A Phase 1A/1B, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Subjects With Advanced Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: BeiGene

BeiGene Aus Pty Ltd 
 
CONFIDENTIAL 
BGB-A317_Study_001 
 
21 May 2018 
Protocol Amendment 6.0 
Page 1 of 207 
 
 
Clinical Study Protocol 
Protocol Title: 
A Phase 1A/1B, Open Label, Multiple Dose, Dose 
Escalation and Expansion Study to Investigate the 
Safety, Pharmacokinetics and Antitumor Activities of 
the anti-PD-1 Monoclonal Antibody BGB-A317 in 
Subjects with Advanced Tumors 
Protocol Number: 
BGB-A317_Study_001 
Date of Protocol: 
21 May 2018, Version 6.0 (Final) 
Study Phase: 
1 
Sponsor: 
BeiGene Aus Pty Ltd 
c/o Becis Pty Ltd, 1C/528 Compton Road, Stretton 
Queensland 4116, Australia 
Sponsor Medical Monitors: 
 
Coordinating Investigator: 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or consultant for review by you, your 
staff, and the applicable Institutional Review Board/Independent Ethics Committee.  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without written authorization 
from the Sponsor. 

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Signatures 
PROTOCOL TITLE: 
A Phase 1A/1B, Open Label, Multiple Dose, Dose Escalation 
and Expansion Study to Investigate the Safety, 
Pharmacokinetics and Antitumor Activities of the anti-PD-1 
Monoclonal Antibody BGB-A317 in Subjects with Advanced 
Tumors 
PROTOCOL NO: 
 
BGB-A317_Study_001 
 
____________________________________ 
 
 
___________________ 
 
 
 
 
 
 
Date 
Sponsor Medical Monitor 
 
 
 
 
 

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CONFIDENTIAL 
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21 May 2018 
Protocol Amendment 6.0 
Page 3 of 207 
 
PROTOCOL AMENDMENT, VERSION 6.0 RATIONALE 
The primary purpose of this amendment was to address the following requests from the FDA:  
 To include additional hepatitis viral load testing in patients who had detectable 
hepatitis B (HBV) or hepatitis C (HCV) viral load at Screening,  
 To add myocarditis and myositis/rhabodmyolysis as potential immune-related 
adverse events and provide guidelines for their treatment and study drug 
management,  
 To add serum creatine kinase (CK) and creatine kinase cardiac muscle isoenzyme 
(CK-MB) monitoring due to 2 cases of myositis reported with tislelizumab, and  
 To add additional ophthalmologic evaluation time points. 
 
Additional changes made in the amendment are noted below.  Minor editorial changes were 
also made throughout the protocol. 
Applicable Sections 
Description of Revision 
Change: Changed BGB-A317 to the compound’s INN name, tislelizumab, throughout the 
document (did not change the study number or protocol name). 
Reason:  INN name for BGB-A317 is available 
Change: Included additional hepatitis viral load testing every 4 cycles throughout the study for 
patients who had detectable hepatitis B (HBV) or hepatitis C (HCV) viral load at Screening, and 
how to manage subjects with HCC who test positive for HBV or HCV. 
Reason: Based on a request from the FDA, in order to reduce the risk of significant hepatic toxicity 
in patients with active or prior HBV infection, and for consistency across protocols. 
Section 5.1: 
Table 5 + footnote 17,  
Table 7 + footnote 16, 
Table 8 + footnote 16, 
Table 9 + footnote 16, 
Table 11 + footnote 17 
 
Section 8.2.2 
 
Section 11.3.10 
 
Appendix 3 
 
In Section 8.2.2, revised heading to “Physical Examination, 
Ophthalmologic Examination and, Vital Signs, and Hepatitis B and C 
testing 
 
In Section 8.2.2, and in Section 5.1 footnotes for Tables 5, 7, 8, 9, 11 
pertaining to hepatitis B and C assessment, added the following text: 
Subjects enrolled in the study who had detectable HBV DNA or HCV 
RNA at Screening should be tested for HBV or HCV viral load, 
respectively, every 4 cycles (± 7 days) throughout the study, eg 
Screening, Cycle 5, Cycle 9, and so on (and whenever clinically 
indicated). For subjects who already received 4 or more doses of study 
drug, the viral load test should be repeated at the subject’s next visit and 
every 4 cycles according to the schedule from first dose (Cycle 1 Day 1), 
and whenever clinically indicated. HCC subjects who test positive for 
HCV will not be discontinued. HCC subjects who test positive for HBV 
should be treated as per local guidelines at the investigator’s discretion. 
 
In Section 5.1, study assessment tables for each phase/part of the study 
(Tables 5, 7, 8, 9, and 11), separated HIV assessment from hepatitis B and 
C assessment for clarity.  For hepatitis B and C assessment, in addition to 
the “x” at Screening, added “x (Cycle 5 and every 4 cycles)” to each table. 

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Applicable Sections 
Description of Revision 
 
Added Section 11.3.10 Hepatitis B and C, to add the assessment as a safety 
analysis. 
 
In Appendix 3, for each separate study phase, added collection of 3-5 mL 
blood for hepatitis B and C analysis on Cycle 5 Day 1 (and every 4 cycles 
thereafter). 
Change: Clarified the timing of ophthalmologic examinations after Cycle 3 (for Q2W patients)/End 
of Week 9 (for Q3W patients) as shown below, including subjects who may not have previously had 
an assessment after Cycle 3/Week 9, respectively. Additionally, all references to “eyesight” as part 
of an ophthalmologic exam were changed to “eyesight/visual acuity”. 
Reason: Changes to ophthalmologic examination were made to ensure all subjects have an 
assessment every 15-16 weeks throughout the study. Reference to visual acuity was specifically 
requested by the FDA to ensure there is no confusion. 
Section 5.1: 
Table 5 footnote 24,  
Table 7 footnote 23, 
Table 8 footnote 23, 
Table 9 footnote 23, 
Table 11 footnote 26 
 
Section 8.2.2 
 
In Section 8.2.2 (first sentence of paragraph 3), and in footnotes for 
Tables 5, 7, 8, 9, 11 (Phases 1a and 1b) pertaining to ophthalmological 
examinations (first sentence), revised the text as follows: 
Ophthalmological examinations (such as eyesight/visual acuity, 
fundoscopy, slit lamp microscopy, and optical coherence tomography [or 
equivalent diagnostic test])…  
 
In Section 8.2.2, revised last sentence of paragraph 3 as follows:  
Subjects dosed on a Q2W schedule will then undergo ophthalmologic 
examinations by an appropriate specialist on Cycle 1 Day 15 
(± 7 days) (Phase 1 A Part 1 only), Cycle 3 Day 1 (± 7 days), and 
thereafter every 4 cycles/16 weeks (± 7 days) during study treatment. 
Subjects dosed on a Q3W schedule will undergo an ophthalmologic 
examination by an appropriate specialist at the end of Week 9 
(± 7 days), and thereafter every 5 cycles/15 weeks (± 7 days) during 
study treatment. Patients Subjects in all groups will undergo repeat 
assessments by an appropriate specialist approximately every 15 weeks 
(± 7 days) during study treatment and a final assessment <30 days after 
the last dose of study treatment. For those subjects who have already 
received 2 or 3 more doses of study drug, respectively, the 
examination should be repeated at the subject’s next visit and then 
approximately either every 4 cycles/16 weeks (± 7 days) for subjects 
dosed on a Q2W schedule or every 5 cycles/15 weeks (± 7 days) for 
subjects dosed on a Q3W schedule, according to the schedule from 
first dose (Cycle 1 Day 1). 
 
In Tables 5, 7, 8, 9, 11, footnotes pertaining to schedule of 
ophthalmological examinations (second sentence), revised sentences in 
accordance with the edits made to Section 8.2.2, above. 
Change: Revised the window for the Safety Follow-up visit from 30 ± 7 days to 30 ± 3 days.    
Reason:  To increase clarity and consistency throughout the protocol.  
Section 5.1 
Tables 5, 7, 8, 9, 11 
(including footnote 2 
in each table) 
 
In each table, in the header column “Safety Follow-up”, the “Days” box 
was changed as follows: “30 ± 73 Days after last dose”.   
 
Table 2 footnote in each table was similarly revised to state: “2.  The 
mandatory Safety Follow-Up visit should be conducted 30 days (± 73 days) 

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Applicable Sections 
Description of Revision 
 
after the last dose of study therapy or before the initiation of a new 
treatment, whichever comes first.” 
Section 10.5 
 
Changed the first sentence as follows: Subjects will be assessed for AEs and 
SAEs beginning immediately after signing the informed consent form and 
continuing through to follow up which is 30 ± 7 3 days of last dose of 
investigational drug.   
Change: For subjects who have confirmed complete response, partial response, or stable disease 
after 2 years and want to take a break in treatment without discontinuing, the frequency of 
assessments and procedures was changed from once every cycle to once every 12 weeks. 
Reason: To reduce the number of subject visits while on break, aligning the timing of assessments 
and procedures with the schedule for radiographic imaging. 
Section 5.2.5.1 
 
Modified last bullet point as follows: 
If subjects have confirmed CR, PR, or SD after 2 years of tislelizumab, 
the treatment can be stopped if the subject agrees. . . The study 
assessment and procedures schedule will remain the same.  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 8.5) rather than every cycle. If a subject has 
evidence of PD within 1 year of treatment interruption, the Investigator 
can consider restarting tislelizumab therapy after discussion with the 
Sponsor, contingent on the continued availability of tislelizumab drug 
product. 
Change: Clarified that during Survival Follow-up phase, in addition to survival data, 
immune-related AEs (irAEs) will be collected through 90 days post-treatment. Further clarified 
that the irAEs will be assessed by phone contact at 90 days rather than via office visit unless a 
suspected irAE is reported.  
Reason: The AE follow-up period for irAEs is 90 days. Thus, information on irAEs needs to be 
collected during early Survival Follow-up, but does not require an office visit. These edits correct 
the discrepancies. 
Section 5.1: 
Tables 5, 7, 8, 9, 11 
(footnote 7 in each 
table), 
Section 8.4, 
Section 10.5 
 
Clarified the following sentence as follows: 
Telephone contacts with patients should be conducted to assess irAEs 
90 days after the last dose of tislelizumab, regardless of whether or not 
the subject starts a new anticancer therapy. If patients report a 
suspected immune-related AE at a telephone follow-up contact, the 
investigator should arrange an unscheduled visit if further 
assessment is indicated. 
Section 8.4 
 
Corrected the last paragraph as follows:  
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 ± 2 weeks by 
either a telephone or in-person contact until subject death or termination 
by the Sponsor.  No With the exception of the collection of irAE data 
through 90 days post-treatment (as described above), no other data 
(eg subsequent therapies, performance status etc.) beyond survival will 
be collected during these calls/visits. 

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Applicable Sections 
Description of Revision 
Change: Clarified that assessment of intensity and causality for each AE must be made at the time 
event is reported. 
Reason: For clarification; and to reduce the number of AEs that are reported by the investigator 
without causality, as such events would automatically be considered Related. 
Section 10.7.1 
 
Corrected the first sentence as follows:  
The Investigator will make an assessment of intensity for each AE and 
SAE reported during the study, at the time the event is reported.   
Section 10.7.2 
 
Corrected the first sentence as follows: 
The Investigator is obligated to assess the relationship between the 
investigational product and the occurrence of each AE or SAE, at the 
time the event is reported.   
Change: In Section 10.13.3, revised length of follow-up period post-birth for any child delivered to 
a female subject or female partner of a male subject who becomes pregnant while on study. In 
Appendix 12, contraception guidance was revised as shown. Additional edits were made to both 
sections for clarity. A cross-reference to Appendix 12 was added in Inclusion Criterion #10. 
Reason: For patient safety, for clarification, and to bring guidance in line with other tislelizumab 
protocols. 
Synopsis Key 
Inclusion Criteria, 
Section 5.2.1 
 
In Inclusion Criterion #10b, added a cross-reference to Appendix 12 for 
contraception guidelines and definition of “women of childbearing 
potential”/”not childbearing potential.” 
Section 10.13.3 
 
The last 2 sentences in paragraph 2 was edited as follows: 
 
Generally, follow up will be no longer than 15 days 8 weeks following the 
estimated delivery date.  Any premature termination (spontaneous or 
elective abortion prior to 20 weeks or stillbirth after 20 weeks 
gestational age) of the pregnancy will be reported. 
Appendix 12 
 
Under “Contraception Guidelines”, edited the following bullet points: 
 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with the inhibition of ovulation (oral, 
intravaginal, transdermal, implants or subcutaneous or 
intramuscular injections). 
 
Combined oral contraceptives (birth control pills) may be used, 
but only if a concurrent barrier method is employed. 
 
Vasectomized male partner (with azoospermia demonstrated by a 
post-procedure medical examination of the semen) 
 
Under “Definitions of “Women of Childbearing Potential,” “Women of No 
Childbearing Potential”, edited the last bullet point and added text below: 
 
< 55 years of age with no spontaneous menses for ≥ 12 months 
AND with postmenopausal follicle-stimulating hormone (FSH) 
concentration > 30 IU/mL and all alternative medical causes for 
the lack of spontaneous menses for ≥ 12 months have been ruled 
out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If an FSH measurement is required to confirm postmenopausal 
state, concomitant use of hormonal contraception or hormonal 
replacement therapy should be excluded. 

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Applicable Sections 
Description of Revision 
Change: Added myocarditis and myositis/rhabodmyolysis as potential immune-related 
adverse events and provided guidelines for their treatment and study drug management. 
Additionally, add CK and CK-MB evaluations to the list of serum chemistry laboratory 
evaluations in Appendix 2 and Schedule of Assessment tables.   
Reason: Based on the request from the FDA, and due to 2 cases of myositis/myocarditis 
reported in the tislelizumab program. 
Section 5.1.2 
 
In the list titled “Tislelizumab will be withheld for any of the following 
treatment related adverse events”, added: 
14.  Grade 2-4 Myositis/Rhabdomyolysis 
15.  Grade 1 Myocarditis 
 
 
In the list titled “Tislelizumab will be permanently discontinued for any of 
the following after consultation with the Sponsor”, added: 
 
Grade 2-4 Myocarditis 
Appendix 10 
 
Edited table titled “Recommended Diagnostic Tests in the Management of 
Possible Immune-Related Adverse Events” to add joint and muscle 
inflammation and myocarditis, and their management. Removed 
rheumatology (covered in joint and muscle inflammation line). 
 
In the section titled “Treatment of Immune Related Adverse Events”, edited 
the table to include myositis/rhabdomyolysis Grade 1-4 and myocarditis 
Grade 1-4 as autoimmune toxicities, their respective treatment guidelines, 
and study drug management. 
Section 5.1: Tables 5, 
7, 8, 9, and 11 
(footnote 8 in each 
table); 
Appendix 2 
 
Added CK and CK-MB to list of serum chemistry laboratory assessments in 
Appendix 2, and to footnote 8 in each Schedule of Assessment table in 
Section 5.1. Specified that in the event CK-MB fractionation is not 
available, troponin I and/or troponin T should be assessed instead. 
Change: In Appendix 10, for the guideline for managing Grade 3 liver function adverse events 
associated with hepatitis, clarified prednisolone should be tapered for 4 weeks.  Additional minor 
editorial changes were made. 
Reason: To make consistent with other tislelizumab protocols, and for clarity. 
Appendix 10 
 
In the section titled “Treatment of Immune-Related Adverse Events”, in the 
subsection for Grade 3 hepatitis, edited Column 3 as follows: “ALT/AST 
< 400 IU/L and normal bilirubin/INR/albumin: Initiate oral prednisolone 
1 mg/kg and taper over at least 2 4 weeks.” 
 
Minor editorial changes were made. 
 

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SYNOPSIS 
Name of Sponsor/Company: 
BeiGene Aus Pty Ltd 
Name of Finished Product: 
Tislelizumab (BGB-A317) 
Name of Active Ingredient: 
tislelizumab 
Title of 
Study:
 
 
A Phase 1A/1B, Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to 
Investigate the Safety, Pharmacokinetics and Antitumor Activities of the anti-PD-1 
Monoclonal Antibody BGB-A317 in Subjects with Advanced Tumors 
Protocol 
No:
 
 
BGB-A317_Study_001 
Investigators: 
Approximately 30 Investigators  
Study 
centers:
 
 
Approximately 30 study centers in Australia, New Zealand, the United States, Korea, 
and Taiwan 
Study duration: Screening (up to 28 days), Treatment (up to 2 years of 
active therapy), and Safety Follow-up (30 days). 
Phase: 1A/1B 
Objectives: 
Phase 1A 
Primary: 
 
To assess the safety and tolerability of tislelizumab in subjects with advanced tumors 
Secondary: 
 
To characterize the pharmacokinetics (PK) of tislelizumab 
 
To determine maximum tolerated dose (MTD), if any, and recommended Phase 2 dose (RP2D) for 
tislelizumab 
 
To assess the preliminary anti-tumor activity of tislelizumab 
 
To assess host immunogenicity to tislelizumab 
Exploratory: 
Phase 1B 
Primary: 
 
To assess the anti-tumor activity of tislelizumab in select tumor types 
Secondary: 
 
To further assess the safety and tolerability of tislelizumab in subjects with advanced tumors. 
 
To further characterize the PK of tislelizumab 
Exploratory: 

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Methodology: 
This is a two-stage study consisting of a Phase 1A dose escalation and dose-finding component to establish 
the MTD, if any, and RP2D(s), followed by a Phase 1B component to investigate efficacy in select tumor 
types and to further evaluate safety and tolerability of tislelizumab at RP2D(s).. Archival tumor tissue will be 
collected for purpose of biomarker analysis, although a fresh tumor biopsy at baseline is strongly 
recommended. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion is required at 
baseline; for these subjects, an optional biopsy for biomarker analysis after two cycles of treatment is 
strongly recommended. Optional biopsy will also be taken at the safety follow up visit for the subjects who 
have confirmed disease progression during the study from accessible tumor sites to obtain samples to explore 
resistance mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion 
as the baseline biopsy. Written patient consent is required for fresh tumor biopsies.  
Mandatory biopsy at baseline and on treatment are required for some tumor types in the Phase 1B study. 
Subjects will be monitored for safety, anti-tislelizumab antibodies and efficacy throughout the study. 
Radiological assessment of tumor response status should be performed approximately every 8 weeks or 9 
weeks depending on dosing schedules in the first year, then every 12 weeks thereafter. 
 
Phase 1A, Part 1 
The Phase 1A, Part 1 component is a multicenter, open-label, multiple-dose, dose escalation, first-in-human 
study. Four dose levels are planned: 0.5, 2.0, 5.0 and 10 mg/kg, Q2W (once every two weeks). The study 
will follow a modified 3+3 dose escalation scheme. At least three (3) subjects will be enrolled into each 
cohort. Additional subject(s), up to a maximum of six (6) subjects in total, will be enrolled if more than 
three (3) have been screened and are eligible for the cohort. The dose-limiting toxicity (DLT) assessment 
will be conducted in the first cycle consisting of 28 days. Dose escalation will continue until identification of 
MTD or 10 mg/kg in the event that a MTD is not identified due to paucity of DLTs. Two (2) or more DLT in 
a cohort of three (3) to six (6) subjects is considered to have exceeded MTD. 
Continuous safety evaluation will be performed by the Sponsor, the Coordinating Investigator, and 
Investigators. A Safety Monitoring Committee (SMC) will be established for the determination of dose levels 
to be administered and dose regimen during dose escalation based on the data available from the previous 
dose levels. 
The SMC may decide to evaluate an intermediate, not pre-defined and not previously-studied dose, if 
evaluation of toxicity at such a dose is desired. If this approach is taken, up to 6 new subjects should be 
enrolled at the new intermediate dose. 
 
Phase 1A, Part 2 
The Phase 1A, Part 2 component will evaluate the safety and PK of two dosing schedules Q2W versus Q3W 
(once every three weeks) at selected doses that have cleared the DLT period without exceeding MTD (eg, 2 
mg/kg or 5 mg/kg, up to 10 mg/kg). Ten to 20 subjects per dose schedule will be enrolled to evaluate the 
safety, the PK and preliminary efficacy. Tumor types to be enrolled include but are not limited to colorectal 
cancer (CRC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, melanoma 
and ovarian cancer. Other cancers that are deemed to be likely to benefit from programmed cell death-1 
(PD-1) inhibition based on high mutational load, preclinical or clinical data from other studies may be 
considered for enrollment subject to discussion with the medical monitor. Q2W and Q3W schedule cohorts 
for each dose may be evaluated sequentially or in parallel. 
To adequately monitor safety of subjects enrolled in dosing schedule expansion, when at least 6 subjects have 
been treated at a specific dose and schedule and ≥33% of the subjects experienced a DLT during the first 28 
days in both Q2W and Q3W schedules, study accrual will be held pending data review by the SMC. 
Tislelizumab will also be withheld in the event of other serious adverse reactions according to pre-specified 
criteria. In the event that a MTD is not identified, RP2D and dosing regimen used in the Phase 1B stage will 
be determined by the SMC and the Sponsor based on the PK, tolerability and preliminary antitumor activities 

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observed in the Phase 1A stage, as well as other available data. Based on the Phase 1A data, more than one 
dose or dosing regimen may be selected to be evaluated in Phase 1B for safety and preliminary efficacy in 
select tumor types.  
 
Phase 1A, Part 3 
The Phase 1A, Part 3 component will evaluate the safety and PK of tislelizumab at flat doses (ie 200 mg, 
Q3W) that do not exceed the exposure of the MTD as determined in the Phase 1A, Part 1 study.  
Approximately 10 to 20 subjects will be enrolled. Tumors types to be enrolled include but not limited to 
NSCLC, RCC, head and neck squamous cell carcinoma (HNSCC), bladder cancer, melanoma, gastric, 
oesophageal, Merkel-cell carcinoma and HCC. Other cancers that are deemed to be likely to benefit from 
PD-1 inhibition based on high mutational load, preclinical or clinical data from other studies may be 
considered for enrollment subject to discussion with the medical monitor in advance.  
The doses selected for the flat dose exploration have been evaluated for DLT and demonstrated as safe in the 
Phase 1A Part 1 study. Nevertheless, to adequately monitor safety of subjects enrolled in flat dose 
exploration, study accrual at a specific dose level will be held pending data review by the SMC when at least 
6 subjects have been treated and ≥33% of the subjects experienced a DLT during the first cycle consisting of 
21 days. A planned formal SMC review of safety data will be performed after all subjects have completed the 
first cycle of treatment, or withdrew due to any reason (progressive disease [PD], adverse event [AE], or 
death). 
This part of the Phase 1A study will be conducted in Australia and/or New Zealand sites only and may be 
conducted in parallel with a Phase 1B study that evaluates a RP2D selected based on the Phase IA, Part 1 and 
2 data as described in Section 2.5.4. 
 
Phase 1B  
The Phase 1B stage is a multicenter, open-label, multiple-dose, multiple-arm, indication expansion study. 
The various arms of the study will investigate RP2D(s) to examine the potential efficacy as well as safety and 
tolerability of tislelizumab in cancer patients who failed standard care therapies. The cancer indications may 
include: 
Arm 1. Subjects with NSCLC (approximately 50 subjects) 
Arm 2. Subjects with ovarian cancer (approximately 20 subjects) 
Arm 3. Subjects with gastric cancer (approximately 50 subjects) 
Arm 4. Subjects with HCC (approximately 50 subjects) 
Arm 5. Subjects with HNSCC (approximately 20 subjects) 
Arm 6. Subjects with esophageal carcinoma (approximately 50 subjects) 
Arm 7. Subjects with triple negative breast cancer (TNBC) (approximately 20 subjects) 
Arm 8. Subjects with cholangiocarcinoma (approximately 20 subjects) 
Arm 9. Subjects with RCC, bladder cancer, melanoma, Merkel-cell carcinoma, sarcoma, 
gastrointestinal stromal tumor (GIST), or cutaneous squamous cell carcinoma (cuSCC). Or any other 
solid tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), such 
as CRC or pancreatic cancer (approximately 50 subjects)  
For Arms 1, 3, 4 and 6, at least 20 subjects each will be enrolled from Taiwan or Korea. Enrollment rates will 
be different for each expansion arm.  Individual arms may be closed at the discretion of the Sponsor once the 
target number of enrolled subjects is reached.  Individual arms may also be closed prematurely due to 
difficulty in recruitment at the discretion of the Sponsor. Subjects will receive tislelizumab at the RP2D as 
described in Section 2.5.4. Each treatment cycle will be 21 days in duration. Subjects will continue treatment 
until confirmed disease progression, intolerable toxicity, subject discontinuation/ withdrawal or at the 
discretion of the Investigator in consultation with Sponsor. 

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To adequately monitor safety of subjects enrolled in the Phase 1B indication expansion, when at least 6 
subjects have been treated and ≥33% of the subjects experienced a DLT during the first 21 days, study 
accrual will be held pending data review by the SMC. 
Tumor response will be assessed by Investigators based on the Response Evaluation Criteria in Solid Tumors 
(RECIST) version (v) 1.1.  
For immune therapies such as tislelizumab, pseudo-progression may occur due to immune cell infiltration 
and other mechanisms as manifested by apparent increase of existing tumor masses or appearance of new 
tumor lesions (Wolchok et al, 2009). Thus for PD suspected by the Investigator as pseudo-progression, 
treatment may continue until confirmation of  PD with repeat imaging at least 4 weeks later or at the next 
regularly scheduled imaging time point, but not to exceed 12 weeks from the initial documentation of PD. 
But the patient must be re-consented and the following criteria must be met in order to continue the treatment 
after initial PD:  
a. Absence of clinical symptoms and signs of disease progression (including worsening laboratory values). 
b. Stable Eastern Cooperative Oncology Group (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.  
Planned number of subjects: 
Phase 1A stage: Approximately 120 subjects for the dose escalation, 
dosing schedule expansion and flat dose exploration. 
Phase 1B stage: Approximately 330 subjects for indication expansion. 
One or more arms may be closed early in the event of difficulty with 
patient recruitment. 
Study population 
Key inclusion criteria 
1. 
Subjects meet the following corresponding requirements for the 
stage of the study they will enroll into: 
a. 
In Phase 1A stage of the study, subjects must have a 
histologically or cytologically confirmed advanced or 
metastatic tumor for which no effective standard 
therapy is available. For Part 1, tumor types to be 
enrolled include but not limited to CRC, NSCLC, 
melanoma, squamous cell carcinoma (SCC), uveal 
melanoma, gastric cancer, pancreatic cancer, ovarian 
cancer, bladder cancer, HNSCC, RCC, TNBC and 
HCC. For Part 2 and Part 3, tumors types to be 
enrolled include but not limited to NSCLC (subjects 
with documented epidermal growth factor receptor 
[EGFR] mutation or anaplastic lymphoma kinase 
[ALK] rearrangement should be excluded), RCC, 
HNSCC, bladder cancer, melanoma, gastric, 
oesophageal, Merkel-cell carcinoma and HCC. Other 
cancers that are deemed to be likely to benefit from 
PD-1 inhibition based on high mutational load, 
preclinical or clinical data from other studies may be 
considered for enrollment subject to discussion with 
the medical monitor in advance. 
b. In Phase 1B stage of the study, subjects recruited to 
one of the following expansion arms must have 
histologically or cytologically confirmed advanced or 
metastatic tumor (of the types described below) for 
which no effective standard therapy is available:  
i. Arm 1. Subjects with NSCLC (subjects with 

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documented EGFR mutation or ALK 
rearrangement should be excluded) 
ii. Arm 2. Subjects with ovarian cancer 
iii. Arm 3. Subjects with gastric cancer  
iv. Arm 4. Subjects with HCC (Barcelona-
Clinic Liver Cancer stage C, stage B not 
amenable to locoregional therapy or 
refractory to locoregional therapy, and not 
amenable to a curative treatment approach, 
and Child-Pugh A) 
v. Arm 5. Subjects with HNSCC 
vi. Arm 6. Subjects with esophageal carcinoma 
vii. Arm 7. Subjects with TNBC 
viii. Arm 8. Subjects with cholangiocarcinoma 
ix. Arm 9. Subjects with RCC, bladder cancer, 
melanoma, Merkel-cell carcinoma, sarcoma, 
GIST, or cuSCC. Or any other solid tumors 
with known MSI-H or dMMR status, such as 
CRC or pancreatic cancer  
2. 
Subjects with previously treated brain metastasis(es) that is 
asymptomatic and radiographically stable and not requiring steroid 
medications for 4 weeks prior to enrollment are permitted. 
3. 
Subjects must have archival tumor tissues or agree to a tumor 
biopsy for analysis of predictive biomarkers such as programmed 
death-ligand 1(PD-L1; fresh tumor biopsies are strongly 
recommended at baseline for biomarker analysis in subjects with 
readily accessible tumor lesions and who consent to the biopsies). 
For Arm 2 (ovarian cancer), Arm 3 (gastric cancer), and Arm 
4 (HCC) of Phase 1B study, a fresh baseline biopsy within 
8 weeks before starting treatment is mandatory for biomarker 
analysis.  
For Arm 9 (melanoma) of Phase 1B study, a fresh baseline 
biopsy within 8 weeks before starting treatment and one 
approximately on Cycle 3 Day 1 are mandatory for biomarker 
analysis.  
All other subjects who have easily accessible lesions are 
strongly recommended for baseline or the paired biopsy. 
Subjects may be permitted to enroll on a case-by-case basis after 
discussion with the medical monitor and in consultation with the 
Sponsor if tissue or biopsy is not available. 
4. 
Subjects must have at least one measurable lesion as defined per 
RECIST v 1.1. Subjects with metastatic castration-resistant 
prostate cancer (mCRPC) and with only non-measurable bone 
lesions must have either progression with 2 or more new lesions or 
have prostate-specific antigen (PSA) progression within the 6-
week period before study drug administration. 
5. 
Male or female and ≥18 years of age on day of signing informed 
consent 
6. 
ECOG performance status of ≤1 
7. 
Life expectancy ≥12 weeks 

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8. 
Subject must have adequate organ function as indicated by the 
following laboratory values 
a. 
Absolute neutrophil count (ANC) ≥1,500 /mcL 
b. Platelets ≥100,000 / mcL, OR ≥75,000 / mcL for 
subjects with HCC 
c. 
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 
d. Serum creatinine ≤1.5 X upper limit of normal (ULN) 
e. 
Serum total bilirubin ≤1.5 X ULN (total bilirubin 
must be <4 X ULN for subjects with Gilbert’s 
syndrome) 
f. 
Aspartate aminotransferase (AST) (SGOT) and 
alanine aminotransferase (ALT) (SGPT) ≤2.5 X ULN, 
OR ≤5 X ULN for subjects with liver metastases or 
HCC 
g. International Normalized Ratio (INR) or Prothrombin 
Time (PT) ≤1.5 X ULN 
h. Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN 
9. 
Subjects have voluntarily agreed to participate by giving written 
informed consent 
10. 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 
i. Has had a hysterectomy 
ii. Has had a bilateral oophorectomy 
(ovariectomy) 
iii. Has had a bilateral tubal ligation 
iv. Is post-menopausal (total cessation of 
menses for ≥1 year) 
b. Childbearing potential, has a negative serum 
pregnancy test at screening (within 7 days before the 
first investigational product administration), not be 
breast feeding, and uses adequate contraception 
(Appendix 12) before study entry and throughout the 
study until 120 days after the last investigational 
product administration. Adequate contraception, when 
used consistently and in accordance with both the 
product label and the instructions of the physician, are 
defined as follows: 
i. Vasectomized partner who is sterile prior to 
the female subject’s entry and is the sole 
sexual partner for that female 
ii. Any intrauterine device with a documented 
failure rate of less than 1% per year 
iii. Double barrier contraception defined as 
condom with spermicidal jelly, foam, 
suppository, or film; OR diaphragm with 

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spermicide; OR male condom and 
diaphragm 
iv. Appropriate hormonal contraceptives that 
include any registered and marketed 
contraceptive agent that contains an estrogen 
and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular 
agents) 
11. Male subjects are eligible to participate in the study if they are 
vasectomized or agree to use of contraception during the study 
treatment period and for at least 120 days after the last dose of 
study drug 
Key exclusion criteria:  
1. 
History of severe hypersensitivity reactions to other monoclonal 
antibodies (mAbs) 
2. 
Prior malignancy active within the previous 2 years except for 
tumor for which a subject is enrolled in the study, and 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 PD-1 or PD-L1 
4. 
Subjects who failed to meet enrollment criteria for other PD-1 or 
PD-L1 trials solely due to low or negative predictive biomarkers, 
including but not limited to PD-L1, MSI, and deoxyribonucleic 
acid (DNA) mutation load 
5. 
Subjects with active autoimmune diseases or history of 
autoimmune diseases 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 (SLE), connective tissue diseases, 
scleroderma, inflammatory bowel disease including Crohn’s 
disease and ulcerative colitis, hepatitis, toxic epidermal necrolysis 
(TEN), Stevens-Johnson syndrome, or antiphospholipid syndrome.  
Note: Subjects are permitted to enroll if they have vitiligo, 
eczema, type I diabetes mellitus, endocrine deficiencies including 
thyroiditis managed with replacement hormones including 
physiologic corticosteroids. Subjects with rheumatoid arthritis and 
other arthropathies, Sjogren's syndrome, controlled celiac disease 
and psoriasis controlled with topical medication and subjects with 
positive serology, such as antinuclear antibodies (ANA), anti-
thyroid antibodies should be evaluated for the presence of target 
organ involvement and potential need for systemic treatment but 
should otherwise be eligible. 
6. 
Subjects should be excluded if they have a condition requiring 
systemic treatment with either corticosteroids (>10 mg daily 
prednisone equivalents) or other immunosuppressive medications 
within 14 days of study drug administration 
Note: Adrenal replacement doses ≤10 mg daily prednisone 
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 

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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. 
Has history of interstitial lung disease or non-infectious 
pneumonitis except for those induced by radiation therapies. 
8. 
Known history of Human Immunodeficiency Virus 
9. 
Except for HCC in Phase 1A or Arm 4 in Phase 1B, subjects who 
are Hepatitis B surface antigen (HBsAg) and Hepatitis B core 
antibody (HBcAb) positive or Hepatitis C virus (HCV) antibody 
positive at screening must not be enrolled until further definite 
testing with Hepatitis B virus (HBV) DNA titers and HCV 
ribonucleic acid (RNA) tests can conclusively rule out presence of 
active infection requiring therapy with Hepatitis B and C, 
respectively 
10. HCC patients with active infection by HCV who are untreated are 
not allowed on study. However HCC patients with successful 
HCV treatment (defined as sustained virologic response [SVR] 12 
or SVR 24) are allowed as long as 4 weeks have passed between 
completion of HCV therapy and start of study drug 
11. HCC patients with evidence of prior HBV infection must fulfill 
the following criteria in order to be eligible for the study: HBV 
viral load (VL) <200 IU/mL (approximately 1000 cps/mL) before 
study enrollment, and subjects with active HBV infection need to 
be on anti-HBV suppression ≥3 months, throughout treatment and 
for 6 months after 
12. Underlying medical conditions that, in the Investigator’s opinion, 
will make the administration of study drug hazardous or obscure 
the interpretation of toxicity determination or AEs 
13. Prior chemotherapy, radiotherapy, immunotherapy or any 
investigational therapies used to control cancer, including local-
regional treatment for HCC, must have been completed at least 
4 weeks before study drug administration, and all AEs have either 
returned to baseline or Grade 0-1, and stabilized 
14. Use of any live vaccines against infectious diseases (eg, influenza, 
varicella, etc.) within 4 weeks (28 days) of initiation of study 
therapy and any intended use until 60 days after the last 
administration of the study medication 
15. Subjects who had prior liver transplant, allogeneic organ 
transplantation or bone marrow transplant (BMT) should be 
excluded 
Test product, dose and mode of 
administration: 
Tislelizumab, 10 ml/vial, 10 mg/ml.  
Phase 1A Part 1: four cohorts dosed at 0.5 mg/kg, 2 mg/kg, 5 mg/kg, 
and 10 mg/kg Q2W 
Phase 1A Part 2: selected doses based on Part 1 at Q2W and/or Q3W 
Phase 1A Part 3: flat doses not exceeding MTD, ie 200 mg Q3W  
Phase 1B: selected dose(s) administered Q2W and/or Q3W as 
determined by SMC.  All cohorts are administered by intravenous (IV) 
infusion. 

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Reference therapy, dose, and 
mode of administration: 
Not applicable 
Criteria for evaluation: 
Primary Endpoints: 
The primary endpoint of the Phase 1A stage is the following: 
 
Tislelizumab safety and tolerability: The safety of tislelizumab will be assessed throughout the study by 
monitoring AEs per the National Cancer Institute Common Terminology for Adverse Events 
(NCI-CTCAE) Version 4.03, physical examination, ophthalmologic examination, electrocardiograms, 
laboratory measurements and severity of AEs. 
The primary endpoint of the Phase 1B stage is the following: 
 
ORR: (complete response [CR] + partial response [PR]) based on RECIST v 1.1 in subjects with select 
tumor types as evaluated by the Investigators. 
Secondary Endpoints: 
The secondary endpoints of the Phase 1A stage of the study are the following: 
 
Pharmacokinetic evaluations: include but not limited to area under the plasma concentration-time curve 
from Day 0 to Day 14 (AUC0-14 day), maximum observed plasma concentration (Cmax), time to maximum 
observed plasma concentration (Tmax), minimum observed plasma concentration (Ctrough), half-life (T½), 
clearance (Cl), and volume of distribution (Vd). 
 
The MTD, if any, and RP2D (s) for tislelizumab will be determined based on safety, tolerability, PK, 
preliminary efficacy, and other available data. 
 
Efficacy evaluations: ORR (CR+PR), CR rate, PR rate, stable disease (SD) rate, progression-free 
survival (PFS), overall survival (OS), and duration of response (DOR) will be determined based on 
RECIST v 1.1 and the results of Investigator evaluations. 
 
Anti-tislelizumab antibody: immunogenic responses to tislelizumab will be assessed to determine 
incidence of anti-drug antibody (ADA).  
The secondary endpoints of the Phase 1B stage of the study are the following: 
 
PFS; disease control rate (DCR: CR + PR + SD); and clinical benefit rate (CBR: CR or PR or durable 
SD [SD ≥24 weeks]). 
 
Safety and tolerability assessment of AEs, serious adverse events (SAEs), physical examination, 
ophthalmologic examination, vital signs, electrocardiograms (ECGs), and laboratory measurements. 
 
Plasma concentrations of tislelizumab at selected time points. 
Exploratory Endpoints for Phase 1A, and Phase 1B: 
 
 
 
 
Statistical methods 
Data will be listed and summarized according to the Sponsor-agreed reporting standards, where applicable.  
Primary safety and efficacy analyses will be conducted approximately 6 months after the last subject being 
enrolled. 

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All subjects who are exposed to (or started receiving) tislelizumab will be included in the safety analysis set 
(SAF).  All subjects for whom valid tislelizumab PK parameters can be estimated will be included in the PK 
Population on an as-treated basis.  
Sample size 
In Phase 1A, the number of dose levels and schedules examined and the emerging tislelizumab toxicities will 
determine the sample size.  It is anticipated that approximately 24 subjects will be required to establish the 
RP2D(s) of tislelizumab when administered as a single agent.  In addition, 10 to 20 subjects will be enrolled 
in each of the schedule expansion and flat dose cohort at one or more dose level (up to 10 mg/kg Q2W or 
Q3W in schedule expansion cohort; 200 mg Q3W in flat dose cohort) not exceeding MTD to further evaluate 
safety, tolerability, PK and preliminary efficacy of tislelizumab. 
In Phase 1B, approximately 20 to 50 subjects for each arm (except Arm 9) will be evaluated to examine the 
potential efficacy as well as safety and tolerability of tislelizumab in select tumor types.   

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT, VERSION 6.0 RATIONALE .............................................3 
SYNOPSIS ................................................................................................................................8 
TABLE OF CONTENTS ......................................................................................................18 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................25 
2.0 
INTRODUCTION......................................................................................................30 
2.1 
Background and Pharmacology ...................................................................30 
2.2 
Nonclinical Pharmacokinetics.......................................................................32 
2.3 
Toxicology .......................................................................................................33 
2.4 
Benefit-Risk Assessment ................................................................................34 
2.5 
Study Rationale ..............................................................................................35 
2.5.1 
Rationale for Starting Dose Selection in Phase 1A Part 1 .................35 
2.5.2 
Rationale for Evaluating Different Dosing Schedules in 
Phase 1A Part 2 .................................................................................36 
2.5.3 
Rationale for Evaluating Flat Dosing in Phase 1A Part 3 .................36 
2.5.4 
Rationale for Dose Selection in Phase 1B .........................................37 
2.5.5 
Rationale for Selection of Different Expansion Arms in 
Phase 1B ............................................................................................40 
3.0 
STUDY OBJECTIVES ..............................................................................................42 
3.1 
Primary Objectives ........................................................................................42 
3.2 
Secondary Objectives.....................................................................................42 
3.3 
Exploratory Objectives ..................................................................................42 
4.0 
STUDY ENDPOINTS ................................................................................................43 
4.1 
Primary Endpoints.........................................................................................43 
4.2 
Secondary Endpoints .....................................................................................43 
4.3 
Exploratory Endpoints ..................................................................................44 
5.0 
INVESTIGATIONAL PLAN ...................................................................................44 
5.1 
Summary of Study Design .............................................................................44 
5.1.1 
Dose-Limiting Toxicity .....................................................................45 
5.1.2 
Dose Modifications, Dose Delay and Missing Dose .........................46 
5.1.3 
Phase 1A Part 1: Dose Escalation .....................................................49 
5.1.3.1 
Dose Escalation and Dose Finding ..................................50 
5.1.3.2 
Schedule of Assessment ..................................................51 
5.1.4 
Phase 1A Part 2: Schedule Expansion ...............................................60 

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5.1.4.1 
Criteria for Stopping Phase 1A Part 2 .............................60 
5.1.4.2 
Schedule of Assessment ..................................................60 
5.1.5 
Phase 1A Part 3: Flat Dose Exploration ............................................73 
5.1.5.1 
Criteria for Stopping Phase 1A Part 3 .............................73 
5.1.5.2 
Schedule of Assessment ..................................................73 
5.1.6 
Phase 1B: Indication Expansion ........................................................82 
5.1.6.1 
Criteria for Stopping Phase 1B ........................................82 
5.1.6.2 
Schedule of Assessment ..................................................83 
5.2 
Selection of Study Population .......................................................................90 
5.2.1 
Inclusion Criteria ...............................................................................90 
5.2.2 
Exclusion Criteria ..............................................................................93 
5.2.3 
Other Eligibility Criteria Considerations ...........................................95 
5.2.4 
Subject Restrictions ...........................................................................95 
5.2.5 
Subject Completion and Withdrawal .................................................95 
5.2.5.1 
Subject Completion .........................................................95 
5.2.5.2 
Subject Withdrawal/Discontinuation ...............................96 
6.0 
STUDY TREATMENTS ...........................................................................................98 
6.1 
Description of Investigational Product ........................................................98 
6.2 
Product Preparation and Administration ...................................................98 
6.3 
Treatment Assignment ................................................................................100 
6.4 
Packaging and Labelling .............................................................................100 
6.5 
Handling and Storage ..................................................................................100 
6.6 
Product Accountability ................................................................................101 
6.7 
Assessment of Compliance ..........................................................................101 
6.8 
Treatment of Investigational Product Overdose .......................................101 
6.9 
Medical Care of Subjects after the End of Trial .......................................101 
6.10 
Occupational Safety .....................................................................................102 
7.0 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .............102 
7.1 
Concomitant Medication(s)/Treatment(s) .................................................102 
7.2 
Prohibited Medications ...............................................................................102 
7.2.1 
Other Drugs to be Used in the Study ...............................................103 
7.2.2 
Other Study Considerations .............................................................103 
7.3 
Special Precautions ......................................................................................103 
7.3.1 
Tumor Lysis Syndrome ...................................................................104 
7.3.2 
Infusion-Related Reactions .............................................................105 
7.3.3 
Severe Hypersensitivity Reactions and Flu-Like 
Symptoms ........................................................................................107 
7.3.4 
Immune-Related Adverse Events ....................................................108 
7.3.5 
Hepatic Abnormalities .....................................................................109 

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8.0 
SAFETY, PHARMACOKINETIC, PHARMACODYNAMIC, AND 
OTHER ASSESSMENTS .......................................................................................111 
8.1 
Demographic and Baseline Assessments ....................................................111 
8.2 
Assessments During Treatment ..................................................................113 
8.2.1 
Laboratory Evaluation .....................................................................113 
8.2.2 
Physical Examination, Ophthalmologic Examination, 
Vital Signs, and Hepatitis B and C Testing .....................................114 
8.2.3 
Electrocardiogram ...........................................................................115 
8.2.4 
Computed Tomography ...................................................................116 
8.2.5 
Adverse Events ................................................................................117 
8.3 
Safety Assessments .......................................................................................117 
8.3.1 
Phase 1A Part 1 ...............................................................................117 
8.3.2 
Phase 1A Part 2 and Part 3 ..............................................................118 
8.3.3 
Phase 1B ..........................................................................................119 
8.4 
Follow-up Assessments ................................................................................119 
8.5 
Efficacy Assessments ...................................................................................120 
8.5.1 
Treatment Beyond Disease Progression ..........................................120 
8.5.2 
Efficacy Endpoints ..........................................................................121 
8.6 
Pharmacokinetics .........................................................................................121 
8.6.1 
Phase 1A Part 1 ...............................................................................122 
8.6.2 
Phase 1A Part 2 ...............................................................................123 
8.6.3 
Phase 1A Part 3 ...............................................................................123 
8.6.4 
Phase 1B ..........................................................................................123 
8.7 
Anti-Drug Antibody .....................................................................................124 
8.8 
Pharmacodynamics Assessments ................................................................124 
8.9 
Biomarker Assessments ...............................................................................125 
8.10 
Appropriateness of Measurements .............................................................126 
9.0 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................126 
9.1 
Monitoring ....................................................................................................127 
9.2 
Data Management/Coding ..........................................................................128 
9.3 
Quality Assurance Audit .............................................................................129 
10.0 
SAFETY MONITORING AND REPORTING ....................................................130 
10.1 
Definition of an Adverse Event ...................................................................130 
10.2 
Definition of a Serious Adverse Event .......................................................131 
10.3 
Lack of Efficacy............................................................................................132 
10.4 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events ....................132 
10.5 
Time Period, Frequency, and Method of Detecting Adverse 
Events and Serious Adverse Events ...........................................................133 
10.6 
Recording of Adverse Events and Serious Adverse Events .....................133 
10.7 
Evaluating Adverse Events and Serious Adverse Events .........................134 
10.7.1 
Assessment of Intensity ...................................................................134 

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10.7.2 
Assessment of Causality ..................................................................134 
10.8 
Follow-Up of Adverse Events and Serious Adverse Events .....................135 
10.9 
Prompt Reporting of Serious Adverse Events...........................................135 
10.9.1 
Timeframes for Submitting Serious Adverse Events ......................135 
10.9.2 
Completion and Transmission of the Serious Adverse 
Event Report ....................................................................................136 
10.10 Regulatory Reporting Requirements for Serious Adverse 
Events 136 
10.11 Post-study Adverse Events and Serious Adverse Events .........................137 
10.12 Serious Adverse Events Related to Study Participation ..........................137 
10.13 Pregnancy .....................................................................................................137 
10.13.1 Contraception and Pregnancy Testing .............................................137 
10.13.2 Time Period for Collecting Pregnancy Information ........................138 
10.13.3 Action to be Taken and Reporting if a Pregnancy Occurs ..............138 
11.0 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ........................139 
11.1 
Sample Size Considerations ........................................................................139 
11.1.1 
Sample Size Considerations for Phase 1A ......................................139 
11.1.2 
Sample Size Considerations for Phase 1B .......................................139 
11.2 
General Considerations for Data Analysis ................................................139 
11.2.1 
Analysis Populations .......................................................................140 
11.2.2 
Interim Analysis ..............................................................................140 
11.2.3 
Efficacy Analyses ............................................................................141 
11.3 
Safety Analyses .............................................................................................142 
11.3.1 
Dose Limiting Toxicity ...................................................................142 
11.3.2 
Adverse Events ................................................................................142 
11.3.3 
Laboratory Assessments ..................................................................143 
11.3.4 
Electrocardiogram ...........................................................................143 
11.3.5 
Vital Signs .......................................................................................143 
11.3.6 
Extent of Exposure ..........................................................................143 
11.3.7 
Physical Examination ......................................................................143 
11.3.8 
Ophthalmologic Examination ..........................................................143 
11.3.9 
Immunogenicity Analysis ................................................................144 
11.3.10 Hepatitis A and B Analysis .............................................................144 
11.4 
Pharmacokinetic Analyses ..........................................................................144 
11.5 
Pharmacodynamic Analyses .......................................................................144 
11.6 
Biomarker Analyses .....................................................................................144 
12.0 
ETHICS ....................................................................................................................145 
12.1 
Regulatory Authority Approval .................................................................145 
12.2 
Ethical Conduct of the Study and Ethics Approval ..................................145 
12.3 
Informed Consent ........................................................................................146 
12.4 
Investigator Reporting Requirements........................................................146 

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13.0 
STUDY ADMINISTRATION ................................................................................146 
13.1 
Study and Study Center Closure ................................................................146 
13.2 
Records Retention ........................................................................................147 
13.3 
Provision of Study Results and Information to Investigators ..................147 
13.4 
Information Disclosure and Inventions .....................................................148 
13.4.1 
Publication Policy ............................................................................149 
14.0 
REFERENCES .........................................................................................................150 
15.0 
APPENDICES ..........................................................................................................153 

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APPENDIX 1:  SIGNATURE OF INVESTIGATOR ......................................................153 
APPENDIX 2:  CLINICAL LABORATORY ASSESSMENTS .....................................154 
APPENDIX 3:  BLOOD REQUIREMENTS ....................................................................155 
APPENDIX 4:  DRUG DILUTION CALCULATION.....................................................167 
APPENDIX 5:  THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES .....................................................................171 
APPENDIX 6:  COCKCROFT-GAULT FORMULA .....................................................182 
APPENDIX 7:  FLOW CHARTS .......................................................................................183 
APPENDIX 8:  GUIDELINES FOR SUPPORTIVE CARE ...........................................187 
APPENDIX 9:  PROSTATE CANCER CLINICAL TRIALS WORKING 
GROUP 2 (PCWG2) CRITERIA TO GUIDE ASCRIBING 
DISEASE RESPONSE ............................................................................................189 
APPENDIX 10:  IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT ............................................................................................191 
APPENDIX 11:  NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION .................................................................................................205 
APPENDIX 12:  CONTRACEPTION GUIDLINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL”, “NO 
CHILDBEARING POTENTIAL” .........................................................................206 
 
 
 

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List of Tables 
 
Table 1 
Summary of All Adverse Events Reported in Phase 1A from 
Study Initiation through March 29, 2016 .........................................................38 
Table 2 
Most Common Drug-related Adverse Events (all Grade ≥5% or 
Grade 3/4 ≥1%) Reported in Phase 1A from Study Initiation 
through March 29, 2016 ...................................................................................39 
Table 3 
Summary of Enrollment and Response by Cohort in Phase 1A as 
of March 29, 2016 ............................................................................................40 
Table 4 
Suggested Dose Escalation Scheme.................................................................50 
Table 5 
Phase 1A Part 1 Study Assessments and Procedures Schedule .......................52 
Table 6 
Phase 1A Part 1 Pharmacokinetic Sampling ....................................................58 
Table 7 
Phase 1A Part 2 Study Assessments and Procedures Schedule (For 
Q2W schedule).................................................................................................61 
Table 8 
Phase 1A Part 2 Study Assessments and Procedures Schedule (For 
Q3W schedule).................................................................................................67 
Table 9 
Phase 1A Part 3 Study Assessments and Procedures Schedule .......................74 
Table 10 
Phase 1A Part 3 Pharmacokinetic Sampling ....................................................80 
Table 11 
Phase 1B Study Assessments and Procedures Schedule..................................84 
Table 12 
Treatment Modification for Symptoms of Infusion-Related 
Reactions Due to Tislelizumab ......................................................................106 
Table 13 
Immune-Related Adverse Events ..................................................................109 
Table 14 
Timeframe for Reporting Serious Adverse Events to the Sponsor 
or Designee ....................................................................................................135 
 
List of Figures 
 
Figure 2-1 
Lack of Correlation between Clearance (Cl) and Patient Body 
Weight ..............................................................................................................37 
Figure 2-2 
Comparison of Tumor Growth Inhibition by the Treatment with 
Tislelizumab versus Nivolumab and Pembrolizumab in the Mouse 
Cancer Model ...................................................................................................41 
Figure 7-1 
Assessment and Initial Management of Tumor Lysis Syndrome ..................104 
 
 

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1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACD 
Acid-citrate-dextrose 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AFP 
Alpha fetoprotein 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibodies 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-14 day 
Area under the plasma concentration-time curve from Day 0 to 
Day 14 
BGB-A317 
Code name for Monoclonal Antibody BGB-A317 
BMI 
Body mass index 
BMT 
Bone marrow transplant 
CA 125 
Cancer antigen 125 
CBR 
Clinical benefit rate 
CD 
Cluster of differentiation, such as CD274, CD279, CD3 and etc. 
CI 
Confidence interval 
Cl 
Clearance 
Cmax 
Maximum observed plasma concentration 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
Ctrough 
Minimum observed plasma concentration 
cuSCC 
Cutaneous squamous cell carcinoma 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
dMMR 
Mismatch repair deficient 
DNA 
Deoxyribonucleic acid 

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Abbreviation 
Definition 
DOR 
Duration of response 
DP 
Drug product 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESMO 
European Society for Medical Oncology 
FACS 
Fluorescence-activated cell sorting, or fluorescence-activated 
cell sorter 
Fc 
Fragment crystallizable region (typically, of 
immunoglobulin G) 
FcR 
Fc gamma receptor, such as Fc-RI, Fc-RIII, etc. 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FIH 
First-in-human 
GBM 
Glioblastoma multiforme 
GCIG 
The Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practices 
GIST 
Gastrointestinal stromal tumor 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacture Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
IB 
Investigator’s Brochure 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IFN- 
Interferon-alpha 
IFN- 
Interferon-gamma 

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Abbreviation 
Definition 
IgG 
Immunoglobulin G, such as IgG1, IgG2, IgG3 and IgG4; other 
types of immunoglobulins include IgM, IgD and etc. 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous 
KM 
Kaplan-Meier 
MABEL 
Minimum anticipated biological effect level 
MAD 
Maximum administered dose 
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
NSAID 
Nonsteroidal anti-inflammatory drugs 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed death-ligand 1, programed death receptor ligand-
1, programmed death-1 ligand-1 
PD-L2 
Programmed death-ligand 2 

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Abbreviation 
Definition 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PSA 
Prostate-specific antigen 
PT 
Prothrombin Time or preferred term 
Q2W 
Once every two weeks 
Q3W 
Once every three weeks 
QTc 
QT interval corrected for heart rate 
RANO 
Response Assessment in Neuro-Oncology 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SLE 
Systemic lupus erythematosus 
SMC 
Safety Monitoring Committee 
SOP 
Standard operating procedure 
T1/2 
Half-life  
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrolysis 
TIL 
Tumor-infiltrating lymphocyte 
tislelizumab 
BGB-A317 
TK 
Toxicokinetics 
Tmax 
Time to maximum observed plasma concentration 

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Abbreviation 
Definition 
TNBC 
Triple-negative breast cancer 
 
 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution  
VL 
Viral load 
WHO-DD 
World Health Organization Drug Dictionary 

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2.0 
INTRODUCTION 
2.1 
Background and Pharmacology 
Immune check point-inhibitory receptor, programmed cell death-1 (PD-1) is mainly 
expressed in activated T-cells including cluster of differentiation (CD) 8+ cytotoxic 
T-lymphocytes and CD4+ T-helper lymphocytes (McDermott and Atkins, 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 negatively regulates T-cell receptor (TCR) and attenuate T-cell 
proliferation and functional activities, leading to T-cell exhaustion.  PD-1 expression is 
markedly up-regulated in tumor-infiltrating lymphocytes (TILs), while the expression of 
programmed death-ligand 1, (PD-L1) is significantly increased in tumor cells and tumor-
associated immune cells in the presence of stimulating cytokines such as interferon-gamma 
(IFN-and interferon-alpha (IFN- in the tumor microenvironment (Riley, 2009).  
Furthermore, the increased PD-1 expression in TILs 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 (SCC), uveal melanoma, non-small 
cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), triple-
negative breast cancer (TNBC), renal cell carcinoma (RCC), bladder cancer, and ovarian 
cancer (Ghebeh et al, 2006; Hamanishi et al, 2007; Konishi et al, 2004; Thompson et al, 
2007; Thompson et al, 2004; Tsushima et al, 2006; Jie et al, 2013; Hino et al, 2010).  This 
evidence provided the basis for cancer immunotherapeutic intervention via the approach of 
antagonizing PD-1.  
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 toxicities (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 (FIH) phase 1 trial on nivolumab (a fully 
human anti–PD-1 immunoglobulin G [IgG] 4 antibody) evaluated its safety profile at 
increasing doses of 0.3, 1, 3 and 10 mg/kg given intravenously Q2W in 39 patients with 
advanced melanoma, colorectal cancer (CRC), castration-resistant prostate cancer (CRPC), 
NSCLC, or RCC (Brahmer et al, 2010; Topalian et al, 2012).  The FIH Phase 1 study on 
pembrolizumab (a humanized anti–PD-1 IgG4 antibody) evaluated its safety at 1 to 10 mg/kg 
given intravenously at 4 week interval followed by bi-weekly doses in cohorts of three to 
six patients with various advanced solid tumors (Hamid et al, 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 

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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.  
Based on the overwhelming positive results that pembrolizumab and nivolumab 
demonstrated in their pivotal studies, the United States (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 objective response rate (ORR) of 32% with 4 complete responses (CRs) and 34 partial 
responses (PRs).  Thirteen patients had objective responses lasting 6 months or longer (FDA 
News Release, Dec. 2, 2014). In the pivotal study of pembrolizumab, 173 patients were 
treated with pembrolizumab at either 2 or 10 mg/kg dose, approximately 24% patients 
demonstrated tumor shrinkage (2 mg/kg regimen; FDA News Release, Sept. 4, 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 et al, 2014). 
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, 2013). 
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 et al, 
2014; Wolchok et al, 2013).  Of note, the immune-related AEs (irAEs) also increased 
significantly in the combination treatment.  
Tislelizumab (also known as BGB-A317) is a humanized IgG4 variant monoclonal antibody 
against PD-1. It is being developed for the treatment of human malignancies. Tislelizumab 
was manufactured under Good Manufacture Practice (GMP) quality control systems.  The 

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clinical trial drug product is formulated in an aqueous buffer with pH 6.5 and isotonic 
osmolality.  The suggested administration route is intravenous (IV) infusion after the 
appropriate dilution in 0.9% sodium chloride solution. 
Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and 
affinity (dissociation constant = 0.15 nM) as demonstrated by receptor binding assays based 
on surface plasmon resonance.  It competitively blocks the binding of both PD-L1 and 
programmed death-ligand 2 (PD-L2), inhibiting PD-1 mediated negative signaling in T-cells.  
In in vitro cell-based assays, the humanized antibody consistently and dose-dependently 
enhanced the functional activity of human T-cells and pre-activated, primary peripheral blood 
mononuclear cells (PBMCs).  In addition, tislelizumab 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, where the PBMCs 
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 fragment crystallizable region 
gamma receptor (FcR) IIIA and complement 1q by in vitro assays, suggesting a low or no 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effect in 
humans.  Unlike natural IgG4 antibody, tislelizumab has no observable fragment antigen-
binding-arm exchange activity by the in vitro assay, predicting the antibody would be stable 
in vivo, unlikely forming bispecific antibody. 
Tislelizumab 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 
tislelizumab.  
2.2 
Nonclinical Pharmacokinetics 
A pharmacokinetic (PK) study of tislelizumab 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 g/mL, and the area under the plasma concentration time curve from 0 to 1008 
hours (AUC0-1008h) ranged from 12,322 to 163,755 h*g/mL; volume of distribution (Vd) was 
low, ranged from 22 to 52 mL/kg. 

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A PK bridging study for tislelizumab manufactured by Boehringer Ingelheim and JHL 
Biotech Inc. 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 tislelizumab in monkeys supported once biweekly dosing in the repeat-dose 
toxicology study with adequate systemic exposure to support toxicology evaluation of 
tislelizumab.  Based on PK results in monkeys, the Vd of tislelizumab in humans is expected 
to be similar to that in monkeys.  The T1/2 of tislelizumab in humans is expected to be 10-20 
days depending on the actual dose levels, which allows multiple-dose treatment of 
tislelizumab 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. 
Refer to the IB for more detailed information on the PK properties of tislelizumab. 
2.3 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized 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 (GLP) 
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 (TK) 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 tislelizumab 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 tislelizumab 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.  

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The tissue cross reactivity of tislelizumab was evaluated in normal human and cynomolgus 
monkey frozen tissues using immunohistochemistry (IHC) method, with appropriate positive 
and negative controls.  Under the study condition, no specific tissue cross reactivity with 
tislelizumab was noted in both human and cynomolgus monkey tissues.  Neither hemolytic 
effects induced by tislelizumab in the rabbit blood cells nor increase of the cytokine release 
from human whole blood cells after treatment with tislelizumab 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.  The 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 (NOAEL) of tislelizumab in 
13-week monkey toxicity study was considered to be 30 mg/kg.  The safety profile of 
tislelizumab is considered adequate to support FIH dose safely and ethically.   
Refer to the IB for more detailed information on the toxicology of tislelizumab. 
2.4 
Benefit-Risk Assessment 
As of March 29, 2016, 100 patients had received at least one dose of tislelizumab in the 
Phase 1A part of the study, ranging from 0.5 mg/kg to 10 mg/kg Q2W (n=62) and from 2 
mg/kg to 5 mg/kg Q3W (n=38).  During dose escalation, the following dose levels: 0.5 mg/kg 
Q2W (n=3), 2 mg/kg Q2W (n=6), 5 mg/kg Q2W (n=6), and 10 mg/kg Q2W (n=7) were 
evaluated for safety and tolerability.  One DLT (1/6) of Grade 3 colitis was observed in the 5 
mg/kg Q2W.  Additional cohorts of 2 mg/kg Q2W (n=20), 5 mg/kg Q2W (n=20), 2 mg/kg 
Q3W (n=19) and 5 mg/kg Q3W (n=19) were further evaluated as tolerated in schedule 
expansion.     
Preliminary safety analysis showed that the most common treatment-emergent adverse events 
(TEAEs) (≥10%) were fatigue (31%), diarrhoea (21%), nausea (20%), constipation (16%), 
abdominal pain (14%), pruritus (13%), rash (12%), decreased appetite (12%), back pain 
(12%) and vomiting (10%). Immune-mediated AEs were reported in 10 subjects including 
colitis (1 Grade 3, 2 Grade 2), diabetes mellitus (1 Grade 3, 1 Grade 2), alanine 
aminotransferase (ALT) increase (1 Grade 3), diarrhea (1 Grade 2), worsening liver functions 
(1 Grade 2), hypothyroidism (1 Grade 1) and onychoclasis (1 Grade 1).  As of March 29, 
2016, 9 drug-related serious adverse events (SAE) were reported including 1 Grade 2 colitis 
in the 2 mg/kg Q2W dose escalation cohort (n=6), 1 Grade 3 colitis in the 5 mg/kg Q2W dose 
escalation cohort (n=6), 1 Grade 2 colitis and 1 Grade 2 infusion reaction in the 5 mg/kg 
Q2W schedule expansion cohort (n=20), 1 Grade 3 diabetic ketoacidosis, 1 Grade 3 diabetes 
mellitus, 1 Grade 3 hypotension and 1 Grade 2 diarrhoea in the 2 mg/kg Q2W schedule 

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expansion cohort (n=20), and 1 Grade 3 hypotension in the 5 mg/kg Q3W schedule 
expansion cohort (n=19).  Other Grade 3/4 AEs that were considered treatment-related by the 
investigators include 1 Grade 3 ALT increase in the 2 mg/kg Q2W dose escalation cohort 
(n=6), 1 Grade 3 hyperglycaemia in the 2 mg/kg Q2W schedule expansion cohort (n=20), 1 
Grade 3 back pain and 1 Grade 3 fatigue in the 5 mg/kg Q2W schedule expansion cohort 
(n=20), and 1 Grade 3 fatigue and 1 Grade 3 hyperglycaemia in 5 mg/kg Q3W schedule 
expansion cohort (n=19).  
In addition, as of May 5, 2016, 12 subjects have been treated with tislelizumab in 
combination with BGB-290 (a PARP1/2 inhibitor) in the BGB-A317/BGB-290_Study_001 
combo study (NCT02660034).  One subject, who was treated with tislelizumab at 2 mg/kg 
Q3W in combination of BGB-290 (a PARP1/2 inhibitor) at 20 mg BID, experienced an 
immune-mediated SAE of Grade 4 drug induced hepatopathy that was attributed to 
tislelizumab by the investigator.  
Refer to the IB for more detailed information regarding the safety of tislelizumab. 
Clinical experience with existing drugs of the same therapeutic class (anti-PD-1 monoclonal 
antibodies) suggests 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 patients in the nivolumab study, and there were three deaths, all 
attributed to pulmonary toxicity (Brahmer et al, 2010, Topalian et al, 2012).  Grade 3/4 AEs 
were also reported in the pembrolizumab studies with one subject died of myocardial 
infarction while being treated for pneumonitis/pneumonia (Hamid et al, 2013).  Drug-related 
AEs of special interest (AEs with potentially immune-related etiology) included vitiligo, 
pneumonitis, hepatitis, colitis, thyroiditis, and hypophysitis may be observed during multiple 
dose escalation in subjects with cancer. 
2.5 
Study Rationale  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, the Declaration of Helsinki and any applicable regulatory requirements. 
This study will evaluate the safety, tolerability, and PK profile of tislelizumab as well as 
preliminary evidence of the anti-tumor activity of tislelizumab.  Through its dose escalation 
and safety, schedule and efficacy expansion components, it will determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for tislelizumab. 
2.5.1 
Rationale for Starting Dose Selection in Phase 1A Part 1 
Selection of the Safe Starting Dose for First-In-Human Clinical Study 
Tislelizumab has demonstrated a favorable toxicology and safety pharmacology profile in 
nonclinical experiments.  Early clinical development of tislelizumab will be conducted in 

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patients with advanced cancer and failed standard-care treatment.  
The relevant species for preclinical safety evaluation is monkey, because tislelizumab binds 
to human and monkey PD-1 almost equally well, but does not bind to mouse or rat PD-1.  
From conservative point of view, the NOAEL (100 mg/kg) observed in the single dose 
toxicity study in monkeys was not used for FIH dose estimation.  Therefore, the NOAEL was 
considered to be 30 mg/kg based on the 3-month repeat dose toxicity study in cynomolgus 
monkeys.  The FIH dose could be estimated based on NOAEL divided by a safety factor 
(10 or larger; FDA Guidance for Industry M3(R2), Zou et al, 2012).  Based on this rule, the 
FIH dose for tislelizumab could be selected as 3 mg/kg. 
Alternatively, the FIH dose for tislelizumab may be estimated based on the minimum 
anticipated biological effect level (MABEL).  For tislelizumab, MABEL was determined to 
be around 0.5 mg/kg, through PK/pharmacodynamic modeling of allogeneic tumor models, 
the monkey PK, and predicted human exposure.  Therefore, the FIH dose projected based on 
the MABEL should be 0.5 mg/kg. 
Predicted efficacious doses in human 
MABEL of tislelizumab as described above was predicted to be 0.5 mg/kg.  Therefore, the 
selected FIH dose at 0.5 mg/kg may have efficacy on human tumor growth inhibition. 
Furthermore, the best efficacious dose rang is predicted to be in the range of 1 to 5 mg/kg 
based on the PK/pharmacodynamic modeling. 
2.5.2 
Rationale for Evaluating Different Dosing Schedules in Phase 1A Part 2  
Preliminary PK data of subjects in Phase 1A study indicate that the half-life of tislelizumab is 
approximately 17 days and there is moderate drug accumulation in the blood when dosed at a 
Q2W schedule.  Thus a decision is made to investigate a less frequent dosing schedule at 
Q3W.  The objective is to identify one or two safe, effective and convenient dose regimen for 
the Phase 1B study.  
2.5.3 
Rationale for Evaluating Flat Dosing in Phase 1A Part 3  
Population PK analysis was conducted using 411 observed tislelizumab serum concentrations 
from 31 patients who received doses of 0.5, 2.0, 5.0 and 10 mg/kg Q2W and 13 patients who 
received doses of 2.0 and 5.0 mg/kg Q3W (Phase 1A Part 1 and Part 2).  As described in 
Section 2.5.4, PK from tislelizumab is linear and was characterized with a 2-compartment 
model with 1st order elimination.  In the covariate analysis, patient body weight was not 
found to be a significant covariate on the clearance of tislelizumab (Figure 2-1), which 
supports the exploration of flat-dosing.  

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Figure 2-1 
Lack of Correlation between Clearance (Cl) and Patient Body Weight 
Thus a decision is made to explore flat dosing as part of the Phase 1A study, conducted in 
parallel with a Phase 1B study that evaluates the RP2D as described in Section 2.5.4.  The 
proposed flat dose of 200 mg Q3W has the dose intensity between 2 mg/kg Q3W and 
10 mg/kg Q2W. Tislelizumab is generally well tolerated between these doses.  
2.5.4 
Rationale for Dose Selection in Phase 1B  
After reviewing safety and PK data from Phase 1A Part 1 (dose escalation) and Phase 1A 
Part 2 (schedule expansion), the Safety Monitoring Committee (SMC) has recommended 
5 mg/kg Q3W as the dose regimen to be taken into Phase 1B of the study, based on the 
following rationales: 
Safety  
As of March 29, 2016, 100 patients received at least one dose of tislelizumab in the Phase 1A 
part of the study, ranging from 0.5 mg/kg to 10 mg/kg Q2W (n=62) and from 2 mg/kg to 
5 mg/kg Q3W (n=38).  Safety and tolerability including dose limiting toxicities, PK, and 
preliminary efficacy were evaluated.  
As described in Section 2.4, all dose levels in the dose escalation part were well tolerated 
with only one reported DLT.  MTD was not reached and 10 mg/kg Q2W was considered the 
maximum administered dose (MAD).  No apparent relationship between dose level and AEs 
was established. 
Drug-related AE from 2 mg/kg Q2W to 10 mg/kg Q2W were similar (Table 1 and Table 2). 
AE profiles from Q3W regimen between 2 mg/kg and 5 mg/kg based on data reported from 
the first 2 cycles slightly favor 2 mg/kg, although with short treatment duration.  

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Tislelizumab is generally well tolerated between these doses with slightly fewer AEs from 
the Q3W regimen. 
Efficacy 
Clinical response (PR or better) was observed in patients who received 0.5 mg/kg, 2 mg/kg, 
5 mg/kg Q2W, and 2 mg/kg Q3W cohorts (Table 3).  The majority of responses came from 
5 mg/kg cohorts.  The proposed Phase 1B dose of 5 mg/kg Q3W has a dose intensity between 
2 mg/kg Q3W and 5 mg/kg Q2W.  Further investigation of 5 mg/kg Q3W is warranted. 
Table 1 
Summary of All Adverse Events Reported in Phase 1A from Study 
Initiation through March 29, 2016 
Number of 
Patients with at 
least one of the 
following 
Dose Escalation 
Schedule Expansion 
0.5mg/kg 
Q2W   
n=3 
2mg/kg 
Q2W   
n=6 
5mg/kg 
Q2W   
n=6 
10mg/kg 
Q2W   
n=7 
2mg/kg 
Q2W  
n=20 
5mg/kg 
Q2W   
n=20 
2mg/kg 
Q3W   
n=19 
5mg/kg 
Q3W   
n=19 
Median 
Treatment 
Duration (days) 
126 
(99-153) 
138 
(41-251) 
87 
(16-210) 
79 
(23-161) 
86 
(15-191) 
93 
(29-160) 
45 
(9-127) 
46 
(13-107) 
Any AE 
3 
6 
6 
7 
20 
20 
10 
11 
Any Drug-
related AE 
0 
5 
4 
4 
15 
14 
2 
9 
Grade 3/4 Drug-
related AE 
0 
1 
1 
0 
2 
2 
0 
3 
Serious Drug-
related AE 
0 
1 
1 
0 
3 
2 
0 
1 
AE leading to 
discontinuation 
from Study 
0 
0 
0 
0 
0 
1 
0 
0 

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Table 2 
Most Common Drug-related Adverse Events (all Grade ≥5% or Grade 3/4 ≥1%) Reported in Phase 1A from 
Study Initiation through March 29, 2016 
SOC/PT 
All Grade 
Grade 3-4 
Number of patients with AE in each cohort 
n* 
% 
n* 
% 
0.5 mg/kg 
Q2W  
Dose 
escalation 
2 mg/kg 
Q2W  
Dose 
escalation 
5 mg/kg 
Q2W  
Dose 
escalation 
10 mg/kg 
Q2W  
Dose 
escalation 
2 mg/kg 
Q2W  
Schedule 
expansion 
5 mg/kg 
Q2W  
Schedule 
expansion 
2 mg/kg 
Q3W  
Schedule 
expansion 
5 mg/kg 
Q3W  
Schedule 
expansion 
(pts) 
(N=100) 
(pts) 
(N=100) 
n=3 
n=6 
n=6 
n=7 
n=20 
n=20 
n=19 
n=19 
General disorders and administration site conditions 
Fatigue 
14 
14% 
2 
2% 
0 
2 
2 
0 
4 
4 
0 
2 
Gastrointestinal disorders 
Diarrhoea 
11 
11% 
0 
0% 
0 
3 
1 
0 
5 
2 
0 
0 
Nausea 
5 
5% 
0 
0% 
0 
0 
1 
1 
1 
2 
0 
0 
Colitis 
2 
2% 
1 
1% 
0 
0 
1 
0 
0 
1 
0 
0 
Skin and subcutaneous tissue disorders 
Pruritus 
8 
8% 
0 
0% 
0 
1 
0 
1 
3 
0 
0 
3 
Rash 
7 
7% 
0 
0% 
0 
0 
1 
1 
1 
3 
0 
1 
Investigations 
Alanine 
aminotransferase 
increased 
3 
3% 
1 
1% 
0 
1 
1 
0 
1 
0 
0 
0 
Metabolism and nutrition disorders 
Hyperglycaemia 
2 
2% 
2 
2% 
0 
0 
0 
0 
1 
0 
0 
1 
Diabetes mellitus 
2 
2% 
1 
1% 
0 
0 
0 
0 
1 
0 
0 
1 
Diabetic 
ketoacidosis 
1 
1% 
1 
1% 
0 
0 
0 
0 
1 
0 
0 
0 
Vascular disorders 
Hypotension 
2 
2% 
2 
2% 
0 
0 
0 
0 
1 
0 
0 
1 
Musculoskeletal and connective tissue disorders 
Back pain 
1 
1% 
1 
1% 
0 
0 
0 
0 
0 
1 
0 
0 
Abbreviations: SOC, System Organ Class; PT, Preferred Term. 
*If a patient experiences more than one occurrence of the same event, only the highest grade event is counted.  

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Table 3 
Summary of Enrollment and Response by Cohort in Phase 1A as of 
March 29, 2016 
Cohort 
Number of 
patients 
Number 
Evaluable 
Number of 
confirmed 
PR 
Number of 
unconfirmed 
PR 
0.5 mg/kg Q2W Dose escalation 
3 
3 
0 
1 
2 mg/kg Q2W Dose escalation 
6 
6 
1 
1 
5 mg/kg Q2W Dose escalation 
6 
6 
0 
0 
10 mg/kg Q2W Dose escalation 
7 
7 
0 
0 
2 mg/kg Q2W Schedule expansion 
20 
20 
1 
0 
5 mg/kg Q2W Schedule expansion 
20 
19 
1 
3 
2 mg/kg Q3W Schedule expansion 
19 
4 
1 
0 
5 mg/kg Q3W Schedule expansion 
19 
3 
0 
0 
Abbreviations: Q2W, every two weeks; Q3W, every three weeks. 
 
Population Pharmacokinetics 
Population PK analysis was conducted using 411 observed tislelizumab serum concentrations 
from 31 patients who received doses of 0.5, 2.0, 5.0 and 10 mg/kg Q2W and 13 patients who 
received doses of 2.0 and 5.0 mg/kg Q3W (Phase 1A Part 1 and Part 2).  PK from 
tislelizumab is linear and was characterized with a 2-compartment model with 1st order 
elimination.  Systemic clearance of A317 was 0.00789 L/h, volume of distribution in the 
central and peripheral compartment are 2.79 and 1.44 L, respectively, and terminal 
elimination half-life is 16 days. 
In conclusion, tislelizumab regimen of 5 mg/kg Q3W was well-tolerated with promising 
clinical activity from a limited number of patients in the Phase 1A trial.  Further testing of 
this regimen is warranted in Phase 1B. 
2.5.5 
Rationale for Selection of Different Expansion Arms in Phase 1B  
Rationale for the selection of cancer indications included in the 9 expansion arms is based on 
in vivo tumor growth inhibition studies, which demonstrated that tislelizumab have 
significantly higher antitumor activities than nivolumab and pembrolizumab in mouse 
models carrying allogenic human cancer cells and PBMCs (see Figure 2-2).  Therefore, we 
hypothesized that tislelizumab may be more efficacious than nivolumab and pembrolizumab 
in certain insensitive cancer types.  
 

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Figure 2-2 
Comparison of Tumor Growth Inhibition by the Treatment with 
Tislelizumab versus Nivolumab and Pembrolizumab in the Mouse Cancer Model 
      
 
We also selected tumor types where nivolumab and pembrolizumab have shown various 
clinical efficacies, including melanoma, lung cancer, RCC, HNSCC, hepatocellular 
carcinoma (HCC), bladder, gastric, ovarian and breast cancer.  The ORRs for nivolumab and 
pembrolizumab in these tumors range from 15 to 35% with durable response shown in most 
cases.  Tislelizumab is expected to be equal or more efficacious in some indications such as 
HCC, ovarian, gastric, TNBC, bladder cancer and NSCLC. It is also hypothesized that 
tislelizumab may show better therapeutic potential when used in combination with certain 
cancer therapeutic agents.  The hypothesis that tislelizumab may pose differential activities 
from nivolumab and pembrolizumab is based on our studies on tumor microenvironment and 
other factors driving tumorigenesis and progression in different cancer types.  
Based on the discussion above, the 9 expansion arms may be classified into the following 
categories: 
1. Indications where nivolumab and pembrolizumab have shown variable efficacy with 
ORR ranging from 10+ to 20+%, but tislelizumab is expected to be more active, such 
as NSCLC, HCC, ovarian cancer, gastric cancer, esophageal cancer and TNBC, 
which are covered in the expansion arms 1-8. 
2. Indications in which nivolumab and pembrolizumab have shown very good efficacy 
and tislelizumab is anticipated to be equally or more active, such as melanoma, RCC 
and bladder cancer, which are covered in the expansion Arm 9.  A recent study 
indicated that a small portion (15%) of CRC patients with mismatch repair deficiency 
(dMMR) responded well to pembrolizumab (Le et al, 2015).  Tislelizumab is 

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expected to be equally or more active based on promising Phase 1A data. Cancers 
with microsatellite instability-high (MSI-H) or dMMR will be explored in this arm. 
3.0 
STUDY OBJECTIVES  
3.1 
Primary Objectives 
The primary objective of the Phase 1A stage of the study is the following: 
 To assess the safety and tolerability of tislelizumab in subjects with advanced or 
refractory malignancies 
The primary objective of the Phase 1B stage of the study is the following: 
 To assess the anti-tumor activity of tislelizumab in select tumor types 
3.2 
Secondary Objectives 
The secondary objectives of the Phase 1A stage of the study are the following: 
 To characterize the PK of tislelizumab 
 To determine MTD, if any, and RP2D for tislelizumab 
 To assess the preliminary anti-tumor activity of tislelizumab 
 To assess host immunogenicity to tislelizumab 
The secondary objectives of the Phase 1B stage of the study are the following: 
 To further assess the safety and tolerability of tislelizumab in subjects with advanced 
tumors 
 To further characterize the PK of tislelizumab 
3.3 
Exploratory Objectives 
 
 
 

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4.0 
STUDY ENDPOINTS 
4.1 
Primary Endpoints 
The primary endpoint of the Phase 1A stage is the following: 
 Tislelizumab safety and tolerability: The safety of tislelizumab will be assessed 
throughout the study by monitoring AEs per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010), physical 
examination, ophthalmologic examination, electrocardiograms, laboratory measurements 
and severity of AEs 
Given the mechanism of action by tislelizumab involves immune regulatory function, 
particular attention should be given to irAEs, which include pruritus, vitiligo, pruritic rash, 
macular rash, hypopigmentation, and other skin disorders; hypo- and hyperthyroidism, 
hypophysitis, pneumonitis, hepatitis, nephritis, allergic rhinitis, diarrhea, abdominal pain, 
fatigue, hypersensitivity and any other irAEs (see Section 7.3.4).  Appropriate investigations 
should be undertaken to exclude toxic, metabolic, infectious, neoplastic or other non-drug-
related etiologic causes of such events. 
The primary endpoint of the Phase 1B stage is the following: 
 ORR (CR + PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 
in subjects with select tumor types as evaluated by the Investigators 
Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (Scher et al, 2008) may 
also be used to evaluate responses in patients with prostate cancer enrolled on the study as 
described in Appendix 9. 
The Gynecologic Cancer Intergroup (GCIG) criteria (Rustin et al, 2011) in addition to 
RECIST v 1.1 may also be used to evaluate response in patients with ovarian cancer enrolled 
on the study. 
Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al, 2010) may also be 
used to evaluate response in patients with glioblastoma multiforme (GBM) enrolled on the 
study. 
4.2 
Secondary Endpoints 
The secondary endpoints of the Phase 1A stage of the study are the following: 
 
Pharmacokinetic evaluations: include but not limited to AUC from Day 0 to Day 14 
(AUC0-14 day), Cmax, time to maximum concentration (Tmax), minimum observed 

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plasma concentration (Ctrough), T½, clearance (Cl), and Vd.  The MTD, if any, and 
RP2D (s) for tislelizumab will be determined based on safety, tolerability, PK, 
preliminary efficacy, and other available data. 
 Efficacy evaluations: ORR (CR+PR), CR rate, PR rate, stable disease (SD) rate, 
progression-free survival (PFS), OS and duration of response (DOR) will be determined 
based on RECIST v 1.1 and the results of Investigator evaluations 
 Anti-tislelizumab antibody: Immunogenic responses to tislelizumab will be assessed to 
determine incidence of ADA 
The secondary endpoints of the Phase 1B stage of the study are the following: 
 PFS as described above; disease control rate (DCR: CR + PR + SD); and clinical benefit 
rate (CBR: CR or PR or durable SD [SD ≥24 weeks]) 
 Safety and tolerability assessment of AEs, SAEs, physical examination, ophthalmologic 
examination, vital signs, ECG, and laboratory measurements 
 Plasma concentrations of tislelizumab at selected time points 
4.3 
Exploratory Endpoints 
 
 
 
 
5.0 
INVESTIGATIONAL PLAN 
5.1 
 Summary of Study Design 
This is a two-stage study consisting of a Phase 1A dose escalation and dose-finding 
component to establish the MTD, if any, and RP2D(s), followed by a Phase 1B component to 

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investigate efficacy in select tumor types and to further evaluate safety and tolerability of 
tislelizumab at RP2D(s).  
Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh 
tumor biopsy at baseline is strongly recommended.  In the absence of archival tumor tissues, 
a fresh biopsy of a tumor lesion is required at baseline; for these subjects, an optional biopsy 
for biomarker analysis after two cycles of treatment is strongly recommended.  Optional 
biopsy will also be taken at the safety follow up visit for the subjects who have confirmed 
disease progression during the study from accessible tumor sites to obtain samples to explore 
resistance mechanism.  If feasible, any follow up biopsy should be ideally taken from the 
same tumor lesion as the baseline biopsy.  Written patient consent is required for fresh tumor 
biopsies.  
Mandatory biopsies at baseline and on treatment are required for some tumor types in the 
Phase 1B study.   
Subjects will be monitored for safety, anti-tislelizumab antibodies and efficacy throughout 
the study.  Radiological assessment of tumor response status should be performed 
approximately every 8 weeks or 9 weeks depending on dosing schedules in the first year, 
then every 12 weeks thereafter. 
A flow chart of the study design is presented in Appendix 7. 
5.1.1 
Dose-Limiting Toxicity 
All toxicities or AEs will be graded according to the NCI-CTCAE Version 4.0.  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 5 adverse events 
2. Grade 4 toxicity  
3. Grade 3 toxicities irrespective of duration, with the exception of laboratory abnormalities, 
diarrhea, nausea and vomiting, and asymptomatic biochemical abnormalities that 
improve to Grade 2 or lesser severity within 3 days of institution of supportive care 
4. Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor) of > 7 day duration 
5. Immune-related adverse events (irAE) of Grade 3 or greater severity 

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6. Grade 4 laboratory abnormalities irrespective of duration 
 
7. Grade 2 ophthalmologic toxicities 
 
Hematologic: 
1. Grade 4 neutropenia lasting >7 days 
2. Febrile neutropenia (defined as absolute neutrophil count [ANC] <1000/mm3 with a 
single temperature of 38.3oC or a sustained temperature of 38oC for >1 hour) 
3. Grade 3 neutropenic infection 
4. Grade 3 thrombocytopenia with bleeding 
5. Grade 4 thrombocytopenia 
6. Grade 4 (life threatening) anemia 
Any grade toxicity which in the judgment of the Investigator or Sponsor requires removal of 
the subject from the study. 
Subjects who received <90% of the tislelizumab infusion in Cycle 1 (eg, because the infusion 
had to be discontinued due to an infusion 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 tislelizumab administration for subjects experiencing DLTs may be permitted 
according to the criteria described in Section 5.1.2, if clinically appropriate, contingent on the 
return of the DLT to ≤ Grade 0-1 severity and interruption or delay of treatment for no more 
than 6 weeks (12 weeks for Phase 1A Part 3 and Phase 1B). 
5.1.2 
Dose Modifications, Dose Delay and Missing Dose 
Dose adjustments will be allowed for tislelizumab for weight changes at the beginning of 
each cycle.  Dose must be adjusted if body weight changes reach 10% or greater (increase or 
decrease).  
In the case that an infusion cannot be administered at a scheduled visit, the instruction below 
should be followed.  If the delay is between 1 and 7 days for Q2W schedule and 1 to 10 days 
for Q3W schedule, the subject should be dosed as soon as possible and procedures at the 
original scheduled visit should be performed.  If the delay is more than 7 (for Q2W) or 10 
(for Q3W) days, the delayed dose should be skipped and considered a missed dose, the 

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subject will be dosed at Day 1 of the next scheduled cycle.  In both cases, subsequent visits 
will follow every 2 weeks (Q2W schedule) or Q3W schedule according to the original 
schedules.  Subjects with infusion delays > 6 weeks from planned dosing date for reason(s) 
other than treatment-related toxicity should normally discontinue treatment and enter the 
Follow-up Period with the exception of delays related to prophylactic vaccinations or after 
specific consultation and agreement between the Investigator and Sponsor medical monitor 
in settings where benefit/risk may justify continued study therapy (eg, subject deriving 
clinical benefit who requires prolonged steroid taper for management of non-DLT irAEs). 
Tislelizumab will be withheld for any of the following treatment-related adverse 
reactions: 
1. Grade 2 pneumonitis 
2. Grade 2 or 3 colitis/diarrhea 
3. Grade 3-4 hypophysitis 
4. Grade 2-3 nephritis 
5. Grade 3-4 thyroid disorders  
6. Grade 2-3 ALT or aspartate aminotransferase (AST) elevations 
7. Grade 2 neurological toxicity 
8. Grade 3 skin reactions 
9. Grade 3-4 diabetes/hyperglycemia 
10. Grade 3 ocular toxicity 
11. Grade 3 pancreatitis 
12. Grade 3 arthritis 
13. Grade 3 mucositis/stomatitis 
14. Grade 2-4 Myositis/Rhabdomyolysis 
15. Grade 1 Myocarditis 
16. Any other severe or Grade 3 treatment-related adverse reaction except for asymptomatic 
laboratory abnormalities 

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Refer to Section 7.3 and Appendix 10 for more detailed information regarding dose 
modification and management of irAEs. 
In Phase 1A Part 1 and 2, tislelizumab dosing can be resumed for subjects whose adverse 
reactions recover to Grade 0-1 within 6 weeks.  The dosing interval in subsequent cycles may 
be increased by 1 week (eg, to 3 weeks in subjects who were on Q2W schedule, and to 
4 weeks in subjects who were on Q3W schedule).  The visit and assessment schedule for 
subjects on 3 week interval will follow those designed for Q3W, and the visit and assessment 
schedule for subjects on 4 week interval will follow those designed for Q2W, but maybe with 
reduced frequency for some of the assessments at the Investigator’s discretion.  The dosing 
interval can only be prolonged once.  
In Phase 1A Part 3, tislelizumab dosing can be resumed for subjects whose adverse reactions 
recover to Grade 0-1 within 12 weeks after last dose of tislelizumab.  The tislelizumab dose 
may be resumed to original dose level and schedule if deemed necessary by the Investigator 
after consultation with the Sponsor.  
In Phase 1B, tislelizumab dosing can be resumed for subjects whose adverse reactions 
recover to Grade 0-1 within 12 weeks after last dose of tislelizumab.  The tislelizumab dose 
may be resumed to original dose level and schedule if deemed necessary by the investigator 
after consultation with the Sponsor. 
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. 
Tislelizumab will be permanently discontinued for any of the following after 
consultation with the Sponsor: 
1. Severe or life-threatening adverse reactions, including any of the following: 
 
Grade 4 non-hematologic toxicity 
 
Grade 4 hematologic toxicity, including Grade 4 neutropenia that last >7 days 
 
Grade 4 colitis/diarrhea, diarrhea with abdominal pain, fever, ileus, or peritoneal 
signs; increase in stool frequency (7 or more over baseline), stool incontinence, need 
for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and 
gastrointestinal perforation 
 
Grade 4 AST or ALT 

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 
Grade 4 skin reactions, Steven-Johnson syndrome, toxic epidermal necrolysis, or 
rash complicated by full thickness dermal ulceration or necrotic, bullous or 
hemorrhagic manifestations 
 
Severe (ie, CTCAE Grade 3 or 4) motor or sensory neuropathy, Guillain-Barré 
syndrome, or myasthenia gravis 
 
Severe (ie, CTCAE Grade 3 or 4) immune-mediated reactions involving any organs 
(eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) 
 
Immune-mediated ocular disease that is unresponsive to topical immunosuppressive 
therapy, Grade 4 ocular toxicity 
 
Grade 4 mucositis/stomatitis 
 
Grade 2-4 Myocarditis 
 
Grade 3 or above infusion reaction (except for a transient Grade 3 infusion reaction 
that resolves within 6 hours of onset) (Section 7.3.2) 
2. Inability to reduce corticosteroid dose for immune-related adverse reactions to <10 mg 
prednisone or equivalent per day  
In case a subject is benefiting from the study treatment while meeting the discontinuation 
criteria described above, discussion between Sponsor and Investigator will be conducted to 
make a decision that will be in the best interest of the subject. 
Refer to Section 7.3.4 and Appendix 10 for more details about irAEs and management 
of such events. 
5.1.3 
Phase 1A Part 1: Dose Escalation 
The Phase 1A, Part 1 component is a multicenter, open label, multiple dose, dose escalation, 
first in human study.  Four dose levels are planned: 0.5, 2.0, 5.0 and 10 mg/kg, Q2W as 
presented in Table 4.  The highest dose to be tested during dose escalation is 10 mg/kg Q2W.  
If 0/3 subjects or ≥ 1/6 subjects develop a DLT at that dose, then MTD is not reached and 
10 mg/kg is considered the MAD. 

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Table 4 
Suggested Dose Escalation Scheme  
 
Step 
Dose1 
1 
0.5 mg/kg Q2W 
2 
2 mg/kg Q2W 
3 
5 mg/kg Q2W 
4 
10 mg/kg Q2W 
Abbreviations: Q2W, every two weeks. 
1  
The actual dose levels and dose regimens administered in each step will depend on the data available 
from the previous step, as determined by the SMC. 
After the first subject in the first dose level receives the Cycle 1, Day 1 dose, subsequent 
subjects in the first cohort will not be dosed until the first subject has been observed for 
at least 24 hours to exclude unexpected acute toxicity. 
Continuous safety evaluation will be performed by the Sponsor, the Coordinating 
Investigator, and Investigators.  An SMC will be established for the determination of dose 
levels to be administered and dose regimen during dose escalation, and will utilize the data 
available from the previous dose levels (see Section 8.3.1 for committee composition). 
5.1.3.1 
Dose Escalation and Dose Finding 
Evaluation of a cohort of at least three (3) subjects completing one cycle of treatment at that 
dose level and dose regimen without a DLT is required prior to determining the next dose 
level and dose regimen for the next cohort.   
The study will follow a modified 3+3 dose escalation scheme.  At least three (3) subjects will 
be enrolled into each cohort.  Additional subject(s), up to a maximum of six (6) subjects in 
total, will be enrolled if more than three (3) have been screened and are eligible for the 
cohort.  Dose-escalation scheme will follow the rules stipulated in the standard 3 + 3 dose 
escalation scheme.  For example, three (3) 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. 
If none (0) of the subjects in the cohort experience a DLT by the end of Cycle 1, escalation to 
the next dose will occur, as determined by the SMC. 
If one (1) out of six (6) subjects experience a DLT by the end of Cycle 1, escalation to the 
next dose will occur, as determined by the SMC. 
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 

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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. 
The SMC may decide to evaluate an intermediate, not pre-defined and not previously-studied 
dose or less frequent dosing schedule (eg, Q3W), if evaluation of toxicity at such a dose or 
schedule is desired.  If this approach is taken, up to 6 new subjects should be enrolled at the 
new intermediate dose or schedule. 
Subjects who received <90% of the tislelizumab infusion in Cycle 1 (eg, because the infusion 
had to be discontinued due to an infusion 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 need to be replaced.  
5.1.3.2 
Schedule of Assessment 
The schedule of events for Phase 1A Part 1 is presented in Table 5 and the PK sampling 
schedule in Table 6.  

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6. Electrocardiogram assessments are to be performed with the subject in semi recumbent supine position and rested for 5 minutes. Electrocardiogram (12-
lead ECG) should be performed at Screening as baseline, at the time of PK blood collection for PK (Cmax) within 30 minutes after the end of the first 
infusion of tislelizumab, after infusion of tislelizumab in Day 15 of Cycle 1 and Day 1 of every subsequent cycle (within 30 minutes after the end of 
infusion), and at the mandatory Safety Follow-up visit. Additional ECGs may be obtained if clinically indicated (refer to Section 8.2.3). 
7. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v 4.03. All adverse experiences, whether gradable by CTCAE 
or not, will also be evaluated for seriousness.  After the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship to study 
drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, whichever occurs first. 
Telephone contacts with patients should be conducted to assess immune-related AEs 90 days after the last dose of tislelizumab regardless of whether or 
not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded by the Investigator after treatment 
discontinuation until subject death or loss to follow-up, whichever occurs first. 
8. Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the local study site laboratory or their contract laboratory.  
Hematology, chemistry, and urinalysis may be collected up to 72 hours prior to any Cycle Day 1 and Day 15 dosing. Of note, creatine kinase (CK) and 
creatine kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Appendix 2).  In the event CK-MB 
fractionation is not available, please assess troponin I and/or  troponin T instead.  
9. Prothrombin Time (PT)/International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (aPTT) should be collected at Screening and 
at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation parameters should be determined throughout the study 
when clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory. 
10. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days before the first investigational 
product administration). 
11. Only for the dose-escalation subjects treated in Melbourne sites due to sample and assay logistics. Cycle 1: predose Day 1 and Day 15; Cycle 2 and 
every cycle in first 6 months: predose Day 1; at the mandatory Safety Follow-Up Visit. Collect 40 mL blood in acid-citrate-dextrose (ACD) on the date 
indicated, transport within 8 hours to the central laboratory. Fluorescence-activated cell sorting (FACS) analysis of lymphocyte subpopulations and 
other immune cells, and analysis of cytokines/chemokines will be performed. 
12. T3, T4, TSH; at every cycle, and at the mandatory Safety Follow-Up Visit. Analysis of T3, T4 and TSH will be performed by the local study site 
laboratory. 

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13. Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 8 weeks thereafter, and at the Safety Follow-Up 
Visit. Analysis will be performed by the local study site laboratory. 
14. Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion every cycle in the first 6 months, every 2 cycles 
in the next 6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who discontinue study therapy 
before 6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months after the first dose. Analysis will be 
performed by a central laboratory. 
15. Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up visit for the subjects who have confirmed disease 
progression during the study to explore resistance mechanism. Samples will be processed according to the Lab Manual. 
16. For timing refer to Table 6 Phase 1A Part 1 Pharmacokinetic Sampling for details on timing of pharmacokinetics sample collection. Procedures for 
collection of samples are described in the Lab Manual. 
17. Testing will be performed by the local laboratory at Screening. Include Hepatitis C virus (HCV) antibody (HCVAb), Hepatitis B surface antigen 
(HBsAg), Hepatitis B core antibody (HBcAb) and human immunodeficiency virus (HIV) 1/2 antibodies. Subjects who are HBsAg and HBcAb positive 
or HCV antibody positive at screening must not be enrolled until further definite testing with Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 
titers and HCV ribonucleic acid (RNA) tests can conclusively rule out presence of active infection requiring therapy with Hepatitis B and C, 
respectively. Subjects enrolled in the study who had detectable HBV DNA or HCV RNA at Screening should be tested for HBV or HCV viral load, 
respectively, every 4 cycles (± 7 days) throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically indicated). For subjects 
who already received 4 or more doses of study drug, the viral load test should be repeated at the subject’s next visit and every 4 cycles according to the 
schedule from first dose (Cycle 1 Day 1), and whenever clinically indicated. HCC subjects who test positive for HCV will not be discontinued. HCC 
subjects who test positive for HBV should be treated as per local guidelines at the investigator’s discretion. 
18. Standard tumor markers (eg, alpha fetoprotein [AFP] for HCC and cancer antigen 125 [CA 125] for ovarian cancer, as appropriate for a given tumor 
type) will be collected within 14 days prior to Cycle 1 Day 1, and while on study approximately every 2 months in the first 12 months and 
approximately every 3 months thereafter, and at the mandatory Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory 
where feasible. If not feasible, tests will be performed by a central laboratory. 
19. Tumor imaging (either computed tomography [CT] or magnetic resonance imaging [MRI], with preference for CT) will be performed within 28 days 
prior to enrollment, and while on study approximately every 8 weeks in the first 12 months and approximately every 12 weeks thereafter. 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 

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regularly scheduled time point will be used for response confirmation. After patient’s re-consenting, Progressive disease (PD) suspected as pseudo-
progression needs to be confirmed in a subsequent imaging at least 4 weeks later or at the next regularly scheduled time point but not to exceed 
12 weeks, before discontinuation of study treatment. Subjects who stop treatment prior to documentation of PD will undergo repeated imaging 
for tumor response assessments during the study approximately every 8 weeks or 9 weeks depending on dosing schedules in the first 12 months 
and approximately every 12 weeks thereafter until unequivocal PD is documented or the subject starts new anticancer therapies or subject 
withdraws consent from the trial. 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 will 
be requested to undergo appropriate imaging to confirm PD.  Every effort will be made to confirm a clinical diagnosis of PD by imaging 
(Section 5.2.5.2). 
20. Bone scans must be done for subjects with metastatic castration-resistant prostate cancer (mCRPC) as described in Section 8.2.4. For other 
subjects, bone scans at baseline or subsequent visits will be performed only if clinically indicated. 
21. Collection of archival tumor tissue for purpose of biomarker analysis. Written patient consent is required for collection of archival tumor tissue. Specific 
instructions for tissue collection and shipment are provided in the Lab Manual. 
22. Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh baseline tumor biopsy (within 8 weeks before starting 
treatment) is strongly recommended. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory; for these subjects, 
an optional biopsy for biomarker analysis after 2 cycles of treatment (approximately Cycle 3 Day 1) is strongly recommended. Optional biopsy will also 
be taken at the safety follow up visit for the subjects who have confirmed disease progression during the study from accessible tumor sites to obtain 
samples to explore resistance mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
Written patient consent is required for fresh tumor biopsies. Fresh biopsies should be limited to readily accessible tumor lesions (eg, skin; peripheral 
lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If performed, a core or excisional biopsy 
of the tumor (cytologic or fine-needle aspiration samples are not acceptable) should be obtained that has proper size for histological examination and 
biomarker analysis (eg, IHC of PD-1, PD-L1, PD-L2; genomic profiling).  
23. 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. 
24. Ophthalmologic exam (such as eyesight/visual acuity, fundoscopic, slit lamp microscopy, and optical coherence tomography [or equivalent diagnostic 
test]) within 28 days prior to first dose, Cycle 1 Day 15 (±1 day), and Cycle 3 Day 1 (±7 days). Subjects will subsequently undergo repeat assessments 

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by an appropriate specialist approximately every 4 cycles/16 weeks (± 7 days) during study treatment and a final assessment <30 days after the last dose 
of study treatment.  For those subjects who have already received 2 or more doses of study drug, the exam should be repeated at the subject’s next visit 
and then approximately every 4 cycles/16 weeks according to the schedule from first dose (Cycle 1 Day1). Investigators should solicit subjects 
regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab treatment.  For any change in 
vision, referral to an appropriate specialist will be made for further management guidance (see Appendix 10).  
  

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Abbreviations:  DLT, dose-limiting toxicity; min, minute. 
Please note: Actual drug dosing and PK sampling times have to be documented by the sites 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. Cycle 2 and subsequently every cycle except for Cycle 4 during the first 12 months of study therapy, approximately every 6 months thereafter. 
5. PK assays should be performed at the mandatory Safety Follow-Up Visit. 
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to Section 7.3.4), additional blood PK samples will 
be taken to determine the plasma concentration of tislelizumab. 

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5.1.4 
Phase 1A Part 2: Schedule Expansion 
The Phase 1A, Part 2 component will evaluate the safety and PK of two dosing schedules 
Q2W versus Q3W at selected doses that have cleared the DLT period without exceeding 
MTD (eg, 2 mg/kg or 5 mg/kg, up to 10 mg/kg). Ten to 20 subjects per dose schedule will be 
enrolled to evaluate the safety, the PK and preliminary efficacy.  Tumors types to be enrolled 
include but not limited to CRC, NSCLC, RCC, bladder cancer, ovarian cancer and 
melanoma.  Other cancers that are deemed to be likely to benefit from PD-1 inhibition based 
on high mutational load, preclinical or clinical data from other studies may be considered for 
enrollment subject to discussion with the medical monitor.  
5.1.4.1 
Criteria for Stopping Phase 1A Part 2 
The doses selected for the Q2W schedule expansion will have been evaluated for DLT and 
demonstrated as safe in the Phase 1A Part 1 study.  These doses administrated at a less 
frequent schedule of Q3W should be safe as well.  Nevertheless, to adequately monitor safety 
of subjects enrolled in dosing schedule expansion, when at least 6 subjects have been treated 
at a specific dose and schedule and ≥33% of the subjects experienced a DLT during the first 
cycle in both Q2W and Q3W schedules (as defined in Section 5.1.1 of the protocol), study 
accrual will be held pending data review by the SMC.  Tislelizumab will also be withheld in 
the event of other serious adverse reactions according to pre-specified criteria (as defined in 
Section 5.1.2 of the protocol).  Q2W and Q3W schedule expansion may be conducted 
sequentially or in parallel. 
In the event that a MTD is not identified, RP2D and dosing regimen used in the Phase 1B 
stage will be determined by the SMC and the Sponsor based on the PK, tolerability and 
preliminary antitumor activities observed in the Phase 1A stage, as well as other available 
data.  Based on the Phase 1A data, more than one dose or dosing regimen may be selected to 
be further evaluated in Phase 1B for safety and preliminary efficacy in select tumor types. 
5.1.4.2 
Schedule of Assessment 
The schedule of events for Phase 1A Part 2 is presented in Table 7 (Q2W schedule) and 
Table 8 (Q3W schedule).

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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 Baseline number when the study informed consent is signed. 
4. 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. Complete 
medication history for 30 days before the first dose (C1D1) of study mediation needs to be reported.  
5. Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
6. Electrocardiogram assessments are to be performed with the subject in semi recumbent supine position and rested for 5 minutes. Electrocardiogram 
(12-lead ECG) should be performed at Screening as baseline, at the time of PK blood collection for PK (Cmax) within 30 minutes after the end of the 
first infusion of tislelizumab, after infusion of tislelizumab in Day 15 of Cycle 1 and Day 1 of every subsequent cycle (within 30 minutes after the 
end of infusion), and at the mandatory Safety Follow-up visit. Additional ECGs may be obtained if clinically indicated (refer to Section 8.2.3). 
7. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v 4.03. All adverse experiences, whether gradable by 
CTCAE or not, will also be evaluated for seriousness.  After the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship 
to study drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, whichever 
occurs first. Telephone contacts with patients should be conducted to assess immune-related AEs 90 days after the last dose of tislelizumab 
regardless of whether or not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up 
contact, the investigator should arrange an unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded by the 
Investigator after treatment discontinuation until subject death or loss to follow-up, whichever occurs first. 
8. Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the local study site laboratory or their contract laboratory. 
Hematology, chemistry, and urinalysis may be collected up to 72 hours prior to any Cycle Day 1 dosing. Of note, creatine kinase (CK) and creatine 
kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Appendix 2).  In the event CK-MB 
fractionation is not available, please assess troponin I and/or troponin T instead. 
9. PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation 
parameters should be determined throughout the study when clinically indicated. PT/INR and aPTT will be analyzed by the local study site 
laboratory. 
10. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days before the first 
investigational product administration). 

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11. T3, T4, TSH; at every cycle, and at the mandatory Safety Follow-Up Visit. Analysis of T3, T4 and TSH will be performed by the local study site 
laboratory. 
12. Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 8 weeks thereafter, and at the Safety Follow-
Up Visit. Analysis will be performed by the local study site laboratory.  
13. Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion every cycle in the first 6 months, every 2 
cycles in the next 6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who discontinue 
study therapy before 6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months after the first dose. 
Analysis will be performed by a central laboratory. 
14. Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up visit for the subjects who have confirmed 
disease progression during the study to explore resistance mechanism. Samples will be processed according to the Lab Manual. 
15. Procedures for collection of PK samples are described in the Lab Manual. Predose (within 60 min before start infusion) and postdose (within 30 min 
after the end of infusion) samples should be collected at Cycle 1 Day 1, Day 15, Day 1 of Cycle 2 and subsequently every cycle in the first 12 
months, then approximately every 6 months thereafter; two PK samples should be collected at Cycle 1 Day 4 (or 5) and Day 8; additional PK 
samples should be collected at the mandatory Safety Follow-Up Visit. Should a subject present with a DLT or any Grade 3 or above immune-related 
adverse event (refer to Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of tislelizumab. 
16. Testing will be performed by the local laboratory at Screening. Include HCV antibody, HBsAg, HBcAb and HIV 1/2 antibodies. Subjects who are 
HBsAg and HBcAb positive or HCV antibody positive at screening must not be enrolled until further definite testing with HBV DNA titers and 
HCV RNA tests can conclusively rule out presence of active infection requiring therapy with Hepatitis B and C respectively. Subjects enrolled in the 
study who had detectable HBV DNA or HCV RNA at Screening should be tested for HBV or HCV viral load, respectively, every 4 cycles (± 7 days) 
throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically indicated). For subjects who already received 4 or more 
doses of study drug, the viral load test should be repeated at the subject’s next visit and every 4 cycles according to the schedule from first dose 
(Cycle 1 Day 1), and whenever clinically indicated. HCC subjects who test positive for HCV will not be discontinued. HCC subjects who test 
positive for HBV should be treated as per local guidelines at the investigator’s discretion. 
17. Standard tumor markers (eg, AFP or HCC and CA 125 for ovarian cancer, as appropriate for a given tumor type) will be collected within 14 days 
prior to Cycle 1 Day 1, and while on study approximately every 2 months in the first 12 months and approximately every 3 months thereafter, and at 
the mandatory Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory where feasible. If not feasible, tests will be 

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performed by a central laboratory. 
18. Tumor imaging (either CT or MRI, with preference for CT) will be performed within 28 days prior to enrollment, and while on study approximately 
every 8 weeks in the first 12 months and approximately every 12 weeks thereafter. 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 regularly scheduled time point will be used 
for response confirmation. After patient’s re-consenting, PD suspected as pseudo-progression needs to be confirmed in a subsequent imaging 
at least 4 weeks later or at the next regularly scheduled time point but not to exceed 12 weeks, before discontinuation of study treatment. 
Subjects who stop treatment prior to documentation of PD will undergo repeated imaging for tumor response assessments during the study 
approximately every 8 weeks or 9 weeks depending on dosing schedules in the first 12 months and approximately every 12 weeks thereafter 
until unequivocal PD is documented or the subject starts new anticancer therapies or subject withdraws consent from the trial. 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 will be requested to undergo appropriate 
imaging to confirm PD.  Every effort will be made to confirm a clinical diagnosis of PD by imaging (Section 5.2.5.2).  
19. Bone scans must be done for subjects with mCRPC as described in Section 8.2.4. For other subjects, bone scans at baseline or subsequent visits will 
be performed only if clinically indicated. 
20. Collection of archival tumor tissue for purpose of biomarker analysis. Written patient consent is required for collection of archival tumor tissue. 
Specific instructions for tissue collection and shipment are provided in the Lab Manual. 
21. Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh baseline tumor biopsy (within 8 weeks before starting 
treatment) is strongly recommended. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory; for these 
subjects, an optional biopsy for biomarker analysis after 2 cycles of treatment (approximately Cycle 3 Day 1) is strongly recommended. Optional 
biopsy will also be taken at the safety follow up visit for the subjects who have confirmed disease progression during the study from accessible 
tumor sites to obtain samples to explore resistance mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion 
as the baseline biopsy. Written patient consent is required for fresh tumor biopsies. Fresh biopsies should be limited to readily accessible tumor 
lesions (eg, skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If 
performed, a core or excisional biopsy of the tumor (cytologic or fine-needle aspiration samples are not acceptable) should be obtained that has 
proper size for histological examination and biomarker analysis (eg, IHC of PD-1, PD-L1, PD-L2; genomic profiling).  
22. 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 

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survival status until subject death or termination by the Sponsor. 
23. Ophthalmologic exam (such as eyesight/visual acuity, fundoscopic, slit lamp microscopy, and optical coherence tomography [or equivalent 
diagnostic test]) within 28 days prior to first dose and Cycle 3 Day 1 (±7 days). Subjects will subsequently undergo repeat assessments by an 
appropriate specialist approximately every 4 cycles/16 weeks (± 7 days) during study treatment and a final assessment  <30 days after the last dose of 
study treatment.  For those subjects who have already received 2 or more doses of study drug, the exam should be repeated at the subject’s next visit 
and then approximately every 4 cycles/16 weeks (± 7 days) according to the schedule from first dose (Cycle 1 Day1). Investigators should solicit 
subjects regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab treatment.  For any 
change in vision, referral to an appropriate specialist will be made for further management guidance (see Appendix 10).   

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number when the study informed consent is signed. 
4. 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. Complete 
medication history for 30 days before the first dose (C1D1) of study mediation needs to be reported. 
5. Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
6. Electrocardiogram assessments are to be performed with the subject in semi recumbent supine position and rested for 5 minutes. Electrocardiogram (12-
lead ECG) should be performed at Screening as baseline, at the time of PK blood collection for PK (Cmax) within 30 minutes after the end of the first 
infusion of tislelizumab, at Cycle 1 Day 15, after infusion of tislelizumab in every subsequent cycle (within 30 minutes after the end of infusion), and at 
the mandatory Safety Follow-up visit. Additional ECGs may be obtained if clinically indicated (refer to Section 8.2.3). 
7. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v 4.03. All adverse experiences, whether gradable by CTCAE 
or not, will also be evaluated for seriousness.  After the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship to study 
drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, whichever occurs first. 
Telephone contacts with patients should be conducted to assess immune-related AEs 90 days after the last dose of tislelizumab regardless of whether or 
not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded by the Investigator after treatment 
discontinuation until subject death or loss to follow-up, whichever occurs first. 
8. Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the local study site laboratory or their contract laboratory. 
Hematology, chemistry, and urinalysis may be collected up to 72 hours prior to any Cycle Day 1 dosing. Of note, creatine kinase (CK) and creatine 
kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Appendix 2).  In the event CK-MB 
fractionation is not available, please assess troponin I and/or troponin T instead. 
9. PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation 
parameters should be determined throughout the study when clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory. 
10. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days before the first investigational 
product administration). 
11. T3, T4, TSH; at every cycle, and at the mandatory Safety Follow-Up Visit. Analysis of T3, T4 and TSH will be performed by the local study site 
laboratory. 

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12. Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 9 weeks thereafter, and at the Safety Follow-Up 
Visit. Analysis will be performed by the local study site laboratory. 
13. Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion every cycle in the first 6 months, every 3 cycles 
in the next 6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who discontinue study therapy 
before 6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months after the first dose. Analysis will be 
performed by a central laboratory. 
14. Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up visit for the subjects who have confirmed disease 
progression during the study to explore resistance mechanism. Samples will be processed according to the Lab Manual. 
15. Procedures for collection of PK samples are described in the Lab Manual. Predose (within 60 min before start infusion) and postdose (within 30 min 
after the end of infusion) samples should be collected at Day 1 of Cycle 1, Cycle 2 and subsequently every cycle in the first 12 months, then 
approximately every 6 months thereafter; three PK samples should be collected at Cycle 1 Day 4 (or 5), Day 8 and Day 15; additional PK samples 
should be collected at the mandatory Safety Follow-Up Visit. Should a subject present with a DLT or any Grade 3 or above immune-related adverse 
event (refer to Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of tislelizumab. 
16. Testing will be performed by the local laboratory at Screening. Include HCV antibody, HBsAg, HBcAb and HIV 1/2 antibodies. Subjects who are 
HBsAg and HBcAb positive or HCV antibody positive at Screening must not be enrolled until further definite testing with HBV DNA titers and HCV 
RNA tests can conclusively rule out presence of active infection requiring therapy with Hepatitis B and C respectively. Subjects enrolled in the study 
who had detectable HBV DNA or HCV RNA at Screening should be tested for HBV or HCV viral load, respectively, every 4 cycles (± 7 days) 
throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically indicated). For subjects who already received 4 or more doses 
of study drug, the viral load test should be repeated at the subject’s next visit and every 4 cycles according to the schedule from first dose (Cycle 1 Day 
1), and whenever clinically indicated. HCC subjects who test positive for HCV will not be discontinued. HCC subjects who test positive for HBV 
should be treated as per local guidelines at the investigator’s discretion. 
17. Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate for a given tumor type) will be collected within 14 days prior 
to Cycle 1 Day 1, and while on study approximately every 2 months in the first 12 months and approximately every 3 months thereafter, and at the 
mandatory Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory where feasible. If not feasible, tests will be performed 
by a central laboratory. 
18. Tumor imaging (either CT or MRI, with preference for CT) will be performed within 28 days prior to enrollment, and while on study approximately 

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every 9 weeks in the first 12 months and approximately every 12 weeks thereafter. 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 regularly scheduled time point will be used for response 
confirmation. After patient’s re-consenting, PD suspected as pseudo-progression needs to be confirmed in a subsequent imaging at least 4 weeks 
later or at the next regularly scheduled time point before discontinuation of study treatment. Subjects who stop treatment prior to 
documentation of PD will undergo repeated imaging for tumor response assessments during the study approximately every 8 weeks or 9 weeks 
depending on dosing schedules in the first 12 months and approximately every 12 weeks thereafter until unequivocal PD is documented or the 
subject starts new anticancer therapies or subject withdraws consent from the trial. 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 will be requested to undergo appropriate imaging to confirm PD.  Every effort will be made to confirm a 
clinical diagnosis of PD by imaging (Section 5.2.5.2). 
19. Bone scans must be done for subjects with mCRPC as described in Section 8.2.4. For other subjects, bone scans at baseline or subsequent visits 
will be performed only if clinically indicated. 
20. Collection of archival tumor tissue for purpose of biomarker analysis. Written patient consent is required for collection of archival tumor tissue. Specific 
instructions for tissue collection and shipment are provided in the Lab Manual. 
21. Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh baseline tumor biopsy (within 8 weeks before starting 
treatment) is strongly recommended. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory; for these subjects, 
an optional biopsy for biomarker analysis after 2 cycles of treatment (approximately Cycle 3 Day 1) is strongly recommended. Optional biopsy will also 
be taken at the safety follow up visit for the subjects who have confirmed disease progression during the study from accessible tumor sites to obtain 
samples to explore resistance mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
Written patient consent is required for fresh tumor biopsies. Fresh biopsies should be limited to readily accessible tumor lesions (eg, skin; peripheral 
lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If performed, a core or excisional biopsy 
of the tumor (cytologic or fine-needle aspiration samples are not acceptable) should be obtained that has proper size for histological examination and 
biomarker analysis (eg, IHC of PD-1, PD-L1, PD-L2; genomic profiling).  
22. 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. 
23. Ophthalmologic exam (such as eyesight/visual acuity, fundoscopic, slit lamp microscopy, and optical coherence tomography [or equivalent diagnostic 

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test]) will be performed within 28 days prior to first dose and at the end of week 9 (±7 days).  Subjects will subsequently undergo repeat assessments by 
an appropriate specialist approximately every 5 cycles/15 weeks (± 7 days) during study treatment and a final assessment <30 days after the last dose of 
study treatment.  For those subjects who have already received 3 or more doses of study drug, the tests should be repeated at the patient’s next visit and 
then every approximately every 5 cycles/15 weeks (± 7 days) according to the schedule from first dose (Cycle 1 Day1). Investigators should solicit 
subjects regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab treatment.  For any 
change in vision, referral to an appropriate specialist will be made for further management guidance (see Appendix 10).  

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5.1.5 
Phase 1A Part 3: Flat Dose Exploration 
The Phase 1A, Part 3 component will evaluate the safety and PK of tislelizumab at flat doses 
(ie 200 mg, Q3W) that do not exceed the exposure of the MTD as determined in the Phase 
1A Part 1 study.  Approximately 10 to 20 subjects will be enrolled.  Tumor types to be 
enrolled include but not limited to NSCLC, RCC, HNSCC, bladder cancer, melanoma, 
gastric, oesophageal, Merkel-cell carcinoma and HCC. Other cancers that are deemed to be 
likely to benefit from PD-1 inhibition based on high mutational load, preclinical or clinical 
data from other studies may be considered for enrolment subject to discussion with the 
Medical Monitor in advance.  
This part of the Phase 1A study will be conducted in Australia and/or New Zealand sites only 
and may be conducted in parallel with a Phase 1B study that evaluates a RP2D selected based 
on the Phase IA, Part 1 and 2 data as described in Section 2.5.4.  
5.1.5.1 
Criteria for Stopping Phase 1A Part 3 
The doses selected for the flat dose exploration will have been evaluated for DLT and 
demonstrated as safe in the Phase 1A Part 1 study.  Nevertheless, to adequately monitor 
safety of subjects enrolled in flat dose exploration, study accrual will be held pending data 
review by the SMC when at least 6 subjects have been treated and ≥33% of the subjects 
experienced a DLT during the first cycles consisting of 21 days (as defined in Section 5.1.1 
of the protocol).  A planned formal SMC review of safety data will be performed after all 
subjects have completed first cycle (21 days) of treatment, or withdrew due to any reason 
(PD, AE, or death). 
5.1.5.2 
Schedule of Assessment 
The schedule of events for Phase 1A Part 3 is presented in Table 9 and the pharmacokinetic 
sampling schedule is presented in Table 10. 

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1. It is preferred that routine laboratory tests (eg, hematology, chemistry; and urinalysis) for screening are conducted within 10 days prior to the first 
dosing, although tests done within 28 days are acceptable.  
2. The mandatory Safety Follow-Up visit should be conducted 30 days (± 3 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 (AE) to Grade 0-1 or stabilization or until beginning of a new therapy for their cancer, whichever occurs first. 
3. Written consent must be obtained prior to performing any protocol specific procedure. Results of a 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 Baseline 
number when the study informed consent is signed. 
4. 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. Complete 
medication history for 30 days before the first dose (C1D1) of study mediation needs to be reported.  
5. Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
6. Electrocardiogram assessments are to be performed with the subject in semi recumbent supine position and rested for 5 minutes. Electrocardiogram (12-
lead ECG) should be performed at Screening as baseline, at the time of PK blood collection for PK (Cmax) within 30 minutes after the end of the first 
infusion of tislelizumab, at Cycle 1 Day 15, after infusion of tislelizumab in every subsequent cycle (within 30 minutes after the end of infusion), and at 
the mandatory Safety Follow-up visit. Additional ECGs may be obtained if clinically indicated (refer to Section 8.2.3). 
7. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v 4.03. All adverse experiences, whether gradable by CTCAE 
or not, will also be evaluated for seriousness.  After the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship to study 
drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, whichever occurs first. 
Telephone contacts with patients should be conducted to assess immune-related AEs 90 days after the last dose of tislelizumab regardless of whether or 
not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded by the Investigator after treatment 
discontinuation until subject death or loss to follow-up, whichever occurs first. 
8. Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the local study site laboratory or their contract laboratory. 
Hematology, chemistry, and urinalysis may be collected up to 72 hours prior to any Cycle Day 1 dosing. Of note, creatine kinase (CK) and creatine 
kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Appendix 2).  In the event CK-MB 

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fractionation is not available, please assess troponin I and/or troponin T instead. 
9. PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation 
parameters should be determined throughout the study when clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory. 
10. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days before the first investigational 
product administration). 
11. T3, T4, TSH; at every cycle, and at the mandatory Safety Follow-Up Visit. Analysis of T3, T4 and TSH will be performed by the local study site 
laboratory. 
12. Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 9 weeks thereafter, and at the Safety Follow-Up 
Visit. Analysis will be performed by the local study site laboratory. 
13. Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion every 2 cycles in the first 6 months, every 
4 cycles in the next 6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who discontinue study 
therapy before 6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months after the first dose. All samples 
should be drawn at the same time as blood collection for Ctrough. Analysis will be performed by a central laboratory. 
14. Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up visit for the subjects who have confirmed disease 
progression during the study to explore resistance mechanism. Samples will be processed according to the Lab Manual. 
15. For timing refer to Table 10 for details on timing of pharmacokinetics sample collection. Procedures for collection of PK samples are described in the 
Lab Manual. All trough samples should be drawn at the same time as blood collection for anti-tislelizumab antibodies.  
16. Testing will be performed by the local laboratory at Screening. Include HCV antibody, HBsAg, HBcAb and HIV 1/2 antibodies. Subjects who are 
HBsAg and HBcAb positive or HCV antibody positive at screening must not be enrolled until further definite testing with HBV DNA titers and HCV 
RNA tests can conclusively rule out presence of active infection requiring therapy with Hepatitis B and C respectively. Subjects enrolled in the study 
who had detectable HBV DNA or HCV RNA at Screening should be tested for HBV or HCV viral load, respectively, every 4 cycles (± 7 days) 
throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically indicated). For subjects who already received 4 or more doses 
of study drug, the viral load test should be repeated at the subject’s next visit and every 4 cycles according to the schedule from first dose (Cycle 1 Day 
1), and whenever clinically indicated. HCC subjects who test positive for HCV will not be discontinued. HCC subjects who test positive for HBV 
should be treated as per local guidelines at the investigator’s discretion. 
17. Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate for a given tumor type) will be collected within 14 days prior 

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to Cycle 1 Day 1, and while on study approximately every 2 months in the first 12 months and approximately every 3 months thereafter, and at the 
mandatory Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory where feasible. If not feasible, tests will be performed 
by a central laboratory. 
18. Tumor imaging (either CT or MRI, with preference for CT) will be performed within 28 days prior to enrollment, and while on study approximately 
every 9 weeks in the first 12 months and approximately every 12 weeks thereafter. 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 regularly scheduled time point will be used for response 
confirmation. After patient’s re-consenting, PD suspected as pseudo-progression needs to be confirmed in a subsequent imaging at least 4 weeks 
later or at the next regularly scheduled time point before discontinuation of study treatment. Subjects who stop treatment prior to 
documentation of PD will undergo repeated imaging for tumor response assessments during the study approximately every 8 weeks or 9 weeks 
depending on dosing schedules in the first 12 months and approximately every 12 weeks thereafter until unequivocal PD is documented or the 
subject starts new anticancer therapies or subject withdraws consent from the trial. 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 will be requested to undergo appropriate imaging to confirm PD.  Every effort will be made to confirm a 
clinical diagnosis of PD by imaging (Section 5.2.5.2).  
19. Bone scans must be done for subjects with mCRPC as described in Section 8.2.4. For other subjects, bone scans at baseline or subsequent visits 
will be performed only if clinically indicated. 
20. Collection of archival tumor tissue for purpose of biomarker analysis. Written patient consent is required for collection of archival tumor tissue. Specific 
instructions for tissue collection and shipment are provided in the Lab Manual. 
21. Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh baseline tumor biopsy (within 8 weeks before starting 
treatment) is strongly recommended. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory; for these subjects, 
an optional biopsy for biomarker analysis after 2 cycles of treatment (approximately Cycle 3 Day 1) is strongly recommended. Optional biopsy will also 
be taken at the safety follow up visit for the subjects who have confirmed disease progression during the study from accessible tumor sites to obtain 
samples to explore resistance mechanism. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
Written patient consent is required for fresh tumor biopsies. Fresh biopsies should be limited to readily accessible tumor lesions (eg, skin; peripheral 
lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If performed, a core or excisional biopsy 
of the tumor (cytologic or fine-needle aspiration samples are not acceptable) should be obtained that has proper size for histological examination and 

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biomarker analysis (eg, IHC of PD-1, PD-L1, PD-L2; genomic profiling).  
22. 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. 
23. Ophthalmological examinations (such as eyesight/visual acuity, fundoscopy, slit lamp microscopy, and optical coherence tomography [or equivalent 
diagnostic test]) will be performed within 28 days prior to first dose and at the end of week 9 (±7 days). Subjects will subsequently undergo repeat 
assessments by an appropriate specialist approximately every 5 cycles/15 weeks (± 7 days) during study treatment and a final assessment <30 days after 
the last dose of study treatment.  For those subjects who have already received 3 or more doses of study drug, the tests should be repeated at the 
patient’s next visit and then every approximately every 5 cycles/15 weeks (± 7 days) according to the schedule from first dose (Cycle 1 Day1). 
Investigators should solicit subjects regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during 
tislelizumab treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance (see Appendix 10). 
24. Visit on Cycle 5 Day 22 is same as Cycle 6 Day 1. 
 

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Abbreviations: h, hour; min, minutes. 
Please note: Actual drug dosing and PK sampling times have to be documented by the sites 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: ±2 hours. 
3. Cycle 2, Cycle 3 and subsequently every 2 cycles except for Cycle 5 during the first 6 months of study therapy, every 4 cycles in the next 6 months, 
approximately every 6 months thereafter. 
4. Visit on Cycle 5 Day 22 is same as Cycle 6 Day 1. 
5. PK assays should be performed at the mandatory Safety Follow-Up Visit. 
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to Section 7.3.4), additional blood PK samples will 
be taken to determine the plasma concentration of tislelizumab. 
 

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5.1.6 
Phase 1B: Indication Expansion 
The Phase 1B stage is a multicenter, open label, multiple dose, multiple arm, indication 
expansion study.  The various arms of the study will investigate RP2D(s) to examine the 
potential efficacy as well as safety and tolerability of tislelizumab in cancer patients who 
failed standard care therapies.  The cancer indications may include: 
 Arm 1. Subjects with NSCLC (approximately 50 subjects) 
 Arm 2. Subjects with ovarian cancer (approximately 20 subjects) 
 Arm 3. Subjects with gastric cancer (approximately 50 subjects) 
 Arm 4. Subjects with HCC (approximately 50 subjects) 
 Arm 5. Subjects with HNSCC (approximately 20 subjects) 
 Arm 6. Subjects with esophageal carcinoma (approximately 50 subjects) 
 Arm 7. Subjects with TNBC (approximately 20 subjects) 
 Arm 8. Subjects with cholangiocarcinoma (approximately 20 subjects) 
 Arm 9. Subjects with RCC, bladder cancer, melanoma, Merkel-cell carcinoma, 
sarcoma, gastrointestinal stromal tumor (GIST), or cutaneous squamous cell 
carcinoma (cuSCC). Or any other solid tumors with MSI-H or dMMR, such as CRC 
or pancreatic cancer (approximately 50 subjects) 
For Arms 1, 3, 4 and 6, at least 20 subjects each will be enrolled from Taiwan or Korea.  
Enrollment rates will be different for each expansion arm.  Individual arms may be closed at 
the discretion of the Sponsor once the target number of enrolled subjects is reached.  
Individual arms may also be closed prematurely due to difficulty in recruitment at the 
discretion of the Sponsor.  Subjects will receive tislelizumab at the RP2D as described in 
Section 2.5.4.  Each treatment cycle will be 21 days in duration depending on selected dosing 
regimen.  Subjects will continue treatment until confirmed disease progression, intolerable 
toxicity, subject discontinuation/ withdrawal or at the discretion of the Investigator in 
consultation with Sponsor. 
5.1.6.1 
Criteria for Stopping Phase 1B 
To adequately monitor safety of subjects enrolled in the Phase 1B indication expansion, 
when at least 6 subjects have been treated and ≥33% of the subjects experienced a DLT 
during the first cycle consisting of 21 days (as defined in Section 5.1.1 of the protocol), study 
accrual will be held pending data review by the SMC.   

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5.1.6.2 
Schedule of Assessment 
The schedule of events for Phase 1B is presented in Table 11.  

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3. Written consent must be obtained prior to performing any protocol specific procedure. Results of a 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 Baseline 
number when the study informed consent is signed. 
4. 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. Complete 
medication history for 30 days before the first dose (C1D1) of study mediation needs to be reported.  
5. Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
6. Electrocardiogram assessments are to be performed with the subject in semi recumbent supine position and rested for 5 minutes. Electrocardiogram (12-
lead ECG) should be performed at Screening as baseline, at the time of PK blood collection for PK (Cmax) within 30 minutes after the end of the first 
infusion of tislelizumab, after infusion of tislelizumab in every cycle (within 30 minutes after the end of infusion), and at the mandatory Safety Follow-
up visit. Additional ECGs may be obtained if clinically indicated (refer to Section 8.2.3). 
7. Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE v 4.03. All adverse experiences, whether gradable by CTCAE 
or not, will also be evaluated for seriousness.  After the first dose of study drug, all AEs and SAEs, regardless of their assessed relationship to study 
drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, whichever occurs first. 
Telephone contacts with patients should be conducted to assess immune-related AEs 90 days after the last dose of tislelizumab regardless of whether or 
not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up contact, the investigator 
should arrange an unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded by the Investigator after treatment 
discontinuation until subject death or loss to follow-up, whichever occurs first. 
8. Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the local study site laboratory or their contract laboratory. 
Hematology, chemistry, and urinalysis may be collected up to 72 hours prior to any Cycle Day 1 dosing. Of note, creatine kinase (CK) and creatine 
kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Appendix 2).  In the event CK-MB 
fractionation is not available, please assess troponin I and/or troponin T instead. 
9. PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation 
parameters should be determined throughout the study when clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory. 
10. Only in women of childbearing potential. Subjects must have a negative serum pregnancy test at screening (within 7 days before the first investigational 
product administration). 

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11. Analysis of T3, T4 and TSH will be performed by the local study site laboratory. Following Cycle 2, testing will be performed every 2 cycles, and at the 
mandatory Safety Follow-Up Visit.  
12. Analysis of IgG and IgM will be performed by the local study site laboratory. Following Cycle 2, testing will be performed approximately every 
9 weeks thereafter, and at the mandatory Safety Follow-Up Visit.  
13. Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion of Cycle 1 and subsequent every 2 cycles in the 
first 6 months, every 4 cycles in the next 6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. All samples 
should be drawn at the same time as blood collection for Ctrough. Analysis will be performed by a central laboratory. 
14. Blood collected at predose on Day 1 of every 4 cycles until 6 months of study, and at the safety follow up visit for the subjects who have confirmed 
disease progression during the study to explore resistance mechanism. Samples will be processed according to the Lab Manual. 
15. Procedures for collection of PK samples are described in the Lab Manual. Predose (trough, within 24 hours before start infusion) and postdose (within 
30 min after the end of infusion) samples should be collected at Day 1 of Cycle 1, and subsequent every 2 cycles in the first 6 months, every 4 cycles in 
next 6 months, then approximately every 6 months thereafter; additional PK samples should be collected at the mandatory Safety Follow-Up Visit. All 
trough samples should be drawn at the same time as blood collection for anti-tislelizumab antibodies. Should a subject present with a DLT or any Grade 
3 or above immune-related adverse event (refer to Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of 
tislelizumab. 
16. Only for subjects in Arm 2 that are enrolled at Melbourne sites. Cycle 1 Day 1: predose; Day 2 (approximately 24 hours after the first dose); Cycle 
2 Day 1 and Cycle 3 Day 1 at predose. Procedures for collection of samples are described in the Procedures Manual. PD-1 receptor occupancy assay 
will be performed in a central laboratory. 
17. Testing will be performed by the local laboratory at Screening. Include HCV antibody, HBsAg, HBcAb and HIV 1/2 antibodies. Except for Arm 4, 
subjects who are HBsAg and HBcAb positive or HCV antibody positive at screening must not be enrolled until further definite testing with HBV DNA 
titers and HCV RNA tests can conclusively rule out presence of active infection requiring therapy with Hepatitis B and C respectively. Subjects enrolled 
in the study who had detectable HBV DNA or HCV RNA at Screening should be tested for HBV or HCV viral load, respectively, every 4 cycles (± 7 
days) throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically indicated). For subjects who already received 4 or more 
doses of study drug, the viral load test should be repeated at the subject’s next visit and every 4 cycles according to the schedule from first dose (Cycle 1 
Day 1), and whenever clinically indicated. HCC subjects who test positive for HCV will not be discontinued. HCC subjects who test positive for HBV 
should be treated as per local guidelines at the investigator’s discretion. 

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18. Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate for a given tumor type) will be collected within 14 days prior 
to Cycle 1 Day 1, and while on study approximately every 2 months in the first 12 months and approximately every 3 months thereafter, and at the 
mandatory Safety Follow-Up Visit. Analysis will be performed by the local study site laboratory where feasible. If not feasible, tests will be performed 
by a central laboratory. 
19. Tumor imaging (either CT or MRI, with preference for CT) will be performed within 28 days prior to enrollment, and while on study approximately 
every 9 weeks in the first 12 months and approximately every 12 weeks thereafter. 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 regularly scheduled time point will be used for response 
confirmation. After patient’s re-consenting, PD suspected as pseudo-progression needs to be confirmed in a subsequent imaging at least 4 weeks later or 
at the next regularly scheduled time point before discontinuation of study treatment. Subjects who stop treatment prior to documentation of PD will 
undergo repeated imaging for tumor response assessments during the study approximately every 8 weeks or 9 weeks depending on dosing schedules in 
the first 12 months and approximately every 12 weeks thereafter until unequivocal PD is documented or the subject starts new anticancer therapies or 
subject withdraws consent from the trial. 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 will be 
requested to undergo appropriate imaging to confirm PD.  Every effort will be made to confirm a clinical diagnosis of PD by imaging (Section 5.2.5.2). 
20. Bone scans must be done for subjects with mCRPC as described in Section 8.2.4. For other subjects, bone scans at baseline or subsequent visits will be 
performed only if clinically indicated. 
21. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the 
underlying cancer should undergo pulmonary function testing which may include but is not limited to spirometry and assessment of diffusion capacity 
done during the screening period to assist the determination of suitability on the study. 
22. Collection of archival tumor tissue for purpose of biomarker analysis. Written patient consent is required for collection of archival tumor tissue. Specific 
instructions for tissue collection and shipment are provided in the Lab Manual. 
23. Archival tumor tissue will be collected for purpose of biomarker analysis, although a fresh baseline tumor biopsy (within 8 weeks before starting 
treatment) is strongly recommended. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory; for these subjects, 
an optional biopsy for biomarker analysis after 2 cycles of treatment (approximately Cycle 3 Day 1) is strongly recommended. Please refer to 
Section 8.9 for mandatory biopsy requirement. Optional biopsy will also be taken at the safety follow up visit for the subjects who have confirmed 
disease progression during the study from accessible tumor sites to obtain samples to explore resistance mechanism. If feasible, any follow up biopsy 

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should be ideally taken from the same tumor lesion as the baseline biopsy. Written patient consent is required for fresh tumor biopsies. Fresh biopsies 
should be limited to readily accessible tumor lesions (eg, skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be 
readily accessed using CT guidance). If performed, a core or excisional biopsy of the tumor (cytologic or fine-needle aspiration samples are not 
acceptable) should be obtained that has proper size for histological examination and biomarker analysis (eg, IHC of PD-1, PD-L1, PD-L2; genomic 
profiling).  
24. 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. 
25. Visit on Cycle 1 Day 2 only apply to subjects in Arm 2 that are enrolled at Melbourne sites. 
26. Ophthalmologic exam (such as eyesight/visual acuity, fundoscopic, slit lamp microscopy, and optical coherence tomography [or equivalent diagnostic 
test]) within 28 days prior to first dose and at the end of week 9 (±7 days). Subjects will subsequently undergo repeat assessments by an appropriate 
specialist approximately every 5 cycles/15 weeks (± 7 days) during study treatment and a final assessment <30 days after the last dose of study 
treatment.  For those subjects who have already received 3 or more doses of study drug, the tests should be repeated at the patient’s next visit and then 
every approximately every 5 cycles/15 weeks (± 7 days) according to the schedule from first dose (Cycle 1 Day1). Investigators should solicit subjects 
regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during tislelizumab treatment.  For any change in 
vision, referral to an appropriate specialist will be made for further management guidance (see Appendix 10).   

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5.2 
Selection of Study Population 
5.2.1 
Inclusion Criteria 
1. Subjects meet the following corresponding requirements for the stage of the study they 
will enroll into: 
a) In Phase 1A stage of the study, subjects must have a histologically or 
cytologically confirmed advanced or metastatic tumor for which no effective 
standard therapy is available.  For Part 1, tumor types to be enrolled include but 
not limited to CRC, NSCLC, melanoma, SCC, uveal melanoma, gastric cancer, 
pancreatic cancer, ovarian cancer, bladder cancer, HNSCC, RCC, TNBC and 
HCC.  For Part 2 and Part 3, tumors types to be enrolled include but not limited 
to NSCLC, (subjects with documented EGFR mutation or ALK rearrangement 
should be excluded), RCC, HNSCC, bladder cancer, melanoma, gastric, 
oesophageal, Merkel-cell carcinoma and HCC.  Other cancers that are deemed to 
be likely to benefit from PD-1 inhibition based on high mutational load, 
preclinical or clinical data from other studies may be considered for enrollment 
subject to discussion with the medical monitor in advance. 
b) In Phase 1B stage of the study, subjects recruited to 1 of the following expansion 
arms must have histologically or cytologically confirmed advanced or metastatic 
tumor (of the types described below) for which no effective standard therapy is 
available:  
 
Arm 1. Subjects with NSCLC (subjects with documented EGFR mutation or 
ALK rearrangement should be excluded) 
 
Arm 2. Subjects with ovarian cancer 
 
Arm 3. Subjects with gastric cancer  
 
Arm 4. Subjects with HCC, Barcelona-Clinic Liver Cancer stage C, stage B 
not amenable to locoregional therapy or refractory to locoregional therapy, 
and not amenable to a curative treatment approach, and Child-Pugh A, 
without encephalopathy of any grade 
 
Arm 5. Subjects with HNSCC 
 
Arm 6. Subjects with esophageal carcinoma 
 
Arm 7. Subjects with TNBC 
 
Arm 8. Subjects with cholangiocarcinoma 

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 
Arm 9. Subjects with RCC, bladder cancer, melanoma, Merkel-cell 
carcinoma, sarcoma, GIST, or cuSCC. Or any other solid tumors with known 
MSI-H or dMMR status, such as CRC or pancreatic cancer 
2. Subjects with previously treated brain metastasis(es) that is asymptomatic and 
radiographically stable and not requiring steroids medications for 4 weeks prior to 
enrollment are permitted 
3. Subjects must have archival tumor tissues or agree to a tumor biopsy for analysis of 
predictive biomarkers such as PD-L1 (fresh tumor biopsies are strongly recommended 
at baseline for biomarker analysis in subjects with readily accessible tumor lesions and 
who consent to the biopsies) 
For Arm 2 (ovarian cancer), Arm 3 (gastric cancer), and Arm 4 (HCC) of Phase 1B 
study, a fresh baseline biopsy within 8 weeks before starting treatment is mandatory 
for biomarker analysis.  
For Arm 9 (melanoma) of Phase 1B study, a fresh baseline biopsy within 8 weeks 
before starting treatment and one approximately on Cycle 3 Day 1 are mandatory 
for biomarker analysis. All other subjects who have easily accessible lesions are 
strongly recommended for baseline or the paired biopsy. 
Subjects may be permitted to enroll on a case-by-case basis after discussion with the 
medical monitor in consultation with the Sponsor if tissue or biopsy is not available. 
4. Subjects must have at least one measurable lesion as defined per RECIST v 1.1.  
Subjects with mCRPC and with only non-measurable bone lesions must have either 
progression with 2 or more new lesions or have prostate-specific antigen (PSA) 
progression within the 6-week period before study drug administration 
5. Male or female and ≥18 years of age on day of signing informed consent 
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 
7. Life expectancy ≥12 weeks 
8. Subject must have adequate organ function as indicated by the following laboratory 
values 
a) Absolute neutrophil count (ANC) ≥1,500 /mcL 
b) Platelets ≥100,000 / mcL, OR ≥75,000 / mcL for subjects with HCC 
c) Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 

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d) Serum creatinine ≤1.5 X upper limit of normal (ULN) 
e) Serum total bilirubin ≤1.5 X ULN (total bilirubin must be <4 X ULN for subjects 
with Gilbert’s syndrome) 
f) AST (SGOT) and ALT (SGPT) ≤2.5 X ULN, OR  ≤5 X ULN for subjects with 
liver metastases or HCC 
g) International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN 
h) 
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN 
9. Subjects have voluntarily agreed to participate by giving written informed consent. 
10. 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 (ovariectomy) 
 
Has had a bilateral tubal ligation 
 
Is post-menopausal (total cessation of menses for ≥1 year) 
b) Childbearing potential, has a negative serum pregnancy test at screening (within 
7 days before the first investigational product administration), not be breast 
feeding, and uses adequate contraception (Appendix 12) before study entry and 
throughout the study until 120 days after the last investigational product 
administration.  Adequate contraception, when used consistently and in 
accordance with both the product label and the instructions of the physician, are 
defined as follows: 
 
Vasectomized partner who is sterile prior to the female subject’s entry and is 
the sole sexual partner for that female 
 
Any intrauterine device with a documented failure rate of less than 1% per 
year 
 
Double barrier contraception defined as condom with spermicidal jelly, 
foam, suppository, or film; OR diaphragm with spermicide; OR male 
condom and diaphragm 

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 
Appropriate hormonal contraceptives that include any registered and 
marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents) 
11. Male subjects are eligible to participate in the study if they are vasectomized or agree to 
use of contraception during the study treatment period and for at least 120 days after the 
last dose of study drug. 
5.2.2 
Exclusion Criteria 
Subjects will not be entered in the study for any of the following reasons: 
1. History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs) 
2. Prior malignancy active within the previous 2 years except for tumor for which a subject 
is enrolled in the study, and 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 PD-1 or PD-L1 
4. Subjects who failed to meet enrollment criteria for other PD-1 or PD-L1 trials solely due 
to low or negative predictive biomarkers, including but not limited to PD-L1, MSI, and 
DNA mutation load 
5. Subjects with active autoimmune diseases or history of autoimmune diseases 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 (SLE), 
connective tissue diseases, scleroderma, inflammatory bowel disease including Crohn’s 
disease and ulcerative colitis, hepatitis, toxic epidermal necrolysis (TEN), Stevens-
Johnson syndrome, or antiphospholipid syndrome 
Note: Subject are permitted to enroll if they have vitiligo, eczema, type I diabetes 
mellitus, endocrine deficiencies including thyroiditis managed with replacement 
hormones including physiologic corticosteroids.  Subjects with rheumatoid arthritis and 
other arthropathies, Sjogren's syndrome, controlled celiac disease and psoriasis controlled 
with topical medication and subjects with positive serology, such as antinuclear 
antibodies (ANAs), anti-thyroid antibodies should be evaluated for the presence of target 
organ involvement and potential need for systemic treatment but should otherwise be 
eligible. 

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6. Subjects should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration 
Note: Adrenal replacement doses ≤10 mg daily prednisone 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. Has history of interstitial lung disease or non-infectious pneumonitis except for those 
induced by radiation therapies 
8. Known history of HIV 
9. Except for HCC in Phase 1A or Arm 4 in Phase 1B, subjects who are HBsAg and HBcAb 
positive or HCV antibody positive at screening must not be enrolled until further definite 
testing with HBV DNA titers and HCV RNA tests can conclusively rule out presence of 
active infection requiring therapy with Hepatitis B and C respectively 
10. HCC patients with active infection by HCV who are untreated are not allowed on study.  
However HCC patients with successful HCV treatment (defined as sustained virologic 
response [SVR] 12 or SVR 24) are allowed as long as 4 weeks have passed between 
completion of HCV therapy and start of study drug 
11. HCC patients with evidence of prior HBV infection must fulfill the following criteria in 
order to be eligible for the study: HBV viral load (VL) <200 IU/mL (approximately 
1000 cps/mL) before study enrollment and subjects with active HBV infection need to be 
on anti-HBV suppression ≥3 months, throughout treatment and for 6 months after 
12. Underlying medical conditions that, in the Investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity 
determination or AEs 
13. Prior chemotherapy, radiotherapy, immunotherapy or any investigational therapies used 
to control cancer, including local-regional treatment for HCC, must have been completed 
at least 4 weeks before study drug administration, and all AEs have either returned to 
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14. Use of any live vaccines against infectious diseases (eg, influenza, varicella, etc.) within 
4 weeks (28 days) of initiation of study therapy and any intended use until 60 days after 
the last administration of the study medication 
15. Subjects who had prior liver transplant, allogeneic organ transplantation or bone marrow 
transplant (BMT) should be excluded 
5.2.3 
Other Eligibility Criteria Considerations 
To assess any potential impact on subject eligibility with regards to 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. 
Re-screening under limited conditions should be allowed after consultation with the Sponsor, 
eg when a subject narrowly misses a lab criterion and it’s correctable and not due to rapidly 
deteriorating condition or PD.  Re-screening is allowed only once. 
5.2.4 
Subject Restrictions 
The following restrictions may affect subject participation in this study: 
 
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 
5.2.5 
Subject Completion and Withdrawal 
5.2.5.1 
Subject Completion 
For Phase 1A, Part 1, a subject will be considered complete if he/she has a valid PK profile 
(including data from Cycle 2 Day 1, predose or Day 29 predose for subjects who discontinue 
after Cycle 1) and has not withdrawn from the study prior to completing DLT period 
(28 days from first dose of tislelizumab).  A subject will be considered complete is he/she 
discontinued study treatment due to a DLT with or without a valid PK profile.  
For Phase 1A Part 2 and Phase 1B, a subject will be considered complete if he/she has had at 
least one post-baseline tumor assessment for objective response.  Subjects who discontinue 
the study due to death or clinical progression without a post-baseline tumor assessment will 
also be considered complete. 
Treatment with tislelizumab may continue until one of the following events occurs: 
 
Confirmed disease progression (refer to Section 8.5.1) 
 
Intercurrent illness that prevents further administration of treatment 

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 
Unacceptable adverse experiences (see Section 5.1.2) 
 
Need for >2 dose delays due to toxicity as per the dose modification guidelines described 
in Section 5.1.2 
 
Subject withdraws consent 
 
If in the opinion of the Investigator, a change or discontinuation of therapy would be in 
the best interest of the subject 
 
Subject is lost to follow-up 
 
Pregnancy in subject 
If a subject discontinues from the study, the procedures will be followed as described in 
Section 5.2.5.2. 
Subject reaches 24 months of treatment (measured from start of study treatment):  
 
Subjects may continue on study therapy beyond 2 years if the Investigator considers this 
to be in the best interest of the subject based on an assessment of clinical benefit and 
potential risks.  Continuation of study therapy beyond 2 years has to be explicitly 
approved by the Sponsor, and will be contingent on the continued availability of 
tislelizumab drug product.  The study assessment and procedures schedule will remain 
the same. 
 
If subjects have confirmed CR, PR, or SD after 2 years of tislelizumab, the treatment can 
be stopped if the subject wishes.  The decision should be based on the Investigator’s 
evaluation, with the subject’s clinical benefit and risk taken into consideration.  A 
treatment-interruption informed consent form must be signed by subjects 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 8.5) rather than every cycle.  If a subject has evidence of PD within 
1 year of treatment interruption, the Investigator can consider restarting tislelizumab 
therapy after discussion with the Sponsor, contingent on the continued availability of 
tislelizumab drug product.  
 
5.2.5.2 
Subject Withdrawal/Discontinuation 
Subjects/patients may withdraw at any time (consent withdrawal) or be dropped from the 
study at the discretion of the Investigator should any untoward effects occur.  In addition, a 

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subject/patient may be withdrawn by the Investigator or the Sponsor (drug withdrawal) 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 (drug withdrawal) due to an adverse experience.  When a 
subject/patient discontinues/withdraws (drug withdrawal) 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 (drug withdrawal) should be followed in accordance with the 
safety requirements outlined in Section 8.3. 
The reason for discontinuation of tislelizumab will be recorded in the electronic case report 
form (eCRF).  These reasons include: 
 Withdrawal of consent by the subject 
 Discontinuation of tislelizumab by the Sponsor 
 Pregnancy 
 Any significant AE that compromises the subject’s ability to participate in the study 
 The Investigator or Sponsor determines it is in the best interest of the subject 
 Intercurrent illness 
 Treatment failure 
 Confirmed progression of disease at any time during the study (refer to Section 8.5.1) 
 Need for prohibited medication 
 Lack of compliance with the study and/or study procedures (eg, administration 
instructions, study visits 
 Significant deviation from the protocol by the Investigator without the consent of the 
Sponsor 
Subjects withdraw prior to documentation of PD: 
Subjects who stop treatment prior to documentation of PD will undergo repeated imaging for 
tumor response assessments during the study approximately every 8 weeks or 9 weeks 
depending on dosing schedules in the first 12 months and approximately every 12 weeks 
thereafter until unequivocal PD is documented or the subject starts new anticancer therapies 
or subject withdraws consent from the trial.  This imaging schedule will be maintained and 
will never be adjusted regardless of any intermediate unscheduled scans.  Subjects who 

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withdraw from the study for clinical or symptomatic deterioration before objective 
documentation of PD will be requested to undergo appropriate imaging to confirm PD.  
Every effort will be made to confirm a clinical diagnosis of PD by imaging. 
6.0 
STUDY TREATMENTS 
6.1 
Description of Investigational Product  
Tislelizumab is a monoclonal antibody drug which is formulated for IV injection in a single-
use vial (20R glass, United States Pharmacopoeia 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. 
6.2 
Product Preparation and Administration 
Tislelizumab 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 and second infusion of Tislelizumab 
must be observed for 2 hours after infusion, in an area with resuscitation equipment and 
emergency agents. 
Tislelizumab will be diluted to a concentration between 1 mg/mL to 10 mg/mL up to 100 mL 
in sterile normal saline (0.9% sodium chloride) as described below.  For the 0.5 mg/kg dose, 
deliver first infusion over 60 min; if well-tolerated, second and subsequent infusions may be 
administered over 30 min. For 2 mg/kg dose and above, along with flat doses, deliver first 
infusion (Cycle 1 Day 1) over 60 min; if well-tolerated, second infusion and each subsequent 
infusion may be administered over 30 min if 60 min infusion tolerated. Do not co-administer 
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. Quarantine the vial for investigation if extraneous particulate matter other than 
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4. Aseptically withdraw the required volume from the vial(s) of tislelizumab 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 used vial(s) and quarantine the vial(s) for investigation if 
extraneous particulate matter other than translucent to white proteinaceous particles is 
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 not more than 100 mL in sterile normal 
saline (0.9% sodium chloride).  In case where the total volume is more than 100 mL, no 
additional dilution is necessary. 
Prepare tislelizumab solution for infusion per the example provided below:  
For 2 mg/kg dose and assume subject body weight of 70 kg (other dose levels and body 
weights can be calculated similarly): 
Total drug to be administered:  
 
 
2 mg/kg x 70 kg =140 mg 
Drug needed for dose preparation:  
 
140 mg / 10 mg/mL = 14 mL 
0.9% sodium chloride needed for dilution:  
50 mL – 14 mL = 36 mL 
Target final concentration:  
 
 
140 mg / 50 mL = 2.8 mg/mL 
For flat dose 200 mg: 
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 detail of drug preparation is presented for reference in Appendix 4. Site can adjust 
preparation process according to common practice in consultation with Sponsor. 
6. Mix diluted solution by gentle inversion   
7. Visually inspect the final solution. If the infusion is not clear or the contents appear to 
contain precipitate, the solution should be quarantined for further investigation 
(according to the instruction in Section 6.5) and documented on the Drug Accountability 
Log 
8. Record the time tislelizumab was prepared on the IV bag label 

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9. Attach the IV bag containing the tislelizumab solution to the infusion set, 0.2 μm in line 
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 5.1.2. 
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.  Each subject receiving 
tislelizumab will also receive a treatment allocation number.  Subject and treatment numbers 
will be assigned in chronological order starting with the lowest number.  Once a subject 
number and treatment number have been assigned to a subject, it cannot be reassigned to any 
other subject. 
6.4 
Packaging and Labelling 
tislelizumab 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 a carton.  
The primary labeling on the vials contain following information: protocol number, content 
and quantity of tislelizumab, 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 dispensed or administered 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 administer 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. 
The investigational product does not contain a preservative.  The diluted solutions of 
tislelizumab cannot be frozen, and must be stored at: 

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 
Either room temperature at 20°C to 25°C (68°F to 77°F) for no more than 4 hours from 
the time of reconstitution.  This includes room temperature storage of drug product vials, 
storage of the infusion solution in the IV bag, and the duration of infusion. 
 
Or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of reconstitution.  If refrigerated, allow the diluted solution to come to room 
temperature prior to 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.  This 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. 
After completion of the study, all unused tislelizumab will be inventoried and destroyed on 
site, after receiving written Sponsor approval. 
6.7 
Assessment of Compliance 
On all visits to the study center, subjects will be questioned in regard to compliance with 
study instructions. 
6.8 
Treatment of 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 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, usual 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. 

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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. 
7.0 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
7.1 
Concomitant Medication(s)/Treatment(s) 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  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 first dose of study 
medication and 30 days after the last infusion of study medication 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, with the specific exception of non-protocol specified chemotherapy, radiotherapy 
(palliative radiotherapy on non-target lesions for emergent symptom relief is allowed, such as 
palliative radiation on bone lesions for pain control), immunotherapy, anti-neoplastic 
biological therapy or investigational agents other than tislelizumab.  Subjects who in the 
assessment by the Investigator require the use of any of the aforementioned treatments for 
clinical management should be removed from the study.  Bisphosphonates or Denosumab is 
allowed as long as the subject is on a stable dose for at least 14 days prior to investigational 
drug administration.  The Investigator should discuss with the Sponsor or designated medical 
monitor if the subject has already been given Bisphosphonates or Denosumab right before 
the investigational drug administration or will be given while on study. 
Subjects with active autoimmune disease or history of autoimmune disease that might recur, 
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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, SLE, connective tissue diseases, scleroderma, 
inflammatory bowel disease, Crohn's, ulcerative colitis, hepatitis, TEN, Stevens-Johnson 
syndrome, or phospholipid syndrome. 
Subjects are prohibited from receiving live vaccines within 28 days prior to the first dose of 
study therapy and while participating in study.  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 5.2.2 of the protocol (Exclusion Criteria) describes other medications which are 
prohibited in this study. 
7.2.1 
Other Drugs to be Used in the Study 
Subjects may be pretreated with H1 blockers (diphenhydramine 50 mg IV, or equivalent), and 
acetaminophen (500 to 650 mg oral or IV), 30 to 60 minutes prior to each tislelizumab infusion.  
Systemic corticosteroids required for the control of infusion reactions or irAEs must be tapered 
over at least 1 month and be at non-immunosuppressive doses (≥10 mg/day of prednisone or 
equivalent) before the next study drug administration.  The use of steroids as prophylactic 
treatment for subjects with contrast allergies to diagnostic imaging contrast dyes will be 
permitted. 
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):  
 Major surgery (excluding prior diagnostic biopsy) 
 Herbal remedies with immunostimulating properties (ie, mistletoe extract) or known to 
potentially interfere with major organ function (ie, hypericin) 
 Subjects should not abuse alcohol or other drugs during the study 
7.3 
Special Precautions 
As a routine precaution, subjects who receive the first and second infusion of tislelizumab 
must be observed for 2 hours after infusion, in an area with resuscitation equipment and 
emergency agents.  
Infusion of tislelizumab will be discontinued in case of Grade 2 or greater hypersensitivity, 
inflammatory response, or infusion-related reaction.  The treatment recommendations for 

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infusion-related reactions, severe hypersensitivity reactions, and tumor lysis syndrome 
according to the NCI are outlined in Sections 7.3.2, 7.3.3, and 7.3.1 respectively.  
7.3.1 
Tumor Lysis Syndrome 
A potential risk of tumor lysis syndrome exists since tislelizumab can induce cytotoxicity.  
As published by Howard et al 2011, once tumor lysis syndrome occurs, subjects should be 
treated as per the local guidelines and the management algorithm (Figure 7-1).  
Figure 7-1 
Assessment and Initial Management of Tumor Lysis Syndrome 
 

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7.3.2 
Infusion-Related Reactions 
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.  Subjects should be 
closely monitored for such reactions.  Treatment modification for symptoms of infusion-
related reactions due to tislelizumab is presented in Table 12.  
Immediate access to an Intensive Care Unit (ICU) or equivalent environment and appropriate 
medical therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, 
and oxygen) must be available to treat infusion-related reactions.  Infusion of tislelizumab 
will be discontinued in case of Grade ≥2 infusion-related, allergic, or anaphylactoid 
reactions.  Following the first and second infusion of tislelizumab, subjects must be observed 
for 2 continuous hours post-infusion for potential infusion-related reactions.  
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical care.  Subjects should be instructed to report any delayed reactions to the 
Investigator immediately based on a complete guideline for emergency treatment of 
anaphylactic reactions according to the Working Group of the Resuscitation Council (UK).

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Table 12 
Treatment Modification for Symptoms of Infusion-Related Reactions Due 
to Tislelizumab 
NCI-CTCAE Grade  
Treatment Modification for Tislelizumab 
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 ≤24 hours.  
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 
Grade 3: 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. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events, NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab 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 subject has a second infusion-related reaction (Grade ≥ 2) on the 
slower infusion rate, infusion should be discontinued and the subject should be withdrawn 
from tislelizumab treatment.  
CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted, 
as indicated per type of the reaction.  This includes but is not limited to an antihistamine (eg, 
diphenhydramine or equivalent), anti-pyretic (eg, paracetamol or equivalent), and if 
considered indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen.  
In the next cycle, subjects should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an anti-pyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 

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CTCAE Grade 3 or 4 infusion reaction: Immediately stop the infusion.  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 anti-histamine, anti-pyretic, 
glucocorticoids, epinephrine, bronchodilators, and oxygen. 
If a subject experiences a Grade 4 infusion-related reaction at any time, tislelizumab must be 
discontinued. 
In the event of a Grade 3 infusion reaction, continuation of study therapy is at the discretion 
of the Investigator after consultation with the Sponsor.  If continued, the infusion time of 
tislelizumab in the next cycle should be at least 1 hour.  Subjects should receive oral 
premedication with an anti-histamine (eg, diphenhydramine or equivalent) and an anti-
pyretic (eg, paracetamol or equivalent), and in addition premedication with 
methylprednisolone 100 mg or its equivalent IV approximately 30 minutes before start of the 
infusion.  Subjects should be closely monitored for clinical signs and symptoms of an 
infusion reaction. 
7.3.3 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the subject 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).  
Subjects 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 subject discontinued from the study.  
The subjects will be administered epinephrine injection and dexamethasone infusion if a 
hypersensitivity reaction is observed and then the subject should be placed on monitor 
immediately and ICU is 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 (NSAID) (ie, 600 mg ibuprofen, 500 mg naproxen 
sodium) may be administered 2 hours before and 8 hours after the start of each dose of 
tislelizumab IV infusion.  Alternative treatments for fever (ie, paracetamol) may be given to 
subjects at the discretion of the Investigator.  

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7.3.4 
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 13.  All conditions similar to those listed 
should be evaluated in patients receiving tislelizumab to determine whether they are immune-
related.  
Recommendation for diagnostic evaluation and management of irAEs is based on a recent 
European Society for Medical Oncology (ESMO) guideline (Haanen et al, 2017) and 
common immune-related toxicities are detailed in Appendix 10.  For any AEs not included in 
Appendix 10, please refer to the recent ESMO guideline (Haanen et al, 2017) for further 
guidance on diagnostic evaluation and management of immune-related toxicities.    

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Table 13 
Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular 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; diabetic ketoacidosis; 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 
 
Dose modification and management for irAEs are detailed in Appendix 10. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug 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. 
7.3.5 
Hepatic Abnormalities 
Patients with advanced HCC generally have underlying cirrhosis with decreased hepatic 
function.  Special attention is needed because they may also have a concomitant chronic viral 
infection.  Therefore, when a hepatic event, such as liver function laboratory abnormalities, is 
observed, the Investigator must evaluate for re-activation of viral hepatitis, consider other 
drug-related toxicity, and exclude PD involving the liver.  For diagnosis and management of 

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patients with AST or ALT values ≥ Grade 1 at baseline, please see Section 7.3.4 and refer to 
Appendix 10.  
In patients with Grade 2 AST/ALT abnormalities at baseline, therapeutic interventions with a 
steroid treatment may be required with rising AST and ALT laboratory abnormalities.  The 
following algorithm is proposed for the use of steroid treatment: 
 If AST or ALT increases by ≥ 50% relative to baseline and lasts for at least 1 week, start 
oral prednisolone 1 mg/kg/day and taper over at least 2-4 weeks; re-escalate dose if liver 
function tests (LFTs) worsen, depending on clinical judgment (manage as per 
Appendix 10).  Study treatment should be held until AST/ALT increase 
resolved/improved to baseline and prednisolone tapered to ≤ 10 mg. 
 If any ALT or AST increases meets Grade 3 criteria, initiate steroid therapy promptly per 
Appendix 10.  Study treatment will be held until AST or ALT improves to value 
≤ Grade 2.  Study drug may be reintroduced only after discussion with the Sponsor. 
 If any ALT or AST increases meets Grade 4 criteria, initiate steroid therapy promptly per 
Appendix 10.  Study treatment will be discontinued permanently 

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8.0 
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 study specific assessments and 
procedures for Phase 1A Part 1 are shown in Table 5, Phase 1A Part 2 are shown in Table 7 
(Q2W) and Table 8 (Q3W) respectively, Phase 1A Part 3 are shown in Table 9, Phase 1B are 
shown in Table 11.  The PK sampling time points for Phase 1A Part 1 and Part 3 are 
presented in Table 6 and Table 10, respectively.  
8.1 
Demographic and Baseline Assessments 
Demographic data will include date of birth, race, height (in cm), body weight (in kg), and 
body mass index (body mass index in kg/m2).  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 criteria listed in 
Section 5.2.  Screening assessments will be completed within 28 days prior to the first dose 
of the investigational product.  In Phase 1B, subjects who are suspected or known to have 
serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to 
the underlying cancer should undergo pulmonary function testing which may include but is 
not limited to spirometry and assessment of diffusion capacity done during the screening 
period to assist the determination of suitability on the study.  Screening assessments 
completed within 72 hours of administration can be used as Day 1 assessments as indicated 
in the schedule of assessment tables.  Please refer to Table 5, Table 7, Table 8, and Table 9 
for Phase 1A, and Table 11 for Phase 1B.  The screening assessments for Phase 1A and 1B 
will include: 
 Baseline demographics 
 Medical history including diagnosis, date of first diagnosis, histology, prior 
anti-neoplastic therapy, and current sites of disease 
 Concurrent medications 
 Disease assessments within past 4 weeks (28 days) 
 Vital signs 
 Physical examinations 

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 Ophthalmologic examinations 
 Evaluation of AEs 
 ECOG performance status 
 Electrocardiogram (ECG) 
 Laboratory tests: hematology, chemistry, urinalysis, pregnancy test, and PT/aPTT  
 Collection of archival tumor specimen or new tumor biopsy 
 Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate 
for a given tumor type) 
 Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), HCV antibody 
and HIV 1/2 antibodies 
 CT/magnetic resonance imaging (MRI) scan 
 Bone scan (for patients with mCRPC as described in Section 8.2.4 or when clinically 
indicated) 
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. 
The Investigator will obtain the patient's medical history at the Screening visit.  Medical 
history will include all active conditions, and any condition that are considered to be 
clinically significant by the Investigator.  History of treatment for the primary diagnosis, 
including prior systemic, radiation treatment, and surgical treatment will be recorded.  Date 
of and response to last prior cancer treatment must be documented.  Radiographic studies 
performed prior to study entry may be collected for review by the investigator.  Complete 
medication history for 30 days prior to the first dose (C1D1) of study mediation needs to be 
reported. 
Date of and response to last platinum-containing chemotherapy treatment for patients with 
ovarian cancer must be documented unless no platinum-containing treatment has been 
received before.  Subjects are defined as platinum-sensitive if disease progression by 
RECIST or GCIG criteria had occurred more than 6 months after their last platinum 
chemotherapy, as platinum-resistant if disease progression occurred less than 6 months after 
their last platinum chemotherapy but after their post-treatment evaluation, and as platinum-
refractory if they experienced disease progression while receiving platinum chemotherapy, 
up to the date of their post-treatment evaluation. 

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8.2 
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 5, 
Table 7, Table 8, and Table 9 for Phase 1A, and Table 11 for Phase 1B, respectively. 
8.2.1 
Laboratory Evaluation 
Laboratory assessments should be performed at a local certified laboratory on Day 1 before 
the investigational product administration.  Laboratory assessments need not be repeated on 
Cycle 1 Day 1 if these assessments were completed for screening within 72 hours of the first 
administration.  Required laboratory assessments are listed in Appendix 2. 
Routine laboratory tests (eg, hematology, chemistry, and urinalysis) will be performed by the 
local study site laboratory.  Subject treatment and overall management decisions will be 
based on local laboratory data.  Details regarding the amount of blood drawn for laboratory 
testing are provided in Appendix 3. 
Clinical chemistry, hematology, coagulation, and urinalysis will be performed at the time 
points specified in Table 5, Table 7, Table 8, and Table 9 for Phase 1A and Table 11 for 
Phase 1B respectively.  In the event of neutropenia (ANC <1000/mm3), thrombocytopenia 
(platelets <50,000/mm3), or Grade 3 clinical chemistry toxicity, the relevant assessments will 
be conducted every other day until toxicity resolves to ≤Grade 2 toxicity.  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, unless these are not likely to improve due to the underlying disease. 
On routine urinalysis, if urine protein is ≥2+ by dipstick, a 24-hour urine sample for total 
protein and a random urine sample for total protein and creatinine will be obtained. Subjects 
should NOT be dosed until the result of 24-hour urine protein is confirmed. If urine protein is 
>2 g/24 hours, the investigational product administration will be interrupted until it returns to 
≤2 g/24 hours.  If urine protein is ≤2 g/24 hours, further clinical evaluation and/or more 
frequent testing may be performed as clinically indicated.  A random urine protein to 
creatinine ratio can serve as a reliable surrogate for the 24-hour urine protein when following 
subjects with urine protein of ≤2 g, documented by a 24-hour urine collection.  In such cases, 
the 24-hour urine for total protein should be repeated only if a clinically significant increase 
is observed in the random urine protein to creatinine ratio.   

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8.2.2 
Physical Examination, Ophthalmologic Examination, Vital Signs, and 
Hepatitis B and C Testing 
A complete physical examination, vital signs (systolic blood pressure, diastolic blood 
pressure, pulse rate, temperature, and respiratory rate), and weight will be performed at the 
time points specified in Table 5, Table 7, Table 8, and Table 9 for Phase 1A, and Table 11 
for Phase 1B, respectively.  During the treatment period, symptom-directed physical 
examinations should be performed.  If there are no complaints and no abnormal findings 
from the previous visit for a particular organ system, a physical examination of that organ 
system is not required. 
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 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. 
Ophthalmological examinations (such as eyesight/visual acuity, fundoscopy, slit lamp 
microscopy, and optical coherence tomography [or equivalent diagnostic test]) will be 
performed at the time points specified in Table 5, Table 7, Table 8, and Table 9 for Phase 1A 
and Table 11 for Phase 1B, respectively.  Eye exam, visual acuity test, and optical coherence 
tomography (or equivalent diagnostic test) will be assessed by an appropriate specialist at 
Screening.  Eye exam, visual acuity test, and optical coherence tomography (or equivalent 
diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of randomization may be used for the Screening 
evaluation. Subjects dosed on a Q2W schedule will then undergo ophthalmologic 
examinations by an appropriate specialist on Cycle 1 Day 15 (± 7 days) (Phase 1 A Part 1 
only), Cycle 3 Day 1 (± 7 days), and thereafter every 4 cycles/16 weeks (± 7 days) during 
study treatment. Subjects dosed on a Q3W schedule will undergo an ophthalmologic 
examination by an appropriate specialist at the end of Week 9 (± 7 days), and thereafter 
every 5 cycles/15 weeks (± 7 days) during study treatment. Subjects in all groups will 
undergo a final assessment <30 days after the last dose of study treatment.  For those subjects 
who have already received 2 or 3 more doses of study drug, respectively, the examination 
should be repeated at the subject’s next visit and then approximately either every 4 cycles/16 
weeks (± 7 days) for subjects dosed on a Q2W schedule or every 5 cycles/15 weeks (± 7 
days) for subjects dosed on a Q3W schedule, according to the schedule from first dose (Cycle 
1 Day 1). 

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In addition, Investigators should solicit subjects regarding changes in vision, visual 
disturbance, or ocular inflammation at each scheduled study visit during study treatment.  For 
any change in vision, referral to an appropriate specialist will be made for further 
management guidance (see Appendix 10).   
Subjects enrolled in the study who had detectable HBV DNA or HCV RNA at Screening 
should be tested for HBV or HCV viral load, respectively, every 4 cycles (± 7 days) 
throughout the study, eg Screening, Cycle 5, Cycle 9, and so on (and whenever clinically 
indicated). For subjects who already received 4 or more doses of study drug, the viral load 
test should be repeated at the subject’s next visit and every 4 cycles according to the schedule 
from first dose (Cycle 1 Day 1), and whenever clinically indicated. HCC subjects who test 
positive for HCV will not be discontinued. HCC subjects who test positive for HBV should 
be treated as per local guidelines at the investigator’s discretion. 
8.2.3 
Electrocardiogram 
Electrocardiograms will be obtained at the time points specified in Table 5, Table 7, Table 8, 
and Table 9 for Phase 1A, and Table 11 for Phase 1B, respectively.  If prolongation of QT or 
QT interval corrected for heart rate (QTc) is noted during the first 15 days (for Q2W 
schedule) or 21 days (for Q3W schedule) of tislelizumab treatment, ECGs will be performed 
weekly during the first cycle, and then within 30 min after the end of every subsequent 
tislelizumab administration, and at the mandatory Safety Follow-up visit. 
Significant QTc prolongation will be defined as an interval ≥500 msec or an interval which 
increases by ≥60 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 to assess the accuracy of the 
equipment being used. 
If a subject has significant QTc prolongation: 
 He/she will be withdrawn from the investigational product administration if the 
Investigator and/or the medical monitor determine the subject is at risk. 
 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.  
 The medical monitor will be consulted prior to administering further doses or 
re-challenging.  
The medical monitor will be consulted prior to administering higher doses.   

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8.2.4 
Computed Tomography 
A computed tomography (CT) scan of the thorax, abdomen, and pelvis plus other relevant 
evaluations as appropriate, including bone scan for subjects with bone metastasis, will be 
performed to assess all known disease.  All known disease must be documented at baseline as 
target or non-target lesions using RECIST v 1.1.  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.  The CT scan will be used for the evaluation of RECIST v 1.1 by the 
Investigator at each study center. 
Unless contraindicated, intravenous contrast product must be used to maximize visualization 
of all lesions.  Five millimeter (mm) contiguous scans at baseline and subsequent scanning 
approximately every 8 weeks for Q2W and 9 weeks for Q3W in the first 12 months and 
approximately every 12 weeks thereafter (as calculated by the date of the first administration 
of the investigational product) until progression, with mandatory imaging coverage from 
thoracic inlet to symphysis pubis should be performed.  Subjects who cannot tolerate 
enhanced CT due to increased risk of allergic reaction to iodinated contrast media should 
follow local practice to obtain diagnostic quality images with an appropriate imaging 
modality and the same imaging modality should be utilized consistently. 
Technetium bone scans will be used to assess bone lesions.  In patients with prostate cancer 
baseline bone scans will be performed during the screening window.  Repeat bone scans will 
be performed every 16 weeks (Q2W) or 18 weeks (Q3W) to keep with the schedule of the 
CT scans.  Bone scan results will be reported as either no lesions or lesions present along 
with the number of bone lesions.  Disease progression by bone scan will be defined per the 
PCWG2 criteria as presented in Appendix 9; progression is defined as 2 new bone lesions at 
the first ‘progression’ scan, confirmed by a subsequent scan at least 6 weeks later with the 
presence of 2 additional lesions. 
Subjects who stop treatment prior to documentation of PD will undergo repeated imaging for 
tumor response assessments during the study approximately every 8 weeks or 9 weeks 
depending on dosing schedules in the first 12 months and approximately every 12 weeks 
thereafter until unequivocal PD is documented or the subject starts new anticancer therapies 
or subject withdraws consent from the trial.  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 will be requested to 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. 

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8.2.5 
Adverse Events 
All AEs and SAEs, regardless of the relationship to the investigational product, will be 
collected from signing the informed consent form and throughout the study. 
8.3 
Safety Assessments 
Vital signs, weight, physical examinations, ophthalmologic examinations, ECOG 
performance status, ECGs and laboratory safety tests (eg, PT/aPTT, urinalysis, hematology, 
serum chemistry, autoantibodies, thyroid function, viral antigen reactions, cytokine / 
chemokine panels) will be obtained and assessed at designated intervals throughout the study 
(see Table 5, Table 7, Table 8, and Table 9 for Phase 1A, and Table 11 for Phase 1B, 
respectively).  Special attention will be given to immune-related adverse effects (eg, gut, 
skin, lung, liver, kidney endocrine organs, others). 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE 
v 4.03.  Characterization of toxicities will include severity, duration, and time to onset.  
Safety endpoints will include all types of AEs, in addition to laboratory safety assessments, 
ECOG performance scale status, ECGs, and vital signs.   
The continuous safety evaluation will be performed by the Sponsor, the Coordinating 
Investigator, and Investigators.  An SMC will be established for the determination of dose 
levels to be administered during dose escalation and dose regimens in this study.  Details of 
the safety monitoring process will be specified in a dedicated SMC charter. 
8.3.1 
Phase 1A Part 1 
The SMC consists of the Coordinating Investigator, selected recruiting Investigators, the 
Sponsor’s medical monitor, and the contract research organization (CRO)’s medical monitor.  
Ad hoc members will be consulted as needed and may include, but are not restricted to the 
biostatistician and pharmacokineticist.   
Before moving to the next dose level, the SMC will review all safety data available to 
determine whether recruitment to the next cohort should be initiated.  At the conclusion of 
the dose escalation phase, the SMC will determine the RP2D(s) to be further investigated. 
The SMC will determine when no further dose escalation is appropriate and whether the 
MTD will be defined as a preceding dose or an intermediate dose.   
The SMC will meet for cohort safety reviews after all subjects in a dosing cohort have 
completed the first treatment cycle.  All available safety data will also be provided for 
subjects who discontinue prior to this time.  Safety data from prior cohorts may also be 
presented.  The decision to escalate dose and the determination of the MTD will be based on 

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the cohort safety reviews.  The SMC will review any protocol violations that may have 
impacted evaluation of potential DLT.  The SMC may weigh collective evidence and may 
determine a DLT for reasons in addition to those explicitly stated in the final protocol. 
Response from all SMC members, including Investigators with subjects enrolled in the 
Phase 1 stage, or their designees, shall be required for each escalation/review. 
Adequate time for review of results will be given to SMC members (approximately 1 to 
2 business days).  Enrollment in subsequent dose levels will be put “on hold” during each 
review period, pending the decision of the SMC. 
The SMC decision points may fall into one of the categories detailed below: 
 
Escalate to a higher dose 
 
Recruit an additional 3 subjects into existing dose level 
 
Stop escalation and investigate lower dose(s) 
 
End part of the study 
 
End the overall study 
Decisions will be made using the criteria defined within the protocol (see Section 5.1.3.1). 
The SMC will make the dose escalation decisions. 
8.3.2 
Phase 1A Part 2 and Part 3 
In order to adequately monitor safety during in the Phase 1A Part 2 and Part 3 stages of the 
study, data review will be routinely conducted by the SMC.  The SMC consists of the 
Coordinating Investigator, representative recruiting Investigators, the Sponsor’s Medical 
Monitor, and the CRO’s Medical Monitor.  Ad hoc members will be consulted as needed and 
may include, but are not restricted to the biostatistician and pharmacokineticist.  
The SMC will review safety data (including but not limited to, AEs, SAEs, laboratory 
parameters, investigational product logs, treatment delays or reductions, and treatment 
discontinuation due to toxicity), when all the subjects have completed the first cycle of 
treatment in each stage, or withdrew due to any reason (PD, adverse event, or death).  The 
SMC will make the decision using the criteria as described in Section 5.1.4.1 (Part 2) or 
Section 5.1.5.1 (Part 3).  Any treatment-related death will also trigger review by the SMC.  
The SMC will determine whether it is safe to proceed. 

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8.3.3 
Phase 1B 
In order to adequately monitor safety during the Phase 1B stage of the study, data review will 
be routinely conducted by the CRO and Sponsor medical and safety monitors.  Serious safety 
issues such as treatment-related death will be reviewed by the SMC.  The SMC consists of 
the Coordinating Investigator, representative recruiting Investigators, the Sponsor’s medical 
monitor, and the CRO’s medical monitor.  Ad hoc members will be consulted as needed and 
may include, but are not restricted to the biostatistician and pharmacokineticist. 
8.4 
Follow-up Assessments 
All subjects have to be followed for at least 30 days after their last dose of study drug or until 
initiation of a new anti-cancer treatment, whichever occurs first.  Telephone contacts with 
patients should be conducted to assess irAEs 90 days after the last dose of tislelizumab 
regardless of whether or not the patient starts a new anticancer therapy. If patients report a 
suspected irAE at a telephone follow-up contact, the investigator should arrange an 
unscheduled visit if further assessment is indicated. All drug-related SAEs will be recorded 
by the Investigator after treatment discontinuation until patient death or loss to follow-up, 
whichever occurs first. 
Subjects who are discontinued from the study due to an unacceptable drug-related adverse 
event will be followed until the resolution of the AE to Grade 0-1 or stabilization or until 
beginning of a new therapy for their cancer, whichever occurs first. 
Subjects who stop treatment prior to documentation of PD will undergo repeated imaging for 
tumor response assessments approximately every 8 weeks or 9 weeks depending on dosing 
schedules in the first 12 months and approximately every 12 weeks thereafter 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 will be requested to undergo appropriate imaging to confirm 
PD.  Every effort will be made to confirm a clinical diagnosis of PD by imaging.  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 ± 2 weeks by either a telephone or in-person contact until subject death or 
termination by the Sponsor.  With the exception of the collection of irAE data through 
90 days post-treatment (as described above), no other data (eg subsequent therapies, 
performance status etc.) beyond survival will be collected during these calls/visits. 

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8.5 
Efficacy Assessments 
This study includes preliminary assessments of efficacy as outlined in the sections below. 
Disease assessment by radiographic imaging (CT or MRI, with a preference for CT) will be 
performed and recorded at screening within 28 days before enrollment and while on study 
approximately every 8 weeks or 9 weeks depending on dosing schedules in the first 
12 months and approximately every 12 weeks thereafter according to the RECIST Guidelines 
as shown in Appendix 5.  The same imaging technique as used at baseline has to be used 
throughout the study.  
After first documentation of CR or PR, imaging performed at the next regularly scheduled 
time point will be used for response confirmation. 
8.5.1 
Treatment Beyond Disease Progression 
Patients must be re-consented to continue treatment beyond initial documentation of disease 
progression. 
There is evidence that a minority of subjects treated with anti-PD1 therapies such as 
tislelizumab may derive clinical benefit despite initial documentation of PD by RECIST v 
1.1.  Pseudo-progression may occur due to immune cell infiltration and other mechanisms as 
manifested by apparent increase of existing tumor masses or appearance of new tumor 
lesions (Wolchok et al, 2009).  These patients may go on to exhibit a partial response at a 
later time point. It is the responsibility of the Investigator to determine if the patient should 
be considered for treatment beyond progression due to clinical benefit.  This decision should 
be considered carefully so as to permit patients who are likely to be benefiting to continue 
treatment while at the same time preventing prolonged exposure of a futile therapy in patients 
who may not be benefitting.  Any decisions to continue treatment beyond initial progression 
must be discussed with the medical monitor and documented in the study records.  
Thus subjects with documented progression in tumor burden or 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 (after re-consenting in 
Phase 1) until confirmation of PD 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 PD. In addition, the following 
criteria must be met: 
 
Absence of clinical symptoms and signs of disease progression (including worsening 
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 
Stable ECOG performance status 
 
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg cord compression) that necessitates urgent alternative medical intervention 
In rare cases, a subject with unequivocal radiographical PD may be allowed to continue study 
treatment if, in the judgment of the investigator, the subject is benefiting from the treatment.  
Prior consultation with the Sponsor is required.  
8.5.2 
Efficacy Endpoints 
Efficacy measures include: 
 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 v 1.1. 
 The PFS and DCR (CR + PR + SD) as assessed by RECIST v 1.1; and CBR 
(CR + PR + durable SD [SD ≥24 weeks]) 
 DOR for responders (CR or PR) 
PCWG2 criteria (Scher et al, 2008) may also be used to evaluate responses in patients with 
prostate cancer enrolled in the study as presented in Appendix 9. 
GCIG criteria (Rustin et al, 2011), in addition to RECIST v 1.1 may also be used to evaluate 
response in patients with ovarian cancer enrolled in the study. 
RANO criteria (Wen et al, 2010) may also be used to evaluate response in patients with 
GBM enrolled on the study. 
8.6 
Pharmacokinetics 
Blood will be collected to describe the PK profile of tislelizumab for Phase 1A and 1B stages 
of the study.  PK analysis will include but is not limited to AUC0-14 day, Cmax and Tmax, Ctrough, 
T1/2, Cl, and Vd. 
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 (3.5 mL) for PK analysis will be collected according to the Lab Manual and 
serum will be separated and immediately frozen.  Samples must remain frozen in a freezer set 
at or below -70°C and in a box with dry ice during shipping. 

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Prior to collection, the collection tube and serum storage tube must be labeled with the 
corresponding labels provided by the sponsor.  The labels must be placed along the length of 
the tube so they can be read easily.  Tape must not be used to secure the labels as the tube 
will not fit into the auto-analyzer test tube rack.  The labels are of high quality and will not 
peel off of the tube even under extreme conditions. 
Samples will be shipped to the central laboratory where all samples will be analyzed for 
serum tislelizumab concentrations using a validated method. 
8.6.1 
Phase 1A Part 1 
Cannulation for blood sampling for PK in Phase 1A Part 1 stage will be performed.  PK 
samples should not be drawn from the infusion line or from the same arm of infusion.  Blood 
will be collected via the intravenous cannula predose and at the time points specified in Table 
6. 
Cycle 1 and Cycle 4 
For subjects in the dose-escalation cohorts, 8 blood samples (3.5 mL each) will be collected 
on Day 1, 2, 4 (or 5), 8 and 15 at the following time points: predose (within 1 hour before the 
investigational product administration) and 0.5 (end infusion to 30 min), 1.5, 6, 24, 72 (or 
96), 168 and 336 hours postdose (the 336-hour PK sample will be collected on Day 15 within 
1 hour before the investigational product administration).  In addition, a postdose sample 
(end infusion to 30 min) on Cycle 1 Day 15 will be collected.  
Cycle 2 and Additional Cycles except Cycle 4 during the First 12 Months of Study 
Two blood samples (3.5 mL each) will be collected on Day 1 of each cycle at the following 
time points: predose (within 1 hour before the investigational product administration) and 
postdose (end infusion to 30 min). 
Safety Follow-up  
One blood samples (3.5 mL) will be collected at the mandatory Safety Follow-up Visit. 
Other Blood Samples  
Unscheduled blood samples may also be collected whenever any notable safety is seen, to 
evaluate if the observation is exposure related. Blood samples (3.5 mL) should be obtained, 
when possible, for analysis of serum tislelizumab in the event of a DLT or any Grade 3 or 
above irAE (refer to Section 7.3.4).  The Investigator must record the time the blood samples 
obtained and the time of the previous administration in the eCRF. 

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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. 
Total Blood Volume 
The maximum total amount of blood collected during the study (including screening safety 
assessments) is presented in Appendix 3.  
8.6.2 
Phase 1A Part 2 
For the Phase 1A Part 2 stage of the study, the approximate amount of blood taken for PK 
assessments and other assessments is listed in Appendix 3.  These samples will be collected 
at the time points presented in Table 7 (Q2W) and Table 8 (Q3W).  Predose (within 60 min 
before start infusion) and postdose (within 30 min after the end of infusion) samples should 
be collected at Cycle 1 Day 1, Day 15 (only for Q2W), Day 1 of Cycle 2 and subsequently 
every cycle in the first 12 months, then approximately every 6 months thereafter; additional 
PK samples should be collected at Cycle 1 Day 4 (or 5), Day 8, Day 15 (only for Q3W) and 
the mandatory Safety Follow-Up Visit.  Should a subject present with a DLT or any Grade 3 
or above irAE (refer to Section 7.3.4), additional blood PK samples will be taken to 
determine the plasma concentration of tislelizumab. 
8.6.3 
Phase 1A Part 3 
For the Phase 1A Part 3 stage of the study, the approximate amount of blood taken for PK 
assessments and other assessments is listed in Appendix 3.  These samples will be collected 
at the time points presented in Table 10.  Predose (trough, within 24 hours before start 
infusion) and postdose (within 30 min after the end of infusion) samples should be collected 
at Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 5 and every 2 cycles in first 6 months, every 
4 cycles in the next 6 months, approximately every 6 months thereafter; additional PK 
samples should be collected at Day 2, Day 4 (or 5), Day 8 and Day 15 of Cycle 1 and 
Cycle 5; a predose sample on Cycle 5 Day 22 (Cycle 6 Day 1) should also be collected; 
additional PK samples should be collected at the mandatory Safety Follow-Up Visit.  All 
trough samples should be drawn at the same time as blood collection for anti-tislelizumab 
antibodies.  Should a subject present with a DLT or any Grade 3 or above irAE (refer to 
Section 7.3.4), additional blood PK samples will be taken to determine the plasma 
concentration of tislelizumab. 
8.6.4 
Phase 1B 
For the Phase 1B stage of the study, the approximate amount of blood taken for PK 
assessments and other assessments is listed in Appendix 3.  These samples will be collected 

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at the time points presented in Table 11.  Predose (trough, within 24 hours before start 
infusion) and postdose (within 30 min after the end of infusion) samples should be collected 
at Day 1 of Cycle 1, and subsequent every 2 cycles in the first 6 months, every 4 cycles in 
next 6 months, then approximately every 6 months thereafter; additional PK samples should 
be collected at the mandatory Safety Follow-Up Visit.  All trough samples should be drawn 
at the same time as blood collection for anti-tislelizumab antibodies.  Should a subject present 
with a DLT (Section 5.1.1) or any Grade 3 or above irAE (refer to Section 7.3.4), additional 
blood PK samples will be taken to determine the plasma concentration of tislelizumab. 
8.7 
Anti-Drug Antibody 
Immunogenic responses to tislelizumab will be assessed to determine occurrence of anti-
tislelizumab antibody.  For subjects in Phase 1A Part 1 stage, as specified in Table 5, 2 mL of 
blood for anti-tislelizumab antibodies should be collected within 24 hours before start of 
Day 1 infusion every cycle in the first 6 months, every 2 cycles in the next 6 months, 
approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit.  For 
subjects in Phase 1A Part 2 stage, as specified in Table 7 and Table 8, 2 mL of blood for anti-
tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion 
every cycle in the first 6 months, every 2 cycles (Q2W) or 3 cycles (Q3W) in the next 
6 months, approximately every 6 months thereafter, and at the mandatory Safety Follow-Up 
Visit.  For subjects in Phase 1A Part 3 stage, as specified in Table 9, 2 mL of blood for anti-
tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion 
every 2 cycles in the first 6 months, every 4 cycles in the next 6 months, approximately every 
6 months thereafter, and at the mandatory Safety Follow-Up Visit.  For subjects in Phase 1B 
stage, as specified in Table 11, 2 mL of blood for anti-tislelizumab antibodies should be 
collected within 24 hours before start of Day 1 infusion of Cycle 1 and subsequent every 
2 cycles in the first 6 months, every 4 cycles in the next 6 months, approximately every 
6 months thereafter, and at the mandatory Safety Follow-Up Visit.  All samples should be 
drawn at the same time as blood collection for Ctrough.  Samples will be processed according 
to the Lab Manual and shipped to a central laboratory for analysis using a validated method. 
8.8 
Pharmacodynamics Assessments 
Pharmacodynamic measurements include effects of tislelizumab on immune cell subtypes 
and cytokine/chemokine in the blood.  At the specified time points (Table 5), 40 mL of blood 
in ACD will be collected and transported at room temperature to the central laboratory within 
8 hours according to the instructions in the Lab Manual.  Due to sample logistics issue, this 

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assay will only be performed on subjects enrolled in Phase 1A Part 1 of the study in 
Melbourne area.  
PD-1 receptor occupancy assay will only be performed in subjects enrolled in Arm 2 in 
Phase 1B stage of the study in Melbourne area.  PD-1 receptor occupancy on circulating 
T cells will be measured as an indication of target engagement. 30 mL of blood will be 
collected at the specified time points (Table 11).  Details on collection of blood samples, 
processing, storage, and shipping details are provided in the Lab Manual. 
Other pharmacodynamic biomarkers could include changes in tumor microenvironment, 
including but not limited to PD-L1 expression and TILs.  These are detailed in the following 
Section 8.9. 
8.9 
Biomarker Assessments 
Tumor biopsy and plasma samples for the development of exploratory biomarkers will be 
collected as stated in Table 5, Table 7, Table 8, and Table 9 for Phase 1A, and Table 11 for 
Phase 1B, respectively. 
The archival tumor tissues are mandatory for all subjects who consent to participate in the 
study and have available archival tumor tissue samples, although a fresh baseline tumor 
biopsy (within 8 weeks before starting treatment) is strongly recommended.  In the absence 
of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is mandatory. For these 
subjects, an optional biopsy for biomarker analysis after approximately 2 cycles of treatment 
is strongly recommended.   
For Arm 2 (ovarian cancer), Arm 3 (gastric cancer), and Arm 4 (HCC) of Phase 1B 
study, a fresh baseline biopsy within 8 weeks before starting treatment is mandatory for 
biomarker analysis  
For Arm 9 (melanoma) of Phase 1B study, a fresh baseline biopsy within 8 weeks before 
starting treatment and one approximately on Cycle 3 Day 1 are mandatory for 
biomarker analysis. 
All other subjects who have easily accessible lesions are strongly recommended for 
baseline or the paired biopsy. 
Optional biopsy will also be taken at the safety follow up visit for the subjects who have 
confirmed disease progression during the study from accessible tumor sites to obtain samples 
to explore resistance mechanism.  If feasible, any follow up biopsy should be ideally taken 
from the same tumor lesion as the baseline biopsy.  Written patient consent is required for 
fresh tumor biopsies.  Fresh biopsies should be limited to readily accessible tumor lesions 

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(eg, skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be 
readily accessed using CT guidance).  Risk assessment of tumor biopsy must be evaluated by 
investigators to ensure that only non-significant risk procedures (ie, those procedures 
associated with an absolute risk of mortality or major morbidity of less than 2% based on 
institutional experience, biopsy location, and patient’s clinical status) will be performed for 
protocol-mandated biopsies. From the baseline biopsy or archived tumor tissue, either a 
formalin-fixed paraffin-embedded block with tumor tissue (preferred) or at least 10 unstained 
slides must be sent to the central laboratory. If performed, a core or excisional biopsy of the 
tumor (cytologic or fine-needle aspiration samples are not acceptable) should be obtained 
that has proper size for histological examination and biomarker. 
Specific instructions for tissue/plasma collection and shipment are provided in the Lab 
Manual. The maximum amount of blood collected during the study is presented in 
Appendix 3.  
The primary biomarker objective is to assess the relationship between PD-L1 expression 
levels, TILs in the tumor tissues and anti-tumor activity of tislelizumab. 
Other candidate biomarkers which will be investigated in the study may include, but are not 
limited to, the following: 
 PD-L2 expression levels 
 RNA and DNA profiling, including but not limiting to neoantigens, in tumor tissue 
 Proteomics and cfDNA profiling in peripheral blood 
8.10 Appropriateness of Measurements 
All efficacy, safety and PK assessments used in this study are standard, ie, widely used and 
generally recognized as reliable, accurate, and relevant. 
9.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
According to the ICH GCP Guidelines, 1996, the sponsor is responsible for implementing 
and maintaining quality assurance and quality control systems with written Standard 
Operating Procedures (SOPs).   
Quality control will be applied to each stage of data handling.   

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The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 
Investigator meeting(s) 
 
Local certified laboratories for laboratory measurements and ECGs 
 
Study center initiation visit 
 
Early study center visits post-enrollment 
 
Routine study center monitoring 
 
Ongoing study center communication and training 
 
Data management quality control checks 
 
Continuous data acquisition and cleaning 
 
Internal review of data 
 
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 laboratories, 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 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: 
 Check the progress of the study 
 Review study data collected 
 Conduct source document verification 

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 Identify any issues and address their resolution 
This will be done in order to verify that the: 
 Data are authentic, accurate, and complete 
 Safety and rights of subjects are being protected 
 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. 
At study closure, monitors will also conduct all activities described in Section 13.1.  
9.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the data management and biostatistics departments of Quintiles. 
An electronic data capture (EDC) system will be used for this study, meaning that all eCRF 
data will be entered in electronic forms at the study center.  Data collection will be completed 
by authorized study center personnel designated by the Investigator.  Appropriate training 
and security measures will be completed with the Investigator and all authorized study center 
personnel prior to the study being initiated and any data being entered into the system for any 
subjects. 
The eCRFs should always reflect the latest observations on the subjects participating in the 
study.  Therefore, the eCRFs are to be completed as soon as possible during or after the 
subject’s visit.  To avoid inter-observer variability, every effort should be made to ensure that 
the same individual who made the initial baseline determinations completes all safety 
evaluations.  The Investigator must verify that all data entries in the eCRFs are accurate and 
correct.  If some assessments are not done, or if certain information is not available or not 
applicable or unknown, the Investigator should indicate this in the eCRF.  The Investigator 
will be required to electronically sign off on the clinical data.   
The monitor will review the eCRFs and evaluate them for completeness and consistency.  
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between critical data.  All entries, corrections, and alterations are to be made 
by the responsible Investigator or his/her designee.  The monitor cannot enter data in the 
eCRFs.  Once clinical data of the eCRF have been submitted to the central server, corrections 

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to the data fields will be audit trailed, meaning that the reason for change, the name of the 
person who performed the change, together with time and date will be logged.  Roles and 
rights of the study center personnel responsible for entering the clinical data into the eCRF 
will be determined in advance.  If additional corrections are needed, the responsible monitor 
or data manager will raise a query in the EDC application.  The appropriate study center 
personnel will answer queries sent to the Investigator. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified.  Source documents are all documents 
used by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria and all records covering the 
subject’s participation in the study.  They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the study monitor at each monitoring visit.  The Investigator must 
submit a completed eCRF for each subject who receives the investigational product, 
regardless of the duration.  All supportive documentation submitted with the eCRF, such as 
laboratory or hospital records, should be clearly identified with the study and subject number.  
Any personal information, including subject name, should be removed or rendered illegible 
to preserve individual confidentiality. 
Electronic CRF records will be automatically appended with the identification of the creator, 
by means of their unique User ID.  Specified records will be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data are 
accurate.  This will be facilitated by means of the Investigator’s unique User ID and 
password; date and time stamps will be added automatically at the time of the electronic 
signature.  If an entry on an eCRF requires change, the correction should be made in 
accordance with the relevant software procedures.  All changes will be fully recorded in a 
protected audit trail, and a reason for the change will be required. 
Adverse events will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA).  Concomitant medications will be coded using the World 
Health Organization Drug Dictionary (WHO-DD).  Concomitant diseases/medical history 
will be coded using the most current version of MedDRA. 
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 

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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. 
10.0 SAFETY MONITORING AND REPORTING 
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE as provided in this protocol.  During the study, when 
there is a safety evaluation, the Investigator or study center personnel will be responsible for 
detecting AEs and SAEs, as detailed in this section of the protocol. 
10.1 Definition of an Adverse Event 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of an investigational product. 
Examples of an AE include: 
 Significant or unexpected worsening or exacerbation of the condition/indication under 
study.  See Section 10.3 for additional information. 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 New conditions detected or diagnosed after investigational product administration even 
though it may have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication (overdose per se should not be 
reported as an AE or SAE) 
 Significant failure of expected pharmacological or biological action.  See Section 10.3 for 
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Examples of an AE do not include: 
 Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
 Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
 The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
10.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
 Results in death 
 Is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject 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 
out-patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 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 

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minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions, but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Medically Significant:  A medical or scientific judgment regarding that the event, such as 
important medical events that may not be immediately life-threatening or result in death 
or hospital admission but may jeopardize the subject or may require medical or surgical 
intervention (in the office or an Emergency Department visit with treatment) to prevent 
one of the other outcomes listed in the above definitions.  These should also be 
considered serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3 Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE.  The signs and symptoms or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE 
definition (including clarifications). 
10.4 Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events  
Abnormal laboratory findings (eg, clinical chemistry, hematology, coagulation, urinalysis) or 
other abnormal assessments (eg, ECGs, X-rays, vital signs, etc.) that are judged by the 
Investigator as clinically significant will be recorded as AEs or SAEs if they meet the 
definition of an AE, as defined in Section 10.1, or an SAE, as defined in Section 10.2.  
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the 
start of the study or require a medical intervention for treatment will be reported as AEs or 
SAEs.  However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the 
Investigator as more severe than expected for the subject’s condition, or that are present or 
detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. 
The Investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 

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10.5 Time Period, Frequency, and Method of Detecting Adverse Events 
and Serious Adverse Events 
Subjects will be assessed for AEs and SAEs beginning immediately after signing the 
informed consent form and continuing through to follow-up which is 30 ± 3 days of last dose 
of investigational drug. Telephone contacts with patients should be conducted to assess irAEs 
90 days after the last dose of tislelizumab regardless of whether or not the patient starts a new 
anticancer therapy. If patients report a suspected immune-related AE at a telephone 
follow-up contact, the investigator should arrange an unscheduled visit if further assessment 
is indicated.  All drug-related SAEs will be recorded by the Investigator after treatment 
discontinuation until patient death or loss to follow-up, whichever occurs first. 
The Investigator or designee will ask about AEs by asking the following standard questions: 
 How are you feeling?  
 Have you had any medical problems since your last visit?  
 Have you taken any new medicines since your last visit?  
All AEs and SAEs will be recorded in the source documents.  All AEs and SAEs will be 
reported in the eCRF. 
10.6 Recording of Adverse Events and Serious Adverse Events 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) relative to 
the event.  The Investigator will then record all relevant information regarding an AE or SAE 
in the eCRF.  It is not acceptable for the Investigator to send photocopies of the subject’s 
medical records to the Sponsor or designee in lieu of completion of the appropriate AE or 
SAE eCRF pages.  However, there may be instances when copies of medical records for 
certain cases are requested by the Sponsor or designee.  In this instance, all subject identifiers 
will be blinded on the copies of the medical records prior to submission to the Sponsor or 
designee. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis should be documented as the 
AE or SAE and not the individual signs/symptoms. Adverse events are independent 
components of the study. 

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10.7  Evaluating Adverse Events and Serious Adverse Events 
10.7.1 
Assessment of Intensity  
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study, at the time the event is reported.  When applicable, AEs and SAEs should be 
assessed and graded based upon the NCI-CTCAE v 4.03.  In addition to performing the 
CTCAE assessment, the intensity of each AE and SAE recorded in the eCRF should also be 
assigned to one of the following categories based on the Investigator’s clinical judgment： 
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities 
 Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities 
 Severe: An event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with a SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 10.2. 
10.7.2 
Assessment of Causality  
The Investigator is obligated to assess the relationship between the investigational product 
and the occurrence of each AE or SAE, at the time the event is reported.  The Investigator 
will use clinical judgment to determine the relationship.  Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational product will be considered and investigated.  
The Investigator will also consult the IB and/or Product Information, for marketed products, 
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 or designee.  However, it is very 
important that the Investigator always makes an assessment of causality for every event prior 
to transmission of the SAE eCRF to the Sponsor or designee.  The Investigator may change 
his/her opinion of causality in light of follow-up information, amending the SAE eCRF 
accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
The Investigator will provide the assessment of causality as per instructions on the SAE 
eCRF. 

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10.8 Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the Investigator is required to proactively follow each 
subject and provide further information to the Sponsor or designee on the subject’s condition. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will 
be reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up.  Once resolved, the 
appropriate AE or SAE eCRF page(s) will be updated.  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 laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
The Sponsor or designee 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 subject dies 
during participation in the study or during a recognized follow-up period, the Sponsor or 
designee will be provided with a copy of any post-mortem findings, including 
histopathology.  
New or updated information will be recorded on the originally completed SAE eCRF.  The 
updated SAE eCRF should be resubmitted to the Sponsor or designee within the time frames 
outlined in Section 10.9. 
10.9 Prompt Reporting of Serious Adverse Events 
10.9.1 
Timeframes for Submitting Serious Adverse Events 
Serious AEs will be reported promptly to the Sponsor or designee as described in Table 14 
once the Investigator determines that the event meets the protocol definition of an SAE. 
Table 14 
Timeframe 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 
All SAEs 
Within 24 hours of 
first knowledge of 
the AE 
SAE Report 
As expeditiously  
as possible  
SAE Report 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
 

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10.9.2 
Completion and Transmission of the Serious Adverse Event Report 
Once an Investigator becomes aware that an SAE has occurred in a subject, he/she will report 
the information to the Sponsor or designee within 24 hours as outlined in Table 14.  The SAE 
eCRF will always be completed as thoroughly as possible with all available details of the 
event.  The SAE should be recorded by the Investigator (or designee) and reported to the 
Sponsor within the designated timeframes.  The data alert letter will be automatically 
submitted to sponsor or designee immediately by EDC system.  If the Investigator does not 
have all information regarding an SAE, he/she will not wait to receive additional information 
before notifying the Sponsor or designee of the event and completing the form.  The form 
will be updated when additional information is received. 
The Investigator will always provide an assessment of causality at the time of the initial 
report as described in Section 10.7.2. 
In case EDC is down, facsimile transmission of the paper SAE form is the preferred backup 
method to transmit this information to the project contact for SAE receipt.  In rare 
circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable, with a copy of the paper SAE form sent by overnight mail.  Initial notification via 
the telephone does not replace the need for the Investigator to complete and sign the paper 
SAE form within the time frames outlined in Section 10.9.1. 
The contact information for assistance with SAE reporting, specific to the site, are listed in 
the investigator folder provided to each site.  The original copy of the SAE Report Form and 
the fax confirmation sheet must be kept with the case report form documentation at the study 
site.  
10.10 Regulatory Reporting Requirements for Serious Adverse Events 
The Investigator will promptly report all SAEs to the Sponsor or designee in accordance with 
the procedures detailed in Section 10.9.1.  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.  Prompt notification of SAEs by the Investigator to 
the appropriate project contact for SAE receipt is essential so that legal obligations and 
ethical responsibilities towards the safety of other subjects are met.  
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 (IRB) /Independent Ethics Committee (IEC).  
This protocol may be filed under an Investigational New Drug (IND) application with the US 
FDA.  Once active, a given SAE may qualify as an IND safety report if the SAE is both 

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attributable to the investigational product and unexpected.  In this case, all Investigators filed 
to the IND (and associated INDs for the same compound) will receive an expedited 
Investigator safety report, identical in content to the IND safety report submitted to the FDA. 
Expedited Investigator safety reports are prepared according to the Sponsor’s policy and are 
forwarded to Investigators as necessary.  Such a report is prepared for an SAE that is both 
attributable to investigational product and unexpected.  The purpose of the report is to fulfill 
specific regulatory and GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised IB) from the Sponsor or designee, the responsible person according to local 
requirements is required to promptly notify his/her IRB or IEC.  
10.11 Post-study Adverse Events and Serious Adverse Events 
A post-study AE or SAE is defined as any event that occurs outside of the AE/SAE detection 
period, defined in Section 10.5. 
Investigators are not obligated to actively seek AEs or SAEs in former subjects.  However, if 
the Investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the 
investigational product, the Investigator will promptly notify the Sponsor or designee. 
10.12 Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (eg, procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre- or post-treatment period, will be reported 
promptly to the Sponsor or designee (see Section 10.9). 
10.13 Pregnancy  
10.13.1 
Contraception and Pregnancy Testing 
Childbearing potential is defined as being physiologically capable of becoming pregnant. 
Refer to Appendix 12 for contraception guidelines and definitions of “women of childbearing 
potential” and “no childbearing potential.” 
A serum pregnancy test will be performed at screening in women of childbearing potential.  
Any female subject who is pregnant will not be eligible for the study (see Section 5.2.1).  A 
urine or serum pregnancy test must be performed if any woman suspects that she has become 
pregnant during the study. 

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10.13.2 
Time Period for Collecting Pregnancy Information 
The time period for collecting information on whether a pregnancy occurs is from screening 
until 30 days after the last investigational product administration.  Information on 
pregnancies identified prior to the investigational product administration does not need to be 
reported to sponsor. 
10.13.3 
Action to be Taken and Reporting if a Pregnancy Occurs 
A subject who has a positive pregnancy test result at any time after the investigational 
product administration will be immediately withdrawn from participation in the study.  All 
post-study assessments will be collected at the time of discontinuation as described in 
Section 5.2.5.2. 
The Investigator, or his/her designee, will collect pregnancy information on any female 
subject or a female partner of a male subject who becomes pregnant while participating in 
this study.  The Investigator, or his/her designee, will record pregnancy information on the 
appropriate form and submit it to the Sponsor or designee within 24 hours of learning of a 
subject’s pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to the 
Sponsor or designee.  Generally, follow-up will be no longer than 8 weeks following the 
delivery date.  Any premature termination (spontaneous or elective abortion prior to 20 
weeks or stillbirth after 20 weeks gestational age) of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE, as 
described in Section 10.6 and will be followed as described in Section 10.8. 
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Section 10.0.  Furthermore, any SAE occurring as a result of a post-study pregnancy and is 
considered reasonably related to the investigational product by the Investigator, will be 
reported to the Sponsor or designee as described in Section 10.11.  While the Investigator is 
not obligated to actively seek this information in former subjects, he/she may learn of an 
SAE through spontaneous reporting. 

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11.0 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
11.1 Sample Size Considerations   
11.1.1 
Sample Size Considerations for Phase 1A 
In the Phase 1A stage, the number of dose levels and schedules examined and the emerging 
tislelizumab toxicities will determine the sample size.  It is anticipated that approximately 
24 subjects will be required to establish the RP2D(s) of tislelizumab when administered as a 
single agent.  In addition, 10 to 20 subjects will be enrolled in each of the schedule expansion 
and flat dose cohort at one or more dose level (up to 10 mg/kg Q2W or Q3W in schedule 
expansion cohort; 200 mg Q3W in flat dose cohort) not exceeding MTD to further evaluate 
safety, tolerability, PK and preliminary efficacy of tislelizumab.  In total approximately 
120 subjects are planned for the study. 
11.1.2 
Sample Size Considerations for Phase 1B 
In the Phase 1B stage, approximately 330 subjects (approximately 20, 30 or 50 subjects for 
each arm except arm 9) will be evaluated for efficacy as well as safety and tolerability of 
tislelizumab in select tumor types.  One or more arms may be closed early due to difficulty in 
patient recruitment. 
Using binomial approach, the 95% confidence interval (CI) width of an observed ORR of 
10% is reduced by 12%, from 30.5% to 18.5%, when sample size increases from 20 to 50. 
The 95% CI width of an observed ORR=50% is reduced by 16.6%, from 45.6% to 29.0%, 
when sample size increases from 20 to 50.  There is approximately 88% chance to observed 
at least one responder in an expansion arm of size 20 when the underlying ORR is 10%; and 
such chance increases while sample size expands. 
11.2 General Considerations for Data Analysis 
Data will be listed and summarized using SAS® v 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.  Primary safety and 
efficacy analyses will be conducted approximately 6 months after the last subject being 
enrolled. 
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 

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• 
Categorical variables: frequencies and percentages 
• 
Time-to-event variables: number of non-missing observations (N), median, minimum 
and maximum. Kaplan-Meier (KM) event rates may also be provided if applicable for 
specific time to event variables 
Efficacy and safety data will be summarized by stage and arm, unless otherwise specified.  
Further description of the statistical methods and analyses will be provided in the statistical 
analysis plan. 
11.2.1 
Analysis Populations 
All Subjects Enrolled Set (ENR) 
The all subjects enrolled (ENR) set will include all subjects who provide informed consent 
for this study.  The ENR analysis set will be used to summarize and describe the subject 
disposition, and deaths, unless stated otherwise. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) will include all subjects in the ENR set who receive at least one 
dose of tislelizumab.  The SAF will be used for all efficacy and safety summaries (except 
DLTs, PK and PD analyses). 
DLT Analysis Set (DLT) 
The DLT Analysis Set includes all subjects who experienced a DLT during Cycle 1 plus 
subjects who received at least 90% of the planned doses of treatment during the DLT 
observation period (Cycle 1).   
PK Analysis Set (PKS) 
The PK Analysis Set will include subjects who have received at least the first dose of 
tislelizumab and provided PK samples as per protocol following first dosing on Day 1. 
PD Analysis Set (PDS) 
The PD Analysis Set will include subjects who have received at least the first dose of 
tislelizumab and have evaluable pharmacodynamic data.  
11.2.2 
Interim Analysis 
Phase 1A stage of this study is a dose escalation and schedule expansion study, safety, PK 
and pharmacodynamic data will be evaluated on an ongoing basis.  The interim analysis will 
be performed once the Phase 1A stage is completed. 

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11.2.3 
Efficacy Analyses 
Efficacy is not a primary objective of the Phase 1A stage of this study.  Objective response is 
the primary endpoint of the Phase 1B stage.  There is no formal statistical testing for the 
efficacy endpoints in Phase 1B.  The efficacy analyses will be descriptive only. 
Response based on Investigators’ judgment will be collected at screening and while on study 
approximately every 8 weeks or 9 weeks depending on dosing schedules 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 v 1.1). 
PCWG2 criteria (Scher et al, 2008) may also be used to evaluate responses in patients with 
prostate cancer enrolled in the study. 
GCIG criteria (Rustin et al, 2011), in addition to RECIST v 1.1 may also be used to evaluate 
response in patients with ovarian cancer enrolled in the study. 
RANO criteria (Wen et al, 2010) may also be used to evaluate response in patients with 
GBM enrolled on the study. 
Listing of the data will be provided.  If data warrant, a summary 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.  The ORR will be determined along with 95% CI. 
Progression Free Survival 
Progression-free survival is defined as the time from the date of first study dose to disease 
progression or death whichever occurs first.  Subjects without an event (no disease 
progression or death) will be censored at the date of “last tumor assessment”.  Subjects with 
no baseline or post-baseline tumor assessments will be censored at Day 1. 
Kaplan-Meier methodology will be used to estimate median PFS and 95% CI.  Kaplan-Meier 
curves will be constructed to provide a visual description of the PFS change with time. 
Duration of Response 
Duration of response 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.  For subjects who are alive without progression following the qualifying 

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response, DOR will be censored on the date of last evaluable tumor assessment or last 
follow-up for progression of disease.  
Kaplan-Meier methodology will be used to estimate median time and 95% CI for DOR.  
Disease Control Rate 
The DCR is defined as the proportion of subjects who achieve CR, PR, and SD based on 
RECIST v 1.1 in subjects with select tumor types.  The DCR will be calculated for each 
tumor type with 95% CI estimated. 
Clinical Benefit Rate 
The CBR is defined as the proportion of subjects who achieve CR, PR, and durable SD [SD 
≥24 weeks] based on RECIST v 1.1 in subjects with select tumor types.  The CBR as well as 
95% CI will be estimated for each tumor type. 
Overall Survival 
Overall survival is defined as the time interval between the date of the first study drug dose 
to the date of death for any cause.  Kaplan-Meier methodology will be used to estimate OS at 
various time points. 
11.3 Safety Analyses 
All subjects who are exposed to (or started receiving) tislelizumab will be evaluated for 
safety.  Safety data will be summarized separately for the Phase 1A and 1B portions of the 
study.   
11.3.1 
Dose Limiting Toxicity 
For Phase 1A, the number and proportion of subjects experiencing DLTs will be reported by 
dose level, based on DLT observations during the first cycle.  The DLT Analysis Set will be 
used for this analysis.  
There is no DLT analysis in Phase 1B. 
11.3.2 
Adverse Events 
The AE verbatim descriptions (Investigator’s description from the eCRF) will be classified 
into standardized medical terminology using MedDRA®.  All AEs will be coded to 
MedDRA® (v 18.1 or later) lower level term closest to the verbatim term.  All TEAEs will be 
summarized. 

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A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy.  The TEAE classification also applies 
to irAEs that are recorded up to 90 days after discontinuation from tislelizumab, regardless of 
whether or not the patient starts a new anticancer therapy.  The SAEs, deaths, TEAEs of 
Grade 3 or above, related TEAEs and TEAEs that led to treatment discontinuation, and AEs 
of particular interest will be summarized. 
11.3.3 
Laboratory Assessments 
Hematology, clinical chemistry, coagulation, and urinalysis values will be flagged as high or 
low relative to the normal range, where applicable.  Predose values will be used to assess 
laboratory shifts occurring at postdose.  A comparison of pre-study and post-study values 
will be performed to identify any parameters that have not returned to pre-study levels.  
11.3.4 
Electrocardiogram 
All ECG parameters including the QT interval corrected for heart rate (QTc) will be listed for 
each subject and summarized by dose level and assessment time.  Change from baseline will 
also be summarized.  Relationship between dose level and QTc changes will be explored by 
graphs.  QTc will be calculated using Fridericia’s formula.  
11.3.5 
Vital Signs 
Blood pressure, pulse, respiratory rate, temperature and weight will be summarized and 
listed. The change from baseline will also be displayed. 
11.3.6 
Extent of Exposure 
Extent of exposure to tislelizumab will be summarized descriptively as the number of doses 
received (number and percentage of patients), duration of exposure (days), cumulative total 
dose received per patient (mg), dose intensity (in mg/3 weeks), and relative dose intensity. 
The number (percentage) of patients requiring drug discontinuation due to AEs will be 
summarized. 
11.3.7 
Physical Examination 
Physical examination results will be listed. 
11.3.8 
Ophthalmologic Examination 
Ophthalmologic examination results will be listed by subject. 

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11.3.9 
Immunogenicity Analysis 
The immunogenicity results will be summarized using descriptive statistics by the number 
and percentage of patients who develop detectable ADA.  The incidence of positive ADA 
and neutralizing ADA will be reported for evaluable subjects.  The effect of immunogenicity 
on PK, efficacy and safety may be evaluated if data allow. 
11.3.10 
Hepatitis A and B Analysis 
Hepatitis B and C analysis results will be listed. 
11.4 Pharmacokinetic Analyses 
Pharmacokinetic parameters will be derived using standard non-compartmental methods with 
WinNonlin Professional v 5.2 or higher (Pharsight Corp., Mountain View, California) or 
SAS® v 9.2 or higher (SAS Institute, Inc., Cary, North Carolina).   
tislelizumab PK variables (eg, Cmax, Tmax, Ctrough, AUC, Cl, and Vd) will be calculated as 
appropriate and summary statistics will be provided
 
  
 
. 
11.5 Pharmacodynamic Analyses 
Summary statistics will be provided for immune cell subtype, chemokine/cytokine 
modulation and PD-1 receptor occupancy in the blood.  
 
. 
11.6 Biomarker Analyses 
The primary predictive biomarker analysis is based on a subset of the subjects with both a 
valid PD-L1 expression and/or TILs measurement and at least one disease assessment post-
treatment.  A supportive analysis is based on subjects with a valid PD-L1 expression and/or 
TILs measurement, irrespective of the availability of post-treatment disease assessments.  In 
this analysis, those without post-treatment disease assessments will be imputed with the 
worst outcome in tumor response
 
 
 
 
  

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. 
12.0 ETHICS 
12.1 Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements before 
the study is initiated at a study center in that country. 
12.2 Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP and all applicable regulatory 
requirements, including, where applicable, current version of the Declaration of Helsinki. 
The Investigator (or Sponsor, where applicable) is responsible for ensuring that this protocol, 
the study center’s informed consent form, and any other information that will be presented to 
potential subjects (eg, advertisements or information that supports or supplements the 
informed consent) are reviewed and approved by the appropriate IEC/IRB.  The Investigator 
agrees to allow the IEC/IRB direct access to all relevant documents.  The IEC/IRB must be 
constituted in accordance with all applicable regulatory requirements.  The Sponsor will 
provide the Investigator with relevant document(s)/data that are needed for IEC/IRB review 
and approval of the study.  Before the investigational product(s) can be shipped to the study 
center, the Sponsor must receive copies of the IEC/IRB approval, the approved informed 
consent form, and any other information that the IEC/IRB has approved for presentation to 
potential subjects. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has 
approved for presentation to potential subjects is amended during the study, the Investigator 
is responsible for ensuring the IEC/IRB reviews and approves, where applicable, these 
amended documents.  The Investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form including obtaining IEC/IRB 
approval of the amended form before new subjects consent to take part in the study using this 
version of the form.  Copies of the IEC/IRB approval of the amended informed consent 
form/other information and the approved amended informed consent form/other information 
must be forwarded to the Sponsor promptly. 

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12.3 Informed Consent 
Informed consent(s) will be obtained before the subject can participate in the study.  The 
contents and process of obtaining informed consent(s) will be in accordance with all 
applicable regulatory requirements. 
12.4 Investigator Reporting Requirements 
As indicated in Section 10.10, the Investigator (or Sponsor, where applicable) is responsible 
for reporting SAEs to the IEC/IRB, in accordance with all applicable regulations.  
Furthermore, the Investigator may be required to provide periodic safety updates on the 
conduct of the study at his/her study center and notification of study closure to the IEC/IRB.  
Such periodic safety updates and notifications are the responsibility of the Investigator and 
not of the Sponsor. 
13.0 STUDY ADMINISTRATION 
13.1 Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or study center personnel, as appropriate: 
 Return of all study data to the Sponsor 
 Data queries 
 Accountability, reconciliation, and arrangements for unused investigational product(s) 
 Review of study records for completeness 
 Return of treatment codes to the Sponsor 
 Shipment of PK samples to assay laboratories 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single study center or at all study centers at any time for reasons 
including, but not limited to, safety or ethical issues or severe non-compliance.  If the 
Sponsor determines such action is needed, the Sponsor will discuss this with the Investigator 
(including the reasons for taking such action) at that time.  When feasible, the Sponsor will 
provide advance notification to the Investigator of the impending action prior to it taking 
effect. 
The Sponsor will promptly inform all other Investigators and/or institutions conducting the 
study if the study is suspended or terminated for safety reasons, and will also inform the 

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regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action.  If required by applicable regulations, the Investigator must inform the IEC/IRB 
promptly and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the Sponsor.  In 
addition, arrangements will be made for all unused investigational product(s) in accordance 
with the applicable Sponsor procedures for the study.  
Financial compensation to Investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and the Sponsor. 
13.2 Records Retention 
Following closure of the study, the Investigator must maintain all study records in a safe and 
secure location.  The records must be maintained to allow easy and timely retrieval, when 
needed (eg, audit or inspection), and, whenever feasible, to allow any subsequent review of 
data in conjunction with assessment of the facility, supporting systems, and personnel.  
Where permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (eg, microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken.  The Investigator must 
assure that all reproductions are legible, are a true and accurate copy of the original, and meet 
accessibility and retrieval standards, including re-generating a hard copy, if required.  
Furthermore, the Investigator must ensure there is an acceptable back up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
The Sponsor will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time will meet 
the strictest standard applicable to that study center for the study, as dictated by any 
institutional requirements or local laws or regulations, or the Sponsor’s standards/procedures; 
otherwise, the retention period will default to 15 years. 
The Investigator must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to, the following: archival at an off-site facility, transfer of 
ownership of the records in the event the Investigator leaves the study center. 
13.3 Provision of Study Results and Information to Investigators 
When the interim clinical study report for Phase 1 and the final clinical study report is 
completed, the Sponsor will provide the major findings of the study to the Investigator.  

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In addition, details of the study treatment assignment will be provided to the Investigator to 
enable him/her to review the data to determine the outcome of the study for his/her subjects. 
The Sponsor will not routinely inform the Investigator or subject of the test results, because 
the information generated from this study will be preliminary in nature, and the significance 
and scientific validity of the results will be undetermined at such an early stage of research.   
13.4 Information Disclosure and Inventions 
All information provided by the Sponsor and all data and information generated by the study 
center as part of the study (other than a subject’s medical records) are the sole property of the 
Sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel 
during the course of or as a result of the study are the sole property of the Sponsor, and are 
hereby assigned to the Sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the Sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the Sponsor and all data and information generated by the study 
center as part of the study (other than a subject’s medical records) will be kept by the 
Investigator and other study center personnel.  This information and data will not be used by 
the Investigator or other study center personnel for any purpose other than conducting the 
study.   
These restrictions do not apply to: 
 Information which becomes publicly available through no fault of the Investigator or 
study center personnel 
 Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
 Information which is necessary to disclose in order to provide appropriate medical care to 
a subject 
 Study results which may be published as described in Section 13.4.1 
If a written contract for the conduct of the study which includes provisions inconsistent with 
this statement is executed, that contract’s provisions shall apply rather than this statement. 

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Protocol Amendment 6.0 
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13.4.1 
Publication Policy  
For multi-center studies, the first publication or disclosure of study results shall be a 
complete, joint multi-center publication or disclosure coordinated by the Sponsor.  
Thereafter, any secondary publications will reference the original publication(s). 
Prior to submitting for publication, presentation, use for instructional purposes, or otherwise 
disclosing the study results generated by the study center (collectively, a “Publication”), the 
Investigator shall provide the Sponsor with a copy of the proposed Publication and allow the 
Sponsor a period of at least 30 days (or, for abstracts, at least 5 working days) to review the 
proposed Publication.  Proposed Publications shall not include any Sponsor information other 
than the study results or any personal data on any subject, such as name or initials. 
At the Sponsor’s request, the submission or other disclosure of a proposed Publication will 
be delayed a sufficient time to allow the Sponsor to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the 
proposed Publication. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall apply 
rather than this statement.  

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14.0 REFERENCES 
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. 
Bristol Myers Squibb (BMS) Press Release, October 25, 2013. https://news.bms.com/press-
release/rd-news/additional-survival-data-nivolumab-investigational-pd-1-immune-
checkpoint-inhi. 
Eisenhauer E A, Therasse P, Bogaerts J, et al., New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): 228-47. 
Food and Drug Administration (FDA), Guidance for Industry: M3(R2) Nonclinical Safety 
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. January 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. 
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. 
Haanen JBAG, Carbonnel F, Robert C, et al.  Management of toxicities from 
immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up.  
Ann Oncol. 2017:28 (supplement 4):iv119-iv142. 
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. 
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 Harmonisation (ICH) Note for Guidance on Good Clinical 
Practice (GCP; 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. 
Le D T, Uram J N, Wang H, et al., PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. N Engl J Med, 2015. 372(26): 2509-20. 
McDermott D F and Atkins M B, PD-1 as a potential target in cancer therapy. Cancer Med, 
2013. 2(5): 662-73. 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03. 
Cancer Therapy Evaluation Program. June 2010. 
Resuscitation Council (UK). Emergency treatment of anaphylactic reactions: Guidelines for 
healthcare providers. 2008. https://www.resus.org.uk/anaphylaxis/emergency-treatment-of-
anaphylactic-reactions/. Accessed 08 August 2017. 
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. 
Scher H I, Halabi S, Tannock I, et al., Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): 1148-59. 
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. 

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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. 
Wen P, Macdonald, D, Reardon D, et al. Updated response criteria for high-grade gliomas: 
Response assessment in Neuro-Oncology Working Group. 2010. 
http://jco.ascopubs.org/content/28/11/1963.abstract. 
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. 
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. 
Zou P, Yu Y, Zheng N, et al., Applications of human pharmacokinetic prediction in first-in-
human dose estimation. AAPS J, 2012. 14(2): 262-81. 
 
 

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15.0 APPENDICES 
APPENDIX 1:  SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
A Phase 1A/1B, Open Label, Multiple Dose, Dose Escalation 
and Expansion Study to Investigate the Safety, 
Pharmacokinetics and Antitumor Activities of the anti-PD-1 
Monoclonal Antibody BGB-A317 in Subjects with Advanced 
Tumors 
PROTOCOL NO: 
 
BGB-A317_Study_001 
This protocol is a confidential communication of BeiGene Research and Development.  I 
confirm that I have read this protocol, I understand it, and I will work according to this 
protocol.  I will also work consistently with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with good clinical practices and the applicable 
laws and regulations.  Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior 
written approval from BeiGene Research and Development. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and 
the name of the center in which the study will be conducted.  Return the signed copy to Quintiles. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________   Date:  _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 

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APPENDIX 2:  CLINICAL LABORATORY ASSESSMENTS 
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
RBC count 
Prothrombin time 
pH 
Alanine aminotransferase 
Hematocrit 
Activated Partial 
thromboplastin  
Specific gravity 
Aspartate aminotransferase 
Hemoglobin 
Time 
Glucose 
Albumin 
MCH 
International  
Protein 
Total bilirubin 
MCHC 
Normalized Ratio 
Ketones 
Bicarbonate1 
MCV 
 
Blood 
Blood urea nitrogen or urea 
Platelet counts 
 
24-hour protein2 
Calcium 
WBC count with differential 
 
Random urine protein  
Chloride 
Neutrophil count 
 
to creatinine ratio 
Creatinine 
Lymphocyte count 
 
 
Glucose 
Monocyte count 
 
 
Lactate dehydrogenase 
Basophil count 
 
 
Phosphate 
Eosinophil count 
 
 
Total protein 
Creatine kinase (CK)3 
Creatine kinase – cardiac 
muscle isoenzyme 
(CK-MB)3 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Abbreviations: CK-MB, creatine kinase cardiac muscle isoenzyme; MCH, mean corpuscular hemoglobin; 
MCHC, mean corpuscular hemoglobin concentration; 
MCV, mean corpuscular volume; RBC, red blood cell; WBC, white blood cell. 
1. Blood CO2 or HCO3 is acceptable. 
2. On routine urinalysis, if urine protein is ≥2+ by dipstick, then obtain a 24-hour urine sample for total 
protein and a random urine sample for total protein and creatinine to determine a protein to creatinine ratio. 
3.  In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
 
 

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APPENDIX 3:  BLOOD REQUIREMENTS 
Phase 1A Part 1 
Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 1 stage  
(dose escalation cohorts) 
Screening 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
HIV, Hepatitis B and C 
5 
  
Serum tumor markers1 
3 
  
Total 
18.5 
Cycle 1 
  
  
Day 1  
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Immune cell subtyping 
and cytokine/chemokine 
panel2 
40 
  
Thyroid function 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab 
antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
Pharmacokinetics6 
14 
  
Total 
76.5 
Day 2 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 4 (or 5) 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 8 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Pharmacokinetics6 
3.5 
  
Total 
11 

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Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 1 stage  
(dose escalation cohorts) 
Day 15 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Immune cell subtyping 
and cytokine/chemokine 
panel2 
40 
  
Pharmacokinetics6 
7 
  
Total 
54.5 
Cycle 2 and 
Additional Cycles 
(except for Cycle 4) 
  
  
Day 1 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Immune cell subtyping 
and cytokine/chemokine 
panel2 
40 
  
Thyroid function 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab 
antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
7 
  
Serum tumor markers1 
3 
  
Total 
72.5 
Day 15 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Total 
7.5 
Cycle 4 
  
  
Day 1  
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Immune cell subtyping 
and cytokine/chemokine 
panel2 
40 
  
Thyroid function 
3 
  
Immunoglubulins3 
5 

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Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 1 stage  
(dose escalation cohorts) 
  
Anti-tislelizumab 
antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
14 
  
Total 
76.5 
Day 2 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 4 (or 5) 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 8 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 15 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Pharmacokinetics6 
3.5 
  
Total 
11 
Cycle 5 
Day 1 
(and every 4 cycles 
thereafter) 
Hepatitis B and C  
3-5 
Safety Follow-up 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
Immune cell subtyping 
and cytokine/chemokine 
panel2 
40 
  
Thyroid function 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab 
antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
3.5 
  
Serum tumor markers1 
3 

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Total 
72 
Other blood samples7 
  
  
 
1. Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate for a given 
tumor type) will be collected within 14 days prior to Cycle 1 Day 1, and while on study approximately 
every 2 months in the first 12 months and approximately every 3 months thereafter, and at the mandatory 
Safety Follow-Up Visit. 
2. 
Only for the dose-escalation subjects treated in Melbourne sites due to sample and assay logistics. 
Blood in ACD will be collected and transported at room temperature within 8 hours according to the 
instructions in the Lab Manual at the time points specified in Table 5. 
3. 
Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 
8 weeks thereafter, and at the Safety Follow-Up Visit.  
4. 
Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion 
every cycle in the first 6 months, every 2 cycles in the next 6 months, approximately every 6 months 
thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who discontinue study therapy before 
6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months 
after the first dose. 
5. 
Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up 
visit for the subjects who have confirmed disease progression during the study to explore resistance 
mechanism. 
6. 
Cannulation for blood sampling for pharmacokinetics will be performed.  Blood will be collected via the 
intravenous cannula predose and at the time points specified in Table 6.   
7. 
Unscheduled blood samples for pharmacokinetic (PK) analysis may also be collected whenever any 
notable safety is seen, to evaluate if the observation is exposure related. Blood samples (3.5 mL) should be 
obtained, when possible, for analysis of serum tislelizumab in the event of a DLT.   
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to 
Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of 
tislelizumab.   
 
 

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Phase 1A Part 2 
Time point 
Assessment 
Blood volume (mL) for 
subjects in the Phase 
1A Part 2 stage  
(Q2W schedule) 
Blood volume (mL) 
for subjects in the 
Phase 1A Part 2 stage  
(Q3W schedule) 
Screening 
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Coagulation 
3 
3 
  
HIV, Hepatitis B and C 
5 
5 
  
Serum tumor markers1 
3 
3 
  
Total 
18.5 
18.5 
Cycle 1 
  
  
  
Day 1  
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Thyroid function 
3 
3 
  
Immunoglubulins2 
5 
5 
  
Anti-tislelizumab 
antibodies3 
2 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
5 
  
Pharmacokinetics5 
7 
7 
  
Total 
29.5 
29.5 
Day 4 (or 5) 
  
  
  
  
Pharmacokinetics5 
3.5 
3.5 
  
Total 
3.5 
3.5 
Day 8 
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Pharmacokinetics5 
3.5 
3.5 
  
Total 
11 
11 
Day 15 
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Pharmacokinetics5 
7 
3.5 
  
Total 
14.5 
11 

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Time point 
Assessment 
Blood volume (mL) for 
subjects in the Phase 
1A Part 2 stage  
(Q2W schedule) 
Blood volume (mL) 
for subjects in the 
Phase 1A Part 2 stage  
(Q3W schedule) 
Cycle 2 and 
Additional Cycles 
  
  
  
Day 1 
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Thyroid function 
3 
3 
  
Immunoglubulins2 
5 
5 
  
Anti-tislelizumab 
antibodies3 
2 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
5 
  
Pharmacokinetics5 
7 
7 
  
Serum tumor markers1 
3 
3 
  
Total 
32.5 
32.5 
Day 15 
  
  
  
  
Serum chemistry 
5 
N/A 
  
Hematology 
2.5 
N/A 
  
Total 
7.5 
0 
Cycle 5 
Day 1 
(and every 4 cycles 
thereafter) 
Hepatitis B and C 
3 
3-5 
Safety Follow-up 
  
  
  
  
Serum chemistry 
5 
5 
  
Hematology 
2.5 
2.5 
  
Coagulation 
3 
3 
  
Thyroid function 
3 
3 
  
Immunoglubulins2 
5 
5 
  
Anti-tislelizumab 
antibodies3 
2 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
5 
  
Pharmacokinetics5 
3.5 
3.5 
  
Serum tumor markers1 
3 
3 
  
Total 
32 
32 
Other blood samples6 
  
  
  
 

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1. 
Standard tumor markers (eg, AFP for HCC and CA 125 for ovarian cancer, as appropriate for a given 
tumor type) will be collected within 14 days prior to Cycle 1 Day 1, and while on study approximately 
every 2 months in the first 12 months and approximately every 3 months thereafter, and at the mandatory 
Safety Follow-Up Visit. 
2. 
Analysis of IgG and IgM at predose of Day 1 of every cycle in the first 12 months, approximately every 
8 weeks thereafter, and at the Safety Follow-Up Visit. 
3. 
Blood for anti-tislelizumab antibodies should be collected within 24 hours before start of Day 1 infusion 
every cycle in the first 6 months, every 2 cycles (Q2W) or 3 cycles (Q3W) in the next 6 months, 
approximately every 6 months thereafter, and at the mandatory Safety Follow-Up Visit. In subjects who 
discontinue study therapy before 6 months, every effort should be made to analyze anti-tislelizumab 
antibodies approximately 6 months after the first dose. 
4. 
Blood collected at predose on Day 1 of every cycle until 6 months of study, and at the safety follow up 
visit for the subjects who have confirmed disease progression during the study to explore resistance 
mechanism. 
5. 
Cannulation for blood sampling for pharmacokinetics will be performed.  Blood will be collected via the 
intravenous cannula predose and at the time points specified in Table 7 and Table 8.   
6. 
Unscheduled blood samples for pharmacokinetic (PK) analysis may also be collected whenever any 
notable safety is seen, to evaluate if the observation is exposure related. Blood samples (3.5 mL) should be 
obtained, when possible, for analysis of serum tislelizumab in the event of a DLT.   
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to 
Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of 
tislelizumab.   
 
 

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Phase 1A Part 3 
Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 3 stage 
Screening 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
HIV, Hepatitis B and C 
5 
  
Serum tumor markers1 
3 
  
Total 
18.5 
Cycle 1 
  
  
Day 1  
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Thyroid function 
3 
  
Immunoglubulins2 
5 
  
Anti-tislelizumab 
antibodies3 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
  
Pharmacokinetics5 
7 
  
Total 
29.5 
Day 4 (or 5) 
  
  
  
Pharmacokinetics5 
3.5 
  
Total 
3.5 
Day 8 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Pharmacokinetics5 
3.5 
  
Total 
11 
Day 15 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Pharmacokinetics5 
3.5 
  
Total 
11 
Cycle 2 and 
Additional Cycles 
(except Cycle 5) 
  
  
Day 1 
  
  
  
Serum chemistry 
5 

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Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 3 stage 
  
Hematology 
2.5 
  
Thyroid function 
3 
  
Immunoglubulins2 
5 
  
Anti-tislelizumab 
antibodies3 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
  
Pharmacokinetics5 
7 
  
Serum tumor markers1 
3 
  
Total 
32.5 
Cycle 5 
  
  
Day 1  
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Thyroid function 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab 
antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6  
Hepatitis B and C  
7 
3-5 
  
Total 
32.5 – 35.5 
Cycle 9  
Day 1 
And every 4 cycles 
thereafter 
Hepatitis B and C  
3-5 
Day 2 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 4 (or 5) 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 8 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Day 15 
  
  
  
Pharmacokinetics6 
3.5 
  
 
Total 
3.5 

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Time point 
Assessment 
Blood volume (mL) for subjects 
in the Phase 1A Part 3 stage 
Day 22 (Cycle 6 Day 
1) 
  
  
  
Pharmacokinetics6 
3.5 
  
Total 
3.5 
Safety Follow-up 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
Thyroid function 
3 
  
Immunoglubulins2 
5 
  
Anti-tislelizumab 
antibodies3 
2 
  
Proteomics and genomics 
biomarkers in blood4 
5 
  
Pharmacokinetics5 
3.5 
  
Serum tumor markers1 
3 
  
Total 
32 
Other blood samples6 
  
  
 
1. Standard tumor markers (as appropriate for a given tumor type) will be collected as specified in Table 9 
footnote 17. 
2. 
Analysis of IgG and IgM will be performed as specified in Table 9 footnote 12. 
3. 
Blood for anti-tislelizumab antibodies should be collected as specified in Table 9 footnote 13. 
4. 
Blood will be collected at the time points specified in Table 9 footnote 14. 
5. 
Cannulation for blood sampling for pharmacokinetics will be performed.  Blood will be collected via the 
intravenous cannula predose and at the time points specified in Table 10.   
6. 
Unscheduled blood samples for pharmacokinetic (PK) analysis may also be collected whenever any 
notable safety is seen, to evaluate if the observation is exposure related. Blood samples (3.5 mL) should be 
obtained, when possible, for analysis of serum tislelizumab in the event of a DLT.   
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to 
Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of 
tislelizumab.   

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Phase 1B 
Time point 
Assessment 
Blood volume (mL) for subjects in 
the Phase 1B stage  
Screening 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
HIV, Hepatitis B and C 
5 
  
Serum tumor markers1 
3 
  
Total 
18.5 
Cycle 1 
  
  
Day 1  
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Thyroid function2 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
7 
  
PD-1 receptor occupancy7 
30 
  
Total 
59.5 
Day 2 
  
  
  
PD-1 receptor occupancy7 
30 
  
Total 
30 
Cycle 2 and 
Additional Cycles 
  
  
Day 1 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Thyroid function2 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
7 
  
PD-1 receptor occupancy7 
30 
  
Serum tumor markers1 
3 

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Time point 
Assessment 
Blood volume (mL) for subjects in 
the Phase 1B stage  
  
Total 
62.5 
Cycle 5 Day 1  
(and every 4 cycles 
thereafter) 
Hepatitis B and C 
3-5 
Safety Follow-up 
  
  
  
Serum chemistry 
5 
  
Hematology 
2.5 
  
Coagulation 
3 
  
Thyroid function2 
3 
  
Immunoglubulins3 
5 
  
Anti-tislelizumab antibodies4 
2 
  
Proteomics and genomics 
biomarkers in blood5 
5 
  
Pharmacokinetics6 
3.5 
Serum tumor markers1 
3 
  
Total 
32 
Other blood samples8 
  
  
 
1. 
Standard tumor markers (as appropriate for a given tumor type) will be collected as specified in Table 11 
footnote 18. 
2. 
Thyroid testing will be performed as specified in Table 11 footnote 11. 
3. 
Analysis of IgG and IgM will be performed as specified in Table 11 footnote 12. 
4. 
Blood for anti-tislelizumab antibodies should be collected as specified in Table 11 footnote 13. 
5. 
Blood will be collected at the time points specified in Table 11 footnote 14. 
6. 
Cannulation for blood sampling for pharmacokinetics will be performed.  Blood will be collected via the 
intravenous cannula predose and at the time points specified in Table 11 footnote 15.   
7. 
Only for subjects in Arm 2 in the Phase 1B stage if enrolled by Melbourne sites. Procedures for 
collection of samples are described in the Procedures Manual. Blood will be collected via the intravenous 
cannula at the time points specified in Table 11 footnote 16. 
8. 
Unscheduled blood samples for pharmacokinetic (PK) analysis may also be collected whenever any 
notable safety is seen, to evaluate if the observation is exposure related. Blood samples (3.5 mL) should be 
obtained, when possible, for analysis of serum tislelizumab in the event of a DLT.   
Should a subject present with a DLT or any Grade 3 or above immune-related adverse event (refer to 
Section 7.3.4), additional blood PK samples will be taken to determine the plasma concentration of 
tislelizumab.   

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APPENDIX 5:  THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES 
The text below was obtained from Eisenhauer et al, 2009. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
(Version 1.1).  Changes in only the largest diameter (uni-dimensional measurement) of the 
tumor lesions are used in the RECIST criteria.  Note: Lesions are either measurable or 
non-measurable using the criteria provided below.  The term “evaluable” in reference to 
measurability will not be used because it does not provide additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm). 
 10 mm caliper measurement by clinical exam (when superficial). 
 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to 
<15 mm with conventional techniques or < 10 mm using spiral CT scan), are considered 
non-measurable disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques are all non-measurable. 

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Bone lesions: 
 Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions.  However, these techniques can be 
used to confirm the presence or disappearance of bone lesions 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Trial protocols should detail the conditions under 
which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should 
be identified as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be representative of 
all involved organ, but in addition should be those that lend themselves to reproducible 
repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor.  Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 

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sum.  The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, saggital, or coronal).  The smaller of these 
measures is the short axis.  For example, an abdominal node which is reported as being 
20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.  In 
this example, 20 mm should be recorded as the node measurement.  All other pathological 
nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions.  
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum.  
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline.  Measurements are not required 
and these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (eg, “multiple 
enlarged pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  
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. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and P10 mm diameter as assessed using calipers (eg, skin nodules).  For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is suggested.  As noted above, when lesions can be evaluated by both clinical 

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examination and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed at the end of the trial. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (eg, for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following CR or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a 
subject to be considered in complete response.  Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer), have been published.  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain).  When effusions are known to 
be a potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 

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or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
RESPONSE CRITERIA 
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 diameters.   
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. 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  Case report recorded in a separate section where, in order to qualify for 
CR, each node must achieve a short axis <10 mm.  For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”.  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being “too small to measure”.  When this occurs it is important that a value be recorded on 
the eCRF.  If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is 
less likely that this rule will be used for lymph nodes since they usually have a definable size 

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when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well).  This default value is 
derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness).  The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon 
measurement error.  To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum.  Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion.  If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
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/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
When the patient also has measurable disease. In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  A modest “increase” in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease.  This circumstance arises in some 
Phase III trials when it is not a criterion of trial entry to have measurable disease.  The same 

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general concept apply here as noted above, however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden.  Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: ie, an increase in tumor burden 
representing an additional 73% increase in “volume” (which is equivalent to a 20% increase 
diameter in a measurable lesion).  Examples include an increase in a pleural effusion from 
“trace” to “large”, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as “sufficient to require a change in therapy”.  If “unequivocal 
progression” is seen, the subject should be considered to have had overall PD at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of pre-existing lesions).  This is 
particularly important when the patient’s baseline lesions show partial or complete response.  
For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this 
is the subject who has visceral disease at baseline and while on trial has a CT or MRI brain 
ordered which reveals metastases.  The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 

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scanning in assessment of progression (particularly possible “new” disease).  New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site 
of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug 
treatment until the end of treatment taking into account any requirement for confirmation.  
On occasion a response may not be documented until after the end of therapy so protocols 
should be clear if post-treatment assessments are to be considered in determination of best 
overall response.  Protocols must specify how any new therapy introduced before progression 
will affect best response designation.  The subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  
Specifically, in non-randomized trials where response is the primary endpoint, confirmation 
of PR or CR is needed to deem either one the “best overall response”. 
The best overall response is determined once all the data for the patient is known.  Best 
response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points 
(for example, a subject who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR).  When SD is believed to be best response, 
it must also meet the protocol specified minimum time from baseline.  If the minimum time 
is not met when SD is otherwise the best time point response, the subject’s best response 
depends on the subsequent assessments.  For example, a subject who has SD at first 
assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD.  The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable. 

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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
CR = complete response; PR = partial response; SD = stable disease; and PD = progressive 
disease. 
Note: 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that subjects with CR may not have a total sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments 
may complicate best response determination.  The analysis plan for the trial must address 
how missing data/assessments will be addressed in determination of response and 
progression.  For example, in most trials it is reasonable to consider a subject with time point 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document objective 

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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response.  FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease specific medical literature 
for the indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes, or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error.  This will 
also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials.  However, in all other 
circumstances, ie, in randomized trials (phase II or III) or trials where stable disease or 
progression are the primary endpoints, confirmation of response is not required since it will 
not add value to the interpretation of trial results.  However, elimination of the requirement 
for response confirmation may increase the importance of central review to protect against 
bias, in particular in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry 
at a minimum interval (in general not less than 6 weeks). 

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Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and 
diseases.  If the proportion of subjects achieving stable disease for a minimum period of time 
is an endpoint of importance in a particular trial, the protocol should specify the minimal 
time interval required between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of 
this guideline to define a standard follow-up frequency.  The frequency should take into 
account many parameters including disease types and stages, treatment periodicity, and 
standard practice.  However, these limitations of the precision of the measured endpoint 
should be taken into account if comparisons between trials are to be made. 

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APPENDIX 6:  COCKCROFT-GAULT FORMULA 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. 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) 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 1A Part 2 (Q2W schedule) 
 
Screening 
Day -28 to Day -11  
Cycle 1 
Day 1 to Day 28 
 
Once Two Weeks 
administration 
 
Subsequent cycles 
Day 1 to Day 28 
 
Once Two Weeks 
administration 
 
Follow-up 
30 days (±7 days) 
after the last 
administration 
 
 
 
 
1. Screening assessments will be completed within 28 days prior to the first dose of the study drug.  It is 
preferred that routine laboratory are conducted within 10 days prior to first dosing, although tests done 
within 28 days are acceptable.   
Flow Chart for Phase 1A Part 2 (Q3W schedule) 
 
Screening 
Day -28 to Day -11  
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 (±7 days) 
after the last 
administration 
 
 
 
 
1. Screening assessments will be completed within 28 days prior to the first dose of the study drug. It is 
preferred that routine laboratory tests are conducted within 10 days prior to first dosing, although tests 
done within 28 days are acceptable.   
 
 

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Flow Chart for Phase 1A Part 3 
 
Screening 
Day -28 to Day -11  
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 (±7 days) 
after the last 
administration 
 
 
 
 
1. Screening assessments will be completed within 28 days prior to the first dose of the study drug. It is 
preferred that routine laboratory tests are conducted within 10 days prior to first dosing, although tests 
done within 28 days are acceptable.   
 
Flow Chart for Phase 1B  
 
Screening 
Day -28 to Day -11  
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 (±7 days) 
after the last 
administration 
 
 
 
 
1. Screening assessments will be completed within 28 days prior to the first dose of the study drug. It is 
preferred that routine laboratory tests are conducted within 10 days prior to first dosing, although tests 
done within 28 days are acceptable.   

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APPENDIX 8:  GUIDELINES FOR SUPPORTIVE CARE 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 
 Diarrhea: Patients should be monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, 
infectious etiologies should be ruled out, and if symptoms are persistent and/or 
severe, endoscopic evaluation should be considered. 
o In patients with severe enterocolitis, tislelizumab will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at 
a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month.  
o In patients with moderate enterocolitis, tislelizumab should be withheld and 
antidiarrheal treatment should be started. If symptoms are persistent for more 
than one week, systemic corticosteroids should be initiated (eg, 0.5 mg/kg/day 
of prednisone or equivalent). When symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and continued over at least 1 month. 
Regarding guidelines for continuing treatment with tislelizumab, see 
Section 5.1.2. 
 All patients who experience diarrhea should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. 
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice. Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 
 Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for 
the treatment of anemia, but should be clearly noted as concurrent medications. 
 Neutropenia: Prophylactic use of colony-stimulating factors including Granulocyte 
Colony-Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use of 
G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 

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 Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. 
Immune thrombocytopenic purpura should be ruled out before initiation of platelet 
transfusion. 
 Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice. 
 Immune-related adverse events: Patients who develop a G2 or higher irAE (eg, 
colitis, skin rash, hepatitis, uveitis, hypo- or hyperthyroidism, hypophysitis, or any 
other), should be discussed immediately with the Sponsor. Depending on the type and 
severity of an irAE, oral or intravenous treatment with a corticosteroid should be 
considered, in addition to appropriate symptomatic treatment of a given condition. 
 Infusion reaction: Infusion reactions may consist of 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 an infusion reaction 
during and immediately following drug infusion. 
o In the event of a Grade 1 or 2 infusion reaction, reduce the infusion rate by 
50% for the entire remaining duration of that infusion. Proper medical 
management should be instituted, as indicated per type of the reaction. This 
includes but is not limited to an antihistamine (eg, diphenhydramine or 
equivalent), anti-pyretic (eg, paracetamol or equivalent), and if considered 
indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and 
oxygen. 
o In the event of a Grade 3 or 4 infusion reaction, immediately stop the infusion. 
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 anti-histamine, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
o Regarding continuation of study therapy after an infusion reaction has 
occurred, see the guidelines in Section 7.3.2. 
 

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APPENDIX 9:  PROSTATE CANCER CLINICAL TRIALS WORKING 
GROUP 2 (PCWG2) CRITERIA TO GUIDE ASCRIBING DISEASE 
RESPONSE 
Variable 
PCWG2 (2007) 
PSA 
Record serial PSA. PSA partial response is defined as a ≥ 
50% decline in PSA from screening (baseline) PSA value. 
This PSA decline much be confirmed to be sustained by a 
second PSA value obtained 4 or more weeks later. 
Target Lesions 
Nodal or visceral progression sufficient for trial entry 
independent of PSA 
Measurable lesions not required for entry 
Use RECIST to record soft-tissue (nodal and visceral) 
lesions as target or nontarget 
Only lymph nodes ≥ 2 cm in diameter should be used to 
assess for a change in size 
Record presence of nodal and/or visceral disease separately 
Bone 
≥ 2 new lesions at the first scheduled reassessment 13 
weeks from Cycle 1 Day 1 compared with baseline must be 
confirmed by a second scan performed 6 or more weeks 
later. 
Confirmatory scans should show an additional 2 new lesions 
compared to the first post treatment scan (ie a total of ≥ 4 
new lesions compared with the baseline bone scan). 
Confirm ambiguous results by other imaging modalities (eg, 
CT or MRI) 
≥ 2 new lesions at the first scheduled reassessment >13 
weeks from Cycle 1 Day 1 compared with baseline must be 
confirmed by a second scan performed 6 or more weeks 
later. 
Confirmatory scans should confirm the presence of the 2 
new lesions compared the baseline scan. (ie a total of ≥ 2 
new lesions compared with the baseline bone scan). 
Confirm ambiguous results by other imaging modalities (eg, 
CT or MRI) 

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Abbreviations: PCWG2, Prostate Cancer Clinical Trials Working Group 2; PSA, prostate-specific antigen; 
PSA-DT; RECIST, Response Evaluation Criteria in Solid Tumors; CT, computed tomography; MRI, 
magnetic resonance imaging; PET, positron emission tomography 
* Modified Table 2 from Scher et al, 2008. 

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APPENDIX 10:  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 judgment (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:  
 What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
 How did the patient respond to withdrawal of tislelizumab? 
 Did the event recur when tislelizumab was reintroduced? 
 Was there a clinical response to corticosteroids? 
 Is the event an autoimmune endocrinopathy? 
 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.  
Recommended Diagnostic Tests in the Management of  
Possible Immune-Related Adverse Events 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
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. 
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.  

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Recommended Diagnostic Tests in the Management of  
Possible Immune-Related Adverse Events 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
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.  
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for 
all CNS 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. 
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.  
Eye Disorders 
If patients experience eye inflammation, blurred vision or other visual 
disturbance refer the patient urgently to an ophthalmologist for 
evaluation and management. 
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.  
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.  
Dermatology 
Consider other causes by conducting a physical examination, consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete 
musculoskeletal examination. Consider joint X-ray and other imaging 

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Recommended Diagnostic Tests in the Management of  
Possible Immune-Related Adverse Events 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
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. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous 
system; 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 cystolic 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 
 Immune-related AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, 
with patients is required 
 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 
 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 
 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]) 
 Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
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 0.5-1.6 µg/kg/day 
(for the elderly or those with 
comorbidities the suggested 
starting dose is 0.5 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. 
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. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
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. 
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 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and 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 
Discontinue study 
treatment. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
empiric antibiotics and 
consider prophylaxis for 
Pneumocystis infection and 
other adverse steroid effects, 
eg, blood glucose monitoring, 
vitamin D/calcium supplement. 
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 4 weeks.  Obtain 
neurology consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
grade 0-1. 
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 
4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response 
within 72-96 hours. 
Discontinue study 
treatment. 
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, 
consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Initiate IV methylprednisolone 
1-2mg/kg/day. 
Hold study treatment; 
retreatment may be 
considered when 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
Severe symptoms: 
> 6 liquid stools per 
day over baseline, or 
if episodic within 
1 hour of eating 
Convert to oral prednisolone 
and taper over at least 4 weeks.  
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. 
resolved/improved to 
baseline grade and 
after discussion with 
the study medical 
monitor. 
4 
Life-threatening 
symptoms 
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.  Consider a short 
course of oral steroids. 
Continue study 
treatment. 
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 judgment: 
 
For moderate symptoms: 
oral prednisolone 0.5-1 
Hold study treatment. 
Retreat when AE is 
resolved or improved 
to mild rash (grade 1-
2) after discussion 
with the study medical 
monitor. 
 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
mg/kg/day for 3 days then 
taper over 2-4 weeks. 
 
For severe symptoms: IV 
methylprednisolone 0.5-1 
mg/kg/day; convert to oral 
prednisolone and taper 
over at least 4 weeks. 
 
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. 
Admit to a hospital and seek 
urgent dermatology 
consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN 
to 3X ULN 
Check LFTs within 1 week and 
before the next dose check 
LFTs to verify that there has 
been no worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving.  Hold 
study treatment if 
LFTs are worsening 
until improvement is 
seen. 
 
2 
ALT or AST  
3-5X ULN 
Recheck LFTs every 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 2-4 weeks; 
reescalate dose if LFTs worsen, 
depending on clinical 
judgment.  
Hold study treatment, 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered 
to ≤ 10 mg. 
3 
ALT/AST < 400 IU/L and 
normal bilirubin/INR/albumin: 
Initiate oral prednisolone 
Hold study treatment 
until improved to 
baseline grade; 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
ALT or AST  
5-20X ULN 
1 mg/kg and taper over at least 
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 4 weeks. 
reintroduce only after 
discussion with the 
study medical 
monitor. 
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 
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 
48-72 hours. 
Hold study treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered 
to < 10 mg 
prednisolone. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
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 
4 weeks. 
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. 
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. 
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 

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21 May 2018 
Protocol Amendment 6.0 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
for insulin maintenance and 
monitoring. 
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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Protocol Amendment 6.0 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
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. 
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. 
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 guideline, treat 
with analgesics, topical 
treatments and oral hygiene 
care.  Ensure adequate 
hydration.  If symptoms 
worsen or there is sepsis or 
bleeding, manage as grade 3. 
Continue study 
treatment. 
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. 

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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines  
(Subject to Clinical 
Judgment) 
Study Drug 
Management 
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 3 X 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 
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. 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
construction 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 

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BGB-A317_Study_001 
 
21 May 2018 
Protocol Amendment 6.0 
Page 204 of 207 
 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CK-MB, creatine kinase – cardiac muscle isoenzyme; CHF, congestive heart failure; ECG = 
electrocardiogram; INR, international 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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21 May 2018 
Protocol Amendment 6.0 
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APPENDIX 11:  NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest.  If any physical activity is undertaken, discomfort 
increases. 
 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, 
MA: Lippincott Williams and Wilkins; March 1, 1994. 
 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 

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Protocol Amendment 6.0 
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APPENDIX 12:  CONTRACEPTION GUIDLINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL”, “NO 
CHILDBEARING POTENTIAL” 
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: 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (transdermal, implants or subcutaneous or 
intramuscular injections) 
 Combined oral contraceptives (birth control pills) may be used, but only if a 
concurrent barrier method is employed 
 Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized male partner (with azoospermia demonstrated by a post-procedure 
medical examination of the semen)  
 Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment) 
o 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 another acceptable method listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of the 
following criteria: 

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Protocol Amendment 6.0 
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 Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
 Postmenopausal, defined as: 
o ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal  
follicle-stimulating hormone (FSH) concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of hormonal 
contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Faciliation Group (CFTG):  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