chemotherapeutics in each subsequent cycle will be adjusted based on the 
lowest platelet and neutrophil counts in the previous cycle. 
• 
Dose adjustments for chemotherapeutics are permanent. Once the dose is reduced, the 
reduced dose will be maintained or reduced in subsequent cycles. A dose increase is not 
permitted in the study. 
• 
During treatment suspension due to hematologic toxicity, routine blood parameters 
should be followed up until recovery to the lowest level at which the treatment can be 
received. 


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• 
Prior to the start of any chemotherapy, growth factor support (e.g., GM-CSF) can be 
adopted to prevent hematologic toxicity induced by chemotherapeutics, but routine 
prophylactic medications are prohibited. 
• 
All the dose adjustments should be documented, including the reasons and actions 
taken. 
• 
For Cohorts D, E, F, G, and H in the phase Ib study, IBI308 therapy may be continued if 
the chemotherapy is terminated due to toxicity. The chemotherapy may be continued if 
IBI308 therapy is discontinued due to irAEs. 
• 
If chemotherapy is delayed in a 3-week treatment cycle, all the subsequent 
administration days should be delayed to ensure a dosing interval of 21 ± 2 days 
between two chemotherapy cycles. If the administration of irinotecan on day 8 is 
delayed for more than 7 days due to toxicity, skip the administration on day 8 and 
resume the treatment in the next cycle. 
• 
The chemotherapy cycle and the IBI308 cycle should be kept in synchronization as far 
as possible by adjusting the permitted window period. 
5.4.2. IBI308 administration adjustments 
Dose adjustments of IBI308 are not permitted throughout the trial. Refer to Table 10 for 
principles for interruption and permanent discontinuation of IBI308 therapy. 
Table 10. Dose adjustments of IBI308 
IBI308-related AE 
Severity level 
Dose adjustment 
Pneumonia 
Grade 2 pneumonia 
Interruptiona 
Grade 3 or 4 pneumonia, or recurrent grade 2 pneumonia 
Permanent discontinuation 
Diarrhea/enterocolitis 
Grade 2 or 3 diarrhea or enterocolitis 
Interruptiona 
Grade 4 diarrhea or enterocolitis 
Permanent discontinuation 
Dermatitis 
Grade 3 dermatitis 
Interruptiona 
Grade 4 dermatitis 
Permanent discontinuation 
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% 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 by ≥ 50% 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 


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IBI308-related AE 
Severity level 
Dose adjustment 
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 
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 
Other AEs 
First occurrence of other grade 3 AEs 
Interruptiona 
Second occurrence of the same grade 3 AE 
Permanent discontinuation 
Grade 3 AE that cannot resolve to grade 0–2/baseline levels 
within 7 days or grade 0–1/baseline levels within 14 days 
Permanent discontinuation 
Grade 4 AE 
Permanent discontinuationc 
a: Resume administration of the investigational drug after symptoms improve to grade 0–1 or baseline levels. 
b: Resume administration of the investigational drug if hypophysitis, adrenocortical insufficiency, or type I diabetes 
is adequately controlled and require only physiological hormone replacement. 
c: For grade 4 laboratory abnormalities, whether to terminate the treatment shall be determined based on clinical 
signs/symptoms and the clinical judgment of the investigator. 
Investigational drug is allowed to be interrupted for up to 6 weeks. If the symptoms do not 
resolve 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 for evaluation efficacy should not be affected by treatment interruption and 
should be performed as scheduled. 
• 
IBI308 interruption > 6 weeks due to the treatment of AEs possibly related or unrelated 
to IBI308. Consult the sponsor's medical manager prior to resuming IBI308. Tumor 
imaging for evaluation efficacy should not be affected by treatment interruption and 
should be performed as scheduled. 
• 
The IBI308 therapy is resumed when related AEs resolve to grade 0–1 or baseline level 
and a ECOG PS score of 0–1. 


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5.4.3. Dose adjustments of pemetrexed and cisplatin 
One drug whose dose has been reduced twice must be discontinued permanently if the 3rd dose 
reduction is required due to toxicity (or the dose following the 3rd reduction is lower than that 
after the second one). Pemetrexed and/or cisplatin therapy must be permanently discontinued if it 
has been interrupted for over 6 weeks. But the necessity for continuation of pemetrexed and/or 
cisplatin therapy will be discussed with the sponsor's medical manager if this therapy is 
interrupted for over 6 weeks due to an AE that is possibly-unrelated or unrelated to this therapy 
(since day 1 after the last dose). Tumor imaging for evaluation efficacy should not be affected by 
treatment interruption and should be performed as scheduled. 
5.4.3.1 Hematological toxicity 
Growth factor support can be adopted, but routine prophylactic medications are prohibited. The 
dose adjustment at the start of each subsequent cycle will be based on the lowest ANC and PLT 
counts in the previous cycle. The guidelines for dose adjustments due to hematological toxicity 
are shown in Table 11. 
Table 11. Dose adjustments of pemetrexed and cisplatin due to hematological toxicity 
Toxicity 
Dose adjustments 
PLT ≥ 50 × 109/L and ANC ≥ 0.5 × 109/L 
100% of the previous dose 
PLT ≥ 50 × 109/L and ANC < 0.5 × 109/L 
75% of the previous dose 
PLT < 50 ×109/L, any ANC level 
75% of the previous dose 
PLT < 50 × 109/L with bleeding of grade 3 or greater, any ANC level 
50% of the previous dose 
Febrile agranulocytosis, any PLT level 
75% of the previous dose 
5.4.3.2 Nephrotoxicity 
The same CCr calculation as that at baseline should be used throughout the study. CCr must be ≥ 
45 mL/min before each cycle of chemotherapy. If CCr is < 45 mL/min, the pemetrexed and/or 
cisplatin therapy should be delayed until subjects recover from the toxicity. 
5.4.3.3 Other non-hematological toxicity 
The guidelines for dose adjustments due to other non-hematological toxicity are shown in Table 
12. 
Table 12. Dose adjustments of pemetrexed and cisplatin due to other non-hematological 
toxicity 
Toxicity 
Grade 
Dose adjustment of pemetrexed 
Dose adjustment of cisplatin 
Mucositis 
Grade 1 or 2 
100% of the previous dose 
100% of the previous dose 
Grade 3 or 4 
50% of the previous dose 
100% of the previous dose 


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Toxicity 
Grade 
Dose adjustment of pemetrexed 
Dose adjustment of cisplatin 
Diarrhea 
Grade 3 or 4 
75% of the previous dose 
100% of the previous dose 
Sensory neurotoxicity 
Grade 1 
100% of the previous dose 
100% of the previous dose 
Grade 2 
50% of the previous dose 
100% of the previous dose 
Grade 3 or 4 
Permanent discontinuation 
Permanent discontinuation 
Folic acid or vitamin 
B12 deficiency 
- 
Pemetrexed therapy is interrupted. 
In Cycle 1, the subject must receive vitamin B12 injection and at least 5 
days of oral folic acid within 7 days before the first dose of pemetrexed. 
In Cycle 2 and thereafter, the subject must receive at least 14 days of oral 
folic acid within 21 days before dosing of pemetrexed in this cycle. 
Other toxicities 
Grade 3 or 4 
The chemotherapeutics are interrupted until the AE resolves to grade 0–1 
or baseline level, and then resuming the pemetrexed and cisplatin therapy 
at 75% of the previous dose can be considered based on the investigator's 
judgment. 
In case of other laboratory test abnormalities, the necessity for permanent 
discontinuation of the pemetrexed and cisplatin therapy should be 
determined based on accompanying clinical symptoms and signs as well 
as clinical judgments of the investigator. 
5.4.4. Dose adjustments of gemcitabine and cisplatin 
The dose adjustment method for gemcitabine and cisplatin is shown in Table 13. The dose levels 
of these two drugs are unrelated and can be adjusted independently. 
For any patient, one drug whose dose has been reduced twice must be discontinued permanently 
if the 3rd dose reduction is required due to toxicity (or the dose following the 3rd reduction is 
lower than that after the second one). The gemcitabine and/or cisplatin therapy must be 
discontinued permanently if this therapy is interrupted for over 6 weeks (since day 1 after the last 
dose) due to toxicity (the necessity for continuation of gemcitabine and/or cisplatin therapy will 
be discussed with the sponsor's medical manager if this therapy is interrupted for over 6 weeks 
due to an AE that is possibly-unrelated or unrelated to this therapy. Tumor imaging for evaluation 
efficacy should not be affected by treatment interruption and should be performed as scheduled). 
If the use of one chemotherapeutic agent must be interrupted, the treatment with other drugs can 
be continued once it is deemed reasonable by the investigator. 
Table 13. Dose adjustments of gemcitabine and cisplatin 
Dose 
Gemcitabine 
Cisplatin 
Starting dose 
1250mg/m2 
75mg/m2 
1st dose reduction 
950mg/m2 
56 mg/m2 
2rd dose reduction 
625mg/m2 
38mg/m2 


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5.4.4.3 
Hematological toxicity 
The guidelines for dose adjustments due to hematological toxicity are shown in Table 14. 
Table 14. Dose adjustments of gemcitabine and cisplatin due to hematological toxicity 
Toxicity 
Dose adjustment of 
gemcitabine 
Dose adjustment of 
cisplatin 
ANC < 0.5 × 109/L and PLT ≥ 50 × 109/L 
Reduction by 1 dose level 
Reduction by 1 dose level 
PLT < 50 × 109/L without bleeding manifestation, any 
ANC level 
Reduction by 1 dose level 
Reduction by 1 dose level 
PLT < 50 × 109/L with bleeding manifestations, any ANC 
level 
Reduction by 2 dose levels Reduction by 2 dose levels 
ANC < 1 × 109/L with fever > 38.5 °C, any PLT level 
Reduction by 1 dose level 
Reduction by 1 dose level 
Note: If the above criteria are not met, the investigator will make dose adjustments based on clinical practice and 
benefits to subjects after communication with and approval by the sponsor's medical manager. The level and 
frequency of dose adjustments are the same as above. 
5.4.4.4 Non-hematological toxicity 
The dose adjustment method in case of non-hematological toxicity is shown in Table 15. In the 
event of grade ≥ 3 non-hematological toxicity, the treatment must be delayed until this event 
resolves to grade 2 or below or baseline level. The treatment with the dose reduced by one dose 
level can be allowed if deemed suitable by the investigator, but it is necessary to determine 
whether the toxicity causes the loss of an opportunity to receive the best treatment or prodrug(s). 
When SCr > 1.2 × ULN or CCr < 50 mL/min, it is allowed not to reduce the dose of cisplatin, 
but the treatment must be delayed or interrupted. 
Table 15. Dose adjustments of gemcitabine and cisplatin due to non-hematological toxicity 
Toxicity 
Grade 
Dose adjustment of 
gemcitabine 
Dose adjustment of cisplatin 
Diarrhea 
Grade 3 or 4 
Reduction by 1 dose level 
No dose adjustment 
Mucositis/stomatitis 
Grade 3 or 4 
Reduction by 1 dose level 
No dose adjustment 
Neurotoxicity 
Grade 1 
No dose adjustment 
No dose adjustment 
Grade 2 
No dose adjustment 
Reduction by 2 dose levels 
Grade 3 or 4 
Permanent discontinuation 
Permanent discontinuation 
Ototoxicity 
Grade 2, 3, or 4 
No dose adjustment 
Permanent discontinuation considered 
Others 
Grade 3 or 4a 
Reduction by 1 dose levelb 
Reduction by 1 dose levelb 
a Grade 3 emesis/nausea and grade 3 paronychia are excluded. 
b Permanent discontinuation can be considered, at the discretion of the investigator. 


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5.4.5. Dose adjustments for oxaliplatin and capecitabine 
Oxaliplatin and capecitabine should be administered at the original dose instead of being 
interrupted in case of toxicity that is considered by the investigator to impossibly cause serious 
or life-threatening events and delay or discontinuation of treatment (e.g., asthenia, alopecia, and 
taste alterations). 
In case of an AE that is judged by the investigator to be related to both oxaliplatin and 
capecitabine, a comprehensive evaluation should be conducted to determine which drug is more 
closely associated with this AE and leads to worse outcomes, and then the dose of this drug is 
adjusted first, minimizing the need for a simultaneous dose adjustment of both drugs. 
The oxaliplatin/capecitabine therapy must be discontinued permanently if this therapy is 
interrupted for over 6 weeks. But the necessity for continuation of oxaliplatin and capecitabine 
therapy will be discussed with the sponsor's medical manager if this therapy is interrupted for 
over 6 weeks due to an AE that is possibly-unrelated or unrelated to this therapy (since day 1 
after the last dose). Tumor imaging for evaluation efficacy should not be affected by treatment 
interruption and should be performed as scheduled). 
5.4.5.1 Hematological toxicity 
The dose adjustment at the start of each subsequent cycle will be based on the lowest PLT and 
ANC counts in the previous cycle. Growth factor support can be adopted, but routine 
prophylactic medications are prohibited. After recovery, the dose of oxaliplatin and/or 
capecitabine should be adjusted according to Table 16. When the dose of capecitabine is reduced 
to 75% of the starting dose, the routine daily administration of 1000 mg (2 tablets) in the 
morning and 1500 mg (3 tablets) at night is recommended. When the dose is reduced to 50% of 
the starting dose, the routine daily administration of 1000 mg (2 tablets) in the morning and 1000 
mg (2 tablets) at night is recommended. The dose to each subject can be adjusted by the 
investigator based on the actual body surface area of the subject. Discontinuation of oxaliplatin 
and capecitabine is recommended in case of the third occurrence of the following hematological 
toxicity following standard dose adjustments. 
Table 16. Dose adjustments of oxaliplatin and capecitabine 
Toxicity 
First occurrence 
Second occurrence 
Capecitabine 
Oxaliplatin 
Capecitabine 
Oxaliplatin 
Grade 4 neutropenia for 
over 5 days 
75% of the starting dose 
75% of the starting dose 
50% of the 
starting dose 
50% of the 
starting dose 
Grade 4 thrombocytopenia 
Maintain initial dose 
75% of the starting dose 
75% of the 
starting dose 
50% of the 
starting dose 


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Toxicity 
First occurrence 
Second occurrence 
Capecitabine 
Oxaliplatin 
Capecitabine 
Oxaliplatin 
Grade 3 neutropenic fever 
(ANC < 1.0 × 109/L and 
fever ≥ 38.5 °C) 
75% of the starting dose 
75% of the starting dose 
50% of the 
starting dose 
50% of the 
starting dose 
Grade 4 neutropenic fever 
(ANC < 1.0 × 109/L with 
fever ≥ 38.5 °C and 
life-threatening sepsis) 
As guided by the 
investigator, the 
treatment with 50% of 
the starting dose is 
continued when toxicity 
recovers to grade 0–1 
As guided by the 
investigator, the 
treatment with 50% of 
the starting dose is 
continued when toxicity 
recovers to grade 0–1 
Discontinue 
the treatment 
Discontinue 
the treatment 
5.4.5.2 Hematological toxicity 
The dose adjustment method in case of non-hematological toxicity is shown in Table 17. 
Table 17. Dose adjustments of capecitabine and oxaliplatin due to non-hematological 
toxicity 
Toxicity 
Grade 2 
Grade 3 
grade 4 
First occurrence 
 
Interrupt until resolve to 
grade 0–1, then resume at 
the same dose level, provide 
prophylactic treatment if 
possible 
Interrupt until resolve to 
grade 0–1, then resume at 
75% of the starting dose, 
provide prophylactic 
treatment if possible 
Discontinue, unless the 
investigator determines that it is 
for the best interest of the 
subjects to resume at 50% of the 
starting dose when the toxicity 
reduces to grade 0–1 (must be 
approved by the sponsor) 
Second 
occurrence 
Interrupt until resolve to 
grade 0–1, then resume at 
75% of the starting dose 
Interrupt until resolve to 
grade 0–1, then resume at 
50% of the starting dose 
- 
Third occurrence 
Interrupt until resolve to 
grade 0–1, then resume at 
50% of the starting dose 
Permanently discontinue 
- 
Fourth 
occurrence 
Permanently discontinue 
- 
- 
Management of common capecitabine toxicities 
• 
Grade 2 or 3 hand-foot syndrome  
Provide symptomatic treatment (emollients are recommended). Refer to Table 16 for dose 
adjustments of capecitabine. 
• 
Grade 2 or 3 diarrhea, nausea, and emesis  
Interrupt capecitabine and provide symptomatic treatment. Loperamide is recommended for the 
treatment of diarrhea. If the symptoms are well-controlled after 2 days, resume the treatment at 
100% of the initial dose. If more time is required to control symptoms, adjust the dose according 
to Table 16. Capecitabine can be resumed after diarrhea resolves to grade 0–1 and until 24 h has 
passed since the last dose of loperamide. 


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When capecitabine-related nausea and emesis occur, adequate secondary prophylactic treatment 
should be provided. If AEs occur despite of prophylactic treatment, adjust the dose according to 
Table 16. 
• 
Grade 2/3 stomatitis 
If grade 2/3 stomatitis occurs, immediately interrupt capecitabine until symptoms resolve or 
toxicity reduces to grade 1. Provide symptomatic treatment. Then, administer capecitabine at the 
dose listed in Table 16. 
• 
Cardiotoxicity 
If capecitabine-related grade 2 cardiotoxicities occur, permanently discontinue capecitabine 
treatment.  
Management of common oxaliplatin toxicities 
• 
Grade 3/4 nausea and emesis 
If grade 3/4 nausea or emesis occurs, prophylaxis and/or treatment with antiemetics should be 
provided immediately. Reduce the dose to 75% of the original dose for subsequent treatment 
cycles. 
• 
Neurotoxicity 
In case of a nervous system symptom (sensory disturbance and spasm), the following oxaliplatin 
dose adjustment methods are recommended based on duration and severity level of the symptom. 
The dose of oxaliplatin should be reduced by 25% if this symptom lasts for over 7 days and is 
serious. 
The dose of oxaliplatin will be reduced by 25% if sensory disturbance without functional 
impairment lasts until the next cycle. 
Oxaliplatin should be discontinued if sensory disturbance with insufficiency lasts until the next 
cycle. 
Continuation of oxaliplatin can be considered if this symptom has improved after interruption. 
5.4.6. Dose adjustments of etoposide 
Toxicity-induced dose adjustments of etoposide are allowed. The initial dose should not be 
adopted once it is reduced. Etoposide should be permanently discontinued in the following cases. 
• 
Occurrence of toxicity requiring a dose reduction after two reductions. 


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• 
Toxicity-induced etoposide interruption for over 6 weeks (since day 1 after the last 
dose). But the necessity for continuation of etoposide therapy will be discussed with the 
sponsor's medical manager if this therapy is interrupted for over 6 weeks due to an AE 
that is possibly-unrelated or unrelated to this therapy (since day 1 after the last dose). 
Tumor imaging for evaluation efficacy should not be affected by treatment interruption 
and should be performed as scheduled). 
5.4.6.1 Hematological toxicity 
Growth factor support can be adopted, but routine prophylactic medications are prohibited. The 
dose adjustment methods in case of hematological toxicity are shown in Table 18. No dose 
adjustment is recommended for anemia patients. 
Table 18. Dose adjustments of etoposide due to hematological toxicity 
Toxicity 
Dose adjustments 
ANC < 0.5 × 109/L and PLT ≥ 50 × 109/L 
75% of the previous dose 
PLT < 50 ×109/L, any ANC level 
75% of the previous dose 
ANC < 1.0 × 109/L with body temperature ≥ 38.5 °C 
75% of the previous dose 
PLT < 50 × 109/L with bleeding of grade 3 or greater, any ANC level 
50% of the previous dose 
5.4.6.2 
Nephrotoxicity 
The dose adjustment methods in case of nephrotoxicity are shown in Table 19. 
Table 19. Dose adjustments of etoposide due to nephrotoxicity 
CCr (mL/min) 
Dose adjustments 
> 50 
100% of the previous dose 
15–50 
75% of the previous dose 
5.4.6.3 Other non-hematological toxicity 
The dose adjustment methods in case of other non-hematological toxicities are shown in Table 
20. 
Table 20. Dose adjustments of etoposide due to other non-hematological toxicity 
Toxicity 
Grade 
Dose adjustments 
Diarrhea 
Grade 3 or 4a, or diarrhea of any 
grade requiring hospitalization 
75% of the previous dose 
Nausea/emesis 
Grade 3 or 4b 
75% of the previous dose 
Neurotoxicity 
Grade 2 
75% of the previous dose 
Grade 3 or 4 
50% of the previous dose or 
permanent discontinuation 


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Toxicity 
Grade 
Dose adjustments 
Transaminase increased 
Grade 3 
75% of the previous dose 
grade 4 
Permanent discontinuation 
Other toxicities 
Grade 3 or 4 
75% of the previous dose 
a Grade 3 or 4 diarrhea that still persists after adequate antidiarrheal therapy. 
b Grade 3 or 4 nausea/emesis that still persists after antiemetic therapy. 
5.4.7. Dose adjustments of irinotecan 
Toxicity-induced dose adjustments of irinotecan are allowed. The initial dose should not be 
adopted once it is reduced. The next cycle of irinotecan therapy cannot be initiated unless the 
treatment-related diarrhea is eliminated completely and no anti-diarrheal drug is required at least 
24 h before this cycle. Irinotecan should be discontinued permanently if it is interrupted for over 
6 weeks (since day 1 of the previous cycle) due to toxicity. But the necessity for continuation of 
irinotecan therapy will be discussed with the sponsor's medical manager if this therapy is 
interrupted for over 6 weeks due to an AE that is possibly-unrelated or unrelated to this therapy 
(since day 1 after the last dose). Tumor imaging for evaluation efficacy should not be affected by 
treatment interruption and should be performed as scheduled. 
In case of toxicities listed in Table 21, the dose of irinotecan will be reduced by one or more 
dose levels (one dose level is 25 mg/m2) in the next cycle. 
Table 21. Dose adjustments of irinotecan 
Toxicity 
Grade 
Dose adjustments 
Neutropenia 
Grade 1–3 
Dose maintenance 
grade 4 
Reduction by 1 dose level 
Neutropenic fever 
- 
Reduction by 1 dose level 
Diarrhea 
Grade 1 or 2 
Dose maintenance 
Grade 3 
Reduction by 1 dose level 
grade 4 
Reduction by 2 dose levels 
Allergic reaction 
Any grade 
Permanent discontinuation 
5.4.8. Dose adjustments of 5-FU 
Toxicity-induced dose adjustments of 5-FU are allowed. The initial dose should not be adopted 
once it is reduced. 5-FU whose dose has been reduced twice must be discontinued permanently if 
the 3rd dose reduction is required due to toxicity. The 5-FU therapy must be discontinued 
permanently if this therapy is interrupted for over 6 weeks (since the start of dosing on day 1 of 
the previous cycle) due to toxicity (the necessity for continuation of 5-FU therapy will be 
discussed with the sponsor's medical manager if this therapy is interrupted for over 6 weeks due 


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to an AE that is possibly-unrelated or unrelated to this therapy. Tumor imaging for evaluation 
efficacy should not be affected by treatment interruption and should be performed as scheduled). 
5.4.8.1 Hematological toxicity 
Growth factor support can be adopted, but routine prophylactic medications are prohibited. The 
dose adjustment methods in case of hematological toxicity are shown in Table 22. 
Table 22. Dose adjustments of 5-FU due to hematological toxicity 
Toxicity 
Dose adjustment of 5-FU 
ANC < 0.5 × 109/L and PLT ≥ 50 × 109/L 
75% of the previous dose 
PLT < 50 ×109/L, any ANC level 
75% of the previous dose 
ANC < 1.0 × 109/L with body temperature ≥ 38.5 °C 
75% of the previous dose 
PLT < 50 × 109/L with bleeding of grade 3 or greater, any 
ANC level 
50% of the previous dose 
5.4.8.2 Non-hematological toxicity 
The dose adjustment methods in case of non-hematological toxicities are shown in Table 23. 
Table 23. Dose adjustments of 5-FU due to non-hematological toxicity 
Toxicity 
Dose adjustment of 5-FU 
Grade 3 or 4 hand-foot syndrome 
75% of the previous dose 
Angina or myocardial infarction 
Permanent discontinuation 
Grade 3 or 4 diarrhea 
or 
Diarrhea complicated with fever or 
grade 3 or 4 neutropenia 
First occurrence 
75% of the previous dose 
Second occurrence 
50% of the previous dose or 
permanent discontinuation 
5.5. Principles of Managing Immune Checkpoint Inhibitor Toxicities 
AEs related to IBI308 exposure may be etiologically associated with immunity. These irAEs may 
occur within a short period after the first dose or within months after the last dose. They may 
influence more than one systems simultaneously. Therefore, early diagnosis and treatment are 
critical to reduce complications. Based on the existing clinical trial data, most irAEs are 
reversible, and can be managed through discontinuation of IBI308, administration of 
glucocorticoids, and/or other supportive therapies. For suspected irAEs, an appropriate 
evaluation should be ensured to confirm pathogenesis or rule out other reasons. Other procedures 
or examinations, such as bronchoscopy, endoscopy, or skin biopsy, may be included into this 
evaluation. Temporary or permanent discontinuation of IBI308 and administration of 
glucocorticoids are adopted depending on the severity level of irAEs. 


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See Appendix 7 for dose adjustments and toxicity management of potential irAEs, potential 
non-irAEs, and infusion reactions. 
5.6. Concomitant Treatment 
5.6.1. Prohibited treatments 
• 
Other chemotherapy, immunotherapy, targeted therapy, and hormonal therapy used for 
systemic anti-tumor treatment, as well as traditional Chinese medicines, proprietary 
Chinese medicines, and replacement therapy with anti-tumor indications. 
• 
Immunosuppressive agents and high-dose glucocorticoids (except for the treatment of 
AEs or pretreatment for special examinations; high-dose glucocorticoids are defined as 
10 mg/d of prednisone or an equivalent dose of other glucocorticoids). 
• 
Blood products such as albumin, immunoglobulin, gamma globulin, whole blood or 
component blood, and cytapheresis blood cells (except for the treatment of AEs). 
• 
Receiving live attenuated vaccine. 
5.6.2. Permitted treatments 
• 
Medications judged by the investigator to meet the protocol requirements and 
specification in Section 5.6.1 (for example, concomitant medications for the treatment 
of disease-related symptoms and various 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. 
5.6.3. Drug-drug interactions 
5.6.3.1 IBI308 
There are no data on drug interactions with IBI308 at present. 


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5.6.3.2 
Pemetrexed 
For subjects with mild to moderate renal insufficiency, non-steroidal anti-inflammatory drugs 
(NSAIDs) with short half-lives are not recommended at least 2 days before, on the day when, 
and at least 2 days after pemetrexed is administered, and those with long half-lives are not 
recommended at least 5 days before, on the day when, and at least 2 days after pemetrexed is 
administered. 
5.6.3.3 Cisplatin 
Cisplatin in combination with aminoglycoside antibiotics, amphotericin B, or cefalotin may 
aggravate renal toxicity; cisplatin in combination with probenecid may induce hyperuricemia; 
chloramphenicol, furosemide, or ethacrynate sodium can worsen the ototoxicity of cisplatin; 
antihistamine may cover up tinnitus, vertigo, and other symptoms caused by cisplatin. 
5.6.3.4 Gemcitabine 
Cumulative myelosuppression should be considered when combining gemcitabine with other 
anti-tumor drugs or sequentially using gemcitabine and chemotherapy. Gemcitabine cannot be 
administered in parallel with radiotherapy (because of the risk of radiosensitization and serious 
pulmonary and esophageal fibrinoid degeneration). The combination of gemcitabine and 
cisplatin is prohibited in subjects with severe renal insufficiency. 
5.6.3.5 Capecitabine 
• 
Coumarin anticoagulants: Altered coagulation parameters and/or hemorrhage have been 
reported in subjects receiving capecitabine concomitant with coumarin-derivative 
anticoagulants such as warfarin and phenprocoumon. These events occurred within 
several days to several months after capecitabine treatment and, in a few cases, within 1 
month after discontinuing capecitabine. In a drug-drug interaction study with a single 20 
mg dose of warfarin followed by capecitabine, the mean AUC of S-warfarin increased 
by 57% and INR increased by 91%. For subjects receiving capecitabine concomitant 
with oral coumarin-derivative anticoagulant therapy, the anticoagulant parameter (INR 
or PT) should be monitored frequently, and the anticoagulant dose should be adjusted 
accordingly. 
• 
Cytochrome P-450 2C9 substrates: No formal drug-drug interaction studies between 
capecitabine and other medications known to be metabolized by P-450 2C9 have been 
conducted. Care should be exercised when capecitabine is coadministered with these 
medications. 
• 
Phenytoin: The co-administration of capecitabine and phenytoin has been reported to 
result in elevated serum phenytoin concentration. Formal drug-drug interaction studies 


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with phenytoin have not been conducted, but the mechanism of interaction is presumed 
to be inhibition of the CYP2C9 isoenzyme by capecitabine (see coumarin 
anticoagulants). The level of phenytoin should be carefully monitored in subjects 
coadministered capecitabine and phenytoin. 
• 
Drug-food interactions: In all clinical trials, subjects were instructed to administer 
capecitabine within 30 minutes after a meal. As all safety and efficacy data currently 
available are based on the administration with food, it is recommended that capecitabine 
should be administered with food. 
• 
Antacids: The effects of an aluminum hydroxide- and magnesium hydroxide-containing 
antacid (Maalox) on the PK of capecitabine was studied in subjects with malignant 
tumors. Serum concentrations of capecitabine and one of its metabolites (5-capecitabine) 
increased slightly. No effect was observed on the other three major metabolites 
(5'-DFUR, 5-FU, and FBAL) of capecitabine. 
• 
Sorivudine and its analogues: It has been reported that there is a clinically significant 
drug-drug interaction between sorivudine and 5-fluorouracil due to inhibition of 
dihydropyrimidine dehydrogenase by sorivudine. This interaction leads to an increase in 
the toxicity of fluoropyrimidine, which can be fatal. Therefore, capecitabine should not 
be coadministered with sorivudine and its analogues (such as brivudine). There must be 
at least a 4-week waiting period from the treatment end of sorivudine and its analogues 
(such as brivudine) to capecitabine. 
5.6.3.6 Etoposide 
When warfarin is combined with etoposide, the international normalized ratio (INR) may be 
extended, and the INR needs to be monitored at a higher frequency. 
5.6.3.7 
Irinotecan 
• 
Neuromuscular blockers: The interaction between irinotecan hydrochloride and 
neuromuscular blockers can not be ruled out. Because irinotecan hydrochloride has the 
activity of a cholinesterase inhibitor, drugs with cholinesterase inhibitory activity can 
prolong the neuromuscular blockade of chlorosuccinylcholine and can fight 
neuromuscular blockade of non-depolarizing drugs effect. 
• 
Anticonvulsants: Combined use of CYP3A-induced anticonvulsants (such as 
carbamazepine, phenobarbital, or phenytoin) can cause reduced exposure to SN-38. For 
patients requiring anticonvulsant therapy, consideration should be given to starting or 
switching to a non-enzyme-induced anticonvulsant at least one week prior to the initial 
treatment with irinotecan hydrochloride. 


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• 
Ketoconazole: Simultaneous treatment with ketoconazole can cause a significant 
reduction in the clearance of irinotecan hydrochloride, leading to increased exposure of 
its active metabolite SN-38. Ketoconazole should be stopped at least one week before 
starting irinotecan hydrochloride treatment. Of course, it can not be co-administered 
with irinotecan hydrochloride. 
• 
St. John's wort: In patients receiving St. John's wort at the same time, the exposure of 
active metabolite SN-38 is reduced. St. John's wort should be discontinued at least one 
week before the first use of irinotecan hydrochloride, and the drug cannot be used 
simultaneously with irinotecan hydrochloride. 
• 
Atazanavir: Simultaneous use of atazanavir, an inhibitor of CYP3A4 and UGT1A1, may 
increase SN-38 exposure. Physicians should consider this when using these drugs at the 
same time. 
• 
Dexamethasone: Lymphopenia has been reported in patients receiving irinotecan 
hydrochloride, which may be exacerbated when dexamethasone is used as an antiemetic 
drug. However, neither serious opportunistic infections were found, nor any 
complications due to lymphopenia. Patients receiving this product have reported with 
increased blood glucose. Usually this happens in patients who have a history of diabetes 
or have impaired glucose tolerance before treatment with this product. The increase in 
blood sugar in some patients may be caused by receiving dexamethasone. 
• 
Prochlorperazine: In a clinical study of a single-dose weekly dosing regimen, patients 
who were given prochlorperazine on the same day as irinotecan hydrochloride had a 
higher incidence of akathisia (8.5%, 4/47 patients), when these two drugs are not given 
on the same day, the incidence is relatively low (1.3%, 1/80 patients). However, the 
incidence of 8.5% of akathisia is still within the range of reports of akathisia as a 
pre-chemotherapy with prochlorperazine. 
• 
The combination of laxatives with this product may increase the severity level or 
incidence of diarrhea, but no research in this area has been conducted. 
• 
Diuretics: Because of the potential risk of secondary dehydration after vomiting and/or 
diarrhea, physicians should avoid the use of diuretics during irinotecan hydrochloride 
treatment, and of course they should not use diuretics during diarrhea or vomiting. 
5.6.3.8 5-FU 
• 
Tinidazole: Tinidazole will affect liver metabolism, increase the accumulation of 5-FU, 
and thus the combination of the two should be avoided. 


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• 
Warfarin and heparin: 5-FU will increase the anticoagulant effect of warfarin and 
heparin and may increase the risk of bleeding in the latter. 
• 
Allopurinol: Allopurinol may affect the efficacy of 5-FU, and thus the combination of 
the two should be avoided. 
• 
Pavlimin: Pavlimin increases the toxicity of 5-FU, and thus the infusion of pavlimin 
should be avoided 24 h before and after the infusion of 5-FU. 
• 
Iron chelating dose (deferiprone): A synergistic effect was observed when using with 
5-FU, and thus the combination will increase toxicity and the combination of the two 
should be avoided. 
5.7. Dosing During Pregnancy, Childbearing Age and Lactation 
5.7.1. Pregnancy 
So far, human IgG4 is known to be able to penetrate the placental barrier and is not 
recommended for use during pregnancy. Therefore, pregnant women should not be enrolled into 
this study. 
5.7.2. Childbearing age 
For women of childbearing age who are sexually active with male partners who have not 
undergone sterilization, and men who have not undergone sterilization and are sexually active 
with women of childbearing age, the subjects and their partners must use one of the acceptable 
methods of contraception listed in Table 24 from screening to 6 months after the last dose of 
study treatment, and discuss with a responsible physician about the discontinuation of 
contraception after this time point. Periodic abstinence, calendar-based method, and withdrawal 
method are not the acceptable forms of contraception. Women of childbearing age is defined as 
females who have experienced menarche, have not undergone surgical sterilization (bilateral 
tubal ligation, bilateral salpingectomy, or panhysterectomy), and are not postmenopausal. 
Table 24. Effective methods of contraception (one of the followings 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 injection 
Diaphragm with spermicide 
Levonorgestrel-releasing intrauterine 
system (e.g. Mirena®)a 
Combined oral contraceptive pill 
Low-dose oral contraceptive pill 
Contraceptive patch 
a．Also considered as a hormonal method. 


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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 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, and luteinizing hormone and follicle stimulating 
hormone levels within the postmenopausal range, are considered menopausal; 
• 
Females ≥ 50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, radiation-induced ovariectomy and the time from the last 
menorrhea > 1 year, chemotherapy-induced amenorrhea and the time from the last 
menorrhea > 1 year, or surgical sterilization (bilateral ovariectomy or hysterectomy), 
are considered menopausal. 
5.7.3. During Lactation 
IBI308 is unknown for secretion from breast milk. Considering that many drugs are present in 
breast milk, IBI308 may be potentially toxic to infants. Therefore, lactating women should not be 
enrolled into this study. 
5.8. 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 electronic case report forms 
(eCRFs). 
5.9. Drug Return and Destruction 
The containers, vials, infusion bags, and syringes of used and partially used study drugs can be 
destroyed on-site 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 study drugs were made by 
the clinical research associate (CRA) designated by the sponsor. 
5.10. Study Drug-related Records 
The designee of the study sites should make timely records of receiving, dispensing, using, 
storing, returning, and destroying the study drugs in accordance with the relevant regulations and 
guidelines. 
5.11. 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. 


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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 should be used to document product 
complaints and relevant description completely. 
• 
The completed product complaint form should be submitted to the sponsor or designee 
by fax within 24 hours. 
If the investigator is asked to return the product for further investigation, the investigator should 
return the product along with a copy of the complaint form. 
6. STUDY EVALUATIONS AND RELEVANT PROCEDURES 
6.1. Enrollment and Randomization 
6.1.1. Subject enrollment 
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. 
The sponsor will monitor the enrollment for each cohort to ensure the sample size in each cohort 
meets study requirements. 
Subjects who fail 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. 
6.1.2. 
Enrollment error handling 
The inclusion/exclusion criteria must be followed strictly. If an ineligible subject is enrolled, the 
sponsor's medical manager and investigator must discuss whether to allow the subject to 
continue participating in the study and whether to use the 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, then 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, then the subject shall not continue participating in the study (regardless of 


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receiving the study drug or not). The investigator must not allow the subject to continue with the 
study until receive the written approval from the sponsor. 
6.1.3. Randomization and blinding 
To avoid bias in the selection of subjects, the investigator will randomize subjects at 1:1 as per 
the random number table provided by the sponsor when the dose level is escalated to 3 mg/kg IV 
Q2W and 200 mg IV Q3W in the phase Ia dose-escalation study. 
Blinding is not adopted in this study. 
6.2. Study Plan and Schedule 
6.2.1. Screening period 
The following procedures must be completed during the screening (Days -28 to -1) period of 
phase Ia and Ib studies to ensure subject eligibility: 
• 
Signing of informed consent form 
• 
Confirming the inclusion/exclusion criteria 
• 
Recording the demographics, medical history, and previous medications 
• 
Recording the vital signs, height, and weight (for cohort D of phase Ib, the body surface 
area needs to be calculated) 
• 
Physical examination 
• 
ECOG PS score 
• 
12-lead electrocardiogram (ECG) 
• 
Routine blood test/blood chemistry/routine urinalysis (within 7 days prior to the first 
dose) 
• 
Coagulation function (within 7 days prior to the first dose) 
• 
Pregnancy test (within 3 days prior to the first dose) 
• 
Thyroid function (within 7 days prior to the first dose) 
• 
Autoantibody 
• 
HIV, HBV, and HCV 
• 
AE evaluation 
• 
Concomitant medications 
• 
Tumor imaging evaluation 


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• 
Archived or fresh tumor tissue sample (not for patients in cohorts G and H in phase Ib) 
Refer to Sections 6.3 and 6.4 for details regarding tumor imaging evaluation and safety 
evaluation. 
6.2.2. Treatment visits 
• 
Recording of vital signs and body weight; If the weight fluctuation is less than 10% 
compared to baseline (the day of the first dose), the baseline weight will be used to 
calculate the chemotherapeutic dose. Otherwise, the actual dose will be calculated 
based on the weight of scheduled dosing days. 
• 
Physical examination 
• 
ECOG PS score 
• 
The examination of 12-lead ECG, performed within 60 min after the infusion of IBI308 
• 
Routine blood test/blood chemistry/routine urinalysis 
• 
Thyroid function 
• 
Immunogenicity 
• 
PK/PD 
• 
AE evaluation 
• 
Concomitant medication 
• 
Tumor imaging evaluation 
• 
Administration: of study drug: 
- 
Phase Ia study: The cycle 1 for every dose group is the period of DLT observation 
(28 days) and the drug is only administered on Day 1. Since cycle 2, IBI308 is 
intravenously infused once every 2 weeks in the 1 mg/kg, 3 g/kg, and 10 mg/kg 
groups and once every 3 weeks in the 200 mg group. All reatment will be carried 
out until PD, intolerable toxicity, withdrawal of informed consent, or other reasons 
requiring treatment discontinuation (whichever occurs first). Some subjects could 
continue to use the investigational drug if they met certain conditions after PD 
(Protocol 5.1.2). 
- 
A-C cohorts in the phase Ib study: Subjects receive 200 mg IV Q3W of IBI308 
until PD is found for the first time, intolerable toxicity, withdrawal of informed 
consent, 24 months of treatment, or other reasons for discontinuation of the study 
treatment (whichever occurred first). Some subjects could continue to use the 
investigational drug if they met certain conditions after PD (Protocol 5.1.2). 


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- 
Cohort D in the phase Ib study: Each treatment cycle contained 3 weeks. And 200 
mg IV of IBI308, 500 mg/m2 IV of pemetrexed, and 75 mg/m2 IV of cisplatin are 
given on D1 of each cycle. Up to 4 cycles of triple drug combination therapy are 
given. Subsequently, the subjects experiencing no PD can receive a maintenance 
treatment of 200 mg IV Q3W of IBI308 and 500 mg/m2 IV Q3W of pemetrexed 
until PD, intolerable toxicity, withdrawal of informed consent, 24 months of 
treatment, or other reasons for discontinuation of the study treatment (whichever 
occurs first). 
- 
Cohort E in the phase Ib study: Each treatment cycle contains 3 weeks. The dosing 
regimen is IBI308 200 mg IV D1 + gemcitabine 1250 mg/m2 IV D1, D8 + cisplatin 
75 mg/m2 IV D1. Up to 6 cycles of triple drug combination therapy are given. 
Subsequently, the subjects experiencing no PD can receive a maintenance treatment 
of 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, withdrawal of 
informed consent, 24 months of treatment, or other reasons for discontinuation of 
the study treatment (whichever occurs first). 
- 
Cohort F in the phase Ib study: 200 mg of IBI308 are given via intravenous 
infusion every 3 weeks. Capecitabine 1000 mg/m2 PO BID D1-14+ oxaliplatin 130 
mg/m2 IV D1, with 3 weeks in a cycle (XELOX regimen). After up to 6 cycles of 
treatment of IBI308 in combination with XELOX, the subjects showing no PD 
could subsequently receive a maintenance treatment of 200 mg IV Q3W of IBI308 
until PD, intolerable toxicity, withdrawal of ICF, 24 months of total treatment, or 
other reasons for discontinuation of the study treatment (whichever occurred first). 
- 
Cohort G in the phase Ib study: Each treatment cycle contains 3 weeks. The dosing 
regimen is IBI308 200 mg IV D1, etoposide100 mg/m2 IV D1-3, and cisplatin 75 
mg/m2 IV D1. After up to 6 cycles of treatment of IBI308 in combination with 
chemotherapy, the subjects showing no PD could subsequently receive a 
maintenance treatment of 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, 
withdrawal of ICF, 24 months of total treatment, or other reasons for 
discontinuation of the study treatment (whichever occurred first). 
- 
Cohort H in the phase Ib study: Each treatment cycle contains 3 weeks. The dosing 
regimen is IBI308 200 mg IV D1, irinotecan 125 mg/m2 IV D1, and D8+5-FU 
1000 mg/m2 IV D1-3. After up to 6 cycles of treatment of IBI308 in combination 
with chemotherapy, the subjects showing no PD could subsequently receive a 
maintenance treatment of 200 mg IV Q3W of IBI308 until PD, intolerable toxicity, 
withdrawal of ICF, 24 months of total treatment, or other reasons for 
discontinuation of the study treatment (whichever occurred first). 


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• 
Tumor tissue samples from an exploratory study (optional, biopsy again after receiving 
the first dose of study medication until PD or termination of study treatment). 
See Table 1 and Table 2 for the flow chart of the visit during the treatment period of phase Ia; 
see Table 3 and Table 6 for the flow chart of the visit during the A-C treatment period of the 
phase Ib study cohort; see the flow chart of the visit during the D/E/F treatment period of the 
phase Ib study cohort in Table 4 and Table 6; see Table 5 for the flow chart of the I/B study 
cohort during the G/H treatment period. 
Refer to Sections 6.3, 6.4, 6.5, 6.6, and 6.7 for details regarding tumor imaging evaluation, safety 
evaluation, blood sampling for PK, PD, and immunogenicity. 
6.2.3. End-of-treatment visit/safety follow-up 
If the treatment ends or the study drug is discontinued prematurely for any reasons, an 
end-of-treatment visit shall be carried out as soon as possible the study drug within 7 days after 
the end of treatment and before the subject receives new anti-tumor therapy. The visit shall 
include the followings: 
• 
Vital signs and body weight 
• 
Physical examination 
• 
ECOG score 
• 
12-lead electrocardiogram (ECG) 
• 
Routine blood test/blood chemistry/routine urinalysis 
• 
Coagulation function 
• 
Thyroid function 
• 
AE evaluation 
• 
Concomitant medication 
• 
Tumor imaging examination 
A safety follow-up should be carried out within 90 days ± 7 days after the last dose or before the 
start of a new anti-tumor treatment (whichever occurred first). Subjects of treatment 
discontinuation due to drug-related AE should be followed up until the AE is resolved to grades 
0–1, with stable symptoms or withdrawal of ICF (whichever occurs first). The visit shall include 
the followings: 
• 
Vital signs and body weight 
• 
Physical examination 


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• 
ECOG score 
• 
12-lead electrocardiogram (ECG) 
• 
Routine blood test/blood chemistry/routine urinalysis 
• 
Coagulation function 
• 
Thyroid function 
• 
Autoantibody 
• 
Immunogenicity 
• 
PK/PD 
• 
AE evaluation 
• 
Concomitant medication 
• 
Subsequent anti-tumor therapy (if applicable) 
• 
Tumor imaging examination (if applicable) 
6.2.4. Survival follow-up 
After the last dose of the study treatment, the subject shall be contacted every 90 (± 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. 
6.3. Efficacy Evaluation 
There is no central imaging evaluation in this study. The methods used for the evaluation of 
tumor burden in the baseline period should be the same as the methods used for each subsequent 
follow-up evaluation (contrast-enhanced CT/MRI were usually used), and the sites of imaging 
examination included the chest, abdomen, and pelvic cavity. Other affected sites should be 
examined based on the signs and symptoms of each subject. 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. 
Tumor imaging evaluation should be carried out every 9 weeks (± 7 days) after first dose of the 
study drug. For patients who recorded disease remission (CR or PR) for the first time in the 
phase Ia study, an imaging evaluation will be performed after 4 weeks (±7 days) to confirm the 
remission, and thereafter every 12 weeks (±7 days) until the time of imaging PD is recorded; for 
patients with disease remission (CR or PR) recorded in the phase Ib study, an imaging evaluation 
will be performed after 4 weeks (±7 days) to confirm the remission, and thereafter every 9 weeks 
(±7) until the time of imaging PD was recorded. For cohorts A–C in phase Ia and Ib studies, the 


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patients who are first recorded as progressive disease (PD) in cohorts A–C during the imaging 
evaluation and then confirmed as irPD by the imaging evaluation carried out 4 weeks later, if 
they could continue to receive the treatment of the study drug, imaging evaluations should be 
carried out every 9 weeks (± 7 days) until the recurrence of PD. The recurrence of PD is defined 
as the increase in the sum of the longest diameter of the tumor target lesion by > 10% on the 
basis of the initial imaging-based PD or the appearance of a new measurable lesion. Cohorts D-H 
in the phase Ib study: Imaging studies confirm the tumor progression and need to stop the 
treatment with the study drug. For subjects with first imaging PD but an unstable clinical 
situation or rapid progression who are deemed as not suitable for continued drug treatment, it is 
not necessary for them to undergo further imaging examinations to confirm PD. 
For subjects who discontinue the treatment for reasons other than PD, an imaging evaluation 
should be carried out at the end of the treatment, and another imaging evaluation should be 
carried out every 9 weeks (± 7 days) after the drug treatment is discontinued until one of the 
following events occurred: start of a new anti-tumor therapy, PD, withdrawal of ICF, and death. 
Subjects who are known or suspected of having brain metastases at the time of screening should 
undergo a CT/MRI examination of the brain before the start of study treatment. During the study, 
such subjects should be followed up, and the CT/MRI assessment should be repeated at the same 
frequency as required by the RECIST V1.1 assessment. Brain metastases are evaluated as 
non-target lesions. 
The subject may continue the treatment if PD cannot be confirmed, especially for non-target 
lesions and new lesions, until clinically indicated disease or the next scheduled evaluation time 
point. The subject's disease status will then be re-evaluated. If repeated scans confirm PD, then 
the PD should be recorded using the date of the initial scan. 
In this study, the tumor evaluations are performed based on RECIST V1.1 at the study site. Refer 
to Appendix 3 for the evaluation methods. 
6.3.1. RECISIT 1.1 efficacy evaluation 
The efficacy evaluation is based on RECIST V1.1. For more information, see Appendix 3. The 
ORR, TTR, DOR, PFS, 6-month and 1-year PFS rates, DCR, OS, and 6-month and 1-year 
survival rates after medication are evaluated. 
6.3.2. Efficacy evaluation by immune-related remission standard (irRECIST) 
Immune-related RECIST (irRECIST) is a revised RECIST V1.1, which takes into account the 
unique tumor remission pattern seen in immunotherapy and is first proposed by Nishino et al. 
Immunotherapy drugs (such as IBI308) can exhibit an anti-tumor effect by strengthening the 
endogenous tumor-specific immune response. The remission patterns that are observed this 


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therapy can not only extend the typical remission time course shown in cytotoxic drug therapy, 
but also lead to clinical remission after the initial increase in tumor burden or even after the 
findings of new lesions. Therefore, RECIST V1.1 may not provide an accurate response 
assessment protocol for immunotherapy drugs such as IBI308. The evaluation standard for 
one-dimensional target lesions based on irRECIST is generally the same as RECIST V1.1. The 
main difference between this standard and RECIST V1.1 is that when the first imaging 
examination is evaluated as PD, the irRECIST evaluation is initiated 4 weeks (±7 days) later, and 
the evaluation results are defined as follows: 
• irPD: The total tumor diameter (if there is a measurable new lesion, the diameter of the 
new lesion should be added to the total diameter of the target lesion according to the 
RECIST V1.1 standard) increases by ≥ 20% from the minimum value, or the absolute 
value increases by at least 5 mm; If irPD is not confirmed, the tumor evaluation will be 
continued by the previous imaging evaluation time point according to the RECIST 
standard until the next imaging PD is confirmed as irPD. 
• irCR: The evaluation standard is the same as RECIST V1.1, which occurs after irPD is 
confirmed; 
• irPR: The evaluation standard is the same as RECIST V1.1, which occurs after irPD is 
confirmed; 
• irSD: The evaluation standard is the same as RECIST V1.1, which occurs after irPD is 
confirmed; 
The irRECIST is explored as a methodology to evaluate the clinical benefits of IBI308, and 
evaluate irORR, irDCR, irPFS, and irDOR according to the immune-related remission standard. 
6.4. Safety Evaluation 
6.4.1. Routine laboratory safety evaluation 
Table 25. Routine laboratory safety evaluation 
Routine blood test 
RBC, HGB, HCT, WBC, PLT, LYM, ANC, MONO, EOS, and BASO 
Coagulation function 
TT, PT, APTT, and INR 
Blood chemistry 
TBILa, ALT, AST, γ-GT, ALP, ALB, TP, LDH, Urea, Cr, Na, K, Cl, Mg, Ca, P, 
amylase, and FBG 
Urinalysis 
PH, UWBC, UPROb, URBC, and UGLU 
a. If TBIL is ≥ 2 × ULN (and no evidence of Gilbert syndrome), direct and indirect bilirubin will be measured 
separately. 
b. Any subject with urine protein ≥ 2+ from urinalysis blood cells undergo a 24-hour urine protein test. 


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6.4.2. 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 in Tables 1, 3, 4, and 5 for examination time. Refer to Appendix 2 
for ECOG PS score. 
6.4.3. 12-lead electrocardiogram (ECG) 
A resting 12-lead ECG is performed at the local laboratory in accordance with the schedule of 
visits in Tables 1, 3, 4, and 5. 
All resting 12-lead ECGs are performed while the subjects are resting in the supine position. 
Further ECG will be performed if clinically indicated, such as a cardiac AE. The investigators 
review the ECG on the day it is performd, and documented the results on the ECG. The same 
method of evaluation is used throughout the trial. 
The investigators evaluate all the ECG as either a clinically significant or insignificant 
abnormality. For a clinically significant abnormality, the investigators should document the 
result as an AE in the eCRF. 
6.4.4. Vital signs 
Vital signs are examined in accordance with the schedule of visits in Tables 1, 3, and 4. 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 eCRF when an AE/SAE occurs (if 
applicable). The time and date of collection and measurement should be documented in the 
appropriate section of the eCRF. 
6.4.4.1 Pulse and blood pressure 
The subject's blood pressure and pulse in the supine position are measured after a rest for at least 
5 minutes. The time and date of collection and measurement should be documented in the 
appropriate section of the eCRF. 
In the phase Ia study, the blood pressure and pulse are collected at the following time points 
before, during and after each infusion of IBI308 (based on a 60-minute infusion): 
• 
At the start of infusion (minute 0) 


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• 
Every 15 minutes during infusion (minute 15, 30, and 45) (all ± 5 minutes) 
• 
At the end of infusion (minute 60, ± 5 minutes) 
• 
During the observation period 1 hour after infusion: 30 and 60 minutes after infusion 
(i.e., 90 and 120 minutes from the start of the infusion) (± 5 minutes). 
In the event that the infusion is longer than 60 minutes, the blood pressure and pulse are 
measured following the above principles or at a higher frequency when clinically indicate. 
For the Phase Ib study, pulse and blood pressure are only measured before the infusion of 
IBI308. 
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. 
6.4.5. Weight and height 
Height is measured only during screening. 
Weight must be measured before every planned dose during the study. If the weight fluctuation 
is less than 10% compared to baseline (date of chemotherapy: first dose), then use the baseline 
weight to calculate the chemotherapeutic dose. Otherwise, the actual dose will be calculated 
based on the weight of scheduled dosing days. 
6.4.6. Pregnancy test 
Urine or serum human chorionic gonadotropin (hCG) pregnancy test is performed in women of 
childbearing age (for the definition, see Section 5.6.2) within 3 days prior to the first dose of the 
study treatment. 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. 
6.4.7. Autoantibody 
The testing items during the screening period include ANA, anti-dsDNA antibodies, and 
anti-thyroglobulin antibodies, and then the investigators will judge whether to check the relevant 
autoimmune antibody parameters based on clinical indications. 
6.4.8. Other safety inspections include the followings: 
• 
HBV-related tests, including five items for hepatitis B: HBsAg, HBsAb, HBcAb, 
HBeAg, and HBeAb. HBV-DNA should be further tested for subjects positive to 
HBsAg and/or HBcAb; 


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• 
HIV 1/2 antibody and HCV antibody tests; 
• 
Thyroid function: T3, T4, TSH, FT3, and FT4. 
6.4.9. Safety Review Committee 
The Safety Review Committee is composed of the sponsor and the investigators. After 
completing the DLT observation of the previous dose group in the phase Ia dose escalation, the 
Safety Review Committee will evaluate and decide whether the group can enter the next dose 
group for treatment. The discussion in the Safety Review Committee can also be triggered by a 
sudden safety event during the phase Ib trial. 
6.5. Pharmacokinetics: 
6.5.1. Collection of specimens 
6.5.1.1 Phase Ia study 
A total of 9 PK sampling time points are designed for cycle 1: within 1 h before IBI308 infusion, 
at 0 h (+ 5 min) and 1 h ± 5 min after the end of infusion, and at 6 h ± 15 min, 24 ± 1 h, 48 ± 2 h, 
168 ± 8 h (day 8), 336 ± 12 h (day 15), and 504 ± 24 h (day 22) after the start of infusion. 
From cycle 2, blood collection for PK testing is performed every 2 cycles (i.e., cycles 2, 4, 6...). 
Except for cycle 4, the blood collection times are all within 1 h before the start of the infusion 
and immediately after the end of the infusion (+ 5 min). 
In Cycle 4 (dense sampling), for the 200 mg cohort, blood is sampled within 1 h before the start 
of infusion, at 0 h (+ 5 min) and 1 h ± 5 min after the end of infusion, and at 6 h ± 15 min, 24 ± 1 
h, 48 ± 2 h, 168 ± 8 h (Day 8), 336 ± 12 h (Day 15), and 504 ± 24 h (Day 22) after the start of 
infusion; and for 1 mg/kg, 3 mg/kg, and 10 mg/kg cohorts, blood is sampled within 1 h before 
the start of infusion, at 0 h (+ 5 min) and 1 h ± 5 min after the end of infusion, and at 6 h ± 15 
min, 24 ± 1 h, 48 ± 2 h, 168 ± 8 h (Day 8), and 336 ± 12 h (Day 15) after the start of infusion. 
6.5.1.2 Phase Ib study 
The same PK collection method is used in cohorts A–F in the phase Ib study. No PK sampling 
will be performed for cohorts G and H in the phase Ib study. 
There are a total of 8 PK blood sampling points in Cycle 1: within 1 h before the start of IBI308 
infusion, immediately after the end of infusion (+ 5 min), 1 h ± 5 min after the end of infusion, 
and 6 h ± 15 min, 24 h ± 1 h, 48 h ± 2 h, 168 h ± 8 h (D8), and 336 h ± 12 h (D15) after the start 
of infusion. 


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From cycle 2, samples are collected every 2 cycles (i.e., cycles 2, 4, 6...), with 2 blood sampling 
points per cycle: within 1 h before the start of infusion, and immediately after the end of infusion 
(+ 5 min).If the dosing on Day 1 of Cycle 2 is delayed due to an AE or other reasons, additional 
sampling is required at 504 ± 24 h (Day 22) in Cycle 1. 
In the phases Ia and Ib studies, one PK sampling was required in each safety follow-up of 
cohorts A–F. 
A vacutainer with coagulant will be used to collect 2 mL of whole blood. Then, the serum will be 
separated from the whole blood sample and frozen in aliquots for the PK analysis. Refer to the 
Laboratory Manual provided by the sponsor-designated central laboratory for sampling methods, 
sample storage, transport, and analysis. 
6.5.2. Measurement of drug concentration 
The concentration of IBI308 in the serum is measured by ELISA, and tested by the central 
laboratory designated by the sponsor. The plasma drug concentration needs to be determined in 
all subjects at the sampling time points specified in the study protocol. 
6.6. Pharmacodynamics 
6.6.1. Phase Ia study 
There are a total of three PD blood collection points in cycle 1: within 1 h before the start of 
IBI308 infusion, and 24 h ± 1 h, and 168 h ± 8 h (day 8) after the start of the infusion. From 
Cycle 2, sample collection will be performed every four cycles (Cycles 6, 10, 14…), with blood 
sampling points within 1 h before the start of infusion. One blood sample must be collected 
during safety follow-ups. 
6.6.2. Phase Ib study 
There are a total of three PD blood collection points in cycle 1: within 1 h before the start of 
IBI308 infusion, and 24 h ± 1 h, and 168 h ± 8 h (day 8) after the start of the infusion. From 
cycle 2, blood collection is performed every 4 cycles (i.e., cycles 6, 10, 14...). Blood collection 
time point: within 1 h before the start of the infusion. Blood samples must be collected during 
safety follow-ups. 
A vacutainer with anticoagulant will be used to collect 1 mL of whole blood for the analysis of 
PD-1 receptor occupancy. Refer to the Laboratory Manual provided by the sponsor-designated 
central laboratory for sampling methods, sample storage, transport, and analysis. 
No PD sampling will be performed for cohorts G and H in the phase Ib study. 


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6.7. Immunogenicity 
Immunogenicity assays are performed within 1 h prior to IBI308 infusion in cycles 1, 2, and then 
every 2 cycles thereafter (cycles 4, 6, 8...) and during the safety follow-up visits. If an IBI308 
infusion-related reaction occurs, blood samples should be taken near the start of the event, end of 
event, and around 30 days after the reaction, for comparative analysis of immunogenicity. 
ADA titer should be tested for each subject. ADA-positive samples should be further tested for 
neutralizing antibodies (NAbs). 
For ADA and NAb assays, 4 mL of whole blood will be collected using vacutainers with 
coagulant. Then, the serum will be 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. 
No immunogenicity assay will be performed for cohorts G and H in the phase Ib study. 
6.8. Biomarker Analysis 
When permitted by the IEC, subjects who met the inclusion criteria are required to provide 
diagnosed tumor tissues at baseline (except for cohorts G and H in the phase Ib study). For the 
acceptable tumor tissues, including the archived tumor tissues or those newly collected and 
prepared during the screening period, at least 5 unstained sections of 4 micron will be required. 
With the subject's informed consent, a biopsy is performed again after the use of the study drug 
and before the PD or termination of the treatment. The tumor tissues are submitted to the central 
laboratory for testing, and the relationship between the changes in PD-L1 expression before and 
after treatment and the efficacy is compared. The samples could also be used for exploratory 
biomarker analysis, including but not limited to PD-L1 expression, tumor mutation burden (TMB) 
test, multicolor immunohistochemistry, and PD-L1 and CD8 double staining assay. 
For the study sites participating in cohorts D/E/F studies, after the protocol V2.0 takes effect, 
tumor tissues and peripheral blood (as a reference standard) that meet the following requirements 
must also be provided at the baseline, in order to analyze biomarkers (such as TMB) based on the 
whole exome sequencing. 
For the study sites participating in cohorts A/B/C studies, the TMB test must be optional. 


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Tumor tissues: (any samples meeting one of the following requirements for sources) 
Sample type 
Sample collection 
Storage temperature 
Transportation 
method 
Notes 
Formalin-fixed 
and parrffin- 
embedded tissues 
(FFPE) 
10–15 (at least 5) pieces 
of surgical tissue 
sections; 
Puncture tissues > 15 
pieces; 
Paraffin block of 50 mg 
(with bean size) 
<37°C 
Transportation at 
ambient 
temperature 
Paraffin samples 
within half a year 
should be submitted 
for tests in sections 
without staining 
Puncture tissues 
2 needles, at least 1, 
with a sample diameter 
of 1–2 mm and a length 
of more than 0.5 m 
With tissue storage 
buffer: < 25 °C 
Without tissue storage 
buffer: < -20 °C 
Mail with dry ice 
Formalin immersion 
should be possibly 
avoided 
Fresh tissues 
No less than 60 mg for 
submission (with bean 
size) 
With tissue storage 
buffer: < 25 °C 
Without tissue storage 
buffer: < -20 °C 
Mail with dry ice 
In case of using the 
tissue storage buffer, 
the tissues must be 
completely immersed 
into the buffer 
Normal reference standard: 
Sample type 
Sample collection 
Storage 
temperature 
Transportation method 
Notes 
Peripheral 
blood 
A collection of ≥ 2 
mL, with sodium 
citrate or EDTA as 
an anticoagulant  
<-20°C 
Mail with dry ice 
Using heparin as an 
anticoagulant is not 
recommended 
Refer to Laboratory Manual for details regarding sample processing, handling, and transport. 
6.9. 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. 


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7. 
SAFETY REPORTS AND AE MANAGEMENT 
7.1. 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 study drug, regardless of whether 
or not considered as related to the study drug. AEs include but are not limited to the followings: 
• 
Worsening of pre-existing (prior to enrollment) medical conditions/diseases (including 
symptoms, signs, and laboratory test abnormalities); 
• 
Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
• 
Clinically significant laboratory test abnormalities.  
7.2. Definition of SAEs 
A SAE refers to an AE meeting at least one of the followings: 
• 
Death, except for the cases caused by PD; 
• 
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). 
• 
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 due 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 starts); hospitalization for 
administrative reasons (e.g. annual routine physical examinations); hospitalizations 
during the study as specified in the protocol (e.g. hospitalization performed in 
accordance study protocol); elective hospitalization unrelated to worsening of AEs 
(e.g. elective surgery); scheduled treatment or surgical procedures, which 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. 
• 
Resulting in permanent or severe disability/incapacity. 


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• 
Resulting in congenital abnormalities/birth defects. 
• 
Other important medical events: defined as events that may jeopardize the subjects 
and require medical or surgical interventions to prevent one of the other outcomes 
listed in the definition above. 
7.3. Criteria for Severity Levels of AEs 
The severity level of AEs is evaluated using the 5-level criteria of NCI CTCAE version 4.03. 
AEs not included in NCI CTCAE version 4.03 are graded in accordance with the following 
CTCAE grading principles: 
• 
Grade 1 Mild; asymptomatic or mild sings; clinical or diagnostic observations only; 
medical intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or non-invasive intervention required; limiting 
age-appropriate instrumental activities of daily living (e.g., cooking, shopping, using 
telephone and managing money, etc.). 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolonged hospitalization indicated; disabling; limiting self-care 
activities of daily life (e.g. bathing, dressing and undressing, feeding self, using toilet, 
and taking medications), but not bedridden. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
7.4. Correlation Between AEs and Study Drug 
The relationship between the study drugs and AEs can be determined by the classification and 
the criteria in Table 26. 
Table 26. Correlation determination between AEs and study 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. 


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Correlation 
Criteria 
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). 
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. 
7.5. Documentation of AEs 
The investigator should document AEs and SAEs using medical terms and concepts. Avoid 
colloquialisms/abbreviations. All the AEs (including SAEs) shall be documented on the AE 
forms in the eCRFs. 
7.5.1. Collection and Time of AEs 
The investigators learn about AEs by asking the subjects non-leading questions. 
All the AEs, including SAEs, that occurr from the signing of the ICF to 90 days after the last 
dose are collected, regardless of whether it is observed by the investigator or self-reported by the 
subject. If the subject initiates other anti-tumor therapies within 90 days after the last dose of the 
study 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 study drugs or study procedure. 
7.5.2. AE follow-up 
The AE should be followed until the events return to the baseline values or grade 0–1, or until 
the investigator believes that no further follow-up is required for reasonable reasons (if the event 
cannot be resolved or has already been improved). If the event cannot be resolved, a reasonable 
explanation 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 
study drugs. 


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7.5.3. Contents of AE documentation 
The investigator must document all the AEs, including the diagnosis (document signs and 
symptoms including the laboratory abnormalities if there is no diagnosis), time and date of 
occurrence (if applicable), CTCAE grade of severity and changes in severity (events ≥ grade 3), 
whether it is an SAE, whether it is an adverse event of special interest (AESI), measures taken 
for the study drugs, treatment for the AE and outcome of the event, and relationship between the 
event and study drugs. 
For an SAE, the investigator shall also provide the date when the AE meets the criteria for an 
SAE, the date when the investigator is informed of the SAE, the reason of being an SAE, date of 
hospitalization, date of hospital discharge, possible cause of death, date of death, whether an 
autopsy has been performed, causality assessment of the study procedures, causality assessment 
of other drugs, and other possible causes of the SAE. The investigator shall provide the 
rationales of the causality and a description of the SAE. In the SAE description, the followings 
shall also be included: the subject number, age, gender, height, and weight; indication for 
receiving the investigational drug, cancer staging, and overall condition; SAE occurrence, 
development, outcome, and result; laboratory results related to the SAE (the time of the 
examination, units, and normal ranges must be provided); medical history, onset and duration of 
concurrent diseases related to the SAE; medication history and initiation, duration, and dosage of 
concomitant medications related to the SAE; initiation, duration, and dosage of the study drug. 
Descriptions of the AE are as follows: 
Diagnosis, signs, and symptoms 
Document the definite diagnosis, if there is one, rather than just listing the independent signs and 
symptoms (e.g. hepatic failure rather than jaundice, elevated transaminase, and asterixis). Signs 
and symptoms 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, included the signs and symptoms. The record of signs and symptoms 
shall then be deleted. A follow-up SAE report shall be submitted. 
AEs secondary to other events 
Generally, AEs secondary to other events (such as result of another event or clinical sequelae) 
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, 
document them as separate events in the eCRFs. 


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Ongoing or recurrent AEs 
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment 
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. 
Recurring AEs refer to AE that have resolved between the two time points of assessment 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 investigators has 
responsibilities to review all the laboratory test abnormalities and determine whether the 
abnormalities should be reported as AEs. 
Death 
During the entire course of the study, all the deaths that occurr within 90 days after the last dose 
are documented in the Death Report Form in the eCRFs and reported to the sponsor timely, 
regardless of the causality with the study drug. 
For a death with a known cause, record the cause of death as an AE and the outcome of the AE 
as "death" and submitt an SAE report; for a death with an unknown cause, the AE is recorded as 
"unknown cause of death" in the AE form, and submitted an SAE report. Further investigation is 
performed for the exact cause of the death. 
Pre-existing medical conditions 
Symptoms/signs presenting during the screening period will be recorded and reported as AEs 
only if their severity level, frequency, or property becomes aggravated (except for worsening of 
the studied disease). The relative change should be documented, such as increased frequency of 
headaches. 
Progressive disease 
A PD 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 of the primary 
lesion. Expected PD should not be reported as an AE. Any deaths, life-threatening events, 
hospitalization or prolonged hospitalization, permanent or significant disability/incapacity, 
congenital anomaly/birth defects, or other important medical events caused by PD should not be 
reported as an SAE. 


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7.6. 
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 "CFDA (now NMPA) SAE Report Form", regardless 
of whether it is the initial report or a follow-up report, and sign and date the form. The 
investigator must report the SAE to the sponsor, CFDA (now NMPA), and EC within 24 hours 
of noticing the event. Refer to the table below for contact details. 
For SAEs occurring outside of the above-mentioned period, those considered related to the study 
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. 
The investigator should also report the event to the CFDA (now NMPA), health administration 
departments, and ECs in accordance with the regulations. 
Table 27. SAE report contacts 
Unit 
Contact 
Fax/Telephone/Address 
Hospital Name 
Ethics committee 
Hospital Fax/Telephone 
Innovent Biologics (Suzhou) Co., 
Ltd. 
Clinical Study 
Department PV 
Fax: 021-31652800 
Email: drugsafety@innoventbio.com 
National Medical Products 
Administration 
 
Address: No. 1, Lu Yuan, North Zhanlan Road, 
Xicheng District, Beijing, China 
Postal code: 100037 
Switchboard: 010-68313344 
Medical Administrative Department, 
Health Administration 
 
Address: No. 38, Lishi Road, Xicheng District, 
Beijing 
Tel.: 010-68792001 
Fax: 010-68792734 
Province, Autonomous Region, 
Municipality Food and Drug 
Administration 
Based on the requirements of the food and drug administration department 
of each province, autonomous region or municipality  
Pregnancy 
The risk of embryotoxicity exists for the similar kind of drugs. All the subjects with childbearing 
potential must take effective contraceptive measures. 


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During the study, if a female subject exposed to the study drugs 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 exposed to the study drugs becomes 
pregnant, the subject will continue in the study. The investigator must report to the sponsor 
within 24 hours of noticing the event and submit the "Innovent Clinical Study Pregnancy 
Report/Follow-Up Form". 
The investigator must continuously monitor and visit on the outcome of the pregnancy until the 
8th week 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 a SAE during the pregnancy, the "CFDA (now NMPA) SAE 
Report Form" should also be filled out and reported according to SAE's procedures. 
7.7. 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 conditions in Table 28 are met without other possible 
causes. Such cases should always be considered as important medical events. 
Table 28. 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 TBIL ≥ 2 × ULN 
and ALP ≤ 2 × ULN 
and no hemolysis 
ALT or AST ≥ 8 × ULN 
and TBIL increase ≥ 1× ULN or value ≥ 3× 
ULN 
Once being notified with the abnormalities, the subject must return to the study site promptly 
(ideally within 48 hours) and receive an assessment. The assessment must include the laboratory 
tests, detailed medical history, and physical assessment, and the possibility of hepatic tumor 
(primary or secondary) shall be considered. 
Other than repeated AST and ALT tests, albumin, creatine kinase, TBIL, direct and indirect 
bilirubin, γ-GT, PT/INR, and ALP shall also be tested. Detailed medical history include history 
of alcohol, acetaminophen, soft drugs, various supplements, traditional Chinese medicine, 
chemical drug exposure, family diseases, occupational exposure, sexual behavior, travel, contact 
with patients with jaundice, surgery, blood transfusion, hepatic diseases or allergies, cardiac 
diseases, and immune diseases. Further tests may include the detection of acute hepatitis A, B, C 


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and E, hepatic imaging (such as biliary tract), autoantibodies, and echocardiography. If a retest 
showed consistency with the criteria outlined in Table 28 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 shall be reported as 
SAEs, and the Appendix 4: Abnormal Hepatic Function Monitoring and Follow-Up Report shall 
be submitted to the sponsor. 
7.8. Management of Drug-Related Toxicities 
During the course of the trial, the sponsor will conduct regularly monitoring of safety. Detailed 
information regarding the frequency of review and type of data to be reviewed will be presented 
in a separate safety review plan. 
7.8.1. Immune related adverse events 
Since the mechanism of action of IBI308 involves T-cell activation and proliferation, irAEs are 
likely to be observed during this study. Signs and symptoms of irAEs are monitored. In case of 
no alternative causes (e.g. infections), signs and symptoms of the subjects during the study may 
be related to the immune system. 
Refer to Sections 5.4 and 5.5 for dose adjustments of IBI308 and principles of AE management. 
Refer to Appendix 8 (Tables 1 to 3) for a detailed guide on irAE management. 
7.8.2. 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. AESIs can be non-serious events. 
Examples of irAE are as follows: 
• 
Immune-related pneumonia of grade 2 or above. 
• 
Immune-related nervous system disorders of grade 2 or above. 
• 
IrAE except for pneumonia and nervous system disorders of grade 3 or above. 
For the AESIs specified in the clinical trial protocol, the "Innovent Clinical Study Adverse Event 
of Special Interest Report Form" should be completed within 24 hours of the investigator's 
knowledge of the event, and reported to the sponsor. If the SAE standards are met, the "CFDA 
(now NMPA) Serious Adverse Event Report Form" must also be completed, while reporting 
based on the requirements and the deadlines for SAE. 


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8. STATISTICS 
8.1. Statistics Analysis Plan 
A detailed statistics analysis plan (SAP) will be written after the first enrollment and finalized 
prior to database locking. All analyses and the expression methods for the results proposed for 
this study will be detailed in the SAP. 
8.2. Hypothesis Test 
The main objectives of this study include: to evaluate the safety and tolerability of IBI308 in 
subjects with advanced malignant solid tumors, and to assess the anti-tumor activities of IBI308 
in monotherapy or combination chemotherapy in subjects with advanced solid tumors. The main 
evaluation endpoints are AEs (including DLT), and efficacy evaluation endpoints (ORR, PFS, 
DcR, DOR, TTR, and OS based on RECIST V1.1 standard). No formal hypothesis test will be 
performed, while 95% CI will be provided if necessary. 
Also, the endpoints related to secondary and exploratory objectives are based on descriptive 
statistics, without formal hypothesis test. 
8.3. Statistical Populations 
The analysis sets include the safety set (SS), full analysis set (FAS), and PK analysis set. 
1. SS: subjects who receive at least one dose of the study drug. 
2. FAS: subjects who has a measurable lesion at baseline, and who has used the study drug 
at least once. 
3. PPS: a subset of the FAS, including subjects with good compliance and no serious 
protocol deviations or prohibited medications. 
4. PK analysis set: subjects who has no major protocol deviation or significant PK blood 
sample collection missing. 
Regardless of phases Ia or Ib, anti-tumor activity (clinical efficacy or PD parameters) will be 
evaluated using the FAS, SS for the safety analysis, and PK analysis set for the analysis of PK 
parameters. 
The PFS and OS are analyzed simultaneously using the SS. 
8.4. Statistical Analysis Methods 
8.4.1. General statistical analysis 
Variable data are summarized using the mean, standard deviation, median, maximum, and 
minimum. Attributes data are described using frequency and percentage. 


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No formal hypothesis testing is performed and 95% CI is calculated when necessary. 
For phase Ia study, the tumor evaluation for each subject will be tabulated, with items of optimal 
overall response, PFS, OS, and DOR. For phase Ib study, each endpoint indicator will be 
analyzed by sub-cohort (tumor species) according to Sections 8.4.2 and 8.4.3. 
All statistical analyses are carried out using SAS 9.2 or above. 
8.4.2. Analysis of the primary endpoint 
1. Safety indicators: For the analysis, see the section "8.4.4 Safety Analysis". 
2. All efficacy endpoints (excluding OS) are evaluated based on the RECIST V1.1. 
• 
ORR 
%
100
*
subjects
 
all
 
of
Number 
PR
 
achieving
 
subjects
 
of
Number 

CR
ORR
, 95% CI is calculated using the 
binomial distribution 
• 
DCR 
%
100
*
subjects
 
all
 
of
Number 
SD
 
achieving
 
subjects
 
of
Number 



PR
CR
DCR
, 95% CI is calculated using 
the binomial distribution 
The ORR and DCR are calculated based on the optimal tumor efficacy evaluation that is 
secondarily confirmed during the study period. 
• 
PFS 
PFS: The time from the first use of the study drug to the time of first PD (imaging). For patients 
died of any cause before PD, the PFS is the time from the first use of the study drug to death. 
Subjects who do not have PD or die will be censored on the date of their last imaging evaluation. 
For subjects who do not undergo imaging evaluation after baseline, the censoring date is the date 
when the first dose of the study drug is given. 
The PFS analysis uses Kaplan-Meier to estimate mPFS, 6-month and 1-year PFS rates, and their 
95% CI, and survival curves are plotted. 
• 
OS 
OS: The time from the first dose of the study drug to the death of the subject. At the end of the 
study, if the subject is still alive, the known "last date of subject survival" will be used as the 
censoring date. 
The Kaplan-Meier method is used in the OS analysis to estimate mOS, 6-month and 1-year 
survival rates, and their 95% CI, and survival curves are plotted. 


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• 
DOR 
For subjects showing a response (CR or PR), their DOR: the time from the date of 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. 
The DOR of the responded subjects will be tabulated; and if the data is acceptable, a survival 
curve will be plotted. 
• 
TTR 
For subjects with an objective response (CR or PR), their time to objective response: the time 
from the first dose of the study drug to the first confirmation of objective response. 
The TTR for subjects will be tabulated; and if the data is acceptable, a survival curve will be 
plotted. 
• 
Maintenance response rate 
For subjects with an objective response (CR or PR), the ratio of those whose response is 
maintained till the end of the study. 
8.4.3. Analysis of secondary endpoints 
• 
PK parameters. 
• 
PK parameters: AUC0-tlast, AUC0-inf, Cmax, Tmax, CL, Vz, t1/2, MRT, accumulation ratio, 
Css_min, Css_max, Css_av, AUCss, fluctuation coefficient, mean descriptive statistics, 
standard deviation, CV, maximum, and minimum. 
• 
Immunogenicity indicators. 
• 
The rates of ADA and NAb development will be calculated. Subjects' antibody titer will 
be tabulated. 
• 
PD parameters. 
• 
Variations of PD indicators (including but not limited to receptor saturation) will be 
descriptively statistically analyzed. 
8.4.4. Safety analysis 
Safety analysis is performed using the SS. The safety parameters include DLT, other AEs, 
laboratory tests, vital signs, ECG, etc. The data will be summarized by stages and by queue. AEs 
will be summarized (8 cohorts in phases Ia and phase Ib). 


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8.4.4.1 Drug exposure 
The subjects will be summarized by the drug exposure, administration time (number of cycles), 
tumor species, and overall conditions. 
8.4.4.2 Adverse events 
All the AEs will be coded according to MedDRA. 
According to NCI CTCAE V4.03, the distributions of incidences (frequency) and severity levels 
of AEs, TEAEs, ADRs, SAEs, and AESIs should be summarized by SOC and PT in the 
MedDRA coding. 
Subjects who discontinue the treatment due to AEs, develop SAE, or die will be listed (include at 
least the followings: start and end date of the AEs, severity levels, relationship with study drugs, 
measures taken, and outcomes). 
The subjects with DLT will be described in a list and the incidence of DLT will be calculated. 
8.4.4.3 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. 
The proportion of subjects with "clinically significant abnormalities" will be presented. The 
clinical significance should be determined by the investigator. The severity level and the 
incidence rates of each disease will be calculated by the NCI CTCAE 4.03 (when performing the 
same test item, the case of the highest severity level and the incidence rate should be counted), 
and tabulated by the changes before and after the treatment. 
Subjects with abnormal changes after treatment (whether clinically significant or not) will be 
listed. 
8.4.4.4 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. 
8.4.4.5 Vital signs, physical examination, and other safety-related examinations 
Descriptive statistics of vital signs and relative changes from baseline will be shown. 
Abnormal changes from baseline in physical examination will be listed. 


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8.4.5. Compliance analysis 
The frequency and proportion of subjects who violated the expecte 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. 
8.4.6. Subjects' baseline characteristics 
Subjects' demographic characteristics (sex and age), tumor diagnosis information (tumor types, 
pathological diagnosis, tumor staging, and 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, ECOG PS scores, laboratory tests, past/concomitant 
medications) will be analyzed using descriptive statistics. 
8.4.7. Interim analysis 
N/A. 
8.4.8. Subgroup analysis 
A subgroup analysis of anti-tumor activity (ORR) will be carried out on factors that are clinically 
considered to affect prognosis, such as gender, age, and ECOG PS score. 
8.4.9. Multiple comparisons and adjustments 
Multiplex adjustments are not considered. 
8.4.10. 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. 
8.4.11. Exploratory analysis 
The parameters of the clinical benefit evaluation are based on the irRECIST criteria, including 
irORR, irDOR, irPFS, and irDCR (see Section 8.4.2 for the analytical procedure). 
Descriptive statistics will be given for baseline PD-L1 expression, the ratio of subjects at 
different levels of PD-L1 expression, and their corresponding ORR and DOR; 
Exploratory analysis will be carried out on the relationship between PK-PD and the relationship 
between AUC and anti-tumor activity (ORR, DOR). 


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8.5. Sample Size Determination 
No formal estimation of sample size will be performed in this clinical study. 
Phase Ia study: This dose escalation study uses the standard "3 + 3" design to evaluate 4 dose 
levels. It is planned to enroll around 12–24 patients with advanced solid tumors that have failed 
standard treatment. 
Phase Ib study: A total of 10–20 subjects will be enrolled into cohorts A and C, 50–100 for 
cohort B, 20 each for cohorts D, E, and F. and 15 each cohorts G and H. 
8.6. Methods for Controlling Bias 
8.6.1. Randomization and blinding 
To avoid bias in the selection of subjects, the investigator will randomize subjects at 1:1 as per 
the random number table provided by the sponsor when the dose level is escalated to 3 mg/kg IV 
Q2W and 200 mg IV Q3W in the phase Ia dose-escalation study. 
Blinding is not adopted in this study. 
8.6.2. Blinding maintenance evaluation 
N/A. 
8.6.3. Unblinding and emergency unblinding 
N/A. 
8.7. Statistical Analysis and Clinical Study Report 
The first data analysis for cohorts A–F in phase Ib of this study will be performed about 6 
months after the last subject in each cohort was enrolled. And the results of the first data analysis 
will be presented in the statistical analysis report. No clinical study report will be prepared 
separately for cohorts A–F. The clinical study reports for this study will be completed in two 
individual parts, each of which will include the corresponding cohorts and deadlines of statistical 
analyses, as shown in Table 29. 
Table 29. Schedule of clinical study reports 
Clinical study report 
Included cohort 
Deadline of statistical analysis 
Report 1 
Phase Ia 
Completed by the finalization of study protocol V3.0 
Report 2 
Cohorts A–F of phase Ib 
6 months after the enrollment of the last subject in 
cohort F of phase Ib 
Report 3 
Cohorts G and H of phase Ib 
6 months after the enrollment of the last subject in 
cohort H of phase Ib 


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After completing the data cut-off at each time point of statistical analysis, each study site should 
continue to complete the treatment, follow-up, and data entry for the subjects in the study groups, 
until all the subjects of the site complete all follow-ups. Cohorts G and H in the phase Ib study 
are cohorts added for the protocol V3.0. The study sites that have not participated in the study of 
these two cohorts will be closed after the completion of the clinical studies on cohorts A–F. 
9. QUALITY ASSURANCE AND QUALITY CONTROL 
According to the GCP guidelines, the sponsor is responsible for implementing and maintaining 
quality assurance and quality control systems in accordance with the corresponding standard 
operation procedures to ensure that the implementation of the clinical trial and the collection, 
recording, and reporting of clinical trial data comply with the requirements in the protocol, GCP, 
and corresponding regulations. 
9.1. Clinical Monitoring 
The sponsor or its authorized contract research organization (CRO) will conduct clinical 
monitoring of this study. The CRA shall 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 CRA should maintain regular 
communication with the investigator and the sponsor. 
Before the start of the study, the CRA assesses the qualifications of each study site, and reports 
issues related to facilities, technical equipment, or medical staff to the sponsor. During the course 
of the study, the CRA is responsible for the monitoring of whether the written ICF from all 
subjects has been obtained and whether the data records are correct and complete. Also, the CRA 
compares the data entered into the eCRF with the source data, and informs the investigator of 
any errors or omissions. The CRA shall also control the study center's adherence to the protocol, 
arrange for the supply of trial drugs and ensure that the drugs are preserved in the proper 
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 investigator, the CRA should submit a written report to the sponsor. 
9.2. Data Management/Coding 
This study will use an electronic data collection (EDC) system, and the research data will be 
recorded in the eCRFs by the investigators or its authorized personnel. Before the initial of the 
study site or data entry, the investigators and authorized personnel should be properly trained and 
appropriate security measures should be taken for the computer and other equipment. 


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Data entry into the eCRFs should be completed as soon as possible during or after visiting. 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, it is 
recommended that the baseline and all the subsequent efficacy and safety evaluations of a given 
subject shall be performed by the same individual. The investigators are required to review the 
data to ensure the accuracy and correctness of all the data entered into the eCRFs. 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 shall review the eCRF and assess its completeness and consistency. The CRA shall 
compare the eCRF with the source documents to ensure consistency of key data. Data entry, 
corrections, and modifications should be performed by the investigator or his/her designee. The 
data in the eCRFs is submitted to the data server and any modifications in the data should be 
recorded in the audit trail, including reasons, operator names, time, and dates of modification. 
The roles and permission levels of the personnel responsible for data entry in the study site will 
be determined in advance. The CRA or data 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 used by the investigators or hospital, 
including all records related to the subjects, which are able to demonstrate the presence, 
inclusion criteria, and participation of subjects (laboratory records, ECGs, pharmaceutical 
records, and subject folders etc.). 
The investigators are required to maintain all source documents and to offer the documents to the 
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for 
each enrolled subject, regardless of the duration of participation. The protocol number and 
subject numbers of all supporting documents (such as laboratory records or hospital records) 
submitted with the eCRFs 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 investigators 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 could 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. 


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AEs, and concurrent diseases/medical history will be coded. The medical dictionary used for 
coding will be described in the Clinical Study Report (CSR). 
9.3. Quality Assurance Audits 
During the course of the study, the sponsor or his/her authorized representative may conduct 
quality assurance audits on the study site, study database and related documents. At the same 
time, the corresponding regulatory authority may conduct inspections on the study site, study 
database and related documents. The investigator must inform the sponsor immediately when an 
inspection notice is received from the regulatory authorities. 
The sponsor's quality assurance department conducts an audit on the clinical study sites, which 
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 trials 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 study drugs have been processed, reported and pre-planned. In addition, the 
protocol, facility, ethical standard operation procedures, GCP and applicable regulatory 
requirements are consistent. The investigators should have direct access to all trial files, source 
records, and source data. 
10. ETHICS 
10.1. Ethics Committee 
The sponsor or designee will prepare the relevant documents including the trial protocol, ICF, 
Investigator's Brochure, subject recruitment materials or advertising, and other documents 
required by regulations, which are to be submitted to the corresponding EC in of the study site 
for approval. Prior to the start of the trial, written approval from the EC must be obtained and 
submitted to the sponsor. The written approval from the EC should specify the name, number, 
version number of the study protocol and other documents (such as ICF), and date of approval. 
The investigator is required to notify the sponsor of the EC's written comments regarding delay, 
interruption, and re-approval of the study. 
The study site must follow the requirements of the EC in the study site. Protocol modifications, 
ICF or recruitment materials 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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10.2. Ethics 
The process of study and informed consent are subject to the Declaration of Helsinki, relevant 
GCP requirements, as well as laws and regulations related to the protection of drug and data in 
China. 
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 deviations must be 
reported to the EC, sponsor, or regulatory authorities. 
10.3. 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 ICF 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 consent 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. 
10.4. 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 


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investigator will have access to the subject identification code and the subject's genetic data. In 
addition, relevant regulatory authorities require access to relevant documents. 
11. STUDY MANAGEMENT 
11.1. 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. 
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. 
11.2. 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. 
11.3. Protocol Revisions 
Any possible revisions 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 changes 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 
the exception of changes to the protocol that eliminate direct hazards to the trial subjects.) 
11.4. Responsibilities of the Investigator 
The investigator shall adhere to the protocol, ethical principles of the Declaration of Helsinki, 
Chinese GCP and requirements of the corresponding regulations for this study. 
The detailed responsibilities of the relevant investigators are listed in Chapter 5 (Investigator's 
Responsibilities) of the Chinese GCP (Order No. 3). 


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11.5. Publishing Policy 
All the data generated in this study is the confidential information owned by the sponsor. The 
sponsor has the right to publish study results. Information on the publishing policies of the 
sponsor and investigator will be described in the clinical trial agreement. 
All the information on this trial (not limited to the protocol and 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. The sponsor must obtain the consent of the investigator if the 
name of the investigator is included in the content of the announcement, publication or 
advertising. 
11.6. Financing and Insurance 
The sponsor shall purchase insurance for participants in the study in accordance with local 
regulations and minimum requirements. Insurance related terms shall be saved in the study 
folder. 
 
 


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Chinese Cancer Registry Annual Report 2012. National Cancer Center, Disease Prevention and Control Bureau 
of Ministry of Health (2012). Military Medical Science Press, Beijing. ISBN 978-7-5163-0081-7. 
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Barbee MS, Ogunniyi A, Horvat TZ, et al. Current status and future directions of the immune checkpoint 
inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother 2015; 49(8): 907-37. 
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(ONO-4538-37). Ann Oncol 2017; 28(suppl 5S): 671P. 
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APPENDIX 


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Appendix 1: Signature Page for Investigator 
Protocol Title: An Open-Label, Multi-Center, and Phase Ia/Ib Study Evaluating the 
Monotherapy or Combination Chemotherapy of IBI308 in the Treatment of Chinese Subjects 
with Advanced Malignant Tumors 
Protocol No.: CIBI308A101 
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and 
fully understood this protocol, and agree to conduct this study in accordance with the 
requirements found in this protocol and the 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): 
__________________________ 
Title of Investigator: 
__________________________ 
Name and 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 chair 
5 
Dead 
 
REFERENCES 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
 
 
 
 


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Appendix 3: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V1.1) 
The following is an excerpt from the RECIST V1.1. 
1. MEASURABILITY OF TUMOR AT BASELINE 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 
Measurable lesion 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 
10 mm by CT scanning (with a 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: measurable with pathological enlargement and a short diameter of 
a single lymph node by CT scanning of ≥ 15 mm (it is recommended that the thickness 
measured by CT scanning should be no more than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
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. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
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; 
 
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 


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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 therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
1.2.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline assessments of tumor lesion size should be possibly completed within 21 days (3 weeks) 
before the start of treatment. 
1.2.2 Assessment methods 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
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. As noted above, when lesions can be evaluated by both clinical 
exam and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 


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Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. The measurability definition in this guideline is based on the thickness 
by scanning of ≤ 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 is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm CR when biopsies are obtained or to determine 
relapse in trials where recurrence following CR or surgical resection is an endpoint. 
Tumor markers: Tumor markers 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 
TUMOR ASSESSMENT 
2.1 Evaluation 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., only one or two subject[s] with 
accumulated organs can be selected for the measurement of at most 2 or 4 target lesions at the 
baseline). 
Target lesions must be selected based on size (the maximum diameter), can represent all involved 
organs, and measurements must be well reproducible. 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, 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: a minimum diameter by CT scanning 
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 
short 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 
evaluation. For examples, 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 Evaluation 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): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
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); except that the absolute value of the sum of the diameter must be increased by at least 
5 mm (the appearance of one or more new lesions is also considered to be PD). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 Considerations for non-target lesion assessment 
Lymph nodes: Even if the lymph nodes were 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 evaluations, 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 longest diameter of the entire combined lesion. 
2.3.3 Evaluation 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. 
Complete response (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-PD: At least 1 non-target lesion is found with/without persistent tumor 
marker levels that exceed normal levels. 
Progressive disease (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 is stable or partially resolved, 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 evaluation 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 evaluation 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 was 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 was performed at baseline. 


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If a new lesion is not definitive due to its 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 (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 optimal overall efficacy refers to the optimal efficacy 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 optimal overall efficacy. Also in the protocol, it must 
be specified that how any new therapy before progression affects the optimal response. The 
optimal 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 optimal overall efficacy. 
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. 


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If no measurable lesions (no target lesions) are found in subjects, see Table 2 for the 
corresponding evaluation. 
2.4.2 Description of missing evaluation 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 optimal 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 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 CR or PR 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. 
2.4.4 Special notes on efficacy evaluation 
When nodular lesions are included in the overall target lesion assessment and the diameter of 
such lesions is 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 


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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 with CR will not be 
recorded as 0 on the eCRF. 
If the efficacy confirmation is required during the study, the optimal overall efficacy 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 global exacerbation 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 exacerbation 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 CRs, 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 literature. 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). 
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 
Absent 
CR 
CR 
Non-CR/non-PD 
Absent 
PR 
CR 
NE 
Absent 
PR 
PR 
Non-progressive or 
not completely evaluable 
Absent 
PR 


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Target lesion 
Non-target lesion 
New lesion 
Overall response 
SD 
Non-progressive or 
not completely evaluable 
Absent 
SD 
Not completely 
evaluable 
Non-progressive 
Absent 
NE 
PD 
Any 
Present or absent 
PD 
Any 
PD 
Present or absent 
PD 
Any 
Any 
Present 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = non-evaluable 
Table 2. Time point efficacy: subjects with non-target lesions only 
Non-target lesion 
New lesion 
Overall response 
CR 
Absent 
CR 
Non-CR/non-PD 
Absent 
Non-CR/non-PD 
Not completely evaluable 
Absent 
NE 
PD that cannot be determined 
Present or absent 
PD 
Any 
Absent 
PD 
Note: 'Non-CR/non-PD' is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.  
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. 
Table 3. ptimal 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 


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Overall response at 
the first time point 
Overall response at the 
subsequent time points 
Optimal overall response 
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 Ⅱ trials where the therapeutic benefits are unclear, it is rational to perform a follow-up 
every 6–8 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. 
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 unbalanced treatment arms in the timing of disease 
evaluation. 


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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 is 
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 ones) 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 import in preventing 
deviations, especially for non-blind experimental 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 SD 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 relativity of SD period varies with different studies 
and diseases. For a specific trial using the proportion of patients 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. 


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2.7. PFS/TTP 
2.7.1. Phase II clinical trials 
This guideline is mainly about using objective response as a study endpoint in phase II clinical 
trials. 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 said evaluation as an endpoint. However, for certain tumors with 
consistent clinical manifestations (usually in a persistent, poor condition), 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: Abnormal Hepatic Function Monitoring and Follow-Up Report 
Please submit the report to Innovent PV: 
Fax: 021-31652800 
Email: drugsafety@innoventbio.com 
 
Contact information of reporter (please provide the followings in order to receive a timely 
response): 
Reporter's Email: 
Reporter's Telephone:  
Reporter's Signature: 
Date of Report: 
 
Abnormal Hepatic Function Follow-Up Information: 
Trial No.: 
Subject ID: 
1) Symptoms of abnormal hepatic function (check the followings if present): 
Decreased appetite □, tired of grease □, indigestion □, nausea □, emesis □, bloating □, 
abdominal pain □, diarrhea □, constipation □, clay stool □, fatigue □, weakness □, 
lethargy □, weight loss □, asterixis □, mental state changes □, hemorrhagic tendency □, 
fever □, others □ 
2) Signs of abnormal hepatic function (check the followings if present): 
Facial appearance of liver disease □, spider nevus □, liver palm □, ascites □, 
abdominal wall varicose veins □, jaundice □, yellow body fluid □, hepatomegaly □, 
splenomegaly □, liver area tenderness □, hepatic encephalopathy □, hepatic dyspnea □, 
crackles □, pulmonary peripheral edema □, jugular varicose veins □, abnormal heart 
sounds □, and others □ 
3) Medical history (check the followings if present): 
Viral hepatitis (HBV-A □; HBV-B □; HBV-C □; HBV-D □; HBV-E □), alcoholic 
hepatitis □, fatty liver □, hepatic cancer □, hepatic metastasis □, hepatic cirrhosis □, 
liver transplantation □, blood transfusion □, elevated liver enzymes prior to 
investigational drug administration □, autoimmune disease □, biliary tract disease □, 
cardiovascular disease □, hypotension □, diabetes □, surgery □, bone metastasis or 
bone damage □, HIV infection □, EB virus infection □, drug toxicity □, obesity □, and 
others □ 


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4) Family history (check the followings if present): 
5) Concomitant medication and diet (check the followings if present): 
Chemotherapeutics □, Chinese herbal medicine □, OTC drug □, dietary supplement □, 
alcohol consumption □, drug abuse □, history of chemical exposure □, anti-infective □, 
paracetamol □, NSAIDs □, metronidazole □, and others □ 
6) All the relevant laboratory test results (include those at baseline, and during and after 
the treatment. If tested, please check and provide the test results, units, and reference 
ranges): 
Routine blood test □, 
Eosinophil count □, 
AST and ALT levels □, and laboratory test results (including those at baseline and 
during the treatment) □, 
TBIL □, and direct bilirubin □, 
Total serum protein □, albumin □, and immunoglobulin □, 
Total cholesterol □, cholesterol ester □, 
Coagulation function □, such as: 
Other □, such as: 
 
7) Serological tests (if performed, please check and provide the test results):  
Epstein-Barr virus (EBV) □, 
Cytomegalovirus (CMV) □, 
Herpes simplex virus (HSV) □, 
Toxoplasmosis □, 
Hepatitis (A □, B □, C □, D □, E □), 
HIV □, 
Anti-nuclear antibodies □, 
Anti-smooth muscle antibodies □, 
Other antibodies □, such as: 
Others □, such as: 


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8) Auxiliary tests or operations (if performed, please check and provide the test results): 
Liver ultrasound □, 
Abdominal CT □, 
Liver biopsy □, 
Liver transplantation (planned or completed) □, 
Others □, such as: 


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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-glomerulonephrit
is 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: Definition and Main Pathological Types of Interstitial Lung Disease 
Interstitial lung disease (ILD) is a generic term of the clinicopathological entities that are 
composed by an inhomogeneous group of diseases based on the pathological basic changes of 
diffuse lung parenchyma, alveolar inflammation, and interstitial fibrosis, as well as the clinical 
manifestations of active dyspnea, diffuse infiltrating shadows on chest X-rays, restrictive 
ventilation disorder, decreased diffusing capacity for carbon monoxide (DLCO), and hypoxemia. 
Based on the pathological changes, ILD can be classified as follows: 
① Non-inflammatory non-tumor diseases, such as sarcoidosis and exogenous allergic 
granulomatous alveolitis. 
② Granulomatous interstitial lung diseases, such as chronic interstitial pulmonary edema, 
alveolar proteinosis, primary pulmonary hemosiderinosis, and uremia. 
③ Lung-specific inflammation, such as common interstitial pneumonia, bronchiolitis obliterans 
combined with organizing pneumonia (BOOP), chronic interstitial pneumonia due to exogenous 
irritant smog/fluid/other toxic and irritant factors, acute respiratory distress syndrome (ARDS), 
idiopathic pulmonary fibrosis, and pulmonary vasculitis. 
④ Inorganic dust inhalation occupational disease. 
⑤ Hyperplasia and neoplastic lesions, such as primary bronchioloalveolar carcinoma-induced 
pulmonary interstitial lesions and diffuse Hodgkin's lymphoma. 
 
 


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Appendix 7: Child-Pugh Grading and Evaluation System 
The Child-Pugh score is used to assess the prognosis of chronic liver disease, which is mainly for 
cirrhosis. Although the method was initially used to predict mortality during surgery, it is now 
used to determine the prognosis, necessary treatment intensity, and whether liver transplantation 
is required. 
Scoring 
Overall, 5 clinical indicators of liver disease are applied in the scoring. Each indicator will be 
scored on a scale of 1–3, with 3 points representing the highest severity. 
Measurement 
1 point 
2 point 
3 point 
TBIL1 (mg/dL) 
<2.0 
2.0–3.0 
>3.0 
Serum albumin (g/dL) 
>3.5 
2.8–3.5 
<2.8 
INR2 
or 
Prothrombin time (PT) prolonged 
(in seconds) 
<1.7 
 
<4.0 
1.7–2.3 
 
4.0-6.0 
> 2.3 
 
>6.0 
Ascites 
Absent 
Mild (prone to be controlled 
by medications) 
Moderate to severe (poorly 
controlled) 
Hepatic encephalopathy3 
Absent 
Grades I–II (mild to 
moderate) 
Grades III–IV (severe or 
unconscious) 
1 
As for primary sclerosing cholangitis and primary biliary cirrhosis, the reference ranges of bilirubin have been 
modified to reflect the excessively high levels of combined bilirubin in these diseases. The upper limit for 
1-point cases is 68 μmol/L (4 mg/dL), and 170 μmol/L (10 mg/dL) for 2-point cases. 
2 
The measures are varied from different textbooks and publications. Some old bibliographies use PT instead of 
INR. 
3 
The classification of hepatic encephalopathy is based on the West Haven criteria for semiquantitative grading of 
mental state. Source:Conn H, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore: Williams & 
Wilkins; 1979. 
As for primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin reference values 
have been changed to reflect the fact that these diseases are characterized by high direct bilirubin 
levels. The upper limit for 1-point cases is 68 μmol/L (4 mg/dL), and 170 μmol/L (10 mg/dL) for 
2-point cases. 
Explanation 
Using the added score described above, the chronic liver disease is graded from Child-Pugh A to C. 
Score 
Grade 
1-year survival rate 
2-year survival rate 
5–6 
A 
100% 
85% 
7–9 
B 
81% 
57% 
10–15 
C 
45% 
35% 


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Appendix 8: Dose Adjustments and Toxicity Management of IBI308 
Table 1. Dose adjustments and toxicity management of potential irAEs 
AE Grade/Dose Adjustments 
Toxicity Management 
General principles 
AEs are graded according to NCI CTCAE V4.03. 
Refer to this guideline if the event is an irAE 
It is recommended to manage irAEs according to the guideline in this table 
- 
Subjects should be fully evaluated to rule out any alternative causes 
(e.g., PD, concomitant medication, and 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 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 (e.g., 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 pneumonia or interstitial lung disease 
(e.g., new shortness of breath, cough, chest pain or exacerbation of 
existing symptoms and signs), and 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 based on clinical indications 
- 
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, and consider hospitalization 
- 
Discuss with sponsor's medical manager, and consider systemic 
glucocorticoid treatment 
- 
Repeat imaging based on clinical indications 
- 
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 sponsor's medical manager 
- 
Consider consulting a respirologist and infectious diseases specialist 
- 
Hospitalization 
- 
Supportive care (oxygen, etc.) 
- 
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 


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


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 4 
Permanent discontinuation 
For grade 4 events 
- 
Monitor frequency and volume of bowel movement, and 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 
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, and concomitant 
medication) 
 
The dose adjustments and toxicity management in this table is 
applicable only to subjects with normal ALT, AST, and TB at baseline; 
for subjects with ALT, AST, or TB > ULN at baseline, interrupt the 
drug if ALT, AST, or TB elevation of ≥ 50% for < 7 days and 
discontinue permanently if ALT, AST, or TB elevation of ≥ 50% for ≥ 
7 days. Toxicities should be managed based on the investigator's 
clinical judgment 


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AE Grade/Dose Adjustments 
Toxicity Management 
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 sponsor's 
medical manager 
- 
For ALT, AST, or TBIL elevations, retest hepatic function within 3–4 
days and increase monitoring frequency 
- 
If the event persists for > 3–5 days or worsens, consider systemic 
corticosteroid treatment 
- 
If no improvement is seen within 3–5 days, consider other tests and 
increasing the glucocorticoid dose 
- 
If no improvement is seen within 3–5 days, consider stronger 
immunosuppressants (e.g., mycophenolate mofetil)  
- 
Once improved, taper steroids within ≥ 4 weeks, and consider 
prophylactic antibiotics 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 3 or 
grade 4 
Permanent discontinuation 
 
 
For grade 3–4 events 
- 
Discuss with sponsor's medical manager 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If no improvement is seen within 3–5 days, consider stronger 
immunosuppressants (e.g., mycophenolate mofetil) 
- 
If no further improvement is seen within 3–5 days, consider other 
immunosuppressants based on local guidelines 
- 
If applicable, consult a gastroenterologist and 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 
- 
Consider consulting a dermatologist 
- 
Perform skin biopsy when necessary 
Grade 1 
No dose adjustments required 
For grade 1 events 
- 
Consider symptomatic treatment, including oral antipruritic agents (e.g., 
diphenhydramine or hydroxyzine) and local treatment (e.g., urea cream 
or topical glucocorticoids) 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 2 
No dose adjustments required 
• 
For a refractory (> 1–2 
weeks) grade 2 event, 
interrupt until reduces to 
grades 0–1 or baseline, 
continue the treatment at 
the next scheduled date 
For grade 2 events: 
- 
Consider symptomatic treatment including oral antipruritic agents and 
local treatment 
- 
Consider a medium-potent topical glucocorticoid 
- 
If no improvement or exacerbation is seen with 3–5 days, discuss with 
sponsor's medical manager and consider systemic glucocorticoid 
treatment 
- 
Consider consulting 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 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 


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AE Grade/Dose Adjustments 
Toxicity Management 
Hypopituitarism 
All grades 
 
- 
Monitor signs and symptoms of endocrine disorders, including 
weakness, fatigue, drowsiness, nausea, emesis, chills, changes in bowel 
habits, behavioral changes, mental state changes, hypotension, 
hypoglycemia, dizziness, headache, impaired vision, low libido in males, 
and irregular menstruation in females 
- 
Subjects should be fully evaluated to rule out any alternative causes 
(e.g., PD, brain 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 indexes 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 submitting a blood sample for appropriate autoantibody testing 
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 


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


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AE Grade/Dose Adjustments 
Toxicity Management 
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 submitting a blood sample for appropriate autoantibody testing 
Grade 1 
No dose adjustments required 
For grade 1 events 
 
Appropriately monitor adrenal function tests of the subjects 
 
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 events 
 
Discuss with sponsor's medical manager 
 
Evaluate adrenal function, begin hormone replacement therapy when 
necessary 
Grade 3 or 
Permanent discontinuation 
For grade 3–4 events: 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 4 
 
- 
Discuss with sponsor's medical manager 
- 
Consult an endocrinologist 
- 
Consider systemic corticosteroid treatment 
- 
Begin corticosteroids with mineralocorticoid activity immediately for 
adrenal crisis, severe dehydration, hypotension, or shock 
- 
Once improved, taper glucocorticoids within ≥ 4 weeks (the dose of 
cortisone used for hormone replacement may be adjusted accordingly, 
but subjects whose endocrine function do not recover require long-term 
treatment); consider prophylactic antibiotics when tapering to prevent 
infections 
Hyperthyroidism/ 
hypothyroidism 
Any grade 
 
- 
Monitor signs and symptoms of thyroid dysfunction, e.g., those 
associated with 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 submitting a blood sample to test thyroid autoantibodies 
(antithyroglobulin antibodies, anti-thyroid peroxidase antibodies, and 
thyroid-stimulating hormone receptor antibodies) 
Grade 1 or 
grade 2 
No dose adjustments required 
For grade 1–2 events: 
- 
Monitor thyroid function and thyroid autoantibodies regularly 
- 
L-thyroxine replacement therapy or anti-thyroid medications when 
necessary 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 3 or 
grade 4 
Hyperthyroidism 
• 
Permanent 
discontinuation 
Hypothyroidism 
• 
No dose adjustments 
required 
For grade 3–4 events: 
- 
Discuss with sponsor's medical manager 
- 
Monitor thyroid function and thyroid autoantibodies 
- 
Consult an endocrinologist 
Hyperthyroidism 
- 
Anti-thyroid medications 
- 
Consider β-blockers for tachycardia 
Hypothyroidism 
- 
L-thyroxine replacement therapy 
Type I diabetes 
Any grade 
 
- 
Closely monitor the related signs and symptoms, 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 indexes related to type I diabetes 
Grade 1 or 
grade 2 
No dose adjustments required 
For grade 1–2 events 
- 
Monitor and assess pancreas islet function 
- 
Start insulin therapy when necessary 
Grade 3 
Interrupt 
- 
Resume treatment after 
blood glucose is under 
control 
For grade 3–4 events 
- 
Consult with sponsor's medical manager 
- 
Monitor and assess pancreas islet function 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 4 
Permanent discontinuation 
- 
Consider consulting an endocrinologist 
- 
Control the blood glucose level with insulin, and adjust the dose 
accordingly 
- 
If ketoacidosis occurs, subjects should be hospitalized to receive 
insulin, fluid replacement, and alkali therapy 
Renal insufficiency 
(blood Cr elevated) 
Any grade 
 
- 
Closely monitor signs and symptoms (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 Cr levels Q1W 
- 
If returns to baseline level, resume routine Cr monitoring according to 
the study protocol 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 2 or 
grade 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 sponsor's medical manager 
- 
Monitor Cr levels every 2–3 days 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If reduces to grade 1, taper glucocorticoid for at least 1 month, and 
consider prophylactic antibiotics to prevent opportunistic infections 
- 
Consider kidney puncture biopsy 
- 
Consult a nephrologist 
Grade 4 
Permanent discontinuation 
For grade 4 events 
- 
Discuss with sponsor's medical manager 
- 
Monitor Cr levels once daily 
- 
Begin systemic glucocorticoid treatment based on experience 
- 
If reduces to grade 1, taper glucocorticoid for at least 1 month, and 
consider prophylactic antibiotics to prevent opportunistic infections 
- 
Consult a nephrologist 
- 
Consider kidney puncture biopsy 
Immune-related 
neurotoxicities (except 
for myasthenia gravis 
and Guillain-Barré 
syndrome) 
 
Any grade 
 
- 
Monitor the subject's systemic symptoms (headache, nausea, dizziness, 
behavioral changes, or weakness) 
- 
Subjects 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 test) 
- 
If applicable, begin symptomatic treatment and consult a neurologist 


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AE Grade/Dose Adjustments 
Toxicity Management 
Grade 1 
No dose adjustments required 
- 
Closely follow up 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 sponsor's medical manager 
- 
Consider consulting a neurologist 
- 
Hospitalization when necessary 
- 
Manage neuropathy and neuropathic pain with appropriate medications 
(e.g., gabapentin and duloxetine) 
- 
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 
Permanent discontinuation 
Grade 4 


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AE Grade/Dose Adjustments 
Toxicity Management 
Immune-related 
peripheral neuropathy, 
e.g., Guillain-Barré 
syndrome and 
myasthenia gravis 
Any grade 
 
- 
Closely monitor signs and symptoms (myasthenia gravis: eye or limb 
soreness and discomfort, blurred vision, and fatigue, which worsens as 
the day goes on; and Guillain-Barré syndrome: sudden and severe nerve 
pain, paralysis of the limbs, and prickling or burning sensation in the 
limbs) 
- 
Timely diagnosis of immune-related peripheral neuropathy is very 
important, as subjects may suffer from unpredictable acute 
compensation, which may lead to severe disease or death.Pay special 
attention to signs and symptoms that may indicate serious consequences, 
e.g., significant dysphagia, rapidly progressive weakness, respiratory 
insufficiency, or autonomic dysfunction 
- 
Neuroelectrophysiological tests 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 


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AE Grade/Dose Adjustments 
Toxicity Management 
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 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 result in initial exacerbation of symptoms) 
- 
Subjects intolerant to glucocorticoids may be treated with 
plasmapheresis or IVIgG 
- 
For myasthenia gravis-like neurotoxicities, consider acetylcholinesterase 
inhibitors in addition to glucocorticoids 
Guillain-Barre Syndrome 
- 
Plasmapheresis or IVIgG should be considered for subjects with 
Guillain-Barré syndrome (glucocorticoids are generally ineffective) 
Grade 3 or 
grade 4 
Permanent discontinuation 
 
 


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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 grades 0–1 or baseline 
Grade 3 
• 
First occurrence: Interrupt until reduces to grades 0–1 
or baseline 
• 
Second occurrence: permanently discontinue 
• 
For an AE that reduces to grades 0–2 within 7 days, or 
grades 0–1 or baseline within 14 days, interrupt and 
then resume the treatment at the next scheduled date. 
Otherwise, permanently discontinue 
Grade 4 
Permanently discontinue (Note: for grade 4 laboratory 
abnormalities, the event 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 pre-medications 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, and 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)