Clinical trial NCT04068519
Conditions: Advanced Solid Tumors
Sponsor: BeiGene
Start date: 2016-12-28; Completion date: 2020-05-31
Enrollment: 300 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a dose verification, pharmacokinetic (PK) assessment of products derived from two manufacturing processes and scales (500L-FMP and 2000L-FMP; FMP: Final Manufacturing Process) and indication expansion clinical study of monoclonal antibody conducted in Chinese subjects with advanced solid tumors, with a purpose of exploring the safety, tolerability, pharmacokinetics and preliminary efficacy.

Detailed description:

Arms: arm 1: Tislelizumab 200 mg intravenously (IV) once every 3 weeks (21 days per cycle) until no evidence of continued clinical benefits, unacceptable toxicity, or withdrawal of informed consent at the discretion of the investigator. There were 3 parts in this study: dose verification, pharmacokinetic (PK) sub-study, and indication expansion.
Interventions: intervention 1: Tislelizumab
Intervention descriptions: intervention 1: Administered intravenously

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Clinical Study Protocol
Protocol Title: 
Phase I/II Study Investigating Safety, Tolerability, 
Pharmacokinetics and Preliminary Antitumor Activities 
of Anti-PD-1 Monoclonal Antibody BGB-A317 in 
Chinese Patients with Advanced Solid Tumors
Protocol No.:
BGB-A317-102
Date of Final Protocol:
July 15, 2016, Version 1
Date of Protocol Amendment:
January 20, 2017, Version 2
September 08, 2017, Version 3
January 30, 2019, Version 4
Study Phase:
I/II
Sponsor:
BeiGene (Shanghai) Co., Ltd.
4th Floor, Building D
780 Cailun Road
China (Shanghai) Pilot-free Trade Zone
Shanghai, China 201203
Medical Monitor:
 China
Principle Investigator:
Coordinating Investigator:
Coordinating Investigator:
If there are any discrepancies between the English and the Chinese version of the protocol, the 
Chinese version is the one to be used.
Confidentiality Statement
This confidential document is only provided for review or view by this project’s investigators, consultants, research team 
members, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this document 
constitutes agreement that you will not disclose the relevant information contained herein to others without written 
authorization from the sponsor.
1&7


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PROTOCOL APPROVAL SHEET
PROTOCOL TITLE:
Phase I/II Study Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activities of Anti-PD-1 Monoclonal 
Antibody BGB-A317 in Chinese Patients with Advanced Solid 
Tumors
PROTOCOL NO:
BGB-A317-102, Version 4, Dated 30 January 2019
BeiGene (Shanghai) Co., Ltd., Approval:
___________________________________
____________________________________
Date


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
Phase I/II Study Investigating Safety, Tolerability, Pharmacokinetics 
and Preliminary Antitumor Activities of Anti-PD-1 Monoclonal 
Antibody BGB-A317 in Chinese Patients with Advanced Solid 
Tumors 
Protocol No.: 
BGB-A317-102 
The protocol is a confidential document of BeiGene (Shanghai) Co., Ltd., and only disseminated 
under the premise of confidentiality. I confirm that I have read the protocol, understood the contents 
herein, and will carry out work in accordance with the protocol. In addition, I will carry out work 
according to the ethical principles in the Declaration of Helsinki, Good Clinical Practice and 
applicable laws and regulations. Signing the document means that I agree: without the prior written 
permission of BeiGene (Shanghai) Co., Ltd., I am prohibited to publicize or disclose non-public 
information herein. 
Instructions for investigator: Please sign on the signature page and specify the date. Write your name in 
regular script, title and the name of the center to carry out the study. Please return a duplicate of the signed 
document to BeiGene. 
 
I have read the entire protocol and agreed to carry out the study according to this protocol: 
Investigator’s Signature:  
 
_____________________________ 
 
Investigator’s Printed Name and title:  
_____________________________ 
Date (dd mmm yyyy):  
 
_____________________________ 
Name of the center in which the study will be conducted: ______________________________ 


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PROTOCOL AMENDMENT RATIONALE, VERSION 4.0
The main purpose of this protocol amendment is to define the end of the study and add an extension 
program to allow for maintenance of remaining ongoing patients. In addition, the assessment of 
adverse event causality has been changed to a 5-point scale, incorporating the note to file issued after 
the protocol amendment 3.0. Changes were made to the synopsis to match changes made in the 
protocol body.
In addition, the language and format of the protocol (including the protocol synopsis) are amended to 
improve the clarity and consistency throughout the document. This protocol amendment version 
number is updated to version 4.
Section
Key Changes
Rationale for Change
Title Page
x
Update sponsor address
x
Update medical monitor, address
Consistency with 
protocols of other 
studies
Synopsis
Section 3.3
Table 1
Table 4
Section 8.9
Revise exploratory endpoint for 
Clarify 
 
investigation
Section 4.3
Clarify direction for dose delays
Incorporation of Note to 
File
Section 4.3
Section 10.7.1
Section 14
x
Remove guidance from Section 4.3 on
withholding treatment and 
discontinuing treatment that duplicates 
guidance in Appendix 3
x
Add ASCO guidelines on management 
of immune-related adverse events
x
Add Brahmer 2018 reference
Consistency with 
Appendix 3, incorporate 
updated guidelines
Section 4.4
Table 1
Table 2
Table 3
Table 4
x
Add section describing End of 
Treatment visit
x
Allowed for End of Treatment Visit to 
be used for Safety Follow-up Visit in 
some circumstances
x
Increase window to 7 days for routine 
laboratory tests to be usable for End of 
Treatment Visit
x
Increased Safety Follow-up Visit 
window to 30 ± 7 days after last dose
Consistency with 
protocols of other 
studies
Table 1
Table 4
Section 8.2
Appendix 4
Remove assessment of serum tumor 
markers
Will not be assessed


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Section 
Key Changes 
Rationale for Change 
Section 5.1 
Appendix 5 
x Add contraception guidelines 
x Add appendix on contraceptive 
guidelines 
Consistency with 
protocols of other 
studies 
Section 5.6 
Clarify access for patients who wish to 
continue therapy beyond 2-year treatment 
period. 
Increase patient access 
Section 5.7 
Provide for patients who choose to 
discontinue therapy once 2-year treatment 
period ends, but subsequently experience 
progressive disease and wish to reinitiate 
treatment. 
Increase patient access 
Section 5.7 
Add End of Study definition 
Clarify planned study 
end 
Section 5.8 
Specify that drug product will be provided 
to patients who wish to continue therapy 
beyond end of study 
Increase patient access 
Section 10.2.2 
Section 10.6.1 
Extend immune-related adverse event 
recording 
Consistency with 
protocols of other 
studies 
Section 10.3.3 
Modify the assessment of AE causality 
back to 5 scales method as “definitely 
related” / “probably related” / “possibly 
related” / “possibly unrelated” and 
“unrelated” 
Incorporate Note to File 
Section 10.3.5 
Clarify recording of laboratory test 
abnormalities as adverse events 
Consistency with 
protocols of other 
studies 
Section 10.5 
Clarify definition of suspected unexpected 
serious adverse reaction 
Consistency with 
protocols of other 
studies 
Section 10.6.2.1 
Table 7 
Section 10.6.2.2 
Section 10.6.2.3 
Minor changes to reporting of serious 
adverse events 
Consistency with 
protocols of other 
studies 
Section 10.6.x 
Remove sections on “Recording Diagnosis 
Versus Signs and Symptoms,” “Recording 
Adverse Events Occurring Secondary to 
Other Events,” and “Recording Poststudy 
Adverse Events” 
Consistency with 
protocols of other 
studies 


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Section 
Key Changes 
Rationale for Change 
Section 10.6.4 
Remove direction to record persistent 
adverse events only once. 
Consistency with CRF 
completion guidelines 
Section 10.6.5 
Section 10.6.6 
Clarify reporting Disease Progression, 
Death  
Consistency with 
protocols of other 
studies 
Section 14 
Update Investigator’s Brochure to new 
version 
Update references 
Appendix 3 
Appendix 4 
x Add guidance for additional 
autoimmune toxicities 
x Add additional safety measures of 
myocarditis/myositis 
x Sorted tables 
Consistency with 
protocols of other 
studies. Address reports 
of fatal immune 
checkpoint inhibitor-
associated myocarditis 
 


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SYNOPSIS 
Name of Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
Name of Finished Product: 
BGB-A317 Injection 
Name of Active Ingredient: 
BGB-A317 
Title of Study: 
Phase I/II Study Investigating Safety, Tolerability, Pharmacokinetics and 
Preliminary Antitumor Activities of Anti-PD-1 Monoclonal Antibody BGB-
A317 in Chinese Patients with Advanced Solid Tumors 
Protocol No.: 
BGB-A317-102 
Study centers: 
Approximately 8 centers for Phase I. Approximately 20 centers for Phase II 
Study duration: Screening (up to 28 days), Treatment (up to 2 
years of active therapy), Safety Follow-up (30 days) and Survival 
Follow-up. 
Phase: I/II 
Study Objectives: 
Primary: 
Phase I 
Dose Verification study 
• 
To assess the safety and tolerability of BGB-A317 in subjects with advanced solid 
tumors.  
• 
To determine the maximum tolerated dose (MTD), if any, and/or the recommended 
Phase II dose (RP2D) for BGB-A317 in Chinese subjects 
Pharmacokinetics (PK) sub-study 
• 
To assess the PK of the products derived from two manufacturing processes and scales 
(500L-FMP and 2000L-FMP; FMP: Final Manufacturing Process) following the first 
dose of BGB-A317 
Notes: 500L-FMP indicates a final manufacturing process and scale of 500L; 2000L-
FMP indicates a final manufacturing process and scale of 2000L.  
• 
To assess the safety and tolerability of BGB-A317 of two manufacturing processes and 
scales (500L-FMP and 2000L-FMP) in patients with advanced solid tumors 
Phase II 
• 
To assess the preliminary anti-tumor activity of BGB-A317. 
 


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Secondary:
Phase I
Dose Verification Study
•
To characterize the pharmacokinetics of BGB-A317
•
To assess the preliminary anti-tumor activity of BGB-A317
•
To assess the host immunogenicity to BGB-A317
PK sub-study
•
To assess the PK of products derived from two manufacturing processes and scales 
(500L-FMP and 2000L-FMP) following the multiple doses of BGB-A317
•
To assess the host immunogenicity to BGB-A317 of two manufacturing processes and 
scales (500L-FMP and 2000L-FMP)
•
To assess the preliminary anti-tumor activities of BGB-A317 of two manufacturing 
processes and scales (500L-FMP and 2000L-FMP)
Phase II
•
To further assess the safety and tolerability of BGB-A317
•
To further assess the pharmacokinetic characteristics of BGB-A317
•
To assess the host immunogenicity to BGB-A317
Exploratory Objective (Phase I & II)
Study design
This is a multi-center, open-label, non-randomized Phase I/II 
clinical study, of which the Phase I PK sub-study is a parallel 
and multiple-dose study that is assessing PK of BGB-A317 
derived from two manufacturing process and scales (500L-FMP
and 2000L-FMP)
Planned number of 
subjects:
Approximately 288 subjects will be enrolled in the study. Of 
them, 68 subjects will be enrolled in the Phase I study (the first 
20 subjects for dose verification study and the remaining 48 
subjects for PK sub-study assessing the pharmacokinetics of the 
products derived from two manufacturing process [500L-FMP
and 2000L-FMP]). The other 220 subjects will be enrolled in 
the Phase II study.
Study Population


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Inclusion criteria:  
Subjects eligible for this study must meet all following criteria: 
1. Voluntarily signed informed consent form for the study 
2. Aged ı18 years on the day of signing informed consent 
3. Subjects must have a histologically or cytologically 
confirmed advanced or metastatic tumor (unresectable), have 
had progression or intolerability since last standard anti-
tumor treatment, or have no standard treatment or have 
refused standard therapy, as well as meet following 
requirements of tumor types in the corresponding stages: 
a) Phase I: Including but not limited to non-small cell lung 
cancer (NSCLC), melanoma, gastric cancer, esophageal 
carcinoma, ovarian cancer, urothelial carcinoma, head 
and neck squamous cell carcinoma (HNSCC), renal cell 
carcinoma (RCC) and triple negative breast cancer 
(TNBC) 
b) Phase II: 
x Arm 1 - melanoma, excluding uveal or ocular 
melanoma 
x Arm 2 - NSCLC (Program Death Ligand 1 [PD-L1]) 
positive) and Arm 3 - NSCLC (PD-L1 negative): 
i. PD-L1 detection must be confirmed prospectively at the 
central laboratory designated by the sponsor (refer to 
Section 8.9 for the definition of PD-L1 positive) 
ii. Subjects with known EGFR mutations (EGFR detection 
methods and results need to be approved by the study site) 
are excluded; subjects with non-squamous carcinoma of 
unknown EGFR mutations must be tested prospectively at 
the central laboratory designated by the sponsor, and 
subjects are excluded if tested positive 
iii. Subjects with known ALK gene translocation are 
excluded 
x Arm 4 - gastric cancer: gastric adenocarcinoma 
(including gastroesophageal junction adenocarcinoma) 
x Arm 5 - esophageal carcinoma: esophageal squamous 
cell carcinoma 
x Arm 6 - RCC: RCC containing the component of clear 
cell 
x Arm 7 - urothelial carcinoma: locally advanced or 
metastatic urothelial transitional cell carcinoma 
(including renal pelvis, ureter, bladder and urethra) 
x Arm 8 - microsatellite instability-high (MSI-H) or 
mismatch repair deficient (dMMR) colorectal cancer 
(CRC): subjects with documented MSI-H or dMMR are 


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eligible if tumor samples and blood samples are 
provided for retrospective confirmation at the central 
laboratory designated by the sponsor; subjects with 
unknown MSI or MMR mutations status must be tested 
prospectively before enrollment at the central laboratory 
designated by the sponsor (refer to Section 8.1 for 
detection methods)
x Arm 9 - TNBC, HNSCC, small cell neuroendocrine 
carcinoma (SCNEC) or other tumors with known MSI-
H or dMMR (subjects with documented MSI-H or 
dMMR are eligible if tumor samples and blood samples 
are provided for retrospective confirmation at the 
central laboratory designated by the sponsor, refer to 
Section 8.9 for detection methods)
x Arm 10 - nasopharyngeal carcinoma (NPC): WHO type 
II-III (differentiated non-keratinizing type and 
undifferentiated non-keratinizing type)
x Arm 11 - Child-pugh Class A hepatocellular carcinoma, 
excluding mixed hepatocellular and cholangiocellular 
carcinoma 
4. Subjects must be able to provide archival tumor tissues 
(paraffin blocks or at least 10 unstained tumor specimen 
slides; subjects may be permitted to be enrolled on a case-by-
case basis after discussion with the medical monitors from the 
sponsor if less than 10 unstained slides are provided), or 
newly obtained tumor tissue that has not been radiated, and 
relevant pathological reports. Refer to Section 8.9 for the 
requirements for tumor samples
For subjects who have easily accessible tumor lesions and 
consent to biopsies, fresh baseline or paired tumor biopsies 
are strongly recommended for 
. For Arm 
1 (melanoma) in Phase II, tumor biopsies must be performed 
at baseline if feasible (biopsy is not required for subjects who 
provide archival tissue samples obtained within 12 weeks 
before treatment starts). Subjects may be permitted to be 
enrolled on a case-by-case basis after discussion with the 
medical monitors if biopsy specimens are not available
5. Subjects must have at least one measurable lesion as defined 
per Response Evaluation Criteria in Solid Tumors (RECIST)
Version 1.1
6. Eastern Cooperative Oncology Group (ECOG) performance 
status of İ 1
7. Life expectancy ı 12 weeks
8. Subject must have adequate organ function as indicated by 
the following laboratory values:


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a) 
Absolute neutrophil count (ANC) ı 1.5 x 109/L 
b) 
Platelets ı 75 x 109/L 
c) 
Hemoglobin ı 90 g/L 
d) 
Serum creatinine İ 1.5 X upper limit of normal (ULN) 
e) 
Serum total bilirubin İ 1.5 X ULN (total bilirubin 
must be < 3 X ULN for subjects with Gilbert’s 
syndrome)  
f) 
International Normalized Ratio (INR) or Prothrombin 
Time (PT) İ 1.5 X ULN 
g) 
Activated Partial Thromboplastin Time (aPTT) İ 1.5 
X ULN 
h) 
Aspartate transaminase (AST) and alanine 
aminotransferase (ALT) İ 2.5 X ULN, or AST and 
ALT İ 5 X ULN for subjects with liver metastases or 
hepatocellular carcinoma 
9. Female subjects are eligible to participate in the study if they 
are: 
a) 
Non-childbearing potential (ie, physiologically 
incapable of becoming pregnant) who: 
• 
Has had hysterectomy 
• 
Has had bilateral oophorectomy 
• 
Has had bilateral tubal ligation or are 
post-menopausal (total cessation of menses for 
ı 1 year) 
b) Childbearing potential: 
• 
Must be willing to use a highly effective method of 
birth control for the duration of the study, and for 
at least 120 days after the last dose of BGB-A317, 
and have a negative urine or serum pregnancy test 
within 7 days of the first dose of study drug 
10. Non-sterile males must be willing to use a highly effective 
method of birth control for the duration of the study and for 
at least 120 days after the last dose of BGB-A317  
Exclusion criteria: 
Subjects who meet any of the following criteria must be 
excluded from this study: 
1. History of severe hypersensitivity reactions to other 
monoclonal antibodies 
2. Prior malignancy active within the previous 2 years except 
for the tumor under investigation in this trial, cured or locally 
curable cancers, such as basal or squamous cell skin cancer, 


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superficial bladder cancer or carcinoma in situ of the cervix 
or breast 
3. Prior therapies targeting PD-1 or PD-L1 
4. Active brain or leptomeningeal metastases. Subjects with 
brain metastases are permitted if they are asymptomatic, eg, 
diagnosed incidentally by brain imaging, or subjects with 
previously treated brain metastases that are asymptomatic at 
screening, radiographically stable and not requiring steroid 
medications for at least 4 weeks prior to the first 
administration of study treatment 
5. Subjects with active autoimmune diseases or history of 
autoimmune diseases or immunodeficiency that may relapse 
should be excluded. Subjects with following diseases are 
allowed to be enrolled for further screening: type I diabetes, 
hypothyroidism managed with hormone replacement therapy 
only, skin diseases not requiring systemic treatment (such as 
vitiligo, psoriasis or alopecia), or diseases not expected to 
recur in the absence of external triggering factors 
6. Subjects should be excluded if they have a condition 
requiring systemic treatment with either corticosteroids 
(prednisone > 10 
mg/day 
or 
equivalents) 
or 
other 
immunosuppressive medications within 14 days of study 
drug administration 
Note: Adrenal replacement doses of prednisone İ  10 
mg/day or equivalents are permitted in the absence of active 
autoimmune disease; subjects are permitted to use topical, 
ocular, 
intra-articular, 
intranasal, 
and 
inhalational 
corticosteroids (with minimal systemic absorption); a brief 
course of corticosteroids for prophylaxis (eg, contrast dye 
allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by contact 
allergen) is permitted 
7. With history of interstitial lung disease, non-infectious 
pneumonitis or uncontrolled systemic diseases, including 
diabetes, hypertension, pulmonary fibrosis, acute lung 
diseases, etc  
8. With severe chronic or active infections requiring systemic 
antibacterial, antifungal or antiviral therapy, including 
tuberculosis infection, etc. (Antiviral therapy is permitted for 
subjects with hepatocellular carcinoma.) 
9. With uncontrollable pleural effusion, pericardial effusion or 
ascites requiring repeated drainage 
10. Significant cardiovascular diseases, such as heart failure of 
New York Heart Association cardiac disease Class II or 


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greater, myocardial infarction within the previous 3 months, 
unstable arrhythmias or unstable angina 
Patients with known coronary artery disease, congestive 
heart failure not meeting the above criteria, or left ventricular 
ejection fraction < 50% must be on a stable medical regimen 
that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate 
11. History of alcohol or drug abuse or dependence 
12. Known history of Human Immunodeficiency Virus (HIV) 
13. Subjects with untreated chronic hepatitis B or chronic 
hepatitis B virus (HBV) carriers with HBV DNA 
ı 500 IU/mL (2500 copies/mL), or active hepatitis C should 
be excluded. Subjects with inactive hepatitis B surface 
antigen (HBsAg) carriers, active HBV infection with 
sustained viral suppression (HBV DNA < 500 IU/mL 
[2500 copies/mL]), and subjects whose hepatitis C has been 
cured can be enrolled 
14. Underlying medical conditions that, in the investigator’s 
opinion, will make an administration of study treatment 
hazardous or obscure the interpretation of toxicity 
determination or adverse events; or insufficient compliance 
during the study according to investigator’s judgment 
15. Prior chemotherapy, radiotherapy, immunotherapy or any 
investigational therapies (including Chinese herbal medicine 
and Chinese patent medicines) used to control cancer must 
have been completed at least 2 weeks before the 1st study 
drug administration, and all adverse events have returned to 
either baseline or grade 0~1 according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 
4.03 (except for alopecia) 
16. Use of any live or attenuated vaccines within 4 weeks (28 
days) prior to initiation of study therapy 
17. Major surgical procedure (Grade 3 or 4) within the past 4 
weeks (28 days) prior to study drug administration 
18. Prior allogeneic or solid organ transplantation 
Investigational Drug, dose 
and mode of 
administration: 
Investigational Drug: BGB-A317, 10 mL/vial, 10 mg/mL, 
intravenous infusion (IV) 
Phase I (dose verification study):  
Dose level: BGB-A317 200 mg  
Dosing frequency: once every 3 weeks (Q3W) 


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The proposed dose level can be further adjusted according to 
the safety, tolerability and effectiveness observed in the dose 
verification study, and other doses may be added. 
Phase I (PK sub-study):  
Dose level: BGB-A317 200 mg  
Dosing frequency: Dosing on Day 1 with interval of 4 weeks 
for Cycle 1, Q3W for cycles thereafter 
Phase II (indication expansion study): Dose level and dosing 
frequency are used based on RP2D validated in Phase I dose 
verification study  
Research method: 
This study is a dose-verification, pharmacokinetic evaluation of the products derived from two 
manufacturing processes and scales (500L-FMP and 2000L-FMP) and indication-expansion 
clinical study of monoclonal antibody BGB-A317 in Chinese subjects with advanced solid tumors, 
aiming at exploring the safety, tolerability, pharmacokinetics and preliminary efficacy of BGB-
A317. This study is carried out on the basis of a Phase IA multi-dose and dose-escalation study in 
Australia. According to the preliminary results of the Phase IA clinical study in Australia, 0.5, 2, 
5 and 10 mg/kg, once every two weeks (Q2W) are all tolerable doses. In addition, 2 and 5 mg/kg, 
Q3W have also been confirmed as tolerable doses. 
This study can be divided into 2 parts. Phase I is a study of dose verification and pharmacokinetic 
evaluation of the products derived from two manufacturing processes and scales (500L-FMP and 
2000L-FMP) and Phase II is an indication expansion study. All subjects will receive BGB-A317 
until they have no evidence of continued clinical benefits, unacceptable toxicity, or withdrawal of 
informed consent in the opinion of the investigator. 
Phase I: It is a multicenter and open-label study.  
Dose Verification Study (using BGB-A317 produced by 500L-OMP, OMP=Original 
Manufacturing Process) 
3-6 subjects will be enrolled firstly to assess dose-limiting toxicity (DLT). 
• 
If none of the 3-6 subjects experiences a DLT at the starting dose, enrollment will be 
continued until approximately 20 subjects in total are enrolled 
• 
Three (3) additional subjects will be enrolled if a DLT is observed in one (1) of three (3) 
subjects; two (2) additional subjects will be enrolled if a DLT is observed in one (1) of four 
(4) subjects; and one (1) additional subject will be enrolled if a DLT is observed in one (1) 
of five (5) subjects. No additional subjects will be enrolled if a DLT is observed in one (1) of 
six (6) subjects 
• 
If 2 or more subjects experience DLT in 3-6 subjects, such dose level will be considered as 
exceeding the MTD. All investigators will be informed of such dose level 


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DLT will be assessed among evaluable subjects within Cycle 1 (1-21 days). An evaluable subject 
is defined as the individual who has received at least 80% of the dose and completed all safety 
assessments required in Cycle 1, or any subject who has experienced DLT in Cycle 1. 
A Safety Monitoring Committee (SMC) will be established by the sponsor and investigators. SMC 
will recommend RP2D based on the safety and tolerability of BGB-A317, and decide whether or 
not to add unscheduled doses for trial. 
Dose level 
According to the safety results of the dose-escalation trial on BGB-A317 conducted in Australia, 
this study will assess the safety and pharmacokinetic characteristics of flat dose 200 mg Q3W in 
Chinese patients with advanced malignant solid tumors, and other doses may be further explored 
based on the safety result and necessity.  
Among the 3-6 subjects in the 200 mg Q3W cohort, if 2 or more subjects experience DLT within 
Cycle 1, such starting dose will be considered as exceeding the MTD, and a lower dose, such as 
100 mg Q3W, will be assessed in 3-6 subjects. 
If dose 200 mg Q3W passes the DLT assessment, the cohort at such dose level can be expanded 
to about 20 subjects to further assess the safety, tolerability, pharmacokinetics and preliminary 
pharmacodynamic characteristics of BGB-A317. In order to continuously monitor safety, when 
the cohort has been expanded to 10 subjects and ı33% of them have experienced DLT within 21 
days in Cycle 1, enrollment will be suspended, and an SMC meeting will be immediately held to 
discuss and determine whether such dose is safe. 
Dose-limiting toxicity (DLT) 
All toxicities or adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. The occurrence of any of 
the following toxicities during Cycle 1 will be considered a DLT, if judged by the investigator as 
possibly, probably or definitely related to study drug administration: 
Non-hematologic toxicities: 
1. Grade 4 or above toxicity 
2. Grade 3 toxicity (regardless of duration), except for laboratory abnormalities, diarrhea, 
nausea, vomiting and asymptomatic biochemical abnormalities that is resolved to Grade 2 or 
lesser severity within 3 days after best supportive care 
3. Grade 3 adverse event of tumor flare reaction (defined as local pain, irritation, or rash 
localized at sites of known or suspected tumor) lasting >7 days 
4. Grade 3 or above immune-related adverse events (irAE) 
Hematologic toxicities: 
1. Grade 4 neutropenia lasting >7 days 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] İ1000/mm3 with a 
single temperature of 38.3oC or a sustained temperature of 38oC for >1 hour) 


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3. Grade 3 neutropenia with infection
4. Grade 3 thrombocytopenia with bleeding
5. Grade 4 thrombocytopenia
6. Grade 4 anemia (life-threatening)
And any grade of toxicity per the judgment of the investigator and sponsor requires premature 
discontinuation of the subject from the study.
Subjects who received <80% of the BGB-A317 infusion within Cycle 1 (eg, infusion-related 
reaction-caused infusion discontinuation) and did not experience a DLT will not be taken into 
account in the assessment of the overall DLT rate for the particular dose level cohort and need to 
be replaced.
PK sub-study: It is a parallel and multiple doses study, which analyzes the PK and safety of
BGB-A317 of two manufacturing processes and scales (500L-FMP and 2000L-FMP). DLT and 
RP2D of all subjects are not assessed.
Total 48 subjects (24 per arm) are planned to be enrolled to receive treatment of BGB-A317 of 
two manufacturing processes and scales (500L-FMP and 2000L-FMP). Cycle 1 lasts for 28 
days, and Cycle 2 and those thereafter last for 21 days. If there is any drop-out before the 
complete of the first treatment cycle (28 days) of intensive PK, additional subjects will be 
enrolled until for each arm there are total 24 subjects complete the first treatment cycle. 
Schematic of the trial design is shown as below:  
Abbreviation: FMP = Final Manufacturing Process; PK = pharmacokinetics; Q3W = once every three 
weeks
Phase II (indication expansion): To further assess the efficacy of BGB-A317 in Chinese patients 
with malignant solid tumors, once 200 mg Q3W has been confirmed as a tolerable dose in Chinese 
population and determined as RP2D, an indication-expansion study will be carried out among the 
following 11 groups of indications. Because of the changes of the manufacturing processes and 
scales during study, BGB-A317 of two manufacturing processes and scales (500L-OMP and 
2000L-FMP) will be used for this Phase II study.
Arm 1: Melanoma
Q3W from Cycle 2
Sparse PK
Q3W from Cycle 2
Sparse PK
500L-FMP
n= 24
Cycle 1        
(4 weeks)
Intensive PK
2000L-FMP
n= 24
Cycle 1        
(4 weeks)
Intensive PK


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Arm 2: Non-small cell lung cancer (PD-L1 positive)
Arm 3: Non-small cell lung cancer (PD-L1 negative)
Arm 4: Gastric cancer
Arm 5: Esophageal cancer
Arm 6: Renal cell carcinoma 
Arm 7: Urothelial carcinoma
Arm 8: MSI-H or dMMR colorectal cancer (CRC)
Arm 9: Triple negative breast cancer (TNBC), head and neck squamous cell carcinoma 
(HNSCC), small cell neuroendocrine carcinoma, or other tumors with MSI-H or dMMR
Arm 10: Nasopharyngeal carcinoma (NPC)
Arm 11: Hepatocellular carcinoma (HCC)
In the indication-extension study, about 20 subjects will be enrolled into each arm. For tumors 
that are difficult to enroll sufficient subjects, the sponsor may adopt premature termination of
further subject enrollment in this arm. To fully assess the safety of BGB-A317, the contract 
research organization (CRO) and medical monitors from the sponsor will regularly review the 
safety data, and if necessary, will convene a temporary SMC meeting.
If subjects with a certain kind of tumor experience significant toxicities in the indication expansion 
study, the investigator and the sponsor will discuss and decide whether to conduct an independent 
study or to terminate the study in such tumors. Paraffin-embedded tumor tissue will be collected 
for purpose of 
. However, if there is clinically appropriate biopsy lesion (biopsy 
is a must in specific cancer types in Phase II), a fresh tumor biopsy at baseline is strongly 
recommended. For these subjects, if possible, a biopsy for potential 
 after two cycles of treatment is strongly recommended. A written informed consent form 
(ICF) is required for fresh tumor biopsies.
Subjects will be monitored for safety, anti-BGB-A317 antibodies and efficacy throughout the 
study. Radiological assessment of tumor-response status should be performed approximately 
every 9 weeks in the first year, then every 12 weeks thereafter.
Tumor response will be assessed by investigators based on RECIST Version 1.1. For immune 
therapies such as that mediated by BGB-A317, pseudo-progression may occur due to immune-
cell infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, for progressive disease (PD) suspected by the investigator
as pseudo-progression, the following criteria must be met in order to treat patients continuously 
until PD is confirmed by repeated imaging at least 4 weeks later or at the next scheduled imaging 
time point, but not exceeding 12 weeks from the date of initial documentation of PD: a. Absence 
of clinical symptoms and signs of disease progression (including clinically significant worsening 
laboratory values). b. Stable ECOG performance status. c. Absence of rapid progression of disease 
or of progressive tumor at critical anatomical sites (eg cord compression) that necessitates urgent 
alternative medical intervention.


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Criteria for evaluation: 
Primary Endpoints: 
Phase I 
Dose Verification Study 
x 
Safety and tolerability of BGB-A317: The safety of BGB-A317 will be assessed throughout 
the study by monitoring adverse events (AEs) and serious adverse events (SAEs) per 
NCI-CTCAE Version 4.03, physical examination, electrocardiograms and laboratory 
assessments 
x 
The MTD (if any) and/or RP2D (s) for BGB-A317 will be determined based on safety, 
tolerability, pharmacokinetics, preliminary efficacy, and other available data 
Pharmacokinetics (PK) sub-study 
x 
PK: Single-dose pharmacokinetic parameters (maximum observed plasma concentration 
[Cmax], and area under the plasma concentration and time curve [AUClast and AUCinf]) will be 
assessed to evaluate the PK characteristics of BGB-A317 derived from both manufacturing 
processes and scales  
x 
Safety: The safety of BGB-A317 will be assessed throughout the study by monitoring adverse 
events (AEs) and serious adverse events per the NCI-CTCAE Version 4.03, physical 
examination, electrocardiograms, laboratory measurements 
Phase II 
x 
The objective response rate (ORR) in different tumor types will be determined by the 
investigator based on RECIST Version 1.1 
Secondary Endpoints: 
Phase I 
Dose Verification Study 
x 
Evaluations of Pharmacokinetics: include but not limited to AUC0-21 day, Cmax and time to 
maximum observed plasma concentration (Tmax), minimum observed plasma concentration 
(Ctrough), t1/2, clearance (Cl) and volume of distribution during terminal phase (Vz) 
x 
Efficacy evaluations: ORR, complete response (CR) rate, partial response (PR) rate, stable 
disease (SD) rate, progression-free survival (PFS), duration of response (DOR), and duration 
of SD will be determined by investigator based on RECIST Version 1.1; overall survival (OS) 
will be evaluated 
x 
Anti-BGB-A317 antibodies: immunogenic responses to BGB-A317 will be assessed by 
monitoring the occurrence of anti-drug antibody (ADA) 
Pharmacokinetics sub-study 


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x
PK: Steady-state pharmacokinetic parameters (include but not limit to Ctrough) will be assessed 
for both manufacturing processes and scales following the multiple doses of BGB-A317 to 
evaluate the PK characteristics at steady state
x
Immunogenicity: Immunogenic responses to BGB-A317 of both manufacturing processes 
and scales will be assessed to evaluate the comparability of the occurrence of anti-drug 
antibody
x
Efficacy evaluations: ORR, Complete Response rate, Partial Response (PR) rate, SD rate, 
PFS, and DOR and duration of SD will be determined by investigator based on RECIST 
Version 1.1; OS will be evaluated
Phase II
x
Evaluations of Efficacy: Complete Response rate, PR rate, SD rate, PFS, DOR, duration of 
SD, disease control rate (DCR) and clinical benefit rate will be determined by investigator 
based on RECIST Version 1.1; OS will be evaluated
x
Safety and tolerability of BGB-A317: The safety of BGB-A317 will be assessed throughout 
the study by monitoring adverse events and serious adverse events per NCI-CTCAE Version 
4.03, physical examination, electrocardiograms and laboratory assessments
x
Evaluations of Pharmacokinetics: including but not limited to Ctrough
x
Anti-BGB-A317 antibodies: immunogenic responses to BGB-A317 will be assessed by 
monitoring the occurrence of anti-drug antibody (ADA)
Exploratory Endpoints:


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Statistical methods: 
Phase I Dose verification study: The sample size in the dose-verification study in Phase I depends on 
the number of dose levels to be assessed and the occurrence of DLT in each cohort. The necessity of 
assessing additional cohorts and the corresponding sample size will be determined by the safety of the 
dose to be investigated. Approximately 20 subjects will be enrolled. 
Phase I PK sub-study: Total 48 subjects (receiving BGB-A317 either from 500L-FMP or from 2000L-
FMP, respectively; 24 per arm) are planned to be enrolled in the PK sub-study. If there is any drop-
out before the complete of the first treatment cycle (28 days) of intensive PK, additional subjects will 
be enrolled until for each arm there are total 24 subjects complete the first treatment cycle. Under the 
assumption of 30% variability (coefficient of variation [CV], from Study BGB-A317_001 PK data), 
this sample size will provide approximately 75 - 82% power to reject the null hypothesis to 
demonstrate that the population means of the 2 manufacturing processes and scales are equivalent. 
The power will be increased to 89% - 95% provided that the CV = 24% (from recent Study BGB-
A317-102 PK data). The sample size calculation is only to provide a general guidance to enroll enough 
number of subjects in the descriptive PK analysis, no formal hypothesis testing of PK equivalence will 
be conducted. 
Approximately 220 subjects are expected to be enrolled in the indication expansion stage in Phase II 
in order to analyze preliminary efficacy for BGB-A317 monotherapy. The statistical basis for the 
number of subjects enrolled into each cohort in Phase II will be illustrated in the Statistical Plan.  
Data will be listed and summarized according to the sponsor-approved reporting standards, where 
applicable. 
All subjects who have received (or about to receive) BGB-A317 will be included in the safety-analysis 
set. All subjects with valid BGB-A317 PK parameters after treatment will be included in the PK-
analysis set. For other parameters, all evaluable data will be included in the summaries. 
Statistical methods will be described in detail in the Statistical Plan. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................................................... 1 
PROTOCOL APPROVAL SHEET ....................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE ................................................................................................ 3 
PROTOCOL AMENDMENT RATIONALE, VERSION 4.0 ............................................................... 4 
SYNOPSIS ............................................................................................................................................. 7 
TABLE OF CONTENTS ..................................................................................................................... 21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................... 25 
1. 
INTRODUCTION ................................................................................................................... 28 
1.1 
Background and Pharmacology ...................................................................................... 28 
1.2 
Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion ................ 30 
1.3 
Toxicology ...................................................................................................................... 31 
1.4 
Clinical Study ................................................................................................................. 32 
1.5 
Dose Determination in the Study .................................................................................... 33 
1.6 
Manufacturing Process Change of BGB-A317 ............................................................... 34 
2. 
STUDY OBJECTIVES ........................................................................................................... 36 
2.1 
Primary Objectives ......................................................................................................... 36 
2.2 
Secondary Objectives ..................................................................................................... 36 
2.3 
Exploratory Objectives ................................................................................................... 37 
3. 
STUDY ENDPOINTS ............................................................................................................ 38 
3.1 
Primary Endpoints .......................................................................................................... 38 
3.2 
Secondary Endpoints ...................................................................................................... 38 
3.3 
Exploratory Endpoints .................................................................................................... 39 
4. 
INVESTIGATIONAL PLAN ................................................................................................. 40 
4.1 
Study Design ................................................................................................................... 40 
4.1.1 
Phase I ................................................................................................................ 40 
4.1.2 
Phase II ............................................................................................................... 41 
4.2 
Dose-Limiting Toxicity .................................................................................................. 42 
4.3 
Dose Modifications, Dose Delay and Missing Dose ...................................................... 43 
4.4 
End of Treatment Visit ................................................................................................... 44 
4.5 
Schedule of Assessment.................................................................................................. 44 
5. 
STUDY POPULATION .......................................................................................................... 59 
5.1 
Inclusion Criteria ............................................................................................................ 59 
5.2 
Exclusion Criteria ........................................................................................................... 61 
5.3 
Other Eligibility Criteria Consideration.......................................................................... 62 
5.4 
Subject Restrictions ........................................................................................................ 63 
5.5 
Subject Discontinuation (Dropout/Withdrawal) ............................................................. 63 
5.6 
Medical Treatment of Subject after Treatment Period Completion ................................ 63 
5.7 
Reinitiation of Study Therapy for Subjects in Follow-up Period ................................... 63 
5.8 
End of Study ................................................................................................................... 64 
5.9 
Drug Supply for Patients Who are Still on Treatment at End of Study .......................... 64 
6. 
STUDY TREATMENTS ........................................................................................................ 65 
6.1 
Description of Investigational Product ........................................................................... 65 
6.2 
Product Preparation and Administration ......................................................................... 65 
6.3 
Treatment Assignment .................................................................................................... 66 
6.4 
Packaging and Labelling ................................................................................................. 67 
6.5 
Handling and Storage...................................................................................................... 67 
6.6 
Product Accountability ................................................................................................... 67 


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6.7 
Assessment of Compliance.............................................................................................67 
6.8 
Investigational Product Overdose...................................................................................67 
6.9 
Medical Care of Subjects after the End of Trial .............................................................68 
6.10 
Occupational Safety........................................................................................................68 
7. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES.................................69 
7.1 
Concomitant Medication(s)/Treatment(s).......................................................................69 
7.2 
Prohibited Medications...................................................................................................69 
7.2.1 
Other Drugs to be Used in the Study..................................................................70 
7.2.2 
Other Study Considerations................................................................................70 
7.3 
Special Precautions.........................................................................................................70 
7.3.1 
Tumor Lysis Syndrome ......................................................................................70 
7.3.2 
Infusion-Related Reaction..................................................................................71 
7.3.3 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .............................73 
8. 
SAFETY, PHARMACOKINETIC, PHARMACODYNAMIC, AND OTHER 
ASSESSMENTS .....................................................................................................................74 
8.1 
Screening and Pre-screening...........................................................................................74 
8.2 
Demographic and Baseline Assessments........................................................................74 
8.3 
Assessments During Treatment ......................................................................................76 
8.3.1 
Laboratory Evaluation........................................................................................76 
8.3.2 
Physical Examination, Vital Signs and ECOG Score.........................................77 
8.3.3 
Electrocardiogram ..............................................................................................77 
8.3.4 
Ultrasonic Echocardiography .............................................................................78 
8.3.5 
Pulmonary function testing.................................................................................78 
8.3.6 
Computed Tomography and Magnetic Resonance Imaging...............................78 
8.3.7 
Adverse Events...................................................................................................78 
8.4 
Safety Assessments.........................................................................................................79 
8.5 
Follow-up Assessments ..................................................................................................79 
8.6 
Efficacy Assessments .....................................................................................................79 
8.6.1 
Treatment after Disease Progression ..................................................................80 
8.6.2 
Efficacy Endpoints .............................................................................................80 
8.7 
Pharmacokinetics............................................................................................................81 
8.7.1 
Phase I ................................................................................................................81 
8.7.2 
Phase II...............................................................................................................82 
8.8 
Anti-Drug Antibody........................................................................................................82 
8.9 
................................................................................................82 
8.10 
Appropriateness of Measurements..................................................................................83 
9. 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................84 
9.1 
Monitoring......................................................................................................................84 
9.2 
Data Management/Coding..............................................................................................85 
9.3 
Quality Assurance Audit.................................................................................................86 
10. 
SAFETY MONITORING AND REPORTING ......................................................................87 
10.1 
Risks Associated with BGB-A317 .................................................................................87 
10.2 
General Plan to Manage Safety Concerns ......................................................................87 
10.2.1 
Eligibility Criteria...............................................................................................87 
10.2.2 
Safety Monitoring Plan.......................................................................................87 
10.3 
Adverse Events...............................................................................................................88 
10.3.1 
Definitions and Reporting ..................................................................................88 
10.3.2 
Assessment of Severity.......................................................................................89 
10.3.3 
Assessment of Causality.....................................................................................89 


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10.3.4 
Following Adverse Events..................................................................................90 
10.3.5 
Laboratory Test Abnormalities...........................................................................91 
10.4 
Definition of a Serious Adverse Event ...........................................................................91 
10.5 
Suspected Unexpected Serious Adverse Reaction..........................................................92 
10.6 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events .............................................................................................................................92 
10.6.1 
Adverse Event Reporting Period ........................................................................92 
10.6.2 
Reporting Serious Adverse Events.....................................................................92 
10.6.3 
Eliciting Adverse Events ....................................................................................94 
10.6.4 
Recording Persistent or Recurring Adverse Events............................................94 
10.6.5 
Disease Progression............................................................................................94 
10.6.6 
Deaths.................................................................................................................94 
10.6.7 
Pregnancies.........................................................................................................94 
10.6.8 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees.....................................................95 
10.7 
Assessing and Recording Immune-Related Adverse Event............................................95 
10.7.1 
Immune-Related Adverse Events .......................................................................95 
11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS..........................................97 
11.1 
Sample Size Considerations............................................................................................97 
11.2 
General Considerations for Data Analysis......................................................................97 
11.2.1 
Analysis Sets ......................................................................................................97 
11.2.2 
Study Analysis....................................................................................................98 
11.3 
Efficacy Analyses ...........................................................................................................98 
11.4 
Safety Analyses ..............................................................................................................99 
11.4.1 
Dose-Limiting Toxicity......................................................................................99 
11.4.2 
Adverse Event ....................................................................................................99 
11.4.3 
Laboratory Assessments...................................................................................100 
11.4.4 
Electrocardiogram ............................................................................................100 
11.4.5 
Vital Signs ........................................................................................................100 
11.4.6 
Extent of Exposure ...........................................................................................100 
11.4.7 
Physical Examination .......................................................................................100 
11.5 
Pharmacokinetic Analyses............................................................................................100 
11.6 
......................................................................................................101 
12. 
ETHICS.................................................................................................................................102 
12.1 
National Regulations and the Declaration of Helsinki .................................................102 
12.2 
Informed Consent .........................................................................................................102 
12.3 
Independent Ethics Committee/Institutional Review Board (IEC/IRB).......................102 
12.4 
Protocol Modifications .................................................................................................102 
13. 
PRESERVATION OF STUDY DOCUMENTS, CASE REPORT FORM AND RECORDS
...............................................................................................................................................103 
13.1 
Study Documents and Document Preservation.............................................................103 
13.2 
Original Documents and Data.......................................................................................103 
13.3 
Audit and Inspection.....................................................................................................103 
13.4 
Case Report Form.........................................................................................................104 
13.5 
Use and Publication of Study Data...............................................................................104 
13.5.1 
Use of Study Data.............................................................................................104 
13.5.2 
Publication........................................................................................................104 
14. 
REFERENCES......................................................................................................................105 
15. 
APPENDICES.......................................................................................................................107 


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APPENDIX 1. 
FLOW CHARTS ............................................................................................ 107 
APPENDIX 2. 
CHILD-PUGH LIVER FUNCTION CLASSIFICATION............................. 110 
APPENDIX 3. 
IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .................................................................................................................. 111 
APPENDIX 4. 
CLINICAL LABORATORY ASSESSMENTS AND AMOUNT OF BLOOD 
SAMPLING  ........................................................................................................................ 123 
APPENDIX 5. 
CONTRACEPTION GUIDELINES .............................................................. 125 
APPENDIX 6. 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1) GUIDELINES ................................................................................................ 126 
 
List of Tables 
Table 1. 
Schedule of Phase I Study Assessments. ........................................................................... 45 
Table 2. 
Pharmacokinetic Sampling and ADA Test for dose verification study of Phase I ............ 51 
Table 3. 
Pharmacokinetic Sampling and ADA Test Schematic of PK Sub-study of Phase I .......... 53 
Table 4. 
Phase II Study Assessments and Procedure Schedule........................................................ 55 
Table 5. 
Product information about three manufacturing processes and scales ............................... 65 
Table 6. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to BGB-A317
 ............................................................................................................................................ 72 
Table 7. 
Timeframes and Documentation Methods for Reporting Serious Adverse Events to the 
Sponsor or Designee .......................................................................................................... 93 
Table 8. 
Immune-Related Adverse Events ....................................................................................... 96 
Table 9. 
Clinical and biochemical parameters of Child-Pugh classification .................................. 110 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration and time curve 
BGB-A317 
Code name for Monoclonal Antibody BGB-A317 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
Cl 
Clearance 
Cmax 
Maximum observed plasma concentration 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Minimum observed plasma concentration 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DP 
Drug product 
DS 
Drug substance 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FMP 
Final manufacturing process 
GCP 
Good Clinical Practices 
GMP 
Good Manufacture Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 


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HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G, such as IgG1, IgG2, IgG3 and IgG4; other types of 
immunoglobulins include IgM, IgD and etc. 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous 
MMR 
Mismatch repair 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-small cell lung cancer 
OMP 
Original Manufacturing Process 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Program Death Ligand-1  
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Prothrombin Time 
Q2W 
Once every two weeks 
Q3W 
Once every three weeks 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
t1/2 
Half-life  
Tmax 
Time to maximum observed plasma concentration 
ULN 
Upper limit of normal 
 


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1. 
INTRODUCTION 
1.1 
Background and Pharmacology 
Immune check point-inhibitory receptor, programmed cell death-1 (PD-1) is mainly expressed in 
activated T-cells including CD8+ cytotoxic T-lymphocytes and CD4+ T-helper lymphocytes 
(McDermott DF, 2013). It is believed that PD-1 plays an important role in immune modulation of tumor 
progression by regulating the key inhibitory signaling in the T-cells when engaged by its ligands. The 
PD-1 signaling cascade reaction negatively regulates T-cell receptor (TCR) and attenuates T-cell 
proliferation and functional activities, leading to T-cell exhaustion. PD-1 expression is markedly up-
regulated in tumor-infiltrating lymphocytes, while the expression of PD-1 ligand, PD-L1, is 
significantly increased in tumor cells and tumor-associated immune cells in the presence of stimulating 
cytokines such as interferon (IFN)-Jand IFN-D in the tumor microenvironment (Riley JL, 2009). 
Furthermore, the increased PD-1 expression in tumor-infiltrating lymphocytes and/or PD-L1 
expression in tumor and tumor-associated stromal cells is observed in many types of solid human 
tumors, including, but not limited to, melanoma, squamous cell carcinoma, uveal melanoma, non-small 
cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), triple-negative breast 
cancer, renal cell carcinoma (RCC), bladder cancer, and ovarian cancer (Ghebeh H, 2006; Hamanishi 
J, 2007; Hino R, 2010; Jie HB, 2013; Konishi J, 2004; Thompson RH, 2007; Thompson RH, 2004; 
Tsushima F, 2006). These evidences provided the basis for use of antagonists of PD-1 as cancer 
immunotherapeutic agents. 
Recent clinical trials have demonstrated significant efficacy for anti-PD-1 monoclonal antibodies such 
as nivolumab and pembrolizumab in advanced melanoma, NSCLC and RCC. These antibodies were 
well tolerated without demonstrating dose-limiting toxicity (DLT) when patients were dosed up to 10 
mg/kg intravenously, once every two weeks (Q2W) or once every three weeks (Q3W). The first-in-
human phase I trial on nivolumab (a fully human anti–PD-1 immunoglobulin G4 [IgG4] antibody) 
evaluated its safety profile at increasing doses of 0.3, 1, 3 and 10 mg/kg given intravenously (IV) Q2W 
in 39 patients with advanced melanoma, colorectal cancer (CRC), castration resistant prostate cancer 
(CRPC), NSCLC, or RCC (Brahmer JR, 2010; Topalian SL, 2012). The FIH Phase I study on 
pembrolizumab (a humanized anti–PD-1 IgG4 antibody) evaluated its safety at 1 to 10 mg/kg IV at 4 
week interval followed by bi-weekly doses in cohorts of three to six patients with various advanced 
solid tumors (Hamid O, 2013). The most common adverse events (AEs) were grade 1/2, including 
arthralgia, cough, diarrhea, fatigue, fever, nausea, pruritus, and rash. However, grade 3/4 treatment-
related AEs occurred in 15% of patients and there were three deaths in the nivolumab study, all 
attributed to pulmonary toxicity. Grade 3/4 AEs were also reported in the pembrolizumab studies and 
one patient died of myocardial infarction while being treated for pneumonitis/pneumonia. Drug-related 
AEs of special interest (AEs with potentially immune-related etiology) included vitiligo, pneumonitis, 
hepatitis, colitis, thyroiditis, and hypophysitis. 


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Based on the overwhelming positive results that pembrolizumab and nivolumab demonstrated in their 
pivotal studies, US Food and Drug Administration (FDA) approved these two drugs for the treatment 
of metastatic melanoma in 2nd or 3rd line. In the nivolumab pivotal study, the cohort of 120 patients 
treated at 3 mg/kg Q2W exhibited an overall response rate (ORR) of 32% with 4 complete responses 
(CRs) and 34 partial responses (PRs). Thirteen patients have objective responses lasting 6 months or 
longer (FDA News Release, 2 Dec. 2014). In the pivotal study on pembrolizumab, 173 patients were 
treated with pembrolizumab at either 2 or 10 mg/kg dose, approximately 24% patients demonstrated 
tumors shrinkage (2 mg/kg regimen) (FDA News Release, 4 Sept. 2014). 
Interestingly, melanoma patients who became resistant to ipilumumab treatment were still sensitive to 
pembrolizumab. The ORRs of ipilumumab-naïve and ipilumumab-resistant are 40% and 28%, 
respectively.  
Anti-PD-1 antibody treatment not only generated higher response rate, but also prolonged overall 
survival (OS). In a cohort of 107 patients treated with nivolumab, 1 and 2 years OSs were 63% and 
48%, respectively, with median OS at 17.3 months. Similarly, in a cohort of 411 patients treated with 
pembrolizumab, 1-year OS was 69% and 18-month OS was 62%, respectively (Weber JS, 2014ASCO). 
In addition to melanoma, anti-PD-1 antibodies were also reported to be efficacious in other cancer types 
including NSCLC, RCC and HNSCC. In the NSCLC study, 129 patients were treated with nivolumab 
in 2nd, 3rd or 4th line, one-year or two-year survival rate were 42% and 24%, respectively, with median 
OS of 9.9 months. Retrospective analysis indicated both patients with K-Ras and EGFR mutations 
responded to the immunotherapy (BMS Press Release, 25 Oct. 2014). 
Recent exploratory studies suggested that combinatory immunotherapies with anti-PD-1 antibody may 
provide more benefits to cancer patients. In one study in patients with metastatic melanoma, nivolumab 
in combination with ipilumumab generated remarkable ORR with two-year OS rate at more than 80%. 
Patients with wild type or mutant BRAF, with or without PD-L1 expression, all responded well to the 
combination treatment (Sznol M, 2014; Wolchok JD, 2013). Of note, the immune-related adverse 
events (irAEs) also increased significantly in the combination treatment.  
BGB-A317 is a humanized IgG4 variant monoclonal antibody against PD-1. It is being developed for 
the treatment of human malignancies. BGB-A317 was manufactured under Good Manufacture Practice 
(GMP) quality control systems. The clinical trial drug product is formulated in an aqueous buffer with 
pH 6.5 and isotonic osmolarity. The suggested administration route is IV infusion after the appropriate 
dilution in 0.9% sodium chloride solution. 
BGB-A317 binds to the extracellular domain of human PD-1 with high specificity and affinity (KD = 
0.15 nM) as demonstrated by receptor binding assays based on surface plasmon resonance. It 
competitively blocks the binding of both PD-L1 and Program Death Ligand L2 (PD-L2), inhibiting 
PD-1 mediated negative signaling in T-cells. In in vitro cell-based assays, the humanized antibody 


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consistently and dose-dependently enhanced the functional activity of human T-cells and pre-activated, 
primary peripheral blood mononuclear cells. In addition, BGB-A317 demonstrated anti-tumor activity 
in several human cancer allogeneic xenograft models, including A431 human epidermoid carcinoma, 
BCCO-028 colon cancer, and BCLU-054 NSCLC models. In these studies, peripheral blood 
mononuclear cells were co-injected with the human cancer cells (A431) or the tumor fragments 
(BCCO-028 and BCLU-054) into the immunocompromised mice.  
The IgG4 variant antibody has very low binding affinity to Fc-gamma receptor III (FcγRIII) and 
Complement 1 q by in vitro assays, suggesting a low or no antibody dependent cellular cytotoxicity 
and complement dependent cytotoxicity effect in humans. Unlike natural IgG4 antibody, BGB-A317 
has no observable Fragment antigen-binding (Fab)-Arm Exchange activity by the in vitro assay, 
predicting the antibody would be stable in vivo, unlikely forming bispecific antibody. 
BGB-A317 binds to the cynomolgus monkey and human PD-1 with similar affinity, but does not bind 
to mouse PD-1 due to the significant sequence divergence from human and monkey PD-1. Therefore, 
cynomolgus monkeys were considered to be the relevant species for nonclinical safety evaluation.  
Refer to the Investigator’s Brochure (IB) for more detailed information on the background of BGB-
A317. 
1.2 
Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion 
A pharmacokinetic study of BGB-A317 was conducted in monkeys at single doses of 3, 10, or 30 mg/kg 
or at repeat dose of 10 mg/kg weekly for 5 doses via IV infusion. The systemic exposure appeared to 
increase dose-proportionally without gender difference or accumulation. After single dose 
administration of 3, 10, or 30 mg/kg, the half-life (t1/2) ranged from 74 to 183 hours; maximum observed 
plasma concentration (Cmax) ranged from 90 to 999 Pg/mL, and area under the plasma concentration 
and time curve (AUC)0-1008h ranged from 12,322 to 163,755 h × μg/mL; volume of distribution (Vd) 
was low, ranged from 22 to 52 mL/kg.  
A pharmacokinetic bridging study for BGB-A317 manufactured from BI and JHL was conducted in 
monkeys at a single dose of 10 mg/kg via IV infusion. No marked differences on t1/2, Cmax, AUC, Vd, 
clearance (CL) and mean residence time were noted between the two batches. 
The t1/2 of BGB-A317 in monkeys supported once biweekly dosing in the repeat-dose toxicology study 
with adequate systemic exposure to support toxicology evaluation of BGB-A317. Based on 
pharmacokinetics (PK) results in monkeys, the Vd of BGB-A317 in humans is expected to be similar 
to that in monkeys. The t1/2 of BGB-A317 in humans is expected to be 10-20 days depending on the 
actual dose levels, which allows multiple-dose treatment of BGB-A317 for humans with a dosing 
interval of 14 or 21 days to provide the target systemic exposure at the projected therapeutic dose of 
0.5 to 10 mg/kg without excessive drug accumulation. 


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Refer to the IB for more detailed information on the pharmacokinetics properties of BGB-A317. 
1.3 
Toxicology 
The toxicity and safety profile of BGB-A317 was elaborated in single dose toxicology studies in mice 
and monkeys and in a 13-week repeat dose toxicology study in monkeys. The tissue cross reactivity 
was evaluated in the normal frozen tissues from both humans and monkeys. The cytokine release assays 
were also evaluated using fresh human whole blood cells. The pivotal studies were conducted following 
Good Laboratory Practice regulations. The single dosing regimens were spanning from the intended 
human doses to 10-fold higher than the maximum of the intended human doses, and the repeat dosing 
regimens spanning to 3-fold higher than the maximum of the intended human doses. Cynomolgus 
monkey was the only relevant species based on the target sequence homology and binding activity.  
No apparent toxicity was noted in both mice and monkeys following a single dose up to 100 mg/kg and 
in monkeys following a repeat dose up to 30 mg/kg biweekly for 13 weeks. The toxicokinetics profile 
was characterized in monkey studies and the systemic exposure appeared to be dose proportional 
without gender difference or accumulation over the dosing period. No apparent immunotoxicity was 
observed as no apparent changes in clinical pathology or histopathology were noted in these studies. 
The immunogenicity with positive anti-drug antibody (ADA) against BGB-A317 was noted in the 
single dose monkey study with one of two monkeys in each of three dose groups and in the repeat dose 
study with 8/12, 6/12, and 5/12 of animals at doses of 3, 10, and 30 mg/kg, respectively. The ADA 
against BGB-A317 was demonstrated to have neutralization function in a cell-based assay and it 
appeared to have some impact on the systemic exposure over the dosing period at 3 mg/kg, but little at 
10 and 30 mg/kg.  
The tissue cross reactivity of BGB-A317 was evaluated in normal human and cynomolgus monkey 
frozen tissues using immunohistochemistry method, with appropriate positive and negative controls. 
Under the study condition, no specific tissue cross reactivity with BGB-A317 was noted in both human 
and cynomolgus monkey tissues. Neither hemolytic effects induced by BGB-A317 in the rabbit blood 
cells nor increase of the cytokine release from human whole blood cells after treatment with BGB-
A317 was observed in in vitro evaluations. 
Overall, no apparent toxicity was noted in mice and monkey toxicity studies. No tissue cross reactivity 
was found in both human and monkey tissues, nor effect on cytokine release was observed in human 
whole blood assay. TK profile was well characterized with dose proportionally increases in systemic 
exposure without apparent accumulation or sex difference. Immunogenicity was observed without 
apparent immunotoxicity and effect on the systemic exposure. The No Observed Adverse Effect Level 
of BGB-A317 in 13-week monkey toxicity study was considered to be 30 mg/kg. The safety profile of 
BGB-A317 is considered adequate to support first-in-human dose safely and ethically.  
Refer to the BGB-A317 IB for more detailed information on the toxicology of BGB-A317. 


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1.4 
Clinical Study 
The first human clinical study of BGB-A317 was conducted in Australia in June 2015. It is an open-
label, multi-dose Phase I trial including stages of dose escalation, schedule expansion, fixed-dose 
exploration and indication expansion, mainly aiming at exploring the safety, tolerability, 
pharmacokinetic characteristics and preliminary anti-tumor efficacy of BGB-A317 in patients with 
advanced tumors. 
As of 29 March 2016, a total of 100 subjects were enrolled. Among them, 22 were enrolled for the 
dose-escalation stage, including 3 subjects for 0.5 mg/kg Q2W, 6 subjects for 2 mg/kg Q2W, 6 subjects 
for 5 mg/kg Q2W and 7 subjects for 10 mg/kg Q2W; 78 subjects were enrolled for the schedule 
expansion stage, including 20 subjects for 2 mg/kg Q2W, 19 subjects for 2 mg/kg Q3W, 20 subjects 
for 5 mg/kg Q2W, and 19 subjects for 5 mg/kg Q3W. 
Within the dose range of 0.5 mg/kg Q2W to 10 mg/kg Q2W, BGB-A317 has demonstrated favorable 
safety and tolerability in the treatment of patients with solid tumors in Australia. During the 28-day 
DLT observation period, only 1 case of grade 3 colitis was reported in the 5 mg/kg Q2W dose-escalation 
cohort, which was determined as DLT (1/6). No DLT occurred in other dose escalation cohorts, and 
maximum tolerated dose (MTD) was not reached. Preliminary safety analysis showed that the most 
common treatment-emergent adverse events (AE) (ı10%) included fatigue (31%), diarrhea (21%), 
nausea (20%), constipation (16%), abdominal pain (14%), pruritus (13%), rash (12%), loss of appetite 
(12%), back pain (12%) and vomiting (10%). Immune-mediated adverse events were reported among 
10 subjects, including colitis (one grade 3, two grade 2), diabetes mellitus (one grade 3, one grade 2), 
alanine aminotransferase (ALT) increase (one grade 3), diarrhea (one grade 2), worsening liver 
functions (one grade 2), hypothyroidism (one grade 1) and onychoclasis (one grade 1). As of 29 March 
2016, 9 drug-related serious adverse events (SAE) were reported, including one grade 2 colitis in the 2 
mg/kg Q2W dose escalation cohort (n=6), one grade 3 colitis in the 5 mg/kg Q2W dose escalation 
cohort (n=6), one grade 2 colitis and one grade 2 infusion-related reactions in the 5 mg/kg Q2W 
schedule expansion cohort (n=20), one grade 3 diabetic ketoacidosis, one grade 3 diabetes mellitus, one 
grade 3 hypotension and one grade 2 diarrhea in the 2 mg/kg Q2W schedule expansion cohort (n=20), 
and one grade 3 hypotension in the 5 mg/kg Q3W schedule expansion cohort (n=19). Other grade 3/4 
adverse events considered as treatment-related by the investigator included one grade 3 ALT increase 
in the 2 mg/kg Q2W dose escalation cohort (n=6), one grade 3 hyperglycemia in the 2 mg/kg Q2W 
schedule expansion cohort (n=20), one grade 3 back pain and one grade 3 fatigue in the 5 mg/kg Q2W 
schedule expansion cohort (n=20), and one grade 3 fatigue and one grade 3 hyperglycemia in the 5 
mg/kg Q3W schedule expansion cohort (n=19). 
The pharmacokinetic data from 31 subjects receiving 0.5 mg/kg to 10 mg/kg Q2W and 13 subjects 
receiving 2 mg/kg and 5 mg/kg Q3W has preliminarily proven that the drug exposure of BGB-A317 in 
the blood after a single dose increases linearly within the range of 0.5-10 mg/kg. The system clearance 
rate was 0.00789 L/h, volumes of distribution were 2.79 L and 1.44 L, and half-life was about 16 days. 


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Tumor types enrolled in the study included ovarian cancer (n=23), colorectal cancer (n=14), renal cell 
carcinoma (n=9), mesothelioma (n=7), urothelial carcinoma (n=6), cervical cancer (n=5), endometrial 
cancer (n=4), gastric cancer (n=4), cholangiocarcinoma (n=3), nasopharyngeal carcinoma (n=3), 
esophageal cancer (n=3), Merkel cell carcinoma (n=2), gallbladder cancer (n=2), pancreatic cancer 
(n=2), anal squamous cell carcinoma (n=2), sarcoma (n=2) and 1 subject each in other 9 tumor types. 
So far, only a limited number of subjects have received at least once effective efficacy evaluation. 
Based on the latest data, significant tumor shrinkage has been observed in several subjects with tumor 
types that are known to be sensitive to PD-1 antibody. Given the limited efficacy data and the fact that 
PD-1 antibody often shows features of lagging effect and pseudo-disease progression, the overall 
efficacy evaluation will be performed after more data becomes available. 
In addition, a combination trial of BGB-A317 plus BGB-290 (PARP inhibitor) has been conducted in 
Australia. As of 5 May 2016, a total of 12 subjects received combination therapy of BGB-A317 with 
BGB-290. Among them, 1 subject in the 2 mg/kg Q3W BGB-A317 and 20 mg BID BGB-290 treatment 
group developed grade 4 immune-related liver disease, which was considered as a drug-related SAE 
by the investigator.  
Clinical trials of other anti-PD-1 drugs suggest the most common AEs were grade 1/2, including 
arthralgia, cough, diarrhea, fatigue, fever, nausea, pruritus, and rash. However, grade 3/4 treatment-
related AEs occurred in 15% of subjects in the early studies of nivolumab, and there were 3 deaths all 
due to pulmonary toxicity (Brahmer JR, 2010; Topalian SL, 2012). Grade 3/4 AEs were also reported 
in the pembrolizumab studies with one death due to myocardial infarction while being treated for 
pneumonitis/pneumonia (Hamid O, 2013). Drug-related AEs of special interest (AEs with potentially 
immune-related etiology) including vitiligo, pneumonitis, hepatitis, colitis, thyroiditis, and 
hypophysitis may be observed during multiple dose escalation in subjects with cancer. Currently the 
guidelines for management of immune-related adverse events have been developed and published 
(Bristol-Myers Squibb, 2012; Bristol-Myers Squibb, 2018), according to which clinicians may 
determine immune-related adverse reactions once they occur and provide appropriate management. For 
the irAEs during BGB-A317 treatment, please refer to the BGB-A317 IB. 
1.5 
Dose Determination in the Study 
This study is a dose verification and indication expansion clinical trial of monoclonal antibody BGB-
A317 conducted in Chinese patients with advanced malignant solid tumors, with a purpose of 
determining the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of BGB-
A317 in Chinese patients with advanced solid tumors. Through dose verification as well as safety and 
efficacy expansion design parts, the study will determine the MTD and recommended Phase 2 dose 
(RP2D) of BGB-A317 in Chinese subjects. 
This study is conducted on the basis of the multi-dose, dose-escalation Phase IA study conducted in 
Australia. According to preliminary results of the Phase IA clinical study in Australia (see Section 1.4), 


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0.5, 2, 5 and 10 mg/kg Q2W are all tolerable doses. In the dose-escalation stage, only 1 of the 22 
subjects developed DLT, and the dose up to 10 mg/kg Q2W did not reach the MTD, so 10 mg/kg Q2W 
was determined as the maximum dosage. No apparent relationship was found between adverse reactions 
and doses. In addition, 2 mg/kg and 5 mg/kg were also explored in Q2W and Q3W administration 
settings, and the safety of each dose and the method of administration had been confirmed. From the 
safety data, drug-related adverse reactions from 2 mg/kg Q2W to 10 mg/kg Q2W were very similar. 
Overall, BGB-A317 has favorable tolerability at all dose levels, and slightly fewer adverse reactions 
occurred in the Q3W group. 
According to the Phase IA pharmacokinetic data in Australia (see Section 1.4), plasma concentrations 
of BGB-A317 showed linear relationships with doses from 0.5 mg/kg Q2W to 10 mg/kg Q2W. 
Furthermore, according to the results of analysis of covariance, there was no significant correspondence 
between the weight of subjects and the in vivo clearance rate of BGB-A317. This conclusion supports 
the hypothesis of fixed-dose administration. Therefore, we have also begun to explore fixed-dose 
administrations in Australia and New Zealand. 200 mg Q3W and 300 mg Q3W have been chosen, 
which are equivalent to 3.3 mg/kg Q3W and 5 mg/kg Q3W (calculated with 60 kg) and still much lower 
than the maximum dose (10 mg/kg Q2W) studied in foreign trials even including extreme 
circumstances (eg, patients with low body weight). Therefore, 200 mg Q3W and 300 mg Q3W should 
be safe doses. 
Up to September 30, 2016, 15 subjects from a total of 99 efficacy evaluable subjects (including various 
solid tumors) achieved confirmed response. These responders were dosed with 2mg/kg or 5mg/kg, 
Q2W or Q3W, and no clear dose-response correlation was observed. In view of safety data, 
pharmacokinetic data and limited preliminary anti-tumor efficacy data from previous studies, 200mg 
Q3W is currently recognized as RP2D. This study will further explore the safety and pharmacokinetic 
profiles of this dose in Chinese subjects during Phase I.  
 
1.6 
Manufacturing Process Change of BGB-A317 
The manufacturing process and scale for BGB-A317 went through some changes during chemistry, 
manufacturing and controls (CMC) development. The original manufacturing process (OMP) was used 
to produce bulk drug substance (DS) under GMP condition at 100L and 500L scales, respectively. The 
investigational drug product (DP) made from the DS lots of IMP was used in phase I and II studies. 
Subsequently, the IMP was modified to the final manufacturing process (FMP), which was used to 
produce bulk DS under GMP condition at 500L and 2,000L scales, respectively. In parallel to the 
process change, specifications for the DS and DP purity were raised up, eg the requirement for 
monomeric faction by HP-SEC method was raised from 90% to 95% meanwhile all the compendial 
specifications/ standards were remained the same, in line with United States Pharmacopoeia, European 
Pharmacopoeia and Chinese Pharmacopoeia. The investigational DPs made by FMP either at 500L 


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scale or 2,000L scale are used for pivotal clinical studies. Due to the criticality of pivotal clinical studies, 
the process scale changes and deviations of investigational DPs made by 500L FMP and 2000L FMP, 
it is rationalized that pharmacokinetics profiles of the DPs made from 500L FMP and 2,000L FMP 
should be compared in human clinical study in addition to the comparability studies by the in vitro 
experiments. 
 
 
 
 


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2. 
STUDY OBJECTIVES  
2.1 
Primary Objectives 
Phase I 
Dose Verification study 
x 
To assess the safety and tolerability of BGB-A317 in subjects with advanced solid tumors 
x 
To determine the maximum tolerated dose (MTD), if any, and/or recommended Phase II dose 
(RP2D) for BGB-A317 in Chinese subjects 
Pharmacokinetics (PK) sub-study 
x 
To assess the PK of products derived from two manufacturing processes and scales (500L-FMP 
and 2000L-FMP) following the first dose of BGB-A317 
Notes: 500L-FMP indicates a final manufacturing process and scale of 500L; 2000L-FMP 
indicates a final manufacturing process and scale of 2000L. 
x 
To assess the safety and tolerability of BGB-A317 of two manufacturing processes and scales 
(500L-FMP and 2000L-FMP) in patients with advanced solid tumors 
Phase II 
x 
To assess the preliminary anti-tumor activity of BGB-A317 
2.2 
Secondary Objectives 
Phase I 
Dose Verification Study 
x 
To characterize the pharmacokinetics of BGB-A317 
x 
To assess the preliminary anti-tumor activity of BGB-A317 
x 
To assess the host immunogenicity to BGB-A317 
PK sub-study 
x 
To assess the PK of products derived from two manufacturing processes and scales (500L-FMP 
and 2000L-FMP) following the multiple doses of BGB-A317 
x 
To assess the host immunogenicity to BGB-A317 of two manufacturing processes and scales 
(500L-FMP and 2000L-FMP)  


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x
To assess the preliminary anti-tumor activities of BGB-A317 of two manufacturing processes and 
scales (500L-FMP and 2000L-FMP)
Phase II
x
To further assess the safety and tolerability of BGB-A317
x
To further assess the pharmacokinetic characteristics of BGB-A317
x
To assess the host immunogenicity to BGB-A317.
2.3
Exploratory Objectives
Phase I and Phase II


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3. 
STUDY ENDPOINTS 
3.1 
Primary Endpoints 
Phase I 
Dose Verification Study 
x 
Safety and tolerability of BGB-A317: The safety of BGB-A317 will be assessed throughout the 
study by monitoring adverse events (AEs) and serious adverse events per the NCI-CTCAE Version 
4.03 
(Common 
Terminology 
Criteria 
Version 
4.03, 
2010), 
physical 
examination, 
electrocardiograms and laboratory assessments. 
x 
The MTD (if any) and/or RP2D (s) for BGB-A317 will be determined based on safety, tolerability, 
pharmacokinetics, preliminary efficacy, and other available data.  
Given the mechanism of BGB-A317 involving immune regulation, particular attention should be paid 
to irAEs which include pruritus, vitiligo, pruritic rash, macular rash, hypopigmentation, and other skin 
disorders; hypothyroidism and hyperthyroidism, hypophysitis, pneumonitis, hepatitis, nephritis, 
allergic rhinitis, diarrhea, abdominal pain, fatigue, hypersensitivity and any other irAEs. Researches 
should be done to exclude toxic, metabolic, infectious, neoplastic or other non-drug-related etiologic 
causes of such events.  
PK sub-study 
x 
PK: Single-dose pharmacokinetic parameters (Cmax, AUClast, and AUCinf) will be assessed to 
evaluate the PK characteristics of BGB-A317 derived from both manufacturing processes and 
scales 
x 
Safety: The safety of BGB-A317 will be assessed throughout the study by monitoring adverse 
events and serious adverse events per the NCI-CTCAE Version 4.03, physical examination, 
electrocardiograms, laboratory measurements  
Phase II 
x 
The ORR in different tumor types will be determined by the investigator per Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 
3.2 
Secondary Endpoints 
Phase I 
Dose Verification Study 
x 
Evaluations of Pharmacokinetics: including but not limited to AUC0-21 day, Cmax and time to 
maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Ctrough), 
t1/2, clearance (Cl) and volume of distribution during terminal phase (Vz) 


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x
Evaluations of Efficacy: ORR, CR rate, PR rate, stable disease (SD) rate, progression-free survival 
(PFS), duration of response (DOR), and duration of SD will be determined by investigator per
RECIST Version 1.1. Overall survival (OS) will be evaluated
x
Anti-BGB-A317 antibodies: immunogenic responses to BGB-A317 will be assessed through the 
monitoring of the occurrence of anti-drug antibody
PK sub-study
x
PK: Steady-state pharmacokinetic parameters (include but not limit to Ctrough) will be assessed for 
both manufacturing processes and scales following the multiple doses of BGB-A317 to evaluate 
the PK characteristics at steady state
x
Anti-BGB-A317 antibody: Immunogenic responses to BGB-A317 of both manufacturing 
processes and scales will be assessed to evaluate the comparability of the occurrence of anti-drug 
antibody
x
Efficacy evaluations: ORR, CR rate, PR rate, SD rate, PFS, and DOR and duration of SD will be
determined by investigator based on RECIST Version 1.1; OS will be evaluated
Phase II
x
Evaluations of Efficacy: CR rate, PR rate, SD rate, PFS, duration of response, duration of SD, 
disease control rate (DCR) and clinical benefit rate (CBR) will be determined by investigator based 
on RECIST Version 1.1; OS will be evaluated
x
Safety and tolerability of BGB-A317: The safety of BGB-A317 will be assessed throughout the 
study by monitoring adverse events and serious adverse events per NCI-CTCAE Version 4.03, 
physical examination, electrocardiograms and laboratory assessments
x
Evaluations of Pharmacokinetics: including but not limited to Ctrough
x
Anti-BGB-A317 antibodies: immunogenic responses to BGB-A317 will be assessed by 
monitoring the occurrence of anti-drug antibody (ADA)
3.3
Exploratory Endpoints


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4.
INVESTIGATIONAL PLAN
4.1
Study Design
This study is a dose verification, PK assessment of products derived from two manufacturing processes 
and scales (500L-FMP and 2000L-FMP; FMP: Final Manufacturing Process) and indication expansion
clinical study of monoclonal antibody BGB-A317 conducted in Chinese subjects with advanced solid
tumors, with a purpose of exploring the safety, tolerability, pharmacokinetics and preliminary efficacy. 
This study is carried out on the basis of a Phase IA multi-dose and dose-escalation study in Australia. 
According to the preliminary results of the Phase IA clinical study in Australia, 0.5, 2, 5 and 10 mg/kg, 
Q2W are all tolerable doses. In addition, 2 and 5 mg/kg, Q3W have also been confirmed as tolerable 
doses.
This study will be carried out in two stages. Phase I is a dose verification and PK assessment of products 
derived from two manufacturing processes and scales (500L-FMP and 2000L-FMP, FMP = Final 
Manufacturing Process) study and Phase II is an indication expansion study. All subjects will receive 
BGB-A317 until they have no evidence of continued clinical benefits, unacceptable toxicity, or 
withdrawal of informed consent in the discretion of the investigator. Paraffin-embedded tumor tissue 
will be collected for purpose of 
. However, if there is clinically appropriate biopsy 
lesion (biopsy is a must in specific cancer types in Phase II), a fresh tumor biopsy at baseline is strongly 
recommended. For these subjects, if possible, a biopsy for potential 
 after two cycles of treatment is strongly recommended. A written informed consent form (ICF)
is required for fresh tumor biopsies.
Subjects will be monitored for safety, anti-BGB-A317 antibodies and efficacy throughout the study. 
Radiological assessment of tumor-response status should be performed approximately every 9 weeks 
in the first year, then every 12 weeks thereafter.
A flow chart of the study design is presented in Appendix 1.
4.1.1
Phase I
Phase I study is a multicenter and open-label study including a dose verification study and a PK sub-
study of both manufacturing processes and scales of BGB-A317 (500L-FMP and 2000L-FMP)
Dose Verification study (using BGB-A317 produced by 500L-OMP,)
3-6 subjects will be enrolled firstly to assess DLT. 
•
If none of the 3-6 subjects experience a DLT at the setting dose, enrollment will be continued until 
about 20 subjects are enrolled in total.
•
3 additional subjects will be enrolled if a DLT is observed in 1 of 3 subjects; 2 additional subjects 
will be enrolled if a DLT is observed in 1 of 4 subjects; and 1 additional subject will be enrolled 
if a DLT is observed in 1 of 5 subjects. No additional subjects are required if a DLT is observed 
in 1 of 6 subjects.


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• 
If 2 or more subjects develop DLT among 3-6 subjects in the cohort, the dose level will be 
considered as exceeding the MTD. All investigators will be informed of such dose level. 
DLT assessments will be assessed among evaluable subjects in Cycle 1 (1-21 days) (refer to Section 
4.2 for detailed assessment standard). An evaluable subject is defined as one who has received at least 
80% of the first dose and completed all safety assessments required in Cycle 1, or any subject who 
has experienced DLT in Cycle 1. 
A Safety Monitoring Committee (SMC) will be established by the sponsor and investigators. SMC 
will recommend RP2D based on the safety and pharmacokinetics of BGB-A317, if necessary, and 
decide whether to add unscheduled doses for trial. 
Dose level 
According to the safety results of the dose-escalation trial on BGB-A317 conducted in Australia, this 
study will assess the safety and pharmacokinetic characteristics of flat-dose 200 mg Q3W in Chinese 
patients with advanced malignant solid tumors, and other doses may be further explored based on the 
safety result and necessity.  
Among the 3-6 subjects in the 200 mg Q3W cohort, if 2 or more subjects experience DLT in Cycle 1, 
such starting dose will be considered as exceeding the MTD, and a lower dose, such as 100 mg Q3W, 
will be assessed in 3-6 subjects. 
If dose 200 mg passes the DLT assessment, the cohort at such dose can be expanded to about 20 
subjects to further assess the safety, tolerability, pharmacokinetics and preliminary pharmacodynamic 
characteristics of BGB-A317. In order to continuously monitor safety, when the cohort has been 
expanded to 10 subjects and ı33% of them has experienced DLT within 21 days in Cycle 1, 
enrollment will be suspended, and an SMC meeting will be immediately held to discuss and 
determine whether such dose is safe. 
PK sub-study: It is a parallel and multiple doses study, which analyzes the PK and safety of BGB-
A317 of two manufacturing processes and scales (500L-FMP and 2000L-FMP). DLT and RP2D of 
all subjects are not assessed.  
Total 48 subjects (24 per arm) are planned to be enrolled to receive treatment of BGB-A317 of two 
manufacturing processes and scales (500L-FMP and 2000L-FMP). Cycle 1 lasts for 28 days, and Cycle 
2 and those thereafter last for 21 days. If there is any drop-out before the complete of the first treatment 
cycle (28 days) of intensive PK, additional subjects will be enrolled until for each arm there are total 
24 subjects complete the first treatment cycle. PK, safety and preliminary anti-tumor activity are 
analyzed between the two arms of patients. Schematic of the trial design is shown in Appendix 1. 
4.1.2 
Phase II 
To further assess the efficacy of BGB-A317 in Chinese patients with malignant solid tumors, once 
200 mg Q3W has been confirmed as a tolerable dose in Chinese population and determined as RP2D, 


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an indication-expansion study will be carried out among the following 11 arms of indications (the 
inclusion and exclusion criteria for each group of indications are shown in Section 5.1). Because of 
the changes of the manufacturing processes and scales during study, BGB-A317 of two 
manufacturing processes and scales (500L-OMP and 2000L-FMP) will be used for this Phase II 
study. 
Arm 1: 
Melanoma 
Arm 2: 
Non-small cell lung cancer (PD-L1 positive) 
Arm 3: 
Non-small cell lung cancer (PD-L1 negative) 
Arm 4: 
Gastric cancer 
Arm 5: 
Esophageal cancer 
Arm 6: 
Renal cell carcinoma 
Arm 7: 
Urothelial carcinoma 
Arm 8: 
Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) CRC 
Arm 9: 
Triple negative breast cancer, head and neck squamous cell carcinoma (HNSCC), 
small cell neuroendocrine carcinoma, or other tumors with MSI-H or dMMR 
Arm 10: Nasopharyngeal carcinoma (NPC) 
Arm 11: Hepatocellular Carcinoma (HCC), excluding mixed hepatocellular and 
cholangiocellular carcinoma. 
In the indication-expansion study, about 20 subjects are enrolled into each arm. For tumors that are 
difficult to enroll, the sponsor may early terminate the enrollment of subjects in this arm. The 
statistical basis for the number of subjects enrolled in each arm of phase II will be specified in the 
statistical plan. 
To fully assess the safety of BGB-A317, the contract research organization (CRO) and medical monitor 
from the sponsor will regularly review the safety data, and if necessary, will convene an interim SMC 
meeting. 
If subjects with a certain kind of tumor experience significant toxicities in the dose-extension stage, the 
investigator and the sponsor will discuss and decide whether to conduct an independent study or to 
terminate the study in such tumor indications. 
4.2 
Dose-Limiting Toxicity 
All toxicities or AEs will be graded according to the NCI-CTCAE Version 4.03. The occurrence of any 
of the following toxicities during Cycle 1 will be considered a DLT, if judged by the investigator to be 
possibly, probably or definitely related to study drug administration: 
Non-hematologic: 
1. Grade 4 or above toxicity.  


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2. Grade 3 toxicity (regardless of the duration), except for laboratory abnormalities, diarrhea, nausea, 
vomiting and asymptomatic biochemical abnormalities that improve to Grade 2 or lesser severity within 
3 days of best supportive care. 
3. Grade 3 adverse event of tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor) lasting > 7 days. 
4. Grade 3 or above irAE. 
Hematologic: 
1. Grade 4 neutropenia lasting > 7 days. 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] < 1000/mm3 with a single 
temperature of 38.3°C or a sustained temperature of 38°C for > 1 hour). 
3. Grade 3 neutropenia with infection. 
4. Grade 3 thrombocytopenia with bleeding. 
5. Grade 4 thrombocytopenia. 
6. Grade 4 anemia (life-threatening). 
And any other grade toxicity which requires premature withdrawal of the subject from the study upon 
discussion of investigator and sponsor. 
Subjects who received < 80% of the BGB-A317 infusion in Cycle 1 (eg, because the infusion had to be 
discontinued due to an infusion-related reaction) and did not experience a DLT will not be taken into 
account in the assessment of the overall DLT rate for the particular dose level cohort and will need to 
be replaced. 
Resumption of BGB-A317 administration for subjects experiencing DLTs may be permitted according 
to the criteria described in Section 4.3, if clinically appropriate, contingent on the restoration of the 
DLT to İ Grade 0-1 severity and interruption or delay of treatment for no more than 12 weeks. 
4.3 
Dose Modifications, Dose Delay and Missing Dose 
If an infusion cannot be administered at a scheduled visit, due to holiday, weekend, or other events (eg, 
AE), it must be administered as soon as possible. Each treatment cycle is 21 (f 3) days. Generally, 
subjects with infusion delays İ 10 days, the infusion/administration will always be performed as 
scheduled. For delays > 10 days, the infusion/administration will be performed according to the next 
scheduled dose (consulting with the sponsor for details if needed). Patients with infusion 
delays > 84 days (12 weeks) for Q3W schedule should discontinue treatment and enter the Follow-up 
Period with the exception of delays related to prophylactic vaccinations or after specific discussion and 
alignment between the investigator and medical monitor in settings where benefit/risk may justify 


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continued study therapy (eg, subject deriving clinical benefit who requires prolonged steroid taper for 
treatment of non-DLT irAEs). 
BGB-A317 will be withheld for irAEs according to dose modification described in Appendix 3. 
BGB-A317 dosing can be resumed for subjects whose adverse reaction has recovered to Grade 0-1 
within 12 weeks after last administration. Dose reduction is not allowed in this study. 
Two dosing delays due to toxicity will be permitted. In the event of a third occurrence of a toxicity 
which would require dosing delay, study therapy will be discontinued permanently after consultation 
with the sponsor. For subjects who have delayed administration for more than 6 weeks due to reasons 
other than treatment toxicity (eg, poor adherence), the investigator will decide whether to discontinue 
the patient’s participation after consultation with the medical monitor. 
BGB-A317 will be permanently discontinued for irAEs as specified in Appendix 3. In case a subject is 
benefiting from the study treatment while meeting the discontinuation criteria described, discussion 
between sponsor and investigator will be conducted to make a decision that will be in the best interest 
of the subject. 
Refer to Appendix 3 for more details about irAEs and management of such events. 
4.4 
End of Treatment Visit 
The End of Treatment (EOT) Visit should ideally occur İ 7 days after study drug is permanently 
discontinued, typically after progressive disease (PD) is documented. If routine laboratory tests (eg, 
hematology, clinical chemistry) is completed İ 7 days before the EOT Visit, these tests do not need 
to be repeated. The EOT Visit may occur later, eg, if study drug was initially held for AEs to then be 
permanently discontinued. If the EOT Visit cannot occur until 30 days (± 7 days) after last dose of 
study drug, the EOT Visit may also be used as the Safety Follow-up Visit. Tumor assessment is not 
required at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last 
assessment. 
See Section 4.5 for assessments to be performed for the EOT Visit. 
4.5 
Schedule of Assessment 
The schedule of Phase I study assessments is presented in Table 1, the pharmacokinetic sampling 
schedule for dose verification study of Phase I in Table 2 and the sampling schedule for PK sub-study 
of Phase I in Table 3. The schedule of Phase II study assessments is presented in Table 4. 


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Table 1. 
Schedule of Phase I Study Assessments. 
Phase I 
Screening1 
Treatment Period 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Cycle 1 
(21 days or 28 days)2 
Cycle 2 and 
subsequent 
cycles  
(except for 
Cycle 5) 
(21 days)  
Cycle 5 
(21 days) 
End of 
Treatment 
Visit3 
Days  
-28 ~ -1 
1 
2 
4 
(or 5) 
8 
15±1 
22±1 
1±3 
1±3 
2 
4 
(or 5) 
8 
15±1 
0 to 7 days 
30 ± 7 days 
after last 
dose 
Every 3 
months 
Informed consent6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic/Medical 
History/Prior 
Medications7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/Weight8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
Physical examination 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
ECOG performance 
status 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
12-lead ECG9 
x 
As clinically indicated 
x 
 
Ultrasonic 
echocardiography 
x 
As clinically indicated 
 


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Phase I 
Screening1 
Treatment Period 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Cycle 1 
(21 days or 28 days)2 
Cycle 2 and 
subsequent 
cycles  
(except for 
Cycle 5) 
(21 days)  
Cycle 5 
(21 days) 
End of 
Treatment 
Visit3 
Days  
-28 ~ -1 
1 
2 
4 
(or 5) 
8 
15±1 
22±1 
1±3 
1±3 
2 
4 
(or 5) 
8 
15±1 
0 to 7 days 
30 ± 7 days 
after last 
dose 
Every 3 
months 
Adverse events (serious 
adverse events)10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
 
Concomitant 
medication  
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
CBC with differential11 
x1 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x3 
x 
 
Serum Chemistry11 
x1 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x3 
x 
 
Coagulation 
Parameters12 
x 
As clinically indicated 
x 
 
Urinalysis11 
x1 
x 
 
 
x 
x 
x 
x 
x 
 
 
 
 
x3 
x 
 
Pregnancy test13 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function14 
x1 
x 
 
 
 
 
 
x14 
x 
 
 
 
 
 
x 
 
Anti-BGB-A317 
antibodies15 
  
x 
  
  
  
  
  
x15 
x 
  
  
  
  
 
x 
 


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Phase I 
Screening1 
Treatment Period 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Cycle 1 
(21 days or 28 days)2 
Cycle 2 and 
subsequent 
cycles  
(except for 
Cycle 5) 
(21 days)  
Cycle 5 
(21 days) 
End of 
Treatment 
Visit3 
Days  
-28 ~ -1 
1 
2 
4 
(or 5) 
8 
15±1 
22±1 
1±3 
1±3 
2 
4 
(or 5) 
8 
15±1 
0 to 7 days 
30 ± 7 days 
after last 
dose 
Every 3 
months 
Pharmacokinetics in 
Dose verification 
study16 
  
x 
x 
x 
x 
x 
 
x16 
x 
x 
x 
x 
x 
 
x 
 
Pharmacokinetics in 
PK sub-study17 
 
x 
x 
x 
x 
x 
x 
x17 
x 
x 
 
x 
x 
 
x 
 
HBV/HCV tests18 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor imaging19 
x 
  
  
  
  
  
  
x19 
x 
 
  
Study drug 
administration  
  
x 
  
  
  
  
  
x 
x 
  
  
  
  
  
  
  
Archival tumor 
tissues20 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Fresh tumor tissues21 
(additional consent 
required) 
x 
  
  
  
  
  
  
x21 
  
  
  
  
  
 
 
  
Survival status 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 


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Phase I 
Screening1 
Treatment Period 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Cycle 1 
(21 days or 28 days)2 
Cycle 2 and 
subsequent 
cycles  
(except for 
Cycle 5) 
(21 days)  
Cycle 5 
(21 days) 
End of 
Treatment 
Visit3 
Days  
-28 ~ -1 
1 
2 
4 
(or 5) 
8 
15±1 
22±1 
1±3 
1±3 
2 
4 
(or 5) 
8 
15±1 
0 to 7 days 
30 ± 7 days 
after last 
dose 
Every 3 
months 
Pulmonary function 
tests22 
x 
As clinically indicated 
 
 
Abbreviations: aPTT, activated partial thromboplastin time; CBC, complete blood count; CR, complete response; CT, computed tomography; DLT, dose-limiting 
toxicity; ECG, Electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; FMP, final manufacture process; FT3, free T3; FT4, 
free T4; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized 
ratio; MRI, magnetic resonance imaging; PD, progressive disease; PK, pharmacokinetics; PR, partial response; PT, prothrombin time; TSH, thyroid-stimulating 
hormone. 
Note: 
1. All tests (except collection of fresh biopsy samples) in the screening period should be performed within 28 days prior to first dosing. If hematology, serum 
chemistry, urinalysis, and thyroid function tests are completed within 3 days before C1D1 administration, it is not necessary to conduct these tests again 
on C1D1. 
2. The duration of the first cycle for the first 20 subjects will be 21 days, and DLT will be conducted in this period; the duration of the first cycle for the rest 
48 subjects will be 28 days, which will be performed for the PK analyses of products derived from two manufacturing processes and scales (500L-FMP 
vs 2000L-FMP), 
3. The End of Treatment Visit is conducted when the investigator determines that the study drug will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End of Treatment Visit, it is not necessary to assess again. Tumor assessment is not 
required at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last assessment. 
4. The Safety Follow-Up visit should be conducted 30 days (± 7 days) after the last dose of study therapy or before the initiation of a new treatment, whichever 
comes first. Subjects who are discontinued from the study due to an unacceptable drug-related adverse event will be followed until the resolution of the 
adverse event to Grade 0-1 or stabilization or until beginning of a new therapy for their cancer, whichever occurs first. The EOT Visit at which a response 
assessment showed PD, resulting in patient discontinuation from treatment, may be used as the Safety Follow-up Visit if it occurred 30 days (± 7 days) 
after the last dose of study drug. 


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5. Following completion of the treatment and Safety Follow-up phases of the study, every effort should be made to follow up all subjects for their survival 
status until subject death or termination by the sponsor.  
6. Written consent must be obtained prior to performing any protocol specific procedure. Results of an imaging test performed as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 28 days prior to Cycle 1 Day 1). Assign 
subject number when the study informed consent is signed. 
7. Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Date of last prior cancer 
treatment must be documented. Radiographic studies performed prior to study entry may be collected for review by the investigator. Report complete 
medication history for 30 days prior to the screening visit (Visit 1).  
8. Vital signs include temperature, pulse, respiratory rate and blood pressure. 
9. Electrocardiogram (12-lead ECG) should be performed at the following time points: within 28 days prior to Cycle 1 Day 1 (screening period) and the 
evaluation result is used as the baseline; and at the Safety Follow-up visit. Additional ECGs may be performed if clinically indicated (refer to Section 
8.3.3).  
10. Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 4.03 (NCI-CTC, June 2010). Characterization of 
toxicities will include severity, duration, and time to onset. All adverse events, including SAEs, will be collected as described in Section 10.6. At the end 
of treatment, ongoing adverse events considered related to study treatment will be followed until the event has resolved to baseline or grade İ 1, the event 
is assessed by the investigator as stable, the patient is lost to follow up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the adverse event.  
11. Routine laboratory tests (eg, CBC with differential; serum chemistry; urinalysis) should be performed by the local study site laboratory or their contract 
laboratory. CBC, serum chemistry and urinalysis should be collected up to 3 days prior to Day 1 of any Cycle. 
12. PT/INR and aPTT should be collected at Screening and at the Safety Follow-up Visit after discontinuation of study therapy. When clinically indicated, 
coagulation parameters should be assessed. PT/INR and aPTT will be analyzed by the local study center’s laboratory. 
13. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days of the first investigational 
product administration). Subsequent examinations should be implemented if clinically indicated. Serological tests are not required if subsequent urine 
pregnancy test is negative.  
14. FT3, FT4 and TSH are analyzed in the screening period and up to 3 days before dosing on Day 1 every cycle during the first 17 cycles, approximately 
every 2 cycles thereafter, and at the Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory.  
15. Dose verification study: Blood for anti-BGB-A317 antibodies should be collected within 60 minutes before infusion on Day 1 in Cycle 1, 2, 3, 5, 7, 9, 
13, 17, about every 8 cycles thereafter; PK sub-study: Blood for anti-BGB-A317 antibodies should be collected within 60 minutes before infusion on 
Day 1 in Cycle 1, 2, 3, 5, 7, 9, 17, about every 8 cycles thereafter; and blood collection for assessing anti-BGB-A317 antibodies in both studies at the 
Safety Follow-Up Visit are required. In subjects who discontinue study therapy before 6 months, every effort should be made to analyze anti-BGB-A317 
antibodies approximately 6 months after the first dose. Analysis will be performed by the central laboratory designated by the sponsor.  
16. Applicable to the first 20 subjects in the dose verification study. Refer to Table 2 for details on timing of pharmacokinetics sample collection. Procedures 
for collection of samples are described in the Lab Manual. 
17. Applicable to the rest 48 subjects in the PK sub-study comparing products derived from two manufacturing processes and scales (500L-FMP and 2000L-
FMP). Refer to Table 3 for details on timing of pharmacokinetics sample collection. Procedures for collection of samples are described in the Lab Manual. 
18. Testing will be performed by the local laboratory at Screening. It includes Hepatitis C virus (HCV) antibody, HBsAg and HBcAb. All HbsAg or HCV 
positive subjects at screening must pass the test of Hepatitis B virus (HBV) DNA titres (< 2500 copies [cps]/mL or 500 IU/mL) and HCV RNA (below 
the lower limit of the assay) before being enrolled to exclude active hepatitis B or hepatitis C virus infection. Subjects with positive HBV DNA at screening 


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should be repeated periodically during the study if clinically indicated.
19. Tumor imaging (either contrast-enhanced CT or MRI) will be performed within 28 days prior to enrollment, and while on study approximately every 9
weeks (±7 days) in the first 17 cycles, approximately every 12 weeks (±7 days) thereafter. If tumor imaging is completed within 6 weeks before the End
of Treatment Visit, it is not necessary to assess again at the End of Treatment Visit. The same imaging technique should be used in a subject throughout 
the study. After first documentation of response (CR or PR), imaging performed at the next scheduled time point will be used for response confirmation. 
Progressive disease (PD) suspected as pseudo-progression needs to be confirmed in a subsequent imaging at least 4 weeks later or at the next scheduled 
time point (but not to exceed 12 weeks), before discontinuation of study treatment. Subjects who stop treatment prior to documentation of disease
progression will undergo repeated imaging every 9 weeks for tumor response assessments as described in Section 8.3.6 and Section 8.6.1.
20. Archival tumor tissue must be collected for purpose of 
(this should be emphasized in the subject’s informed consent). See Section 8.9.
21. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 42 days before starting treatment) is mandatory (written 
subject’s consent is required prior to fresh tumor biopsies). Baseline or paired fresh tumor biopsies are strongly recommended for potential predictive, 
prognostic, or 
 in subjects with readily accessible tumor lesions and who consent to the biopsies. Subjects who 
consent to paired biopsies should undergo biopsies after two cycles (approximately on Cycle 3 Day 1). See Section 8.9.
22. Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant respiratory symptoms unrelated to underlying 
cancer will have pulmonary function testing which may including but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period, to assist the determination of suitability for enrollment on the study.


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Table 2. 
Pharmacokinetic Sampling and ADA Test for dose verification study of Phase I 
 
Phase I 
Week 
Day 
  
PK sampling Time 
Points 
ADA Test Time 
Points 
Treatment 
Period 
Cycle 1 
 
1 
1 
  
  
  
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
˄21 daysˈDLT 
period˅ 
Postdose 
End of infusion to 30 
mins1 
 
  
  
90 mins2 
 
  
  
360 mins3 
 
  
2 
  
24 hours3 
 
  
4˄or 5˅ 
  
72˄or 96˅hours3 
 
  
8 
  
  
 
  
15 + 1 
  
  
 
Cycle 2˄21 days˅ 
 
4 
22 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 3˄21 days˅ 
 
7 
43 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 5˄21 days˅ 
 
 
 
13 
84 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
  
Postdose 
End of infusion to 30 
mins1 
 
  
  
90 mins2 
 
  
  
360 mins3 
 
2 
  
24 hours3 
 
4˄or 5˅ 
  
72˄or 96˅hours3 
 
8 
  
  
 
15 + 1 
  
  
 


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Cycle 6˄21 days˅ 
 
16 
106 + 3 
Predose 
-60 min to 0 hour 
 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 7˄21 days˅ 
 
          19 
127 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 9˄21 days˅ 
 
          25 
169 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 13˄21 days˅ 
 
         37 
253 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
 
Postdose 
End of infusion to 
30 mins1 
 
Cycle 17˄21 days˅ 
 
         49 
337 + 3 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
 
Postdose 
End of infusion to 
30 mins1 
 
 
Every 8 cycles 
Every 24 
weeks 
 
Predose 
-60 mins to 0 hour 
-60 mins to 0 hour 
Postdose 
End of infusion to 
30 mins1 
 
Safety 
Follow-up 
(30 ± 7 days after last 
dose) 
 
  
  
  
 
Abbreviations: ADA, anti-drug antibody; DLT, dose limiting toxicity; irAE, immune-related adverse event; PK, pharmacokinetics. 
Please note: Actual drug dosing and PK sampling times must be documented by the study center and will be captured in the database. 
1. Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection 
for PK should be from a different site. 
2. Window: ± 20 minutes. 
3. Window: ± 1 hour. 
If a subject presents with a DLT or any grade 3 or above irAE (refer to Appendix 3), additional blood PK samples will be taken to determine the serum 
concentration of BGB-A317. 


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Table 3. 
Pharmacokinetic Sampling and ADA Test Schematic of PK Sub-study of Phase I 
Phase I 
Week 
Days 
 
Timepoints of Blood 
sampling 
Timepoints of ADA 
analyses 
Treatment 
Period 
Cycle 1 
(28 days) 
1 
1 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
End of infusion 
 
End of infusion 
 to 30 min1 
Day 22 
3 hours2 
 
6 hours2 
 
Day 23 
 
Day 44 
 
Day 84 
 
Day 154  
 
Day 22 4 
 
Cycle 2˄21 days˅ 
5 
29 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
Cycle 3˄21 days˅ 
 
8 
50 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
End of infusion 
 
End of infusion 
 to 30 min1 
 
Cycle 25˄21 days˅ 
14 
92 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
End of infusion 
 
End of infusion 
 to 30 min1 
 
Day 23 
 
Day 84 
 
Day 154 
 
Cycle 6˄21 days˅ 
17 
113 + 3 
Pre-dose 
-60 min to 0 min 
 
Cycle 7˄21 days˅ 
20 
134 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
End of infusion 
End of infusion 
 to 30 min1 
 
Cycle 9˄21 days˅ 
26 
176 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 


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End of infusion 
End of infusion 
 to 30 min1 
 
Cycle 17˄21 days˅ 
50 
344 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
Cycle 25˄21 days˅ 
74 
512 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
Cycle 33˄21 days˅ 
98 
680 + 3 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
Every 8 cycles 
Every 24 
weeks 
 
Pre-dose 
-60 min to 0 min 
-60 min to 0 min 
Safety 
Follow-up  
(30 + 7 days after last dose) 
 
  
  
  
 
Abbreviations: ADA, anti-drug antibody; irAE, immune-related adverse event; PK, pharmacokinetics. 
Please note: Actual drug dosing and PK sampling times must be documented by the study center and will be captured in the database. 
1. Sample collection must be from opposite arm to that used for study drug infusion. If drug was administered via a central venous catheter, sample collection 
for PK should be from a different site. 
2. Window: ±20 minutes. 
3. Window: ±2 hours. 
4. Window: ±1 day  
If a subject presents with an any grade 3 or above irAE (refer to Appendix 3), additional blood PK samples will be taken to determine the serum concentration of 
BGB-A317. 
 
 
 


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Table 4. 
Phase II Study Assessments and Procedure Schedule 
Phase II 
Pre-
screening 
Screening1 
Treatment Period 
Safety 
Follow-up3 
Survival 
Follow-up4 
Cycle 1 
Cycle 2 and 
Subsequent 
cycles 
End of 
Treatment 
Visit2 
(21 days, DLT 
assessment 
period) 
(Every 21 days) 
Days 
56 days 
before 
screening 
-28 ~ -1 
1±3 
1±3 
0 to 7 days 
30 ± 7 days 
after last dose 
Every 3 
months 
Informed consent5 
x 
x 
 
 
 
 
 
Inclusion/exclusion criteria 
 
x 
 
 
 
 
 
Demographic/Medical 
History/Prior Medications6 
x 
x 
 
 
 
 
 
Vital signs/Weight7 
 
x 
x 
x 
x 
x 
 
Physical examination 
 
x 
x 
x 
 
x 
 
ECOG performance status 
 
x 
x 
x 
 
x 
 
12-lead ECG8 
 
x 
As clinically indicated 
x 
 
Adverse events 
(serious adverse events)9 
x 
x 
x 
x 
x 
x 
 
Concomitant medications 
 
x 
x 
x 
x 
x 
 
CBC with differential10 
 
x1 
x 
x 
x2 
x 
 
Serum chemistry10 
 
x1 
x 
x 
x2 
x 
 
Coagulation parameters11 
 
x 
As clinically indicated 
x 
 
Urinalysis10 
 
x1 
x 
x 
x2 
x 
 
Pregnancy test12 
 
x 
 
 
 
 
 


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Phase II 
Pre-
screening 
Screening1 
Treatment Period 
Safety 
Follow-up3 
Survival 
Follow-up4 
Cycle 1 
Cycle 2 and 
Subsequent 
cycles 
End of 
Treatment 
Visit2 
(21 days, DLT 
assessment 
period) 
(Every 21 days) 
Days 
56 days 
before 
screening 
-28 ~ -1 
1±3 
1±3 
0 to 7 days 
30 ± 7 days 
after last dose 
Every 3 
months 
Thyroid function13 
 
x1 
x  
x13 
 
x 
 
Anti-BGB-A317 antibodies14 
 
 
x 
x14 
 
x 
 
Pharmacokinetics15 
 
 
x 
x15 
 
x 
 
HBV/HCV tests16 
 
x 
 
 
 
 
 
Tumor imaging17 
 
x 
 
x17 
x 
 
 
Study drug administration 
 
 
x 
x 
 
 
 
Archival tumor tissues18 
(additional consent required) 
x 
x 
 
 
 
 
 
Fresh tumor tissues19 
(additional consent required) 
x 
x 
 
x19 
 
 
 
Blood samples required for 
MSI/MMR mutation testing20 
x 
x 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
x 
Pulmonary function tests21 
 
x 
As clinically indicated 
 
 
 Abbreviations: aPTT, activated partial thromboplastin time; CBC, complete blood count; CR, complete response; CT, computed tomography; DLT, dose-
limiting toxicity; ECG, Electrocardiogram; ECOG= Eastern Cooperative Oncology Group; EOT, end of treatment; FT3, free T3; FT4, free T4; HBcAb, hepatitis 
B core antibody; HBsAg, hepatitis B surface antigen;.HBV=Hepatitis B virus; HCV=Hepatitis C virus; INR, international normalized ratio; MMR, mismatch 
repair; MRI, magnetic resonance imaging; MSI, microsatellite instability; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events; PD, progressive disease; PR, partial response; PT, prothrombin time; TSH, thyroid-stimulating hormone. 
 


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Note: 
1. All tests (except collection of fresh biopsy samples) in the screening period should be performed within 28 days prior to 1st dosing. If hematology, serum 
chemistry, urinalysis, and thyroid function are completed within 3 days before C1D1 administration, it is not necessary to conduct these tests again on C1D1. 
2. The End of Treatment Visit is conducted when the investigator determines that the study drug will no longer be used. If routine laboratory tests (eg, hematology, 
serum chemistry) are completed within 7 days before the End of Treatment Visit, it is not necessary to assess again. Tumor assessment is not required at the 
End of Treatment Visit provided that İ 6 weeks have passed since the last assessment. 
3. The Safety Follow-Up visit should be conducted 30 days (± 7 days) after the last dose of study therapy or before the initiation of a new treatment, whichever 
comes first. Subjects who are discontinued from the study due to an unacceptable drug-related adverse event will be followed until the resolution of the adverse 
event to Grade 0-1 or stabilization or until beginning of a new therapy for their cancer, whichever occurs first. The EOT Visit at which a response assessment 
showed PD, resulting in patient discontinuation from treatment, may be used as the Safety Follow-up Visit if it occurred 30 days (± 7 days) after the last dose 
of study drug. 
4. Following completion of the treatment and Safety Follow-up phases of the study, every effort should be made to follow up all subjects for their survival status 
until subject death or termination by the sponsor. 
5. Written consent must be obtained prior to performing any protocol specific procedure. Results of an imaging test performed as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 28 days prior to Cycle 1 Day 1). Assign subject 
number when the study informed consent is signed. 
6. Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment. Date of last prior cancer treatment 
must be documented. Radiographic studies performed prior to study entry may be collected for review by the investigator. Report complete medication history 
for 30 days prior to the screening visit (Visit 1).  
7. Vital signs include temperature, pulse, respiratory rate and blood pressure. 
8. Electrocardiogram (12-lead ECG) should be performed at the following time points: within 28 days prior to Cycle 1 Day 1 (screening period) and the evaluation 
result is used as the baseline; and at the Safety Follow-up visit. Additional ECGs may be performed if necessary (refer to Section 8.3.3).  
9. Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 4.03 (NCI-CTC, June 2010). Characterization of toxicities 
will include severity, duration, and time to onset. All adverse events, including SAEs, will be collected as described in Section 10.6. At the end of treatment, 
ongoing adverse events considered related to study treatment will be followed until the event has resolved to baseline or grade ≤ 1, the event is assessed by the 
investigator as stable, the patient is lost to follow up, the patient withdraws consent, or it has been determined that study treatment or participation is not the 
cause of the adverse event.  
10. Routine laboratory tests (eg, CBC with differential; serum chemistry; urinalysis) should be performed by the local study site laboratory or their contract 
laboratory. CBC, serum chemistry and urinalysis should be collected up to 3 days prior to Day 1 of any Cycle. 
11. PT/INR and aPTT should be collected at Screening and at the Safety Follow-up Visit after discontinuation of study therapy. When clinically indicated, 
coagulation parameters should be assessed. PT/INR and aPTT will be analyzed by the local study center’s laboratory.  
12. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days of the first investigational product 
administration). Subsequent examinations should be implemented if clinically indicated. Serological tests are not required if subsequent urine pregnancy test 
is negative.  
13. FT3, FT4 and TSH are analyzed in the screening period and within 3 days before dosing on Cycle 1 Day 1, Cycle 2 Day 1 and Day 1 of every 2 cycles 
thereafter, and at the Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory.  


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14. Blood for anti-BGB-A317 antibodies should be collected within 60 minutes before infusion on Day 1 in Cycle 1, 2, 5, 9, 13, 17, 25, about every 8 cycles 
thereafter, and at the Safety Follow-Up Visit. Analysis will be performed by the central laboratory designated by the sponsor.
15. Pharmacokinetics samples will be collected 60-minute predose and about 30-minute postdose on Day 1 of Cycle 1, 2, 5, 9, 13, 17, 25, about every 8 cycles 
thereafter, and at the Safety Follow-Up Visit. Procedures for collection of samples are described in the Lab Manual.
16. Testing will be performed by the local laboratory at Screening. It includes Hepatitis C virus (HCV) antibody, HBsAg and HBcAb. All positive HbsAg at 
screening or Arm 11 subjects must pass the test of Hepatitis B virus (HBV) DNA titres (< 2500 copies [cps]/mL or 500 IU/mL) before being enrolled; Positive 
HCV antibody subjects must pass the HCV RNA test (below the lower limit of the assay) before being enrolled (section 5.2). Subjects with positive HBV 
DNA at screening should be repeated periodically during the study if clinically indicated.
17. Tumor imaging (either contrast-enhanced CT or MRI, preferentially CT) will be performed within 28 days prior to enrollment, and while on study 
approximately every 9 weeks (±7 days) in the first 17 cycles, approximately every 12 weeks (±7 days) thereafter. If tumor imaging is completed within 6 
weeks before the End of Treatment Visit, it is not necessary to assess again at the End of Treatment Visit. The same imaging technique should be used in a 
subject throughout the study. After first documentation of response (CR or PR), imaging performed at the next scheduled time point will be used for response 
confirmation. PD suspected as pseudo-progression needs to be confirmed in a subsequent imaging at least 4 weeks later or at the next scheduled time point 
(but not to exceed 12 weeks), before discontinuation of study treatment. Subjects who stop treatment prior to documentation of disease progression will undergo 
repeated imaging every 9 weeks for tumor response assessments as described in Section 8.3.6 and Section 8.6.1.
18. Archival tumor tissue must be collected for purpose of 
 (this should be stressed in the subject’s informed consent). For subjects to be enrolled 
in Arm 8, if their MMR/MSI-mutation status is unknown, corresponding tests must be performed during prescreening period - 56 days (8 weeks) prior to 
screening period. If archival tissue samples have been collected during pre-screening period, no additional collection is required during screening period. See
Section 8.9.
19. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 42 days before treatment starts) is mandatory (written subject’s 
consent is required prior to fresh tumor biopsies). For subjects to be enrolled in Arm 8, if their MMR/MSI-mutation status is unknown and subjects do not 
have archival tumor tissues, fresh tumor biopsy samples must be collected during pre-screening period - 56 days (8 weeks) prior to screening for corresponding 
tests. If sufficient number of tumor tissue samples have been collected during pre-screening period, no additional collection is required during screening period. 
Baseline or paired fresh tumor biopsies are strongly recommended for potential predictive, prognostic, or 
 in subjects 
with readily accessible tumor lesions and who consent to the biopsies. If feasible, subjects in Arm 1 must undergo baseline tumor biopsy (biopsy is not required 
for subjects who provide archival tissue samples obtained within 12 weeks before treatment starts). Subjects who consent to paired biopsies should undergo 
biopsies after two cycles (approximately on Cycle 3 Day 1). See Section 8.9.
20. For subjects to be enrolled in Arm 8, if their MSI/MMR-mutation status is unknown, blood samples must be collected during pre-screening period - 56 days,
(8 weeks) prior to screening period, for MSI/MMR-mutation pre-screening. See Section 8.9.
21. Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant respiratory symptoms unrelated to underlying cancer 
will have pulmonary function testing which may including but is not limited to spirometry and assessment of diffusion capacity done during the screening 
period, to assist the determination of suitability for enrollment on the study.


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5. 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects eligible for study must meet all following criteria: 
1. Voluntarily signed informed consent form for the study 
2. Aged ı 18 years on the day of signing informed consent  
3. Subjects must have a histologically or cytologically confirmed advanced or metastatic tumor 
(unresectable), have had progression or intolerability since last standard anti-tumor treatment, 
or have no available standard treatment or have refused standard therapy, as well as meet 
following requirements for tumor types in the corresponding stages: 
a) 
Phase I: Including but not limited to non-small cell lung cancer (NSCLC), melanoma, 
gastric cancer, esophageal carcinoma, ovarian cancer, urothelial carcinoma, head and 
neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC) and triple negative 
breast cancer (TNBC) 
b) Phase II: 
• Arm 1 - melanoma, excluding uveal or ocular melanoma 
• Arm 2 - NSCLC (PD-L1 positive) and Arm 3—NSCLC (PD-L1 negative): 
i. PD-L1 expression must be tested prospectively at the central laboratory designated 
by the sponsor (refer to Section 8.9 for the definition of PD-L1 positive) 
ii. Subjects with known EGFR mutations (EGFR detection methods and results need 
to be approved by the study site) are excluded; subjects with non-squamous 
carcinoma of unknown EGFR mutations must be tested prospectively at the central 
laboratory designated by the sponsor; and if the EGFR mutations are positive, the 
subjects are excluded 
iii. Subjects with known ALK gene rearrangements are excluded 
• Arm 4 - gastric cancer: gastric adenocarcinoma (including gastroesophageal junction 
adenocarcinoma) 
• Arm 5 - esophageal carcinoma: esophageal squamous cell carcinoma 
• Arm 6 - RCC: RCC containing the component of clear cell  
• Arm 7 - urothelial carcinoma: locally advanced or metastatic urothelial transitional cell 
carcinoma (including renal pelvis, ureter, bladder and urethra) 
• Arm 8 - MSI-H or dMMR CRC: subjects with documented MSI-H or dMMR are 
eligible if tumor samples and blood samples are provided for retrospective analyses at 
the central laboratory designated by the sponsor; subjects with unknown MSI or MMR 
status must be tested prospectively before enrollment at the central laboratory 
designated by the sponsor (refer to Section 8.1) 
• Arm 9 - TNBC, HNSCC, small cell neuroendocrine carcinoma (SCNEC) or other 
tumors with known MSI-H or dMMR (subjects with documented MSI-H or dMMR are 


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eligible if tumor samples and blood samples are provided for retrospective analyses at 
the central laboratory designated by the sponsor, refer to Section 8.9 for detection 
methods)
•
Arm 10 - nasopharyngeal carcinoma (NPC): WHO type II-III (differentiated-non-
keratinizing type and undifferentiated-non-keratinizing type)
•
Arm 11 - Child-Pugh Grade A hepatocellular carcinoma (See Appendix 2, excluding 
mixed hepatocellular and cholangiocellular carcinoma
4.
Subjects must be able to provide archival tumor tissues (paraffin blocks or at least 10 unstained 
tumor specimen slides; subjects may be permitted to be enrolled on a case-by-case basis after 
discussion with medical monitors from the sponsor if less than 10 unstained slides are provided) 
or newly obtained tumor tissue that has not been radiated, and relevant pathological reports. 
Refer to Section 8.9 for the requirements for tumor samples
For subjects who have easily accessible lesions and consent to biopsies, fresh baseline or paired 
tumor biopsies are strongly recommended for 
. For Arm 1 (melanoma) in 
Phase II, tumor biopsies must be performed at baseline if feasible (biopsy is not required for 
subjects who provide archival tissue samples obtained within 12 weeks before treatment starts). 
Subjects may be permitted to enroll on a case-by-case basis after discussion with the medical 
monitors if biopsy specimens are not available 
5.
Subjects must have at least one measurable lesion as defined per RECIST Version 1.1 
6.
Eastern Cooperative Oncology Group (ECOG) performance status of İ1
7.
Life expectancy ı12 weeks
8.
Subject must have adequate organ function as indicated by the following laboratory values
a)
Absolute neutrophil count (ANC) ı1.5h109/L
b)
Platelets ı75h109/L
c)
Hemoglobin ı90 g/L
d)
Serum creatinine İ1.5 X upper limit of normal (ULN).
e)
Serum total bilirubin İ 1.5 X ULN (total bilirubin must be < 3 X ULN for subjects with 
Gilbert’s syndrome) 
f)
International Normalized Ratio (INR) or Prothrombin Time (PT) İ1.5 X ULN 
g)
Activated Partial Thromboplastin Time (aPTT) İ1.5 X ULN
h)
Aspartate transaminase (AST) and alanine aminotransferase (ALT) İ 2.5 X ULN, or 
AST and ALT İ 5 X ULN for subjects with liver metastases or HCC
9.
Female subjects are eligible to enter and participate in the study if they are of:
a)
Non-childbearing potential (ie, physiologically incapable of becoming pregnant), 
including any female who
•
Has had a hysterectomy
•
Has had a bilateral oophorectomy
•
Has had a bilateral tubal ligation or is post-menopausal (total cessation of menses 


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for ı1 year) 
b) Childbearing potential: 
• 
must be willing to use a highly effective method of birth control for the duration of 
the study, and for at least 120 days after the last dose of BGB-A317 (see 
Appendix 5), and have a negative urine or serum pregnancy test within 7 days of 
the first dose of study drug 
10. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for at least 120 days after the last dose of BGB-A317 (see Appendix 5) 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria must be excluded from this study: 
1. History of severe hypersensitivity reactions to other monoclonal antibodies 
2. Prior malignancy active within the previous 2 years except for tumor under investigation in this 
trial, cured or locally curable cancers that have been apparently cured, such as basal or squamous 
cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast. 
3. Prior therapies targeting programmed cell death-1 (PD-1) or PD-L1 
4. Active brain or leptomeningeal metastases. Subjects with brain metastases are permitted if they 
are asymptomatic, eg, diagnosed incidentally at screening by brain imaging, or subjects with 
previously treated brain metastases that are asymptomatic at screening, radiographically stable and 
not requiring steroid medications for at least 4 weeks prior to the first administration of study 
treatment 
5. Subjects with active autoimmune diseases or history of autoimmune diseases or immunodeficiency 
that may relapse should be excluded. Subjects with following diseases are allowed to be enrolled 
for further screening: type I diabetes, hypothyroidism managed with hormone replacement therapy 
only, skin diseases not requiring systemic treatment (such as vitiligo, psoriasis or hair loss), or 
diseases not expected to recur in the absence of external triggering factors 
6. Subjects should be excluded if they have a condition requiring systemic treatment with either 
corticosteroids (prednisone > 10 mg/day or equivalents) or other immunosuppressive medications 
within 14 days of study drug administration 
Note: Adrenal replacement doses of prednisone İ 10 mg/day or equivalents are permitted in the 
absence of active autoimmune disease; subjects are permitted to use topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic absorption); a brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted 
7. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic 
diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.  
8. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral 
therapy, including tuberculosis infection, etc. Antiviral therapy is permitted for subjects with HCC 
9. With uncontrollable pleural effusion, pericardial effusion or ascites requiring repeated drainage. 
10. Significant cardiovascular diseases, such as heart failure of New York Heart Association cardiac 
disease Class II or greater, myocardial infarction within the previous 3 months, unstable 
arrhythmias or unstable angina 


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Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, 
or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate 
11. With history of alcohol or drug abuse or dependence 
12. With known history of human immunodeficiency virus (HIV) 
13. Subjects with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV 
DNA ı 500 IU/mL (2500 copies/mL), or active hepatitis C should be excluded. Subjects with 
inactive hepatitis B virus surface antigen (HBsAg) carriers, active HBV infection with sustained 
viral suppression (HBV DNA < 500 IU/mL [2500 copies/mL]), and subjects whose hepatitis C 
has been cured can be enrolled 
14. Underlying medical conditions that, in the investigator’s opinion, will make an administration of 
study treatment hazardous or obscure the interpretation of toxicity determination or adverse events; 
or insufficient compliance during the study according to investigator’s judgment 
15. Prior chemotherapy, radiotherapy, immunotherapy or any investigational therapies (including 
Chinese herbal medicine and Chinese patent medicines) used to control cancer must have been 
completed at least 2 weeks before the 1st study drug administration, and all adverse events have 
returned to either baseline or grade 0~1 according to CTCAE version 4.03 (except for alopecia) 
16. Use of any live or attenuated vaccines within 4 weeks (28 days) prior to initiation of study therapy 
17. Major surgical procedure (Grade 3 or 4) within the past 4 weeks (28 days) prior to study drug 
administration 
18. Prior allogeneic or solid organ transplantation 
5.3 
Other Eligibility Criteria Consideration 
To assess any potential impact of subject eligibility on safety, the investigator must refer to the IB for 
detailed information regarding warnings, precautions, contraindications, AEs, and other significant data 
pertaining to the investigational product being used in this study. 
For Exclusion Criterion 14, the investigators can discuss with medical monitors from the sponsor to 
decide whether or not to exclude subjects. 
During the screening period, repeated measurements may be performed for ineligible laboratory tests, 
based on the investigator's judgment and with the consent of the sponsor's medical monitor. For subjects 
that repeat their tests based on clinical status, the most up-to-date measurements should be evaluated 
during the screening period. If the most recent measurement is still unacceptable, the subject can be 
recorded as failed screening. 
Screening failed patients may be re-screened under special circumstances, depending on the 
investigator's decision and with the consent of the sponsor's medical monitor. 


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5.4 
Subject Restrictions 
The following restrictions may affect subject participation in this study: 
x 
The investigator must be informed as soon as possible about any medications taken from the time 
of screening until the subject is discharged from the study  
5.5 
Subject Discontinuation (Dropout/Withdrawal) 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn by the 
investigator or the sponsor if he/she violates the study plan or for administrative and/or other safety 
reasons. The investigator or study coordinator must notify the sponsor immediately when a 
subject/patient has been discontinued/withdrawn due to an adverse experience. When a subject/patient 
discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study 
visit should be performed at the time of discontinuation. Any adverse experiences which are present at 
the time of discontinuation/withdrawal should be followed in accordance with the safety requirements 
in Section 8.4. 
The reason for discontinuation of the subject will be recorded in the electronic case report form (eCRF). 
These reasons include: 
x Withdrawal of consent by the subject, 
x Termination of the study by the sponsor,  
x Pregnancy, 
x Any AE that compromises the subject to participate in the study, 
x The investigator or sponsor determines it is in the best interest of the subject, 
x Intercurrent illness, 
x Confirmed progression of disease at any time during the study (refer to Section 8.6.1). 
x Need of prohibited medication, 
x Lack of compliance with the study and/or study procedures (eg, administration instructions, 
study visits),  
x Significant deviation from the protocol by the investigator without the consent of the sponsor. 
5.6 
Medical Treatment of Subject after Treatment Period Completion 
Patients who complete their Treatment Period (2 years after their first dose) may continue to receive 
therapy. The investigator will evaluate whether continued treatment is in the best interest of the patient 
based on clinical benefit and potential risk. Continuation of therapy beyond 2 years must be explicitly 
approved by the sponsor, and will be contingent on the continued availability of BGB-A317 drug 
product. The assessment and procedures schedule will remain the same as during the Treatment Period. 
5.7 
Reinitiation of Study Therapy for Subjects in Follow-up Period 
If patients have confirmed CR, PR, or SD after 2 years of BGB-A317, the treatment can be stopped if 
the patient wishes. The decision should be based on the investigator’s evaluation, with the patient’s 
clinical benefit and risk taken into consideration. A treatment-interruption informed consent form 


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must be signed by patients who stop treatment. The investigator should notify the sponsor that 
treatment will be stopped prior to the event. In such a case, the study assessments and procedures will 
be performed every 12 weeks (in conjunction with repeat radiographic imaging, as described in 
Section 8.6) rather than every cycle. If a patient has evidence of PD within 1 year of treatment 
interruption, the investigator can consider restarting BGB-A317 therapy after discussion with the 
sponsor, contingent on the continued availability of BGB-A317 drug product. 
5.8 
End of Study 
The end of study is defined as the date when the last patient completes the study. A patient’s 
individual completion is defined as the date of one of the following, whichever occurs first: 
x 
Completion of study treatment at 2 years since first dose 
x 
Completion of the Safety Follow-up Visit if study treatment is discontinued 
x 
Condition that precludes completion of the Safety Follow-up Visit, including death, 
withdrawal of consent, or loss to follow-up 
5.9 
Drug Supply for Patients Who are Still on Treatment at End of Study 
After the study finishes, the sponsor will continue to supply BGB-A317 to patients, free of charge, 
through either an extension study or an independent drug supply project to be determined by the 
sponsor. These programs will be contingent on the continued availability of drug product. Patients 
will receive BGB-A317 until intolerable toxicity, disease progression, withdrawal of informed 
consent, or unfavorable risk/benefit assessment at the discretion of the investigator. 
All assessments defined as part of the End of Treatment Visit must be performed before a patient may 
enter one of these programs. 


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6. 
STUDY TREATMENTS 
6.1 
Description of Investigational Product 
BGB-A317 is a monoclonal antibody drug which is formulated for IV injection in a single-use vial 
(20R glass, USP type I) containing a total of 100 mg antibody in 10 mL of isotonic solution. See Section 
6.5 below for handling and product storage conditions. The drugs of 3 manufacturing processes and 
scales that are used in this clinical trial are tabulated as below in Table 5. 
Table 5. 
Product information about three manufacturing processes and scales 
Name of trial 
drug 
Process/Scale 
Utility in This Clinical Trial 
500L-OMP 
CMC-OMP/500L 
Used for Phase I-dose verification 
study and Phase II study 
500L-FMP 
CMC-FMP/500L 
Used for Phase I-PK sub-study 
2000L-FMP 
CMC-FMP/2000L 
Used for Phase I-Dose verification 
study, PK sub-study and Phase II 
study 
Abbreviations: CMC, Chemistry, Manufacturing and Control; FMP, final manufacturing process; OMP, Original 
Manufacturing Process; PK, pharmacokinetics. 
6.2 
Product Preparation and Administration 
BGB-A317 will be administered by IV infusion using a volumetric pump through an intravenous line 
containing a sterile, non-pyrogenic, low-protein binding 0.2 micron in-line or add-on filter. Specific 
instructions for product preparation and administration are provided in the Pharmacy Manual. 
As a routine precaution, subjects who receive the first two infusions of BGB-A317 must be observed 
for 2 hours after infusion, in an area with resuscitation equipment and emergency agents. 
BGB-A317 will be diluted to a concentration between 1 mg/mL to 10 mg/mL in sterile normal saline 
(0.9% sodium chloride) as described below. The first infusion should be administered over 60 min; if 
well-tolerated, the second infusion should be administered over 30 min. Do not co-administrate other 
drugs through the same infusion line. 
1. Slowly swirl solution in the vial. Allow up to 5 minutes for bubbles to clear. Do not shake the vial. 
2. Visually inspect the solution for particulate matter and discoloration prior to preparation. The 
antibody drug solution is a clear to slightly opalescent, colorless to slightly yellow solution. 
3. Isolate the vial for investigation if extraneous insoluble particles other than translucent to white 
proteinaceous particles are observed. 


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4. Aseptically withdraw the required volume from the vial(s) of BGB-A317 into a syringe, and 
transfer into an IV bag (if multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper 
coring, repeated friction of plunger against syringe barrel wall and so on). Visually inspect the used 
vial, and isolate the vial for investigation if extraneous insoluble particles other than translucent to 
white proteinaceous particles are observed. 
5. Please use the following example to guide study drug preparation. The total dose to be administered 
will be diluted to a total volume of no more than 100 mL in sterile normal saline (0.9% sodium 
chloride).  
Prepare BGB-A317 solution for infusion per the example provided below:  
200 mg dose: 
Drug needed for dose preparation:   
200 mg/10 mg/mL = 20 mL 
0.9% sodium chloride needed for dilution:  50 mL – 20 mL = 30 mL 
Target final concentration:   
 
200 mg/50 mL = 4 mg/mL 
The study center can adjust preparation process according to common practice in consultation 
with sponsor. 
6. Mix diluted solution by gentle inversion for several times. 
7. Visually inspect the final solution. If the infusion is not clear or the contents appear to contain 
precipitate, the solution should be isolated for investigation (according to the instruction in Section 
6.5) and documented on the Drug Accountability Log. 
8. Record the time when BGB-A317 was prepared on the IV bag label. 
9. Attach the IV bag containing the BGB-A317 solution to the infusion set, 0.2 μm in-line or add-on 
filter, and infusion pump. 
10. At the end of the infusion period, flush the line with a sufficient quantity of normal saline. 
For management of toxicity refer to Section 4.3. 
6.3 
Treatment Assignment 
Subjects will be identified by a subject number. Each subject enrolled in this study will receive a 
unique subject number after signing the informed consent. Subject numbers will be assigned in 
chronological order starting with the lowest number. Once a subject number has been assigned to a 
subject, it cannot be reassigned to any other subject. 


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6.4 
Packaging and Labelling 
BGB-A317 was aseptically filled in 20R glass vials with a Flurotec-coated butyl rubber stopper and 
an aluminum cap. Each vial contains 10 mL of the drug solution. The vials were packaged in carton 
box. 
The primary labeling on the vials contain following information: protocol number, concentration and 
quantity of BGB-A317, batch number, expiry date, storage instructions, and administration 
instructions. The contents of the label will be in accordance with all applicable regulatory 
requirements. 
6.5 
Handling and Storage 
The investigational product will be dispatched to a study center only after receipt of the required 
documents in accordance with applicable regulatory requirements and the sponsor’s procedures. 
Investigational product must be distributed or given according to procedures described herein. Only 
subjects enrolled in the study may receive investigational product, in accordance with all applicable 
regulatory requirements. Only authorized study center personnel may supply or give investigational 
product. All investigational products must be stored in a secure area with access limited to the 
investigator and authorized study center personnel and under physical conditions that are consistent 
with investigational product-specific requirements. The Investigational product must be kept at 2-8oC. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
6.6 
Product Accountability 
The investigator is responsible for investigational product accountability, reconciliation, and record 
maintenance. In accordance with all applicable regulatory requirements, the investigator or designated 
study center personnel must maintain investigational product accountability records throughout the 
course of the study. Such person(s) will document the amount of investigational product received from 
the sponsor, the amount supplied and/or administered to and returned by subjects, if applicable. If the 
drug that subject received during treatment is changed from a manufacturing process to another, the 
changes will be recorded, including date and manufacturing processes and scales, etc.  
After completion of the study, all unused BGB-A317 will be inventoried on site after receiving written 
sponsor approval, and returned to the sponsor’s supplier for uniform destruction. 
6.7 
Assessment of Compliance 
On all visits to the study center, subjects will be questioned regarding compliance with study 
instructions. 
6.8 
Investigational Product Overdose 
Overdose is defined as: the subject has taken (accidentally or intentionally) a dose exceeding the dose 
prescribed in the protocol by 20%. Subjects with a suspected overdose should be managed with 


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appropriate supportive therapy as determined by the investigator in consultation with the Medical 
Monitor. Any adverse effects occurring as a result of an overdose should be reported to the medical 
monitor as well as being included in standard AE reporting. 
6.9 
Medical Care of Subjects after the End of Trial 
After a subject has completed the trial or has withdrawn early, conventional treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice, and depending on the subject’s individual medical needs. 
6.10 
Occupational Safety 
The investigational product is not expected to pose significant occupational safety risk to the study 
center personnel under normal conditions of use and administration. A material safety data sheet 
describing occupational hazards and recommended handling precautions will be provided to the 
investigator, where this is required by local laws, or is available upon request from the sponsor.  
 
 


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7. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
7.1 
Concomitant Medication(s)/Treatment(s) 
The best supportive care is permitted in the course of the study. Bone metastatic subjects who had been 
previously treated with bisphosphonates and receptor activators of nuclear factor KappaB ligands 
(RANK-L) inhibitors are allowed to continue their use during the trial. Subjects with central nervous 
system metastasis are allowed to undergo Whole brain radiotherapy and / or stereotactic brain 
radiotherapy, but the extra-cranial lesions of the subjects are required to be relatively stable. All 
concomitant medication will be recorded on the eCRF including all prescription, over-the-counter, 
herbal supplements, and IV medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date will also be included on the eCRF. 
All concomitant medications received within 30 days before the screening visit (Visit 1) and within 30 
days after the end of treatment should be recorded. 
The eCRF entry must include the dose, regimen, route, indication, and start and stop dates of use of the 
prior and concomitant medication. 
7.2 
Prohibited Medications 
Subjects may receive other medications that the investigator deems to be medically necessary, except 
for non-protocol specified chemotherapy, radiotherapy, immunotherapy, anti-neoplastic biological 
therapy, anti-neoplastic Chinese patent medicine or Chinese herbal medicine, or investigational agents 
other than BGB-A317 (Palliative radiotherapy for the purpose of alleviating urgent symptoms on non-
target lesions is permitted, for example palliative radiotherapy for the purpose of alleviating pain at 
bone lesions). Subjects who in the assessment by the investigator require the use of any of the 
aforementioned treatments for clinical treatment should be discontinued from the study. 
Subjects with active autoimmune disease or history of autoimmune disease that might recur, who 
require immune suppressive treatment including systemic corticosteroids, should be excluded; these 
include but are not limited to subjects with a history of immune related neurologic disease, multiple 
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, 
systemic lupus erythematosus, connective tissue diseases, scleroderma, inflammatory bowel disease, 
Crohn's, ulcerative colitis, hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, or anti-
phospholipid syndrome. 
Subjects are prohibited from receiving live vaccines 28 days prior to the first dose and until 60 days 
after the last dose. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine. 
Section 5.2 of the protocol (Exclusion Criteria) describes other medications which are prohibited in this 
study. 


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7.2.1 
Other Drugs to be Used in the Study 
H1 blockers (diphenhydramine 50 mg IV, or equivalent) and acetaminophen (500 to 650 mg oral or IV) 
may be used 30 to 60 minutes prior to each BGB-A317 infusion to prevent infusion-related reactions. 
Systemic corticosteroids used for the control of infusion-related reactions or irAEs must be gradually 
tapered for at least 1 month before the next study drug administration, and the tapered dose after 
tapering should not be immunosuppressive (prednisone or equivalentsİ10 mg/day). The use of 
steroids as prophylactic treatment for subjects with contrast allergies to diagnostic imaging contrast 
dyes will be permitted. 
Patients with inactive HBsAg carriers, treated and stable hepatitis B (HBV DNA less than 500 IU/mL 
or 2500 copies/mL) and cured hepatitis C patients were allowed to be enrolled in the trial. Patients with 
positive HbsAg at screening and those enrolled in Arm 11 will be further tested for HBV DNA. In 
terms of definition and treatment of hepatitis B, please refer to the guidelines for the prevention and 
treatment of chronic hepatitis B (Hou J, 2017). Subjects with positive screening HBV DNA should be 
regularly monitored for HBV DNA during the trial. Patients with antiviral treatment indications should 
continue to receive antiviral treatment during the trial. 
7.2.2 
Other Study Considerations 
The following nondrug therapies must not be administered during the study (within 28 days before the 
start of study treatment): 
x 
Major surgery (excluding prior diagnostic biopsy). 
x 
Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to potentially 
interfere with major organ function (eg, hypericin). 
x 
Subjects should not abuse alcohol or other drugs during the study. 
7.3 
Special Precautions 
As a routine precaution, subjects who receive the first two infusions of BGB-A317 must be observed 
for 2 hours after infusion, in an area with resuscitation equipment and emergency agents. 
Infusion of BGB-A317 will be discontinued in case of Grade 3 or 4 hypersensitivity, inflammatory 
response, or infusion-related reactions. Tumor lysis syndrome, the treatment recommendations for 
infusion-related reactions and severe hypersensitivity reactions according to the NCI-CTCAE are 
outlined in Sections 7.3.1, 7.3.2 and 7.3.3, respectively. 
7.3.1 
Tumor Lysis Syndrome 
A potential risk of tumor lysis syndrome exists since BGB-A317 can induce cytotoxicity. As published 
by Howard et al (Howard SC, 2011), once tumor lysis syndrome occurs, subjects should be treated as 
per the local guidelines and the management algorithm (Figure 1). 
 


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Figure 1. Assessment and Initial Management of Tumor Lysis Syndrome. 
 
7.3.2 
Infusion-Related Reaction 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, angioedema, 
hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness or hypertension. 
Severe reactions may include acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock. Patients should be closely monitored for such reactions. Immediate 
access to an Intensive Care Unit or equivalent environment and appropriate medical therapy (including 


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epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen) must be available to treat 
infusion-related reactions.  
Treatment modification for symptoms of infusion-related reactions due to BGB-A317 is presented in 
Table 6. 
Table 6. 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
BGB-A317 
NCI-CTCAE Grade 
Treatment Modification for BGB-A317 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening 
is closely monitored. Medical management as 
needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for İ 24 hrs 
Stop infusion. Infusion may be resumed at 50% 
of previous rate once infusion-related reactions 
has resolved or decreased to at least grade 1 in 
severity. Any worsening is closely monitored. 
Proper medical management should be 
instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 - severe 
Prolonged (eg, not rapidly responsive to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following 
initial 
improvement; 
hospitalization indicated for clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 - life-threatening 
Life-threatening 
consequences; 
urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the BGB-A317 infusion rate has been decreased by 50% or suspended due to an infusion-related 
reaction, it must remain decreased for all subsequent infusions with premedication. If the patient has a 


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second infusion-related reaction ( ı  grade 2) on the slower infusion rate, infusion should be 
discontinued and the patient should be withdrawn from BGB-A317 treatment. 
CTCAE grade 1 or 2 infusion-related reaction: Proper medical management should be instituted, as 
indicated per type of the reaction. This includes but is not limited to an anti-histamine (eg, 
diphenhydramine or equivalent), anti-pyretic (eg, paracetamol or equivalent), and if considered 
indicated oral or IV glucocorticoids, epinephrine, brochodilators, and oxygen. In the next cycle, patients 
should receive oral premedication with an antihistamine (eg, diphenhydramine or equivalent) and an 
antipyretic (eg, paracetamol or equivalent), and they should be closely monitored for clinical signs and 
symptoms of an infusion-related reaction.  
CTCAE grade 3 or 4 infusion-related reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to oral 
or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
7.3.3 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available medical 
practice as described in the complete guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK) (Soar et al, 2008). Patients should 
be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within minutes 
following administration of the drug/antigen, and characterized by: respiratory distress; laryngeal 
edema; and/or intense bronchospasm; and often followed by vascular collapse or shock without 
antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria with/without 
edema; and gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and 
diarrhea), the infusion must be immediately stopped and the patient discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if hypersensitivity 
reaction is observed and then the patient should be placed on monitor immediately and Intensive Care 
Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 h before and 8 h after the start of each dose of study drugs(s) infusion. Alternative 
treatments for fever (ie, paracetamol) may be given to patients at the discretion of the investigator. 
 
 


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8. 
SAFETY, PHARMACOKINETIC, PHARMACODYNAMIC, AND OTHER 
ASSESSMENTS 
A signed, written informed consent must be obtained prior to screening assessments and before any 
study specific assessments are initiated. The Phase I study specific assessments and procedures are 
shown in Table 1. The pharmacokinetic sampling time points for dose verification study of Phase I are 
presented in Table 2. The pharmacokinetic sampling time points for PK sub-study of Phase I are 
presented in Table 3. The Phase II study specific assessments and procedures are shown in Table 4. 
8.1 
Screening and Pre-screening 
Screening evaluations will be performed within 28 days prior to randomization. Patients who agree to 
participate will sign the informed consent form (ICF) prior to undergoing any screening procedure. 
Patients who are suspected or known to have serious respiratory concurrent illness or exhibit significant 
respiratory symptoms unrelated to underlying cancer should take a pulmonary function tests. Screening 
evaluations may be repeated as needed within the screening period; the investigator is required to assess 
patient eligibility according to the latest screening assessment results. 
In Phase II of this study, tumor samples and/or blood samples should be collected during pre-screening 
period (İ 8 weeks prior to screening period) from subjects to be enrolled in Arm 8 when their 
MSI/MMR-mutation status is unknown. Tests of MSI- or MMR-mutation status of collected samples 
will be conducted at the central laboratory designated by the sponsor (see Section 8.9): 
Following actions will be taken during the process of collecting tumor samples and blood samples for 
pre-screening: 
x 
Written informed consent forms for pre-screening should be obtained from subjects or subjects’ 
legal representatives 
x 
During pre-screening period, apart from tumor-mutation status, demographic data, medical history 
and other information will also be collected 
x 
As required by the Lab Manual, tumor samples and blood samples will be prepared and shipped 
to the central laboratory designated by the sponsor for mutation analysis 
x 
Record SAE directly related to the pre-screening procedures (ie, collection of tumor samples and 
blood samples). Do not record AE or unrelated SAE, unless such recording is mandatorily required 
by local regulations 
8.2 
Demographic and Baseline Assessments 
Demographic data will include date of birth, race, height (in cm), and body weight (in kg). For height 
and weight measurements, the subject will be allowed to wear indoor daytime clothing with no shoes. 
This data will be captured in the eCRF and database. 
Having given consent, subjects will be required to undergo a medical screen to determine whether they 
are eligible to participate in the study according to the inclusion and exclusion criteria listed in 


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Section 5.1 and Section 5.2. Fresh tumor biopsy samples need to be collected within 42 days prior to 
the first dosing if subjects have no archival tumor tissue samples. Other screening assessments need to 
be completed within 28 days prior to the first dose of the investigational product. Related assessments 
completed within 3 days of administration can be used as Day 1 assessments as indicated in Table 1 
and Table 4. The Phase I and Phase II screening assessments will include: 
x 
Baseline demographics 
x 
Medical history including diagnosis, date of first diagnosis, histology, prior anti-neoplastic 
therapy, and current sites of disease 
x 
Concurrent medications 
x 
Disease assessments within past 4 weeks 
x 
Vital signs 
x 
Physical examinations 
x 
Evaluation of AEs 
x 
ECOG performance status 
x 
Electrocardiogram (ECG) 
x 
Echocardiography (Phase I) 
x 
Ultrasonic echocardiography 
x 
Laboratory tests: hematology, serum chemistry, urinalysis, coagulation (at screening, at the 
Safety Follow-Up Visit, and during the study when clinically indicated). Refer to Appendix 4 for 
the list of specific laboratory assessments 
x 
Pregnancy test (for women with childbearing potential only, at screening and during the study 
when clinically indicated) 
x 
Collection of archival tumor samples (if archival tumor tissue samples are not available, subjects 
should provide fresh tumor biopsy samples, as detailed in Section 8.9) 
x 
Thyroid function 
x 
HbsAg, HbcAb, hepatitis C virus (HCV) antibody 
x 
Enhanced computed tomography/magnetic resonance imaging (CT/MRI) scan 


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x 
Pulmonary function testing which may including but is not limited to spirometry and assessment 
of diffusion capacity (For patients who are suspected or known to have serious/severe respiratory 
condition or exhibit significant respiratory symptoms unrelated to underlying cancer) 
x 
For subjects to be enrolled in Arm 2 or Arm 3 in Phase II, PD-L1 detection should be performed, 
and subjects with non-squamous carcinoma of unknown EGFR mutations should also receive 
EGFR mutation detection (Refer to Section 8.9) 
The above-mentioned data will be captured in the source documents. Any results falling outside the 
normal range will be repeated at the discretion of the investigator. 
Refer to Appendix 4 for the amount of blood samples required at the local study center’s laboratory. 
The final amount of blood samples depends on the standard of the local study center’s laboratory. 
Refer to the Lab Manual for the amount of blood samples required at the central laboratory 
designated by the sponsor.  
All medical history and prior medication should be recorded in the eCRF during screening period. 
The treatment history of primary diagnosis, including prior systemic treatment, radiation therapy and 
surgical treatment should all be recorded in the eCRF. The response date and progression date of prior 
treatment should be recorded. Radiographic studies performed prior to study entry may be collected 
for review by the investigator. Complete medication history for 30 days prior to the screening visit 
needs to be reported. 
8.3 
Assessments During Treatment 
Safety assessments should be performed at all visits to the study center and throughout the study. The 
list of events and the time when they will be performed are presented in Table 1 and Table 4. 
8.3.1 
Laboratory Evaluation 
During the study, laboratory assessments should be performed at the local study center’s laboratory, 
including serum chemistry, hematology, coagulation, urinalysis, and thyroid function at the time points 
specified in Table 1 and Table 4. Subject treatment and overall treatment decisions will be based on the 
data from study center laboratory. Laboratory assessments need not be repeated on Cycle 1 Day 1 if 
these assessments were completed for screening within 3 days of the first administration. Required 
laboratory assessments are listed in Appendix 4. 
In the event of neutropenia (ANC <1000/mm3), thrombocytopenia (platelets <50000/mm3), or Grade 3 
serum chemistry abnormalities (except some asymptomatic abnormalities), the relevant assessments 
will be conducted every other day until toxicity resolves to İGrade 2. If warranted, additional testing 
can also be done, or the relevant tests done more frequently in accordance with institutional guidelines. 
All subjects who have any Grade 3 or Grade 4 laboratory abnormalities at withdrawal from the study 
must be followed up until they have returned to Grade 1 or Grade 2 or being stable, unless these are not 
likely to improve due to the underlying disease. 


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Urine samples shall be collected over 24 h for total protein analysis if urinary protein dipstick test result 
is ı 2+ and considered as clinically significant by the investigator in performing urinalysis. The study 
drug will be suspended if urine protein is > 2 g /24 h, until it drops to İ 2 g /24 h. If urine protein is 
is2 g /24 h, further clinical evaluation and/or more frequent examinations will be performed when 
clinically indicated. 
8.3.2 
Physical Examination, Vital Signs and ECOG Score 
A complete physical examination, vital signs (systolic blood pressure, diastolic blood pressure, pulse 
rate, temperature, and respiratory rate), weight examination and ECOG score will be performed at the 
time points specified in Table 1 and Table 4.  
For the first infusion of BGB-A317, the subject’s vital signs should be determined within 60 minutes 
before the infusion, and during and 30 minutes after the infusion. For subsequent infusions, vital signs 
will be collected within 60 minutes before infusion and if clinical indicated, during and 30 minutes after 
the infusion. Subjects will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. Refer to Section 7.3.2 
regarding precautionary monitoring of subject post-infusion of BGB-A317. 
To the extent feasible, blood pressure will be taken on the same arm throughout the study. A large cuff 
should be used for obese patients. Subjects must be resting in a sitting position for 10 minutes prior to 
obtaining vital signs. If blood pressure is >150/100 mmHg in a subject without a history of hypertension, 
or increased >20 mmHg (diastolic) from baseline measurement in a subject with a previous history of 
hypertension, the assessment should be repeated in 10 minutes for confirmation. 
8.3.3 
Electrocardiogram 
After the subjects have a rest for at least 5 minutes, electrocardiograms will be obtained at the time 
points specified in Table 1 and Table 4.  
Significant QT interval corrected for heart rate (QTc) prolongation will be defined as an interval ı500 
msec or an interval which increases by ı60 msec over baseline. Either of these conditions should be 
documented on two or more ECG tracings separated by at least 5 minutes. The ECG tracing should be 
examined and a manual measurement by a trained physician should be performed to assess the accuracy 
of the equipment being used. 
If a subject has significant QTc prolongation: 
x 
The subject will be withdrawn from the investigational product administration if the investigator 
and/or the medical monitor determine the subject is at risk 
x 
The subject will be monitored, treated appropriately, and closely followed (ECGs at least three 
times per week) until the QT and QTc interval return to within 30 msec of baseline 


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x 
The medical monitor will be consulted prior to administering further doses or re-challenging 
8.3.4 
Ultrasonic Echocardiography 
Echocardiographic parameters of left ventricular ejection and cardiac function will be measured during 
the screening period of phase I and when clinically indicated. 
8.3.5 
Pulmonary function testing 
Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant 
respiratory symptoms unrelated to underlying cancer will have pulmonary function testing which may 
including but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period, to assist the determination of suitability for enrollment on the study. 
8.3.6 
Computed Tomography and Magnetic Resonance Imaging 
Radiographic assessment of the tumor response state should be conducted during screening period, 
treating period and at the time of disease progression. The frequency of assessment during treatment is 
approximately every 9 weeks within the first 12 months, and every 12 weeks thereafter. 
Sites of enhanced CT scan/MRI (oral or intravenous contrast product) at baseline include chest, 
abdomen and pelvis at least. If subjects are contraindicated to contrast agents, MRI may also be used. 
According to the characteristics of the disease, enhanced CT/MRI scan of bones, head, neck, and 
extremities may be performed. Bone lesions may be evaluated with technetium 99 m bone scan. 
For each subject, throughout the study period, radiographic methods and operating procedures for 
measurable or non-measurable lesions should be consistent with those used at baseline. All target and 
non-target lesions identified during the screening period should be adequately evaluated during 
treatment and at the End of Treatment visit. If disease progression is suspected, the investigator can 
decide to perform unscheduled tumor evaluation at any time. 
Subjects who stop treatment prior to confirmed progressive disease (PD) will continue to undergo 
radiographic examination for tumor response assessments during the study until unequivocal PD is 
documented or the subject starts new anticancer therapies or subject withdraws consent from the trial, 
whichever occurs first. This imaging schedule will be maintained and will never be adjusted regardless 
of any intermediate unscheduled scans. Subjects who withdraw from the study for clinical or 
symptomatic deterioration before objective documentation of PD should undergo appropriate imaging 
to confirm PD. Every effort will be made to confirm a clinical diagnosis of PD by imaging. 
Lesions that are expected to require palliative radiotherapy while in the study should not be included 
as target lesions, but should be listed as non-target lesions. 
8.3.7 
Adverse Events 
Refer to Section 10 for AE collection. 


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8.4 
Safety Assessments 
Vital signs, weight, physical examinations, ECOG performance status, ECGs and laboratory safety tests 
(eg, hematology, serum chemistry, urinalysis, coagulation, anti-BGB-A317 antibodies, thyroid function, 
viral antigen reactions) will be obtained and assessed at designated time intervals throughout the study 
(see Table 1 and Table 4). Special attention will be given to irAEs (eg, gut, skin, lung, liver, kidney, 
endocrine organs, others). 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, version 
4.03. Characterization of toxicities will include severity, duration, and time to onset. Safety endpoints 
will include all types of adverse events, in addition to laboratory safety assessments, ECOG 
performance status, ECGs, and vital signs.  
The continuous safety evaluation will be performed by the sponsor and investigators. An SMC will be 
established to determine the dose levels and dose regimens to be administered during dose verification 
study, and to recommend RP2D based on the safety and tolerability of BGB-A317. Meanwhile, the 
SMC will also decide whether or not to increase unscheduled doses for trial. Details of the safety 
monitoring process will be specified in an SMC charter. 
8.5 
Follow-up Assessments 
All subjects should return to study sites for final assessment at least 30 days, approximately, after end 
of study treatment or until initiation of a new anti-cancer treatment, whichever occurs first. Assessments 
to be performed are listed in Table 1 and Table 4.   
Subjects who are discontinued from the study due to an intolerable drug related adverse event will be 
followed until the resolution of the AE to Grade 0-1 or keeping stable. 
Following completion of the treatment and safety follow-up periods, all subjects will be followed for 
survival status. Subjects will have their survival status assessed approximately every 3 months by either 
a telephone or in-person contact until subject death or termination by the sponsor. No other data (eg, 
subsequent therapies, performance status, etc) beyond survival will be collected during these calls/visits. 
8.6 
Efficacy Assessments 
This study includes preliminary assessments of efficacy. 
Disease assessment by radiographic imaging (enhanced CT or MRI) will be performed and recorded at 
screening within 28 days before enrollment and while on study approximately every 9 weeks during 
first 12 months and approximately every 12 weeks thereafter according to the RECIST V1.1 Guidelines 
as shown in Appendix 6. 
After the first confirmation of CR or PR, an imaging test will be performed at 4 weeks later or at the 
next scheduled time point to confirm the response. 


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8.6.1 
Treatment after Disease Progression 
There is evidence that a minority of subjects having received immune therapy with anti-PD1 therapies 
such as BGB-A317 may still develop pseudo-progression despite initial documentation of progressive 
disease by RECIST Version 1.1. Pseudo-progression may occur due to immune cell infiltration and 
other mechanisms resulting in apparent increase of existing tumor masses or appearance of new tumor 
lesions (Wolchok JD, 2009). If subjects with pseudo-progression continue receiving treatment, they 
may exhibit a PR at a later time point. It is the responsibility of the investigator to determine if the 
subject should be considered for treatment beyond progression due to clinical benefit according to the 
principles described below. This decision should be considered carefully so as to permit subjects who 
are likely to be benefiting to continue treatment while at the same time preventing prolongation of a 
futile therapy in subjects who may not be benefitting. If conditions permit, biopsy of lesions with false 
progression may also be considered to guide further treatment decisions. Any decisions to continue 
treatment beyond initial progression must be discussed with the medical monitor and documented in 
the study records. 
Subjects with documented progression in tumor burden or with the appearance of new lesions in the 
absence of significant clinical deterioration (decline in performance status and/or laboratory values) are 
permitted to continue with treatment until confirmation of disease progression with repeat imaging at 
least 4 weeks later or at the next regularly scheduled imaging time point. The next imaging to confirm 
disease progression must not exceed 12 weeks from initial documentation of disease progression. 
In addition, subjects must meet the following criteria: 
x 
Absence of clinical symptoms and signs of disease progression (including worsening laboratory 
values) 
x 
Stable ECOG performance status 
x 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (eg, 
cord compression) that necessitates urgent alternative medical intervention 
x 
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform patients that this practice is not considered standard in the treatment of 
cancer. 
In rare cases, subjects with unequivocal radiographical disease progression at repeat imaging may be 
allowed to continue to be treated if in investigator’s opinion subjects are benefitting from the treatment. 
Prior consultation with the sponsor is required. 
8.6.2 
Efficacy Endpoints 
Efficacy endpoint measures include: 


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x 
The ORR, defined as the percentage of subjects in the study whose best overall response was either 
CR or PR, as assessed by investigators based on RECIST Version 1.1 
x 
The PFS and DCR (CR + PR + SD) as assessed by RECIST Version 1.1; and CBR (CR + PR + 
durable SD [SD ı24 weeks]) 
x 
Duration of response (DOR) for responders (CR or PR) and duration of SD 
In addition to RECIST Version 1.1, Gynecological Cancer Intergroup (GCIG) criteria (Rustin GJ, 2011) 
may also be used to evaluate response in patients with ovarian cancer enrolled in the study 
8.7 
Pharmacokinetics 
Blood will be collected to characterize the PK profile of BGB-A317. PK analyses of dose verification 
study of Phase I and that of Phase II will include but is not limited to AUC0-21 day, Cmax and Tmax, Ctrough, 
t1/2, Cl and Vz. Phase I PK sub-study aims to assess the PK of the products derived from two 
manufacturing processes and scales, which includes but is not limited to AUCf, AUC0-21 day, Cmax after 
the first dosing, as well as other pharmacokinetic parameters such as Tmax, Ctrough, t1/2, Cl and Vz. This 
will be used for descriptive statistics rather than statistic influence. 
Details concerning handling of PK serum samples, including labeling and shipping instructions will be 
provided in the Lab Manual. The actual time each sample was collected will be captured to the nearest 
minute in the eCRF and recorded in the database. 
Blood samples for PK analysis will be collected according to the Lab Manual and serum will be 
separated, and immediately frozen and shipped per Lab Manual. Samples will be shipped to the 
sponsor-designated central laboratory where all samples will be analyzed for serum BGB-A317 
concentration. 
8.7.1 
Phase I 
For subjects in the dose verification stage, blood-sampling time points are shown in Table 2. For 
subjects in PK sub-study stage, blood-sampling time points are shown in Table 3. 
Unscheduled blood samples may also be collected whenever any notable safety is seen, to evaluate if 
the observation is exposure related. Blood samples should be obtained, when possible, for analysis of 
serum BGB-A317 in the event of a DLT or any grade 3 or above irAE (refer to Appendix 3). The 
investigator must record the time the blood samples obtained and the time of the previous 
administration in the eCRF. 
Should a concomitant medication be suspected, further blood samples for PK analyses may be taken to 
characterize the extent of the interaction as decided by the investigator in consultation with the sponsor. 


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8.7.2
Phase II
For subjects attending in the indication-expansion study, blood-sampling time points are shown in 
Table 4.
Unscheduled blood samples may also be collected whenever any notable safety is seen, to evaluate if 
the observation is exposure related. Blood samples should be obtained, when possible, for analysis of 
serum BGB-A317 in the event of any grade 3 or above irAE(refer to Appendix 3). The investigator
must record the time the blood samples obtained and the time of the previous administration in the 
eCRF.
8.8
Anti-Drug Antibody
Immunogenic responses to BGB-A317 will be assessed to determine occurrence of anti-BGB-A317
antibodies. Blood-sampling time points for subjects both in the dose verification study and in the PK 
sub-study of Phase I are shown in Table 1, and those in Phase II are shown in Table 4. Samples will be 
processed according to the Lab Manual and shipped to the central laboratory designated by the sponsor 
for analysis using a validated method.
8.9


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.
8.10
Appropriateness of Measurements
All efficacy, safety and PK assessments used in this study are standard, namely, widely used and 
generally recognized as reliable, accurate, and relevant.


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9. 
QUALITY CONTROL AND QUALITY ASSURANCE 
According to the good clinical practices (GCP) guidelines (CPMP/ICH/135/95, 1996), the sponsor is 
responsible for implementing and maintaining quality assurance and quality control systems with 
written Standard Operating Procedures.  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and reliability of 
the data: 
x 
Investigator meeting(s). 
x 
Local study center’s laboratories for laboratory measurements and ECGs. 
x 
Study center initiation visit. 
x 
Early study center visits post-enrollment. 
x 
Routine study center monitoring. 
x 
Ongoing study center communication and training. 
x 
Data management quality control checks. 
x 
Continuous data acquisition and cleaning. 
x 
Internal review of data. 
x 
Quality control check of the final clinical study report. 
In addition, the sponsor and/or the CRO clinical quality assurance department may conduct periodic 
audits of the study processes, including, but not limited to the study center, study center visits, PK 
laboratories, local study center’s laboratory, vendors, clinical database, and the final clinical study 
reports. When audits are conducted, access must be authorized for all study-related documents 
including medical history and concomitant medication documentation to authorized sponsor’s 
representatives and regulatory authorities. 
9.1 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor procedures, the sponsor has engaged the 
services of a CRO to perform all monitoring functions within this clinical study. Monitors will work in 
accordance with the sponsor or CRO standard operating procedures (SOPs) and have the same rights 
and responsibilities as monitors from the sponsor’s organization. Monitors will establish and maintain 
regular contact between the investigator and the sponsor. 
During these contacts, the monitor will: 


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x 
Check the procedures of the study. 
x 
Check study data collected. 
x 
Conduct source document verification. 
x 
Identify any issues and address their resolution. 
x 
Ensure that data are authentic, accurate, and complete.  
x 
Ensure that safety and rights of subjects are being protected. 
x 
Ensure that the study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The investigator agrees to allow the monitor direct access to all relevant documents and to allocate 
his/her time and the time of his/her personnel to the monitor to discuss findings and any relevant issues. 
9.2 
Data Management/Coding 
An electronic data management system will be applied in this study. Data administrators will construct 
electronic Case Report Form (eCRF) according to the study protocol and medical records. 
- Authority distribution: the data administrator will create respective accounts and grant different 
authorities to different identities such as data entry personnel, investigators, clinical monitors and others. 
Each site is able to view its own contents. Data entry personnel have authorities of data entering, data 
modifying and query resolving; investigators have authorities of query modifying, query reviewing, 
query resolving and auditing; Monitors have authorities of query reviewing and query initiating; and 
data administrators have authorities of query reviewing, query initiating and data locking.  
- Data entry: clinical investigators or investigator’s designated data entry staffs (Clinical Coordinators) 
should timely and accurately enter the data from source documents into eCRF.  
- Query initiating & resolving: monitors and data administrators initiate queries via eCRF, data entry 
staff or investigators answer queries and modify incorrect data. Query initiation may be repeated if 
necessary. All records are documented in eCRF. 
- Data modification & reviewing: data entry staffs or investigators are able to modify the data after 
verification. Reasons of data modifications should be filled out in eCRF. Investigators have the 
authority of review all final data. 
- Data locking & export: all data review as accurate will be eventually locked by data administrators. 
No further modification is allowed after data locking unless signed permission is obtained from the 
sponsor, investigators, entry personnel, monitors and data administrators. All final data is transferred 
into the database designated by data administrators, and will be analyzed by statisticians.  


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- Coding: Adverse events, concomitant diseases and prior medical history will be encoded using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1 or above, and concomitant 
medications will be encoded using the WHO Drug Dictionary. 
9.3 
Quality Assurance Audit 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may conduct 
a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. 
Such audits/inspections can occur at any time during or after completion of the study. If an audit or 
inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to 
all relevant documents and to allocate his/her time and the time of his/her personnel to the 
auditor/inspector to discuss findings and any relevant issues. 


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10. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the criteria 
and definition of an AE or SAE as provided in this protocol.  
10.1 Risks Associated with BGB-A317  
BGB-A317 is an investigational agent that is currently in clinical development. Limited safety data are 
available in patients and the full safety profile has not been characterized. The following 
recommendation is based on results from nonclinical and clinical studies with BGB-A317 and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the 
risk of irAEs, specifically the induction or enhancement of autoimmune conditions. AEs observed with 
anti-PD-1 therapy are presented in Section 10.7.1. 
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, such 
events should be recognized early and treated promptly to avoid potential major complications. 
Suggested workup procedures, study drug management and treatment for suspected irAEs are provided 
in Appendix 3. 
10.2 General Plan to Manage Safety Concerns  
10.2.1 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial. Results from the nonclinical 
toxicology studies and clinical data with BGB-A317, as well as the nonclinical/clinical data from other 
PD-L1/PD-1 inhibitors, were considered. Specifically, patients at risk for study-emergent active 
autoimmune diseases or history of autoimmune diseases that may relapse, and patients who have 
received a live viral vaccine within 28 days before randomization, are excluded from the study.   
10.2.2 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all serious and non-serious adverse 
events, defined and graded according to NCI-CTCAE v4.03. Patients will be assessed for safety 
(including laboratory values) according to the schedule in Table 1 and Table 4. Clinical laboratory 
results must be reviewed prior to the start of each cycle.  
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs, physical examinations, laboratory measurements (hematology, chemistry, 
etc.) and other assessments. In addition, patients will be closely monitored for the development of any 
signs or symptoms of autoimmune conditions and infection.  


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Serum samples will be drawn for the determination of ADAs to BGB-A317. Administration of 
BGB-A317 will be performed in a setting where emergency medical equipment and staff who are 
trained to respond to medical emergencies are available.   
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the time 
of signing of informed consent) and for up to 30 days after the last dose of study treatment or until the 
initiation of another anticancer therapy, whichever occurs first. At the end of treatment, ongoing 
adverse events considered related to study treatment will be followed until the event has resolved to 
baseline or İ Grade 1, the event is assessed by the investigator as stable, the patient is lost to follow-
up, the patient withdraws consent, or it has been determined that study treatment or participation is not 
the cause of the adverse event. 
All irAEs will be recorded until up to 90 days after the last dose of BGB-A317, regardless of whether 
the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by the investigator 
after treatment discontinuation until patient death, withdrawal of consent, or loss to follow up, 
whichever occurs first. 
Investigators are instructed to report all events (including AEs and pregnancy-related AEs). In addition, 
the medical monitor or safety physician will review and evaluate observed AEs on a regular basis. 
The potential safety issues anticipated in this trial, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections.  
10.3 Adverse Events 
10.3.1 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether 
considered related to study drug or not.   
Examples of AEs include:  
x 
Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse outcome  
x 
New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study  
x 
Signs, symptoms, or the clinical sequelae of a suspected interaction  
x 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. The 
investigator will then record all relevant information regarding an AE or SAE in the eCRF. However, 


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there may be instances when copies of medical records for certain cases are requested by the sponsor. 
In this instance, all patient identifiers will be blinded on the copies of the medical records prior to 
submission to the sponsor.  
10.3.2 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v4.03. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
x 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
x 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)  
x 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL  
x 
Grade 4: Life-threatening consequences; urgent intervention indicated  
x 
Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity (for 
example, grade of a specific AE, mild [grade 1], moderate [grade 2], severe [grade 3], or life-threatening 
[grade 4]), whereas seriousness is classified by the criteria based on the regulatory definitions. 
Seriousness serves as the guide for defining regulatory reporting obligations from the sponsor to 
applicable regulatory authorities as described in Section 10.6.2.1. 
10.3.3 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence of 
each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the AE or 
SAE to the study drug should be considered and investigated. The investigator should consult the BGB-
A317 IB in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the sponsor. However, it is very important that the investigator always 
makes assessment of causality for every SAE prior to transmission of the SAE report to the sponsor, 
since the causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE report accordingly.  
Investigators must also systematically assess the causal relationship of AEs to study drug (including 
any other non-study drugs, radiation therapy, etc) using the following definitions: 


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x 
Definitely related: There is clear evidence to suggest a causal relationship to the study drug, 
and there is reasonable temporal relationship; the occurrence of AE is definitely attributed to 
the pharmacological effect of study treatment. 
x 
Probably related: There is a reasonable temporal relationship to suggest a causal relationship 
to the study drug; the occurrence of AE could not be explained by the patient’s medical 
history, concurrent medical condition, or other signs or symptoms. 
x 
Possibly related: There is some evidence to suggest a causal relationship to the study drug 
(eg, the AE occurred within a reasonable time after administration of the study drug). 
However, the influence of other factors may have contributed to the AE such as the patient’s 
clinical condition or other concomitant AEs. 
x 
Possibly unrelated: There is little evidence to suggest a causal relationship to the study drug. 
There is another reasonable explanation for the AE such as disease or other drugs. 
x 
Unrelated: An AE will be considered “not related” to the use of the study drug if any of the 
following criteria are met: 
o An unreasonable temporal relationship between administration of the drug and the onset 
of the AE (eg, the AE occurred either before or too long after administration of the drug 
for it to be considered drug-related); 
o A causal relationship between the drug and the AE is biologically implausible (eg, death 
as a passenger in an automobile accident); 
o A clearly more likely alternative explanation for the AE is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related AE). 
The causality for cases that were assessed using the 5-point scale will be mapped to 2-point scale 
during aggregate safety data analysis according to the BeiGene latest mapping rule. 
10.3.4 
Following Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient and 
provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be reviewed 
at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered chronic, 
the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient withdraws consent. 
The investigator will ensure that follow-up includes any supplemental investigations as may be 
indicated to elucidate the nature and/or causality of the AE or SAE. This may include additional 


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laboratory tests or investigations, histopathological examinations, radiographic imaging, or 
consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE 
or SAE. The investigator is obligated to assist. If a patient dies during participation in the study or 
during a recognized follow-up period, the sponsor will be provided with a copy of any post-mortem 
findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 10.6.2.1. 
10.3.5 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count (CBC), coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at baseline and 
significantly worsen during the study. The definition of clinically significant is left to the judgment of 
the investigator. In general, these are the laboratory test abnormalities that are associated with clinical 
signs or symptoms, or require active medical intervention, or lead to dose interruption or 
discontinuation, or require close observation, more frequent follow-up assessments, or further 
diagnostic investigation. 
10.4 Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose:  
x 
Results in death 
x 
Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in which the 
patient was at risk of death at the time of the AE. It does not refer to an AE, which 
hypothetically might have caused death, if it were more severe.  
x 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually involving at 
least an overnight stay) to the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting 
x 
Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 


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accidental trauma (eg, sprained ankle), which may interfere or prevent everyday life functions, 
but do not constitute a substantial disruption.  
x 
Is a congenital anomaly/birth defect 
x 
Is considered a significant medical AE by the investigator based on medical judgement (eg, 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
The following are NOT considered SAEs: 
x 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
x 
Hospitalization for social/convenience considerations 
x 
Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience 
10.5 Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets the 
definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the Investigator’s Brochure. 
10.6 Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
10.6.1 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study treatment or initiation of new anticancer therapy, 
whichever occurs first. Immune-related adverse events (serious or non-serious) should be reported until 
90 days after the last dose of BGB-A317, regardless of whether or not the patient starts a new anticancer 
therapy. 
The investigator should report any SAEs that are assessed as related to BGB-A317 treatment, at any 
time after treatment discontinuation. 
10.6.2 
Reporting Serious Adverse Events 
10.6.2.1 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the event 
must be reported promptly (within 24 hours) to the sponsor or designee as described in Table 7. 


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Table 7. 
Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-
up Report 
Documentation 
Method 
Reporting 
Method 
All SAEs 
Within 24 hours 
of first knowledge 
of the SAE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Email or fax 
SAE form or 
pregnancy 
form 
Abbreviation: SAE, serious adverse event. 
10.6.2.2 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 10.6.2.1. The SAE Report will 
always be completed as thoroughly as possible with all available details of the event, and forwarded to 
the sponsor or designee within the designated time frames.  
If the investigator does not have all information regarding an SAE, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE and completing the form. 
The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 10.3.3. 
The sponsor will provide contact information for SAE receipt. 
10.6.2.3 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 10.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the 
local regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
The investigator, or responsible person according to local requirements, will comply with the applicable 
local regulatory requirements related to the reporting of SAEs to regulatory authorities and the 
institutional review board/independent ethics committee (IRB/IEC). 
All SUSARs (as defined in Section 10.5), will be submitted to all applicable regulatory authorities and 
investigators for BGB-A317 studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible person is 
required to promptly notify his/her IRB or IEC. The investigator should place copies of Safety Reports 
from the sponsor in the Investigator Site File. 


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10.6.3 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions:  
x 
How are you feeling?  
x 
Have you had any medical problems since your last visit?  
x 
Have you taken any new medicines since your last visit?  
10.6.4 
Recording Persistent or Recurring Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation time 
points. A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent AEs should be recorded separately on the eCRF (and SAE report, if 
applicable).  
10.6.5 
Disease Progression 
Disease progression (including fatal disease progression), which is expected in this study population 
and measured as an efficacy endpoint, should not be reported as an AE term. Instead, the symptoms, 
signs or clinical sequelae that result from disease progression should be reported as the AE term(s). 
For instance, a patient presents with pleural effusion resulting from disease progression of metastasis 
to lungs. The event term should be reported as “pleural effusion” instead of disease progression. If a 
patient experienced a fatal multi-organ failure due to disease progression, the term “multi-organ failure” 
should be reported as the SAE with death as outcome instead of reporting “fatal disease progression” 
or “death due to disease progression.” 
10.6.6 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is death and 
the cause of death is unknown, then the death is reported as an event, eg “death,” “death of unknown 
cause,” or “death unexplained.” 
10.6.7 
Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving investigational 
therapy or within 120 days after the last dose of BGB-A317, a pregnancy report form is required to be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. Information on 
the status of the mother and child will be forwarded to the sponsor. Generally, follow-up will be no 
longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the 
pregnancy will be reported. 
While pregnancy itself is not considered to be an adverse event, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  


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An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drug 
should be recorded and reported as an SAE. 
10.6.8 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify and 
expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs, and IECs 
based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the expectedness 
of the SAEs using the following reference safety information (RSI) documents: 
x 
BGB-A317 Investigator’s Brochure 
10.7 Assessing and Recording Immune-Related Adverse Event 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related (see Section 10.7.1) should be classified as irAEs and identified as 
such in the eCRF AE page until Day 90, after treatment discontinuation. 
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, which 
are commonly seen with immune checkpoint inhibitors, in Appendix 3. 
An extensive list of potential irAEs appears in Section 10.7.1, Table 8. All conditions similar to those 
listed should be evaluated to determine whether they are irAEs, based on a similar diagnostic process 
to those reactions that are presented in more detail in Appendix 3. 
10.7.1 
Immune-Related Adverse Events  
Immune-related AEs are of special interest in this study. If the events listed below or similar events 
occur, the investigator should exclude alternative explanations (eg, combination drugs, infectious 
disease, metabolic, toxin, disease progression or other neoplastic causes) with appropriate diagnostic 
tests, which may include but is not limited to serologic, immunologic, and histologic (biopsy) data. If 
alternative causes have been ruled out; the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy and is consistent with an immune-mediated mechanism of 
action, the irAE indicator in the eCRF AE page should be checked. 
A list of potential irAEs is shown below in Table 8. All conditions similar to those listed should be 
evaluated in patients receiving BGB-A317 to determine whether they are immune-related.  
Recommendation for diagnostic evaluation and management of irAEs is based on the European Society 
for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) guidelines 
(Brahmer et al., 2018, Haanen et al., 2017). Common immune-related toxicities are detailed in 
Appendix 3. For any adverse events not included in Appendix 3, please refer to the ASCO Clinical 


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Practice Guideline (Brahmer et al., 2018) for further guidance on diagnostic evaluation and 
management of immune-related toxicities. 
Table 8. 
Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common): 
pruritus or maculo-papular rash; vitiligo 
Skin (moderate): 
follicular or urticarial dermatitis; erythematous/lichenoid rash; 
Sweet’s syndrome 
Skin (severe-rare):  
full-thickness necrolysis/Stevens Johnson syndrome 
Gastrointestinal: 
colitis (includes diarrhea with abdominal pain or 
endoscopic/radiographic evidence of inflammation); pancreatitis; 
hepatitis; aminotransferase (ALT/AST) elevation; bowel 
perforation 
Endocrine: 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with 
features of hypopituitarism, eg, fatigue, weakness, weight gain; 
insulin-dependent diabetes mellitus; adrenal insufficiency 
Respiratory: 
pneumonitis/diffuse alveolitis  
Eye: 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular: 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre 
syndrome; aseptic meningitis; myasthenic syndrome/myasthenia 
gravis, meningoencephalitis; myositis 
Blood: 
anemia; leukopenia; thrombocytopenia 
Renal: 
interstitial nephritis; glomerulonephritis; acute renal failure  
Cardiac: 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Dose modification and management for irAEs are detailed in Appendix 3. 
If a toxicity does not resolve to İ Grade 1 within 12 weeks, study drug(s) should be discontinued after 
consultation with the sponsor. Patients who experience a recurrence of any event at the same or higher 
severity grade with rechallenge should permanently discontinue treatment. 


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11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
11.1 Sample Size Considerations  
The sample size at Phase I dose-verification study will depend on the number of dose levels assessed 
and the occurrence of dose-limiting toxicity (DLT) at each dose level. The safety of to-be-assessed 
doses will determine whether it is necessary to evaluate additional doses with corresponding sample 
sizes. It is expected that about 20 subjects will be enrolled.  
In Phase I PK sub-study, total 48 subjects (24 per arm) are planned to be enrolled to receive treatment 
of BGB-A317 of two manufacturing processes and scales (500L-FMP and 2000L-FMP).  
In Phase II dose-expansion study, approximately 220 subjects will be enrolled for preliminary efficacy 
and safety of BGB-A317 monotherapy. The statistical basis for the number of subjects enrolled into 
each group in Phase II will be detailed in the Statistical Plan. 
11.2 General Considerations for Data Analysis 
Data will be listed and summarized using Version SAS® 9.2 or higher (SAS Institute, Inc., Cary, North 
Carolina) according to sponsor agreed reporting standards, where applicable. Complete details will be 
documented in the reporting and analysis plan. 
The following descriptive statistics will be used to summarize the trial data on the basis of their nature 
unless otherwise specified: 
• 
Continuous variables: number of non-missing observations, mean, standard deviation, median, 
minimum, and maximum 
• 
Categorical variables: frequencies and percentages 
• 
Time-to-event variables: number of non-missing observations (N), median, minimum and 
maximum. Kaplan-Meier event rates may also be provided if applicable for specific time to 
event variables 
Efficacy and safety data will be statistically collected by stage and indication unless otherwise specified. 
Further description of the statistical methods and analyses will be provided in the statistical analysis 
plan. 
11.2.1 
Analysis Sets 
Safety analysis set: including all subjects who have received (or begun to receive) BGB-A317.  
PK analysis set; including all subjects who have valid data of BGB-A317 PK parameters after 
receiving treatment.  
Efficacy analysis set: including all subjects who have received any dose of BGB-A317 and had 
measurable disease per investigator according to RECIST v1.1 at baseline and post-baseline. 
All assessable data of other parameters will also be included in the summaries. 


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Detailed statistical methods will be thoroughly described in the Statistical Plan. 
11.2.2 
Study Analysis 
This study protocol includes 3 categories of analyses.  
The first analysis will be performed after the dose-limiting toxicity (DLT) assessments among the Phase 
I subjects has completed, which will focus on evaluation of the safety, tolerability and PK analysis of 
BGB-A317. 
The second analysis will be performed for PK sub-study in Phase I, assessing PK characteristics, safety 
and anti-tumor activity in patients receiving BGB-A317 of two manufacturing processes and scales 
(500L-FMP and 2000L-FMP). 
RP2D and the method of drug administration for the Phase II study will be determined according to the 
results of the first analysis. The third analysis will be carried out after the completion of the entire study, 
including the safety, tolerability, pharmacokinetics and efficacy of BGB-A317. This study will end if 
all subjects experience disease progression, intolerable toxicity, death, withdraw from the study or 
complete the whole 24-month treatment. 
All these three categories of analytical results will be included in the clinical study report. 
11.3 Efficacy Analyses 
Efficacy is not a primary objective of Phase I stage of this study. Objective response rate is a primary 
endpoint of Phase II stage. There is no formal statistical testing for this endpoint, which will serve as a 
descriptive endpoint. 
Response based on investigators’ judgment will be collected in the screening period and while on study 
approximately every 9 weeks in the first 12 months and approximately 12 weeks thereafter in the simple 
form of four categories: PD, SD, CR, and PR (according to RECIST Version 1.1). Listing of the data 
will be provided. If necessary, a summary of data by category will be provided. 
Objective Response 
The number and proportion of subjects who achieve objective tumor response (CR or PR) or SD will 
be summarized. Objective response rate will be determined along with 95% confidence interval. 
PFS 
PFS is defined as the time from the date of first study dose to disease progression or death (whichever 
occurs first).  
Kaplan-Meier methodology will be used to estimate median PFS and 95% confidence interval. 
Kaplan-Meier curves will be constructed to provide a visual description of the PFS change with time. 


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DOR 
DOR for responders (CR or PR) is defined as the time interval between the date of the earliest qualifying 
response and the date of PD or death for any cause (whichever occurs earlier). 
Kaplan-Meier curve will be used to estimate median time and 95% confidence interval for DOR.  
DCR 
DCR is defined as the proportion of subjects in specific tumor types reaching CR, PR and SD in 
accordance with RECIST V1.1 criteria. DCR will be statistically counted within the 95% confidence 
interval by tumor type. 
CBR 
CBR is defined as the proportion of subjects in specific tumor types reaching CR, PR and persistent SD 
(SD ı 24 weeks) in accordance with RECIST V1.1 criteria. CBR will be statistically counted within 
the 95% confidence interval by tumor type. 
OS 
OS is defined as the time from the date of first study dose to death. Kaplan-Meier curve will be used to 
estimate OS at different time points. 
11.4 Safety Analyses 
All subjects who have received (or begun to receive) BGB-A317 will be evaluated for safety. Safety 
data will be summarized according to dose level in dose verification study of Phase I, two 
manufacturing processes and scales in PK sub-study of Phase I and tumor types in Phase II, respectively. 
11.4.1 
Dose-Limiting Toxicity 
The number and proportion of subjects experiencing DLTs will be reported by dose level, based on 
DLT observations during Cycle 1 in the dose verification stage of Phase I. The DLT analysis set will 
be used for this analysis.  
No DLT analysis is conducted in Phase II. 
11.4.2 
Adverse Event 
Adverse events will be coded and grouped using the latest version of MedDRA 16.1 or above. Adverse 
events and toxicities will be graded according to NCI-CTCAE, Version 4.03 (Common Terminology 
Criteria Version 4.03, 2010). Analyses will include but may not be restricted to: 
• 
All Adverse Events 
• 
Serious Adverse Events (SAEs) 


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• 
AEs related to trial medication 
• 
AEs leading to withdrawal of study treatment 
• 
AEs leading to death 
The number and percent of subject will be summarized for various items above. And the number and 
frequency of these adverse events will be also summarized according to MedDRA System Organ 
Classes and Preferred Terms. 
11.4.3 
Laboratory Assessments 
Clinical laboratory (eg, hematology, serum chemistry) values to be evaluated will be specified in the 
Statistical Analysis Plan and collected in the electronic data capture (EDC) system. Collected values 
may be a subset of all the values obtained in the requested sampling, eg, a CBC with differential may 
be requested to allow for evaluation of neutrophils only. Analyzed laboratory values that are abnormal 
will be flagged and identified outside (above or below) the normal range. 
11.4.4 
Electrocardiogram 
Clinically significant abnormalities on ECG should be noted in the EDC and changes from baseline 
will be summarized and listed. 
11.4.5 
Vital Signs 
Specific vital signs, eg, blood pressure and temperature will be summarized and listed. The change 
from baseline will also be displayed. 
11.4.6 
Extent of Exposure 
Exposure to BGB-A317 will be calculated for each subject. Overall exposure will also be summarized. 
11.4.7 
Physical Examination 
Physical examination results collected in association with an adverse event will be listed and 
summarized. 
11.5 Pharmacokinetic Analyses 
Pharmacokinetic parameters will be derived using standard non-compartmental methods with 
WinNonlin Professional Version 5.2 or higher (Pharsight Corp., Mountain View, California) or SAS® 
Version 9.2 or higher (SAS Institute, Inc., Cary, North Carolina). Nominal sampling times will be used 
for interim PK parameter calculations, while actual sampling times will be used in the final PK 
parameter calculations. 
BGB-A317 PK variables (eg, Cmax, Tmax, Ctrough, AUC, Cl, and Vz) will be calculated as appropriate and 
summary statistics will be provided. Graphical, non-compartmental and potentially exploratory 
compartmental analyses will be used for the analysis of the PK data. An exploratory analysis of a 


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potential relationship between dose level, PK variables and clinical safety and anti-tumor activity will 
be performed as appropriate.
11.6


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12. 
ETHICS 
12.1 National Regulations and the Declaration of Helsinki 
The implementation of the study must be in accordance with the Good Clinical Practice (GCP) based 
on Declaration of Helsinki and laws & regulations applicable to clinical trial conducting in order to 
protect subjects to be best extent. 
12.2 Informed Consent 
Investigators or representatives authorized by investigators must obtain the informed consent form 
signed by subjects participating in the study, must explain the nature, objectives, potential risks and 
benefits of the study to subjects, and must inform the subjects that they can withdraw from the study at 
any time without any restriction. If subjects are not able to sign the informed consent form, subjects’ 
legal representatives must sign the informed consent form instead. If subjects and their legal 
representatives are not able to read the informed consent form, a third-party witness must be present 
throughout the entire process of informed consent. After subjects and their legal representatives 
verbally agree to participate in the study, the witness must sign on the informed consent form, and 
ensure that the subjects and their legal representatives have been fully explained and have understood 
the content, and that subjects also have known that they can withdraw from the study at any time without 
any restriction. Subjects' informed consent can be documented in eCRF. If safety results lead to major 
changes in risk/benefit assessment, the informed consent form should be reviewed and modified if 
necessary. All subjects (including those who already started to receive treatments) must be notified of 
updates and may continue with the study only after signing a new informed consent form. 
12.3 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
The clinical study protocol and its amendments, IB, informed consent form, subject information related 
to the study (such as subject recruitment advertisement) as well as other required documents should all 
be reviewed by the Independent Ethics Committee/Institutional Review Board (IEC/IRB). 
The study must be approved by the IEC/IRB before initiation, and the date of the meeting with IEC/IRB 
and date of approval should be indicated in the approval letter to the investigators. 
Any amendment to the protocol must be formally approved or kept on record by the IEC/IRB. 
All serious adverse events will be reported to the relevant ethics committees and regulatory agencies in 
accordance with corresponding regulations. 
In the middle of the study, any protocol deviations that may increase the risk of subjects should also be 
promptly reported to the IEC/IRB by the investigator. 
12.4 Protocol Modifications 
The modified protocol must be submitted to the Ethics Committee for approval. Prior to the approval, 
investigators should still follow the original study protocol, unless the modifications can immediately 


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eliminate potential harm to subjects or only involve changes in study management (eg, change of phone 
numbers, etc.). 
13. 
PRESERVATION OF STUDY DOCUMENTS, CASE REPORT FORM AND 
RECORDS 
13.1 Study Documents and Document Preservation 
Investigators must adequately and accurately record the study process and ensure the study data can be 
verified. These documents can be divided into two categories—one is investigator documents, and the 
other is original subject data. 
Investigator documents include the protocol and its amendments, case report forms and data query 
forms, approval from Ethics Committees & regulatory agencies and correspondence with them, samples 
of informed consent forms, study drug inventory, investigators’ resumes and authorization forms, and 
other required documents and correspondence. 
The subject's original documents (key efficacy/safety data to be recorded should be pre-defined) include 
inpatient/outpatient records, the doctor's medical advice, visit reservation date, original laboratory 
examination results, ECG, CT slices, positron emission tomography reports/slices, pathology reports 
and reports of special assessments, signed informed consent forms, consultation records and subject 
screening and enrollment forms, etc. 
Investigators need to keep these documents intact within 5 years after the study is completed, and must 
contact the sponsor before the destruction of any study document. 
If investigators are willing to transfer these study documents to another party or another place, please 
notify the sponsor in advance. 
If investigators cannot guarantee the quality of document preservation in the study centers, investigators 
and the sponsor can jointly arrange to preserve documents in other places. These documents must be 
preserved sealed, so that investigators will be able to retrieve them in case of audits by regulatory 
agencies. If the documents will be in use, copies can be preserved at different places. 
13.2 Original Documents and Data 
When eCRF is illegible or when errors occur in the middle of data transfer, investigators should provide 
the study documents or original data in medical records upon request of the sponsor. In the cases of 
specific queries, queries from regulatory agencies and/or request during inspections, complete study 
records should be accessible on the condition of subjects’ privacy being protected. 
13.3 Audit and Inspection 
The investigator should understand that when the sponsor, a third party designated by the sponsor or 
the department of drug administration inspects the study, they should be able to directly access the 


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original documents in the study, and that the data in the eCRF should be directly derived from the 
original data. 
13.4 Case Report Form 
The Principal investigator or other designated investigators must complete and sign the eCRF of each 
enrolled subject and subjects who have failed to complete the study (even including subjects who have 
failed the screening). If a subject withdraws from the study, the reason of withdrawal should be recorded 
in the eCRF. If a subject withdraws from the study due to treatment-related adverse events, the outcome 
should be recorded as clearly as possible. 
Investigators should complete eCRF and related forms accurately, completely, clearly and timely. 
13.5 Use and Publication of Study Data 
13.5.1 
Use of Study Data 
All study data related to BGB-A317, such as patent applications, dosage forms, production processes 
and scales, basic research and other information, if not published, should be deemed confidential. 
The data obtained in this study will also be considered as confidential information. BeiGene (Shanghai) 
Co., Ltd. will publicize the data to other clinical researchers, the China National Medical Products 
Administration or other government agencies at an appropriate time. In order to ensure the integrity of 
data analysis in this clinical study, investigators have obligation to provide complete study results and 
data to the sponsor. 
Investigators must ensure that subjects’ privacy is not disclosed to unauthorized third parties. eCRFs 
and other documents submitted to the sponsor must not contain the subjects' names that should be 
replaced with identification codes used for distinction. Investigators may keep enrollment forms 
containing subjects’ identification codes, names and addresses. Informed consent forms and other 
documents should be preserved strictly confidentially and should not be submitted to the sponsor. 
13.5.2 
Publication 
Study results may be published on core journals. The principal investigator who has major contribution 
to the study implementation & management and staffs who have made great contribution to study 
design, explanation or analysis can put names on publications. 
BeiGene (Shanghai) Co., Ltd. guarantees that before publishing any result of this study, articles will be 
provided to investigators for review. Accordingly, investigators should obtain consent from the sponsor 
before submitting any academic paper or abstract. Investigators have the right to publish results of this 
study, as long as requirements of confidential data protection are met. 


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Intellectual property rights of confidential data only belong to BeiGene (Shanghai) Co., Ltd. Without 
any written consent from BeiGene (Shanghai) Co., Ltd., confidential data should not be disclosed to 
other parties and may not be used for purposes beyond the study. 
14. 
REFERENCES 
BeiGene Investigator’s Brochure, BGB-A317. Edition 6.0, November 2018. 
Brahmer J R, Drake C G, Wollner I, et al., Phase I study of single-agent anti-programmed death-1 
(MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
correlates. J Clin Oncol, 2010. 28(19): 3167-75. 
Brahmer J R, Lacchetti C, Schneider B J, et al. Management of immune-related adverse events in 
patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology 
Clinical Practice Guideline. J Clin Oncol, 2018. 36(17): 1714-68. 
Bristol-Myers Squibb, BLA 125377 Yervoy (ipilimumab) risk evaluation and mitigation strategy 
http://www.fda.gov/downloads/Drugs/DrugSafety/PostMarketDrugsafetyInformationforPatientsandPr
oviders/UCM249435.pdf. Published February 2012. Accessed 24 January 2019. 
Bristol-Myers Squibb, Opdivo (nivolumab) immune-mediated adverse reactions management guide. 
http://www.opdivohcp.com/servlet/servlet.FileDownload?file=00P1Y00000sCn4lUAC. 
Published 
June 2018. Accessed 24 January 2019. 
Common Terminology Criteria Version 4.03. Cancer Therapy Evaluation Program. June 2010. 
Ghebeh H, Mohammed S, Al-Omair A, et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule 
is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important 
high-risk prognostic factors. Neoplasia, 2006. 8(3): 190-8. 
Haanen J.B.A.G., et al., Management of toxicities from immunotherapy: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up.Annals of Oncology, 2017. 28(4): 119-142 
Hamanishi J, Mandai M, Iwasaki M, et al., Programmed cell death 1 ligand 1 and tumor-infiltrating 
CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A, 2007. 
104(9): 3360-5. 
Hamid O, Robert C, Daud A, et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med, 2013. 369(2): 134-44 
Hino R, Kabashima K, Kato Y, et al., Tumor cell expression of programmed cell death-1 ligand 1 is a 
prognostic factor for malignant melanoma. Cancer, 2010. 116(7): 1757-66. 
Hou J, Wang G, Wang F, et al., Guideline of prevention and treatment for chronic hepatitis B (2015 
update). J Clin Transl Hepatol, 2017. 5(4):297-318. 
Howard S C, Jones D P, and Pui C H, The tumor lysis syndrome. N Engl J Med, 2011. 364(19): 1844-
54. 
International Conference on Harmonization Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95). July 1996 


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Jie H B, Gildener-Leapman N, Li J, et al., Intratumoral regulatory T cells upregulate 
immunosuppressive molecules in head and neck cancer patients. Br J Cancer, 2013. 109(10): 2629-35. 
Konishi J, Yamazaki K, Azuma M, et al., B7-H1 expression on non-small cell lung cancer cells and its 
relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res, 2004. 
10(15): 5094-100. 
McDermott D F and Atkins M B, PD-1 as a potential target in cancer therapy. Cancer Med, 2013. 2(5): 
662-73. 
Riley J L, PD-1 signaling in primary T cells. Immunol Rev, 2009. 229(1): 114-25. 
Rustin G J, Vergote I, Eisenhauer E, et al., Definitions for response and progression in ovarian cancer 
clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup 
(GCIG). Int J Gynecol Cancer, 2011. 21(2): 419-23. 
Soar J, Pumphrey R, Cant A, et al. Emergency treatment of anaphylactic reactions--guidelines for 
healthcare providers. Resuscitation. 2008 May;77(2):157-69. 
Sznol M, Kluger H M, Callahan M K, et al. Survival, response duration, and activity by BRAF mutation 
(MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) 
concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014.32:5s (suppl; abstr LBA9003^). 
Thompson R H, Dong H, Lohse C M, et al., PD-1 is expressed by tumor-infiltrating immune cells and 
is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res, 2007. 13(6): 
1757-61. 
Thompson R H, Gillett M D, Cheville J C, et al., Costimulatory B7-H1 in renal cell carcinoma patients: 
Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A, 2004. 
101(49): 17174-9. 
Topalian S L, Hodi F S, Brahmer J R, et al., Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med, 2012. 366(26): 2443-54. 
Tsushima F, Tanaka K, Otsuki N, et al., Predominant expression of B7-H1 and its immunoregulatory 
roles in oral squamous cell carcinoma. Oral Oncol, 2006. 42(3): 268-74. 
Weber J S. Anti-PD1 Antibody Therapy for Melanoma. 2014 ASCO Annual Meeting. 
Wolchok J D, Hoos A, O'Day S, et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): 7412-20. 
Wolchok J D, Kluger H, Callahan M K, et al., Nivolumab plus ipilimumab in advanced melanoma. N 
Engl J Med, 2013. 369(2): 122-33. 
 
 


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15.
APPENDICES
APPENDIX 1.
FLOW CHARTS
Test Design
Phase I – Pharmacokinectics (PK) sub-study
Abbreviation: FMP = Final Manufacturing Process; PK = pharmacokinetics; Q3W = once every three weeks
Q3W from Cycle 2
Sparse PK
Q3W from Cycle 2
Sparse PK
500L-FMP
n= 24
Cycle 1        
(4 weeks)
Intensive PK
2000L-FMP
n= 24
Cycle 1        
(4 weeks)
Intensive PK
1A: Dose escalation *
1B: Indication expansion **
* Study design
●
DLT assessment period: 3-6 subjects are enrolled 
into the cohort to confirm safety and RP2D, and 
then it can be expanded to 20 patients
●    May explore lower or higher doses
Melanoma
Non-small cell lung cancer (PD-L1 positive)
Non-small cell lung cancer (PD-L1 negative)
Gastric cancer
Esophageal cancer
Renal cell carcinoma
Urothelial carcinoma
MSI-H or dMMR colorectal cancer
Triple negative breast cancer, head and 
neck squamous cell carcinoma, small 
cell neuroendocrine carcinoma or other 
tumors with known MSI-H or dMMR
** About 20 patients will be enrolled into each cohort, and for 
tumor types with difficulties in enrolling subjects, the sponsor may 
terminate the enrollment for this cohort earlier
Nasopharyngeal carcinoma
Abbreviations: MSI-H, microsatellite instability-high; dMMR, mismatch repair deficient.
Hepatocellular Carcinoma


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Flow chart for Phase I 
Screening 
Day -28 to Day -11  
Cycle 1 
Day 1 to Day 21 or 
Day 1 to Day 282 
 
Dosing on Day 1 
 
Subsequent cycles 
Day 1 to Day 21 
 
Once Three Weeks 
administration 
 
Follow-up 
30 days (±3 days) 
after the end of 
treatment 
 
 
 
 
1. 
Fresh tumor biopsy samples need to be collected within 42 days prior to the first dose if subjects 
have no archival tumor tissue samples. Other screening assessments need to be completed within 
28 days prior to the first dose of the study drug. 
2. 
The duration of the first cycle for the first 20 subjects will be 21 days, and DLT will be conducted 
in this period; the duration of the first cycle for the rest 48 subjects will be 28 days, which will be 
performed for the PK analyses of the products derived from two manufacturing processes and 
scales (500L-FMP vs 2000L-FMP),  
 
Dose Verification for Phase I 
Abbreviations: DLT: dose-limiting toxicity; MTD: maximum tolerated dose; SMC: Safety Monitoring 
Committee. 
a 
If none (0) of the subjects in the cohort experience a DLT by the end of Cycle 1, the study will proceed to 
Phase II, as determined by the SMC. If one (1) out of six (6) subjects experience a DLT by the end of Cycle 
1, whether or not proceeding to Phase II will be determined by SMC.  
b 
No additional subjects will be treated at a given dose level if two (2) or more of the subjects in a cohort 
develop a DLT in Cycle 1. In this instance the MTD is considered to have been exceeded and as noted 
above, the MTD will be considered to be the dose level below this level or an intermediate dose level that 
has been evaluated and has not exceeded the MTD. 
c 
Additional subject(s), up to a maximum of six (6) subjects in total, will be enrolled if more than three (3) 
subjects have been screened and are eligible for the cohort. The DLT assessment and dose-escalation 
scheme will follow the rules stipulated in the modified 3 + 3 dose escalation scheme. For example, three (3) 
SMC determined Dosea 
N=3c 
0/3c DLT 
1/3c DLT 
200 mg Q3W 
N=3c 
Dose (repeat) 
N=3c 
MTD exceededb 
2/3c DLT 
0/3c DLT 
1/3c DLT 
1/6 
DLT 
2/3c 
DLT 
2/6 DLT 


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additional subjects will be enrolled if a DLT is observed in one (1) of three (3) subjects; additional two (2) 
subjects will be enrolled if a DLT is observed in one (1) of four (4) subjects; and additional one (1) subject 
will be enrolled if a DLT is observed in one (1) of five (5) subjects. No additional subjects are required if a 
DLT is observed in one (1) of six (6) subjects. 
 
Flow chart for Phase II 
Pre-
screening 
56 Days 
before 
screening 1 
 
Screening 
Day -28 to 
Day -12 
 
Cycle 1 
Day 1 to Day 21 
Once Three 
Weeks 
administration 
 
Subsequent 
cycles 
Day 1 to 
Day 21 
Once Three 
Weeks 
administration 
 
Follow-up 
30 days 
(±3 days) 
after the 
end of 
treatment 
 
 
 
 
 
1. Tumor samples and blood samples should be collected for detecting MSI or MMR mutation status 
during pre-screening period İ 8 weeks prior to screening period from subjects to be enrolled in Arm 8 
when their biomarkers are unknown. 
2. Fresh tumor biopsy samples need to be collected within 42 days prior to the first dosing if subjects 
have no archival tumor tissue samples. Other screening assessments need to be completed within 
28 days prior to the first dose of the study drug. 


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APPENDIX 2. 
CHILD-PUGH LIVER FUNCTION CLASSIFICATION 
The following data were obtained from the Child-Pugh classification criteria by medical center of 
University of Washington, with references as follows: 
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement 
of adults on the liver transplant waiting list. Liver Transl Surg 1997;3(6):628-637. 
Pugh RNH, Murray-Lyon IN, Dawson DL, Pietroni MC, and Williams R. Transection of the esophagus 
for bleeding esophageal varices. Brit J Surgery 1973; 60:646-645. 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion. 
N Engl J Med. 1996;274(9):473-481.  
Child-Pugh classification is divided into Grade A (mild: 5 to 6 points), B (moderate: from 7 to 9 points), 
or C (severe: 10 to 15 points). Child-Pugh classification is determined by clinical and biochemical 
parameters, please see Table 9 for details. 
 
Table 9. 
Clinical and biochemical parameters of Child-Pugh classification 
 
Clinical and biochemical parameters 
Score of the severity of the anomaly 
1 
2 
3 
Hepatic encephalopathy (Grade) a 
0b 
1c or 2d 
3e or 4f 
Ascites 
No 
mild 
moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prolonged prothrombin time (seconds) 
or 
Activated partial thromboplastin time (APTT) 
INRg 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviation: INR, International standardization ratio 
 
a Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion. N Engl 
J Med. 1996;274(9):473-481. 
b Grade 0: consciousness, personality, neurological examination and ECG are all in normal condition. 
c Grade 1: restlessness, sleep disorders, irritability / anxiety, hand tremor, writing disorders, 5CPS waves. 
d Grade 2: lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e Grade 3: drowsiness, coma, orientation disorder, over reflection, stiff, slow wave. 
f Grade 4: Cannot wake up from coma, no independent personality / behavior, irrational, slow 2-3CPS Delta 
activity. 
g Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list. Liver Transl Surg 1997;3(6):628-637. 


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APPENDIX 3. 
IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE are intended as a guidance. 
This document should be used in conjunction with expert clinical judgement (by specialist physicians 
experienced in the treatment of cancer using immunological agents), and individual institutional 
guidelines or policies. 
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, and 
adverse effects of concomitant drugs. In addition to the results of these tests, the following factors 
should be considered when making an irAE diagnosis:  
x 
What was the temporal relationship between initiation of BGB-A317 and the adverse event? 
x 
How did the patient respond to withdrawal of BGB-A317? 
x 
Did the event recur when BGB-A317 was reintroduced? 
x 
Was there a clinical response to corticosteroids? 
x 
Is the event an autoimmune endocrinopathy? 
x 
Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field, associated 
with the AE in the eCRF should be checked. 
Table 1. 
Recommended Diagnostic Tests in the Management of Possible Immune-related 
Adverse Events 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
Colitis 
Review dietary intake and exclude steatorrhea. Consider 
comprehensive testing, including the following: FBC, UEC, LFTs, 
CRP, TFTs, stool microscopy and culture, viral PCR, Clostridium 
difficile toxin, cryptosporidia (drug-resistant organism). 
In case of abdominal discomfort, consider imaging, eg, X-ray, CT 
scan. If a patient experiences bleeding, pain or distension, consider 
colonoscopy with biopsy and surgical intervention, as appropriate. 
Dermatology 
Consider other causes by conducting a physical examination, consider 
dermatology referral for skin biopsy. 
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye 
inflammation, blurred vision, or other visual disturbances, refer the 
patient urgently to an ophthalmologist for evaluation and management. 


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Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will 
depend on severity of the AE (eg, daily if grade 3-4; every 2-3 days if 
grade 2, until recovering). Review medications (eg, statins, antibiotics) 
and alcohol history. Perform liver screen including Hepatitis A/B/C 
serology, Hepatitis E PCR and assess anti-
ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a 
hepatologist and consider liver biopsy. 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. 
Perform pituitary and whole brain MRI in patients with headache, 
visual disturbance, unexplained fatigue, asthenia, weight loss and 
unexplained constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is 
detected. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete 
musculoskeletal examination. Consider joint X-ray and other imaging 
as required to exclude metastatic disease. Perform autoimmune 
serology and refer to rheumatology for further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, 
CRP, troponin, and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), 
and refer to a cardiologist. 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for 
all central nervous system symptoms; review alcohol history and other 
medications. Conduct a diabetic screen, and assess blood B12/folate, 
HIV status, TFTs, and consider autoimmune serology. Consider the 
need for brain/spine MRI/MRA and nerve conduction study for 
peripheral neuropathy. Consult with a neurologist if there are 
abnormal findings. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or 
signs, such as an upper respiratory infection, new cough, shortness of 
breath or hypoxia should be assessed by high-resolution CT. Consider 
pulmonary function test including DLCO. 
Radiographic appearance is often nonspecific. Depending on the 
location of the abnormality, bronchoscopy and bronchoalveolar lavage 
or lung biopsy may be considered. Consult with a respiratory medicine 
physician for cases of uncertain cause. 


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Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
Renal toxicity 
Review hydration status, and medication history. Test and culture 
urine. Consider renal ultrasound scan, protein assessment (dipstick/24-
hour urine collection), or phase-contrast microscopy. Refer to 
nephrology for further management assistance. 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4). 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CRP, C-reactive protein; CT, 
computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, electrocardiogram; ESR, 
erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency virus; INR, international 
normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney microsomal antibody; 
LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; PCR, 
polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, thyroxine; TFT, 
thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
Treatment of Immune-related Adverse Events 
x 
Immune-related AEs can escalate quickly; study treatment interruption, close monitoring, 
timely diagnostic work-up and treatment intervention, as appropriate, with patients is required 
x 
Immune-related AEs should improve promptly after introduction of immunosuppressive 
therapy. If this does not occur, review the diagnosis, seek further specialist advice and contact 
the study medical monitor 
x 
For some grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after consultation 
with the study medical monitor 
x 
Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory irAEs, 
consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
x 
Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-
term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline. 
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms 
worsen on treatment manage as a 
grade 3 event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
Severe pain with 
inflammation or 
permanent joint 
damage, daily living 
activity limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Colitis/ 
Diarrhea 
1 
Mild symptoms: 
< 3 liquid stool per day 
over baseline and 
feeling well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If grade 1 persists for > 14 days 
manage as a grade 2 event 
Continue study 
treatment. 
2 
Moderate symptoms: 4-
6 liquid stools per day 
over baseline, or 
abdominal pain, or 
blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids 
over 2-4 weeks. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
Initiate IV methylprednisolone 
1-2mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 1 month. 
Consider prophylaxis for adverse 
steroid effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, hepatitis, 
NYHA grade III/IV CHF or other 
immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
Grade 0-1 and after 
discussion with the 
study medical monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline. Check for 
C peptide and antibodies against 
glutamic acid decarboxylase and 
islet cells are recommended 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
2 
Fasting glucose value 
160-250 mg/dL; 
8.9-13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week. Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 
13.9-27.8 mmol/L 
Admit patient to hospital and refer 
to a diabetologist for 
hyperglycemia management. 
Corticosteroids may exacerbate 
hyperglycemia and should be 
avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or Grade 0-1. 
4 
Fasting glucose 
value > 500 mg/dL; 
> 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. Refer the patient to a 
diabetologist for insulin 
maintenance and monitoring. 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week. 
Continue study 
treatment. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs within 48-72 hours: 
For persistent ALT/AST elevation: 
consider oral prednisolone 
0.5-1 mg/kg/day for 3 days then 
taper over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over at least 2-4 weeks; re-escalate 
dose if LFTs worsen, depending on 
clinical judgement.  
Hold study treatment, 
treatment may be 
resumed when 
resolved/improved to 
Grade 0-1 and 
prednisolone tapered 
to İ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper 
over at least 2-4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day. When LFTs improve 
to grade 2 or lower, convert to oral 
prednisolone and taper over at least 
1 month. 
Hold study treatment 
until improved to 
grade 2; reintroduce 
only after discussion 
with the study medical 
monitor. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 
6 weeks. 
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
If on oral prednisolone change to pulsed IV methylprednisolone 
If on IV add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary 
inflammation. Taper corticosteroids 
over at least 1 month. If there is no 
improvement in 48 hours, treat as 
grade 3-4. Taper corticosteroids 
over at least 1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. 
Initiate pulse IV 
methylprednisolone 1 mg/kg for 
patients with headache/visual 
disturbance due to pituitary 
inflammation. Convert to oral 
prednisolone and taper over at least 
1 month. Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until 
resolved/improved to 
grade 2 or less. 
Discontinuation is 
usually not necessary. 
Mucositis/ 
Stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage 
as a grade 3 event. 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management. Initiate IV 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone when symptoms 
improved to grade 2 and taper over 
at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider IV corticosteroids if 
not contraindicated by infection. 
Discontinue study 
treatment. 
Myocarditis 
1 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
If a diagnosis of 
myocarditis is 
confirmed, 
permanently 
discontinue study 
treatment in patients 
with moderate or 
severe symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline 
and after discussion 
with the study medical 
monitor. 
2 
Symptoms on mild 
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 1-2 
mg/kg/day. Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of 
(methyl)prednisolone 1g/day and 
add MMF, infliximab or anti-
thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2 
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse, initiate 
oral prednisolone 0.5 1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. If symptoms do not 
improve add immunosuppressant 
therapy. Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1. 
Discontinue if any 
evidence of 
myocardial 
involvement 
Nephritis 
1 
Creatinine 1.5X 
baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
2 
Creatinine > 1.5-3X 
baseline or > 1.5-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48 
hours. 
Hold study treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
Grade 0-1: Restart 
study drug if tapered 
to < 10 mg 
prednisolone. 
3 
Creatinine > 3X 
baseline or > 3-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 
1 month. 
Hold study treatment 
until the cause is 
investigated.  
If study drug 
suspected: Discontinue 
study treatment. 
4 
Creatinine > 6X ULN 
As per grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 
0.5-1 mg/kg/day. Taper over at 
least 1 month. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms. Taper 
corticosteroids over at least 1 
month.  
Consider azathioprine, MMF, 
cyclosporine if no response 
Discontinue study 
treatment. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment. Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management. Initiate IV 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone when amylase/lipase 
improved to grade 2, and taper over 
at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate 
referral. 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as 
grade 2. 
Consider holding 
study treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: 
exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if 
symptoms/appearance persist for 48 
hours or worsen. Consider 
Pneumocystis infection 
prophylaxis. Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
İ 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Initiate treatment with IV 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 
2 months. Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and 
other adverse steroid effects, eg, 
blood glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10%-30% 
of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch. 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
Rash covers > 30% 
BSA or grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
x 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day 
for 3 days then taper over 
2-4 weeks. 
x 
For severe symptoms: IV 
methylprednisolone 0.5-1 
mg/kg/day; convert to oral 
prednisolone and taper over 2-
4 weeks. 
Hold study treatment. 
Retreat when AE is 
resolved or improved 
to mild rash (grade 1-
2) after discussion 
with the study medical 
monitor. 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Seek urgent dermatology review. 
Discontinue study 
treatment. 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to 
normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with 
a beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.5 μg/kg/day. Add 
oral prednisolone 0.5 mg/kg/day for 
thyroid pain. Thyrotoxic patients 
require treatment with a beta 
blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; 
CHF, chronic heart failure; CK, creatine kinase; CK-MB, creatine kinase-cardiac muscle isoenzyme; INR, international 


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normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; NYHA, New York Heart 
Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and 
electrolytes; ULN, upper limit of normal. 


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APPENDIX 4. 
CLINICAL LABORATORY ASSESSMENTS AND AMOUNT OF BLOOD 
SAMPLING 
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Albumin 
Total bilirubin 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatine kinase-
cardiac muscle 
isoenzyme (CK-MB)a 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Total protein 
Sodium 
Red blood cell (RBC) 
count 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
Platelet counts 
WBC count with 
differential 
Neutrophil count 
Lymphocyte count 
Monocyte count 
Basophil count 
Eosinophil count 
Prothrombin time 
Partial Thromboplastin 
Time 
International Normalized 
Ratio 
Leucocyte 
count 
Protein 
Specific 
gravity 
pH 
RBC 
Glucose 
Nitrite 
Urobilinogen 
Ketones 
24 h proteinb 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme; pH, negative of the logarithm to base 10 of the 
activity of the (solvated) hydronium ion; RBC, red blood cell; MCH, mean corpuscular hemoglobin; MCHC, 
mean corpuscular hemoglobin concentration; MCV mean corpuscular volume; WBC, white blood cell. 
a In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
b Urine samples will be collected over 24 h for total protein analysis if urinary protein dipstick test result is ı 2+ 
in performing urinalysis. 
Note: On the basis of not affecting the assessment of drug safety, if the study center cannot perform a certain 
laboratory assessment, an alternative indicator assessment can be used, which will not be considered as a 
deviation from the protocol. 
Laboratory test 
Amount of blood 
sampling (mL) 
Serum biochemistry 
5 
Hematology 
3 


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Laboratory test 
Amount of blood 
sampling (mL) 
Coagulation  
3 
HBV/HCV 
5 
Thyroid function 
3 
Pregnancy test 
3 
Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus. 


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APPENDIX 5. 
CONTRACEPTION GUIDELINES 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control. These methods 
include the following: 
x 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
x 
Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion 
x 
Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success 
x 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of exposure associated with the study treatment) 
 
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is 
in line with the patient’s usual and preferred lifestyle. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is not 
considered a highly effective method of contraception and if used, this method must be combined 
with a highly effective form of birth control, listed above. 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15, 2014. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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APPENDIX 6. 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1) GUIDELINES 
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts J, 
Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009; 45:228-247. 
1 Inclusion Criteria  
Only subjects with measurable tumors at baseline can be enrolled into the trial protocol with objective 
tumor response rate as the primary endpoint.  
2 Definition 
Measurable Disease—At least 1 measurable lesion. Must be accurately measured, in at least 
1 dimension, ı 10 mm in long axis for a lesion and ı 15 mm in short axis for a lymph node when 
assessed by CT scan slice thickness of 5 mm; ı 20 mm by chest X-ray (if clearly defined); 10 mm 
caliper measurement by clinical exam (when superficial). Color photographs with scale should be used 
to clearly show its size. If evaluation can be achieved through imaging techniques, imaging technique 
assessment should be preferably selected. 
Non-measurable Disease—All other lesions, including small lesions (longest diameter < 10mm or 
pathological lymph node short axis ı 10 to < 15 mm) and really non-measurable lesions. Lesions that 
are deemed as really non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly that is not measurable by reproducible imaging techniques. 
Exceptions of Measurable Disease: Including bone lesions, cystic lesions and lesions with prior local 
treatment. Bone scan, positron emission tomography scan, or X-ray plain films cannot be used for 
measurement of bone lesions, but can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. If non-cystic 
lesions and cystic lesions coexist, non-cystic lesions are preferred for selection as target lesions. Tumor 
lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are 
usually not considered measurable unless there has been demonstrated progression in the lesion.  
All measurements should be recorded in metric notation, using rulers or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment. 


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3 Measurement 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. 
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules, 
palpable lymph nodes). For the case of skin lesions, documentation by color photography including a 
ruler to estimate the size of the lesion is suggested. 
CT and MRI are the best currently available and reproducible methods to measure target lesions. 
Conventional CT and MRI use a continuous d10 mm thick layer. Spiral CT uses 5 mm thick layer for 
continuous reconstruction algorithm. This standard is suitable for thoracic, abdominal and pelvic 
tumors, while head and neck tumors and extremity tumors usually require special schemes. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. CT is preferred. 
Ultrasound (US) should not be used as a method of measurement of tumor lesion when the primary 
endpoint of the trial is objective response evaluation. The method is not readily accepted in clinical 
practice. This method can be used as an alternative method to clinically measure superficially palpable 
lymph nodes, subcutaneous lesions and thyroid nodules. US approach can also be used to confirm the 
complete disappearance of superficial lesions that are usually evaluated by clinical examination. 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, however, they must normalize for a subject to be considered in complete response if all 
tumor lesions disappear. Elevations of tumor markers must be accompanied by visible disease 
progression to meet the requirements of disease progression. 
In a few cases, cytology and histology can be used to differentiate between PR and CR (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or SD in order to 
differentiate between response (or SD) and progressive disease. 
4 Tumor Response Evaluation  
4.1 “Target” and “Non-target” Lesions Recorded at Baseline  
- All measurable lesions, up to two lesions in each organ, the sum of up to 5 lesions, and representing 
all the organs involved as target lesions, are recorded and measured at baseline. 


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- The selection of target lesions should be based on the size (lesions with a maximum diameter) and 
suitability, so that they can be (by imaging techniques or clinically) accurately and repeatedly measured. 
- Calculate the sum of the longest diameter (LD) of all target lesions, and report it as baseline sum LD. 
Use baseline sum LD as a reference value for description of objective tumor. 
- All other lesions (or sites of disease) should be used as non-target lesions and reported at baseline. 
These lesions are not required to be measured, but the presence or absence of each lesion during the 
entire follow-up period should be recorded. 
4.2 Criteria for Response 
Criteria for Evaluation of Target Lesions 
Complete Response 
(CR): 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
Partial 
Response 
(PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum LD. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
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. 
Criteria for Evaluation of Non-target Lesions 
Complete 
Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/SD: 
Persistence of t1 non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive 
Disease (PD): 
Appearance of t1 new lesions and/or unequivocal progression of existing 
non-target lesions. 
* Although unequivocal progression of “non-target” lesions is an exception, the opinion of the 
treating doctor should be referred to, and the progression status later should be confirmed.  
4.3 Criteria for Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (the minimum measurements recorded from the start of the treatment should 


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serve as reference values for PD). The subject’s best overall response will generally depend on the 
completion of two measurements and the confirmation criteria.  
When the treatment is required to be discontinued due to overall deterioration of the health status, and 
there is no objective evidence indicating disease progression, the subject should be reported as 
"symptomatic deterioration." Objective progression should be recorded as far as possible, even after 
cessation of the treatment. 
In some cases, it is difficult to distinguish residual lesion from normal tissue apart. When the evaluation 
of complete response depends on this decision, it is advised to study the residual lesion (fine needle 
extraction/biopsy) to confirm the complete response status.  
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease; 
NE: not evaluable. 

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