Conditions: Locally Advanced or Metastatic Urothelial Bladder Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 113
Healthy volunteers: no

Brief summary:
This was a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the anti- programmed cell death-1(PD-1) monoclonal antibody BGB-A317 in participants with PD-L1+, locally advanced or metastatic Urothelial Bladder Cancer (UBC) who have progressed during or following a platinum-containing regimen

Detailed description:

Arms:
arm 1: 200mg intravenously (IV) every 3 weeks(Q3W)

Interventions: intervention 1: Tislelizumab
Intervention descriptions: intervention 1: 200mg intravenously (IV) every 3 weeks (Q3W)

Protocol document:
Prot_000.pdf: 
BGB-A317-204 
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Clinical Study Protocol 
Protocol Title:  
A Single-Arm, Multicenter Phase 2 Study of BGB-A317 in 
Patients with Previously Treated PD-L1+ Locally Advanced or 
Metastatic Urothelial Bladder Cancer 
Protocol Number: 
BGB-A317-204 
Date of Protocol: 
05 August 2020, Version 5.0 
Study Phase: 
2  
Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
 
4th Floor, Building D 
780 Cailun Road 
China (Shanghai) Pilot-fee Trade Zone 
Shanghai, China 201203 
 
Sponsor Medical Monitor: 
 
 
 
 
 
 
 
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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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
A Single-Arm, Multicenter Phase 2 Study of BGB-A317 in Patients with 
Previously Treated PD-L1+ Locally Advanced or Metastatic Urothelial 
Bladder Cancer 
Protocol No.: 
BGB-A317-204 
The protocol is a confidential document of BeiGene (Shanghai) Co., Ltd., and only disseminated 
under the premise of confidentiality. I confirm that I have read the protocol, understood the 
contents herein, and will carry out work in accordance with the protocol. In addition, I will carry 
out work according to the ethical principles in the Declaration of Helsinki, Good Clinical 
Practice and applicable laws and regulations. Signing the document means that I agree: without 
the prior written permission of BeiGene (Shanghai) Co., Ltd., I am prohibited to publicize or 
disclose non-public information herein. 
Instructions for Investigator: Please SIGN and DATE this signature page prior to implementation of this 
sponsor-approved protocol. PRINT your name, title, and the name of the center in which the study will be 
conducted. 
 
I have read the entire protocol and agreed to carry out the study according to this protocol: 
Signature of Investigator: 
___________________________   Date:  _____________ 
Printed Name:  
 
___________________________ 
Investigator Title: 
 
___________________________ 
Name/Address of Center: 
___________________________ 
 
 
 
 
___________________________ 
 
 
 
 
___________________________ 
 
 
 
 
___________________________ 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL SHEET .................................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS .................................................16 
1. 
BACKGROUND ........................................................................................................19 
1.1. 
Background on Bladder Cancer ..................................................................................19 
1.2. 
Treatment for Metastatic or Unresectable Urothelial Bladder Cancer .......................19 
1.3. 
Targeted Therapy for Urothelial Bladder Cancer .......................................................20 
1.4. 
Immunotherapy in Urothelial Bladder Cancer ...........................................................20 
1.5. 
Background Information on Tislelizumab ..................................................................24 
1.5.1. 
Pharmacology .............................................................................................................24 
1.5.2. 
Toxicology ..................................................................................................................24 
1.5.3. 
Clinical Pharmacology ................................................................................................25 
1.5.4. 
Prior Clinical Experience of Tislelizumab .................................................................25 
1.6. 
Study Rationale and Benefit-Risk Assessment ...........................................................27 
2. 
OBJECTIVES .............................................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
2.3. 
Exploratory Objectives ...............................................................................................29 
3. 
STUDY DESIGN .......................................................................................................30 
3.1. 
Description of Study ...................................................................................................30 
3.1.1. 
Initial Treatment Stage ...............................................................................................30 
3.1.2. 
Independent Review Committee .................................................................................31 
3.2. 
End of Study ...............................................................................................................31 
3.3. 
Rationale for Study Design .........................................................................................31 
3.3.1. 
Rationale for PD-L1 Selection in Urothelial Bladder Cancer ....................................31 
3.3.2. 
Rationale for Tislelizumab Dosage ............................................................................32 
3.3.3. 
Rationale for Pharmacokinetic Evaluation Schedule .................................................32 
3.3.4. 
Rationale for the Use of Modified Response Criteria (Immune-Based) ....................33 
3.4. 
Study Endpoints ..........................................................................................................33 
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3.4.1. 
Primary Endpoints ......................................................................................................33 
3.4.2. 
Secondary Endpoints ..................................................................................................33 
3.4.3. 
Exploratory Endpoints ................................................................................................33 
4. 
MATERIALS AND METHODS ...............................................................................35 
4.1. 
Study Population .........................................................................................................35 
4.1.1. 
Inclusion Criteria ........................................................................................................35 
4.1.2. 
Exclusion Criteria .......................................................................................................36 
4.2. 
Method of Treatment Assignment and Blinding ........................................................38 
4.3. 
Study Treatment ..........................................................................................................38 
4.3.1. 
Formulation, Packaging, and Handling ......................................................................38 
4.3.2. 
Dosage, Administration, and Compliance ..................................................................38 
4.4. 
Concomitant Therapy .................................................................................................39 
4.4.1. 
Permitted Therapy ......................................................................................................39 
4.4.2. 
Prohibited Concomitant Medications/Procedures ......................................................40 
4.4.3. 
Restricted Concomitant Medications/Procedures .......................................................40 
4.5. 
Study Assessments......................................................................................................41 
4.5.1. 
Informed Consent Forms and Screening Log .............................................................41 
4.5.2. 
Medical History and Demographic Data ....................................................................41 
4.5.3. 
Physical Examinations ................................................................................................42 
4.5.4. 
Eastern Cooperative Oncology Group Performance Status ........................................42 
4.5.5. 
Vital Signs ..................................................................................................................42 
4.5.6. 
Tumor and Response Evaluations ..............................................................................43 
4.5.7. 
Laboratory, Biomarker, and Other Biological Samples .............................................44 
4.5.8. 
Tumor Tissue Samples and Biomarkers Assessment .................................................45 
4.5.9. 
Cardiac and Pulmonary Function Tests ......................................................................46 
4.5.10. 
Anti-Drug Antibody Testing.......................................................................................46 
4.5.11. 
Assessments during Treatment ...................................................................................46 
4.5.12. 
Safety Follow-up Visit ................................................................................................47 
4.5.13. 
Survival Follow-Up ....................................................................................................47 
4.6. 
Patient, Treatment, Study, and Site Discontinuation ..................................................48 
4.6.1. 
Patient Discontinuation ...............................................................................................48 
4.6.2. 
Study Treatment Discontinuation ...............................................................................48 
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4.6.3. 
Study and Site Discontinuation ..................................................................................49 
5. 
ASSESSMENT OF SAFETY .....................................................................................50 
5.1. 
Safety Plan ..................................................................................................................50 
5.1.1. 
Risks Associated with Tislelizumab ...........................................................................50 
5.1.2. 
General Plan to Manage Safety Concerns ..................................................................50 
5.1.3. 
Dose Interruption ........................................................................................................51 
5.2. 
Safety Parameters and Definitions ..............................................................................52 
5.2.1. 
Definition of an Adverse Event ..................................................................................52 
5.2.2. 
Definition of a Serious Adverse Event .......................................................................52 
5.2.3. 
Suspected Unexpected Serious Adverse Reaction .....................................................53 
5.2.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................53 
5.2.5. 
Evaluating Adverse Events and Serious Adverse Events ...........................................55 
5.2.6. 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events .........................................................................................................................56 
5.2.7. 
Reporting Serious Adverse Events .............................................................................57 
5.2.8. 
Pregnancy Reporting ..................................................................................................58 
5.2.9. 
Post-study Adverse Event ...........................................................................................58 
5.2.10. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................58 
5.3. 
Management of Adverse Events of Special Interest ...................................................58 
5.3.1. 
Immune-related Adverse Events .................................................................................59 
5.3.2. 
Infusion-related Reactions ..........................................................................................60 
5.3.3. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................62 
5.3.4. 
Renal Function Abnormalities ....................................................................................62 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .............................64 
6.1. 
Statistical Analysis ......................................................................................................64 
6.1.1. 
Analysis Sets ...............................................................................................................64 
6.1.2. 
Patient Disposition ......................................................................................................64 
6.1.3. 
Demographic and Other Baseline Characteristics ......................................................64 
6.1.4. 
Prior and Concomitant Therapy ..................................................................................64 
6.2. 
Efficacy Analyses .......................................................................................................65 
6.2.1. 
Primary Efficacy Analysis ..........................................................................................65 
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6.2.2. 
Secondary Efficacy Analysis ......................................................................................65 
6.3. 
Safety Analysis ...........................................................................................................66 
6.3.1. 
Extent of Exposure .....................................................................................................66 
6.3.2. 
Adverse Events ...........................................................................................................66 
6.3.3. 
Laboratory Analyses ...................................................................................................66 
6.3.4. 
Vital Signs ..................................................................................................................67 
6.4. 
Exploratory Analyses ..................................................................................................67 
6.4.1. 
Pharmacokinetics ........................................................................................................67 
6.4.2. 
Immunogenicity ..........................................................................................................67 
6.4.3. 
Potential Biomarkers ..................................................................................................67 
6.5. 
Determination of Sample Size ....................................................................................67 
6.6. 
Interim Analyses .........................................................................................................67 
7. 
DATA COLLECTION AND MANAGEMENT ........................................................68 
7.1. 
Data Quality Assurance ..............................................................................................68 
7.2. 
Electronic Case Report Forms ....................................................................................68 
7.3. 
Source Data Documentation .......................................................................................68 
7.4. 
Use of Computerized Systems ....................................................................................69 
7.5. 
Retention of Records ..................................................................................................69 
8. 
ETHICAL CONSIDERATIONS................................................................................70 
8.1. 
Compliance with Laws and Regulations ....................................................................70 
8.2. 
Informed Consent .......................................................................................................70 
8.3. 
Institutional Review Board or Ethics Committee .......................................................70 
8.4. 
Confidentiality ............................................................................................................71 
8.5. 
Financial Disclosure ...................................................................................................71 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION .........73 
9.1. 
Study Documentation .................................................................................................73 
9.2. 
Protocol Violations .....................................................................................................73 
9.3. 
Site Inspections ...........................................................................................................73 
9.4. 
Administrative Structure .............................................................................................73 
9.5. 
Protocol Amendments ................................................................................................73 
9.6. 
Publication and Data Sharing Policy ..........................................................................74 
10. 
REFERENCES ...........................................................................................................75 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................78 
APPENDIX 2. IMMUNE-RELATED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (IRRECIST) .................................................................................83 
APPENDIX 3. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES ...........................................................................................88 
APPENDIX 4. PRE-EXISTING AUTOIMMUNE DISEASES.................................................97 
APPENDIX 5. COCKCROFT-GAULT FORMULA .................................................................98 
APPENDIX 6. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .......................................................................................................99 
APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................110 
LIST OF TABLES 
Table 1 Summary of Reported Efficacy Data for PD-1/PD-L1 Antibodies ..................................23 
Table 2: ECOG Performance Status ..............................................................................................42 
Table 3: Timeframe and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee .........................................................................................57 
Table 4: Immune-Related Adverse Events ....................................................................................59 
Table 5 Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................61 
 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
BeiGene (Shanghai) Co., Ltd. 
Name of Finished Product: 
Tislelizumab (BGB-A317) Injection 
Name of Active Ingredient: 
Tislelizumab (BGB-A317) 
Title of Study:  
A Single-Arm, Multicenter Phase 2 Study of BGB-A317 in Patients with Previously 
Treated PD-L1+ Locally Advanced or Metastatic Urothelial Bladder Cancer 
Protocol No: 
 
BGB-A317-204 
Study Centers:  
Approximately 30 sites in China and other Asian countries 
Study Plan: Screening (up to 28 days), treatment (until disease 
progression, intolerable toxicity, or withdrawal for other reasons), 
safety follow-up, and survival follow-up.  
Phase: 2 
Objectives: 
Primary: 
• 
To determine the efficacy of tislelizumab (also known as BGB-A317) in patients with previously 
treated, program death ligand-1 positive (PD-L1+), locally advanced or metastatic urothelial 
bladder cancer (UBC), as measured by the objective response rate (ORR) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 assessed by independent review 
committee (IRC)  
Secondary:  
• 
To evaluate the efficacy of tislelizumab as measured by duration of response (DOR), progression-
free survival (PFS), and disease control rate (DCR) according to RECIST version 1.1 assessed by 
IRC 
• 
To evaluate the efficacy of tislelizumab as measured by overall survival (OS) 
• 
To evaluate the efficacy of tislelizumab as measured by ORR, DOR, PFS and DCR according to 
RECIST version 1.1 and immune-related RECIST (irRECIST) assessed by investigators  
• 
To evaluate the safety and tolerability of tislelizumab as determined by the frequency and severity 
of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for 
Adverse Event (NCI-CTCAE) version 4.03, and the rate of discontinuation of treatment due to AEs 
Exploratory: 
• 
• 
• 
Study Design: 
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the anti-programmed 
cell death-1 (PD-1) monoclonal antibody tislelizumab in participants with PD-L1+, locally advanced or 
metastatic UBC who have progressed during or following a platinum-containing regimen. The study is 
composed of an initial screening phase (up to 28 days), a treatment phase (until disease progression, 
intolerable toxicity, or withdrawal for other reasons), safety follow-up phase, and survival follow-up phase.  
Approximately 110 patients will be allocated to receive 200 milligram (mg) of tislelizumab intravenously 
(IV) every 3 weeks. Radiological assessment of tumor-response status should be performed every 9 weeks 
(±1 week). Tumor response will be assessed by IRC based on the RECIST version 1.1, and by investigators 
based on RECIST version 1.1 and irRECIST.  Pseudo-progression may occur due to immune cell (IC) 
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infiltration and other mechanisms as manifested by apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, for progressive disease (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. 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 clinically significant 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. 
Patients will be evaluated for AEs (all grades, according to NCI-CTCAE version 4.03), serious adverse 
events (SAEs), and any AE that leads to treatment discontinuation will be followed up to 30 days after the 
last dose of study treatment or until the initiation of another anticancer therapy, whichever occurs first. 
Patients who have an ongoing study treatment-related AE upon study completion or at discontinuation from 
the study will be followed until the event has resolved to baseline or ≤ Grade 1, the investigator assesses the 
event as stable, the patient is lost to follow-up, the patient withdraws consent, or it has been determined that 
study treatment or participation is not the cause of the AE. Immune-related AEs will be recorded until up to 
90 days after the last dose of study treatment, regardless of whether or not the patient starts a new anticancer 
therapy. If a patient discontinues study treatment due to the reasons other than disease progression or death, 
then tumor assessments should continue to be performed following the scheduled assessment plan until the 
start of new anti-cancer therapy, disease progression, death, lost to follow-up or withdrawn consent. 
Planned number of patients: 
Approximately 110 patients  
Study Population 
Inclusion criteria:  
1. Patients with histologically or cytologically documented locally 
advanced (T4b, any N; or any T, N2-3) or metastatic (M1, Stage IV) 
transitional cell carcinoma (TCC) of the urothelium (including renal 
pelvis, ureters, urinary bladder, urethra) 
2. Disease progression during or following treatment with at least one 
platinum-containing regimen for inoperable locally advanced or 
metastatic urothelial carcinoma or disease recurrence  
a. Patients who received prior neoadjuvant or adjuvant 
chemotherapy and progressed within 12 months of treatment 
with platinum-containing regimen will be considered as second-
line patients  
b. Patients intolerant to platinum-containing regimen due to Grade 
4 hematologic toxicity or Grade 3 or 4 non-hematologic toxicity 
may also be eligible 
Note: No more than 2 prior lines of systemic therapy for metastatic 
UBC  
3. Patients must submit archival tumor tissue (formalin-fixed paraffin-
embedded block containing tumor [preferred] or at least 5 unstained 
slides) with an associated pathology report, or agree to a tumor 
biopsy for determination of program death ligand-1 (PD-L1) 
expression and other biomarker analyses (fresh tumor biopsies are 
strongly recommended at baseline in patients with readily accessible 
tumor lesions and who consent to the biopsies). PD-L1 expression 
will be assessed centrally, and patients who are tested as PD-L1 high 
are eligible.  
PD-L1 expression is defined as high:  
• If ICs involve >1% of the tumor area, either ≥25% of tumor 
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cells (TCs) or ≥25% of ICs express PD-L1  
• If ICs involve ≤ 1% of the tumor area, TCs ≥25% or ICs=100%  
And PD-L1 expression is defined as low/negative if it did not 
meet the criterion for PD-L1 high. 
Note: Tumor tissue should be of good quality based on total and 
viable tumor content.   
4. Patients must have at least one measurable lesion as defined per 
RECIST version 1.1 assessed by the investigator (imaging report 
must be submitted to the sponsor medical monitor to permit review of 
measurable disease at baseline) 
5. Male or female, aged ≥18 years on day of signing informed consent 
6. Patients have voluntarily agreed to participate by giving written 
informed consent 
7. ECOG performance status of ≤1 
8. Life expectancy ≥12 weeks 
9. Patient must have adequate organ function as indicated by the 
following screening laboratory values obtained within 7 days prior to 
the first study treatment 
a. Absolute neutrophil count (ANC) ≥1.5×109/L 
b. Platelets ≥100×109/L 
c. Hemoglobin ≥9 g/dL or ≥5.6 mmol /L (Note: Criteria must be 
met without a transfusion within 14 days of obtaining the 
sample) 
d. Calculated creatinine clearance ≥ 30 milliliter (mL)/min 
(Cockcroft-Gault formula, see Appendix 5) 
e. Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (total 
bilirubin must be <4 X ULN for patients with Gilbert’s 
syndrome) 
f. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver 
metastases 
10. Female patients 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 agree to remain 
abstinent (refrain from heterosexual intercourse) or uses 
adequate contraceptive methods that result in a failure rate of 
<1% per year before study entry and throughout the study until 
120 days after the last investigational product administration  
Note: Examples of contraceptive methods with a failure rate of 
< 1% per year include bilateral tubal ligation, male sterilization, 
established, proper use of hormonal contraceptives that inhibit 
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ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  
11. Male patients are eligible to participate in the study if they are 
vasectomized or agree to use contraception during the study treatment 
period and for at least 120 days after the last dose of study drug 
Exclusion criteria:  
1. History of severe hypersensitivity reactions to other humanized 
monoclonal antibodies 
2. Prior active malignancy within 2 years prior to Cycle 1 Day 1, 
exceptions include the tumor under investigation in this study, 
localized prostate cancer treated with curative intent and absence of 
prostate-specific antigen (PSA) relapse, and locally recurring cancers 
that have undergone curative intent treatment, such as resected 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. Active brain or leptomeningeal metastases as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) 
evaluation during screening and prior radiographic assessments. 
Patients with brain metastases are permitted if they are asymptomatic, 
eg, diagnosed incidentally at screening by brain MRI, or patients with 
previously treated brain metastases that are asymptomatic, 
radiographically stable and not requiring steroid medications for at 
least 4 weeks prior to Cycle 1 Day 1.  
5. Patients with active autoimmune diseases or history of autoimmune 
diseases that may relapse should be excluded (see Appendix 4 for a 
more comprehensive list of autoimmune diseases). Patients with the 
following diseases are allowed to be enrolled for further screening: 
type I diabetes, hypothyroidism managed with hormone replacement 
therapy only, skin diseases not requiring systemic treatment (such as 
vitiligo, psoriasis or alopecia), controlled celiac disease, or diseases 
not expected to recur in the absence of external triggering factors. 
6. Patients should be excluded if they have conditions 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; patients 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. With severe chronic or active infections (including tuberculosis 
infection, etc) requiring systemic antibacterial, antifungal or antiviral 
therapy within 14 days prior to first dose of study drug. 
9. With uncontrollable pleural effusion, pericardial effusion or ascites 
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requiring pleurocentesis or abdominal tapping less than 4 weeks 
10. Significant cardiovascular disease, such as New York Heart 
Association (NYHA) cardiac disease (Class II or greater), myocardial 
infarction within the previous 3 months, unstable arrhythmias, or 
unstable angina 
Note: Patients with known coronary artery disease, congestive heart 
failure not meeting the above criteria, or left ventricular ejection 
fraction < 50% must be on a stable medical regimen that is optimized 
in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 
11. Known history of Human Immunodeficiency Virus (HIV) 
12. Patients with untreated chronic hepatitis B or chronic hepatitis B 
virus (HBV) carrier with HBV deoxyribonucleic acid (DNA) ≥500 
IU/mL (or 2.5 × 103 cps/mL), or active hepatitis C should be 
excluded. Patient with inactive hepatitis B surface antigen (HBsAg) 
carrier, active HBV infection with sustained anti-HBV suppression 
(HBV DNA <500 IU/mL or 2.5 × 103 cps/mL) and patients whose 
hepatitis C has been cured (hepatitis C virus [HCV] ribonucleic acid 
[RNA] is lower than detection limit) can be enrolled 
13. 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 
14. Prior chemotherapy, radiotherapy, immunotherapy or any 
investigational therapies (including Chinese herbal medicine and 
Chinese patent medicines) used to control cancer within 2 weeks of 
Cycle 1 Day 1. AEs associated with these therapies must be Grade 0-
1, baseline or stabilized (except for alopecia)   
15. Prior allogeneic stem cell or solid organ transplant 
16. Administration of a live or attenuated vaccine within 4 weeks prior to 
study drug administration 
17. Major surgical procedure other than for diagnosis within 28 days 
prior to study drug administration 
Test product, dose and mode 
of administration: 
Tislelizumab, 10 ml/vial, 10 mg/ml.  
200 mg every 3 weeks (Q3W) administered by intravenous (IV) infusion  
Reference therapy, dose, and 
mode of administration: 
Not applicable 
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Study Endpoints: 
Primary Endpoint: 
• 
ORR – defined as the proportion of patients who had confirmed complete response (CR) or partial 
response (PR) assessed by IRC using RECIST version 1.1 
Secondary Endpoints: 
Efficacy: 
• 
DOR – defined as the time from the first determination of a confirmed objective response by IRC 
according to RECIST version 1.1 until the first documentation of progression or death, whichever 
comes first  
• 
PFS – defined as the time from the date of first dose of study drug to the date of first documentation of 
disease progression assessed by IRC using RECIST version 1.1 or death, whichever occurs first  
• 
DCR – defined as the proportion of patients who achieve CR, PR and stable disease (SD) assessed by 
IRC using RECIST version 1.1 
• 
OS – defined as the time from the date of first dose of study drug until the date of death from any cause 
• 
ORR, DOR, PFS and DCR assessed by investigators per RECIST version 1.1 and irRECIST 
respectively 
Safety: 
To evaluate the safety and tolerability of tislelizumab, as defined by: 
• 
The incidence and severity of AEs according to NCI-CTCAE version 4.03 
• 
Changes in vital signs, physical findings, and clinical laboratory results 
Exploratory Endpoints: 
Statistical Methods: 
Analysis Sets: 
The Safety analysis set will include all patients who have received any dose of tislelizumab.  
The Efficacy Evaluable analysis set includes all patients who have received any dose of tislelizumab and 
had measurable disease per IRC according to RECIST version 1.1 at baseline. This will be the primary 
analysis set for the efficacy analyses.  
The Per-Protocol (PP) analysis set includes patients in the Efficacy Evaluable analysis set who had no major 
protocol deviations. Criteria for exclusion from the PP analysis set will be determined and documented 
before the database lock for the primary analysis. This will be the secondary analysis set for efficacy 
analysis when there are over 15% patients, ie, 17 patients, who had major protocol deviations.  
Primary Efficacy Analysis: 
The primary efficacy endpoint is ORR as determined by IRC using the RECIST version 1.1. ORR is defined 
as the proportion of patients achieving best overall responses of CR or PR. 
The ORR in this study is estimated as 25%, which is deemed a clinical meaningful improvement based on a 
historical control of 10%. Hence, the null and alternative hypotheses are set as following: 
H0: ORR=10% 
Ha: ORR ≥25% 
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A binomial exact test will be performed for hypothesis testing among the evaluable patients (ie, patients 
with measurable disease at baseline) in the Efficacy Evaluable analysis set. If the obtained one-sided p-
value is ≤ 0.025, it will be concluded that the single agent tislelizumab statistically significantly increases 
ORR compared with historical control. Therefore, the superiority of single agent tislelizumab will be 
demonstrated. 
Clopper-Pearson 95% confidence interval (CI) of ORR will be constructed to assess the precision of the rate 
estimate.  
The primary efficacy analysis will be conducted no later than 6 months after the first dose of the last patient, 
and will be based on the Efficacy Evaluable analysis set. In case of patients without measurable disease per 
IRC who have been enrolled and treated, they will be excluded from the primary efficacy analysis.  
Secondary Efficacy Analysis:  
DOR will be estimated using the Kaplan-Meier (KM) method. Its 95% CI will be constructed using 
Greenwood’s formula. DOR censoring rule will follow United States Food and Drug Administration (FDA) 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007). 
Only patients who have achieved objective responses will be included in the analysis of DOR. 
PFS and OS will be analyzed similarly as DOR in the Efficacy Evaluable analysis set. PFS at 12 months 
and OS at 12 months will be calculated based on KM method. 
DCR will be summarized similarly as ORR in the Efficacy Evaluable analysis set. 
Efficacy outcomes based on tumor assessment (ORR, DOR, PFS and DCR) per investigator review 
according to RECIST version 1.1 and irRECIST, respectively, will be summarized in the secondary efficacy 
analyses.    
Safety Analysis: 
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v4.03. Laboratory 
values (eg, hematology, clinical chemistry, urinalysis), vital signs, electrocardiograms, and physical 
examinations, will also be used in determining safety. Descriptive statistics will be used to analyze all safety 
data in the Safety analysis set. 
Sample Size: 
The sample size calculation was based on the power of the comparison between estimated ORR in the study 
and the historical rate. It is assumed an ORR of 25% in the study as compared to 10% in the historical 
control. Using a binomial exact text, the power is 0.986 with 110 patients to demonstrate statistical 
significance at a 1-sided alpha of 0.025.  
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LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
BGB-A317 
Humanized monoclonal antibody directed at PD-1 
BOR 
Best overall response 
C1q 
Complement 1q, a subunit of complement 1 
CI 
Confidence Interval 
CK 
Creatine kinase 
CK-MB 
Creatine kinase cardiac muscle isoenzyme 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CSR 
Clinical Study Report 
CT 
Computed tomography 
Ctrough 
Minimum observed plasma concentration 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
Fc 
Fragment crystallizable region (typically, of immunoglobulin G) 
FcγR 
Gamma Fc receptor, such as FcγaRI, FcγIRIII, etc. 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
GC 
gemcitabine + cisplatin 
HBcAb 
Antibody against hepatitis B core antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPF 
High power field 
IB 
Investigator’s Brochure 
IC 
Immune Cell 
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Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G, such as IgG1, IgG2, IgG3 and IgG4; other types 
of immunoglobulins include IgM, IgD and etc. 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRC 
Independent Review Committee 
IRB 
Institutional Review Board 
irRECIST 
immune-related RECIST 
IV 
Intravenous(ly) 
KD 
Dissociation constant 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MIBC 
Muscle Invasive Bladder Cancer 
mL 
milliliter 
MRI 
Magnetic resonance imaging 
MVAC 
methotrexate + vinblastine + adriamycin + cisplatin 
NaF 
Sodium fluoride 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NMIBC 
Non-Muscle Invasive Bladder Cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
OTC 
Over-the-counter 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Program Death Ligand-1 
PD-L1+ 
Program Death Ligand-1 positive 
PD-L2 
Program Death Ligand-2 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial response 
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Abbreviation 
Definition 
PSA 
Prostate-specific antigen 
PT 
Prothrombin Time 
RBC 
Red blood cell 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
System Organ Class 
SPD 
Sum of the products of the two largest perpendicular diameters 
TC 
Tumor Cell 
TCC 
Transitional Cell Carcinoma 
TEAE 
Treatment-Emergent Adverse Event 
TIL 
Tumor-infiltrating lymphocytes 
tislelizumab 
BGB-A317 
TMTB 
Total Measured Tumor Burden 
TSH 
Thyroid-stimulating hormone 
UBC 
Urothelial Bladder Cancer 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
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1. 
BACKGROUND 
1.1. 
Background on Bladder Cancer 
Urothelial bladder cancer (UBC) is the most common cancer of the urinary system worldwide, 
with transitional cell carcinoma (TCC) of the bladder being the predominant histologic type and 
location. Although less common, urothelial cancers may originate in the renal pelvis, ureters, or 
urethra. It was estimated that in 2016, there would be 76,960 new cases of bladder cancer and 
16,390 deaths in the United States (American Cancer Society). Similar worldwide data estimate 
that there were 123,051 deaths in men and 42,033 in women in 2012 (GLOBOCAN 2012).  
In China, bladder cancer is one of the most common urologic malignancies and life-threatening 
diseases. The occurrence of bladder cancer is correlated with both genetic factors and external 
factors. Currently tobacco consumption and long-term exposure to chemicals are two leading 
risk factors. Additional factors such as chronic infections, water pollutions, family disease 
history, etc. also contribute to the incidence of bladder cancer (Chinese Urological Association 
[CUA] 2014). 
In 2008, the incidence of bladder cancer in all cancer registration areas in China was 
7.49/100,000 which is higher than the rate (4.53/100,000) by world standard population. This 
figure ranked first in male urologic malignancies in China as well as eighth in general. In 
addition, the incidence of bladder cancer in males is 3.3 times higher than that in female 
population (Han 2013). In 2015, there were 80,500 new cases of bladder cancer and among them 
32,900 deaths were reported (Chen et al 2016). 
The majority of urothelial tumors arise in the bladder with the remainder originating in the renal 
pelvis, urethra, or ureter. TCC is the most common histologic subtype associated with bladder 
cancer and accounts for greater than 90% of all UBC cases in the industrialized world, whereas 
non-urothelial subtypes, including squamous cell, adenocarcinoma, and small cell carcinoma, are 
more frequent in other areas of the world (Immune Related Adverse Reactions Management 
Guide of Nivolumab). According to the database established by Chinese Bladder Cancer 
Consortium, from 2007 to 2012, the most common histologic types of bladder cancer were 
urothelial carcinoma (91.4%), among which non-muscle invasive bladder cancer (NMIBC) and 
muscle invasive bladder cancer (MIBC) were 74.1 and 25.2%, respectively (Li 2015).  
The overall 5-year survival rate for metastatic UBC is approximately 5.2% (National Cancer 
Institute). Poor prognostic factors for survival in patients with metastatic UBC include advanced 
stage of disease at the time of initial diagnosis, Karnofsky performance status < 80%, visceral 
metastasis (ie, lung, liver, or bone) (Bajorin 1999). The presence of these unfavorable features 
was associated with a median survival of 4 months compared with 18 months in patients without 
these features (Loehrer 1992).  
1.2. 
Treatment for Metastatic or Unresectable Urothelial Bladder Cancer  
Cisplatin-based chemotherapy combination is the preferred first-line therapy worldwide for 
patients with metastatic UBC, for example GC (gemcitabine + cisplatin) and DD-MVAC (a 
modified regimen of methotrexate + vinblastine + adriamycin + cisplatin). Nonetheless, a 
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significant number of patients are not appropriate candidates for cisplatin-based chemotherapy 
combinations because of comorbidities and impaired functional status (Dash 2006). For such 
patients, alternative options such as gemcitabine monotherapy, gemcitabine + paclitaxel, etc. are 
available (NCCN Guidelines Version 2, 2016: Bladder Cancer Version 2.2016). 
Due to various approval situations and limited availability of imaging modalities at some 
facilities and centers in Asian countries, it is difficult to establish the unified clinical practice 
guidelines for bladder cancer in Asia or introduce the western guidelines directly into Asian 
countries. However, a consensus has been reached based on data and experience from the Asian 
region. Both MVAC and GC are available in Asian countries including India, Japan, South 
Korea, Singapore, Indonesia, Malaysia, Philippines, Thailand, etc. In some Asian countries, GC 
is the 1st-line chemotherapy. Growth factor support in the treatment of MVAC depends on the 
patient’s condition (NCCN Guidelines - Asia Consensus Statements: Version 1, 2016: Bladder 
Cancer Version 1.2016). 
At present the first-line standard of care available in China for patients with metastatic or 
unresectable bladder cancer includes: GC, TCG (pactitaxel + cisplatin + gemcitabine) and DD-
MVAC. For patients who are not able to tolerate the standard 1st-line treatment, alternative 
therapies including carboplatin, oxaliplatin, gemcitabine monotherapy, docetaxel monotherapy 
or paclitaxel monotherapy will be applied. Objective response rate (ORR) in first line setting is 
approximately 50-60%, median progression-free survival (PFS) ranges from 7-9 months and 
median overall survival (OS) from 12-16 months (Sheng 2016). 
Currently, the most frequently used the second-line treatments include docetaxel, paclitaxel or 
pemetrexed, however there is no consistent standard of care following the second line. The 
efficacy data of the second-line treatment reported in China is very limited, but according to the 
data reported in the United States and Europe, the ORR is approximately 10% (Oing 2016) and 
median PFS and OS are short, 2-3 months and 5-7 months respectively. Given the safety profile 
of these agents, additional treatments should be tested, as advanced bladder cancer is a serious 
unmet medical need for which there are few effective therapies. (Loehrer 1992). 
There are few drugs approved for the treatment of patients with bladder cancer. Ever since 
cisplatin was approved as a first-line treatment by the US FDA in 1978, no other novel drug has 
been approved in the US; gemcitabine was approved by European Medicines Agency in 2008 for 
the usage in combination with cisplatin and vinflunine in 2009 in the second line. On May 18th, 
2016, atezolizumab was granted accelerated approval by US FDA for treating second-line UBC, 
and represents a breakthrough in immunotherapy targeting advanced bladder cancer.  
1.3. 
Targeted Therapy for Urothelial Bladder Cancer 
Although there is an increasing understanding of the molecular biology and signaling pathways 
underlying bladder cancer development and progression (particularly the fibroblast growth factor 
receptor-, vascular endothelial growth factor-, and epidermal growth factor receptor-pathways), 
no targeted agents currently have a role in the treatment of UBC.  
1.4. 
Immunotherapy in Urothelial Bladder Cancer 
Immune check point-inhibitory receptor, programmed cell death-1 (PD-1) is mainly expressed in 
activated T-cells including CD8+ cytotoxic T-lymphocytes and CD4+ T-helper lymphocytes. It 
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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 and attenuate T-cell proliferation and 
functional activities, leading to T-cell exhaustion. PD-1 expression is markedly up-regulated in 
tumor-infiltrating lymphocytes (TIL), while the expression of PD-1 ligand, program death 
ligand-1 (PD-L1), is significantly increased in tumor cells (TCs) and tumor-associated immune 
cells (ICs) in the presence of stimulating cytokines such as interferon (IFN)-α and IFN-γ in the 
tumor microenvironment. Furthermore, the increased PD-1 expression in TIL and/or PD-L1 
expression in tumor and tumor-associated stromal cells is observed in many types of solid human 
tumors. This evidence provided the basis for cancer immunotherapeutic intervention via the 
approach of antagonizing PD-1. 
Atezolizumab was granted accelerated approval by US FDA based on a Phase 2 single-arm study 
(IMvigor210, Table 1). After a median follow-up of 14 months, efficacy data this revealed an 
ORR of 15% with median duration of response (DOR) not reached (2.1+~13.8+ months) in all 
310 patients. Among 46 patients with confirmed responses, the DORs were over 6 months in 37 
patients; and 6 patients had DORs longer than 12 months. Given the low ORR, short DOR, high 
toxicity and insignificant improvement in OS of other second-line therapies treating advanced 
bladder cancer, atezolizumab has significantly increased ORR, as well as extended DOR, 
supporting the accelerated approval designation. The subgroup analysis based on the expression 
of PD-L1 in ICs indicated that the ORR of the 100 patients in the IC2/3 (PD-L1 ≥ 5%) cohort 
was 26% (95% CI 18-36%) and ORR of the 207 patients in the IC1/2/3 (PD-L1≥1%) cohort was 
18% (95% CI 13-24%), which strongly supported the correlation between the expression of PD-
L1 and ORR. 
Data from a Phase 1 trial of an anti-PD-L1 antibody durvalumab (Study 1108, Table 1) 
demonstrated an ORR of 31% (95% CI 18-47). The median DOR was not reached (1.0+~12.3+ 
months) in the 42 patients enrolled and treated. The subgroup analysis based on the expression of 
PD-L1 in both TCs and ICs indicated that the ORR in the PD-L1 positive (TCs/ICs ≥ 25%) 
cohort (n=28) was 46% (95% CI: 28-66%) and 0% (95% CI: 0-23%) in the PD-L1 negative (TCs 
& ICs < 25%) cohort (n=14). 
In addition, nivolumab was evaluated in patients with advanced UBC who had at least received 
once platinum-containing chemotherapy (CheckMate 032, Table 1). Among the 78 patients 
enrolled, the ORR was 24.4% (95% CI: 15.3-35.4). The ORR in the PD-L1-negative subset (PD-
L1 <1%; n=42) was 26.2% (95% CI: 13.9-42.0%) and 24.0% (95% CI: 9.4-45.1%) in the subset 
of 25 patients whose tumors had PD-L1 expression ≥ 1%. Median DOR was 9.4 months (5.7-
12.5 months). Another Phase 2 single-arm study of nivolumab (CheckMate 275, Table 1) in the 
second-line treatment setting reported an ORR of 19.6% (95% CI: 15.0-24.9%) (n=265). The 
ORR in the PD-L1 < 1% cohort (n=143) was 16.1% (95% CI: 10.5-23.1%) and 23.8% (95% CI: 
16.5-32.3%) in the PD-L1 ≥ 1% cohort (n=122). The ORR in the PD-L1 < 5% cohort (n=184) 
was 15.8% (95% CI: 10.8-21.8%) and 28.4% (95% CI: 18.9-39.5%) in the PD-L1 ≥ 5% cohort 
(n=81). DOR was not reached with a median follow-up of over 7 months and 76.9% of the 
responders had not progressed. 
A Phase 1b study of another anti-PD-1 antibody pembrolizumab (Keynote-012, Table 1) 
involving multiple indications was reported at ASCO in 2015, showing that among 29 evaluable 
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patients with advanced UBC, the ORR reached 27.6% (95% CI: 12.7-47.2%) with DOR ranging 
from 2.0 to 16.0+ months and median OS reached 12.7 months. 
In summary, there has been reported efficacy data suggesting that higher expression of PD-L1 is 
likely associated with higher ORR among patients with UBC. In addition, encouraging clinical 
data emerging in the field of tumor immunotherapy have demonstrated that anti-PD-1/PD-L1 
antibodies can result in a significant clinical benefit in patients with UBC.  
 
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Table 1 Summary of Reported Efficacy Data for PD-1/PD-L1 Antibodies 
Drug 
Trial ID 
Phase 
PD-L1 
Ab 
Sample Size 
ORR, % (95% 
CI) 
Median DOR, 
months (range) 
Median PFS, 
months (95% 
CI) 
Median OS, 
month (95% 
CI) 
Data 
Source 
Atezolizumab 
IMvigor210 
2 
Ventana 
(SP142) 
310 (all patients) 
14.8 (11.1, 19.3) 
NR (2.1+, 
13.8+) 
2.1 (2.1, 2.1) 
7.9 (6.6, 9.3) 
Rosenberg 
2016 
210 (PD-L1<5% in IC) 
9.5 (5.9, 14.3) 
12.7 (2.1+, 
12.7) 
100 (PD-L1≥5% in IC) 
26.0 (17.7, 
35.7) 
NR (4.2, 
13.8+) 
2.1 (2.1, 4.1) 
11.4 (9.0, NE) 
Durvalumab 
Study 1108 
1 
Ventana 
(SP263) 
42 (all patients) 
31 (17.6, 47.1) 
NR (1.0+, 
12.3+) 
Massard 
2016 
14 (PD-L1<25% in TC 
and IC) 
0.0 (0.0, 23.2) 
 
 
 
28 (PD-L1≥25% in TC or 
IC) 
46.4 (27.5, 
66.1) 
Nivolumab 
CheckMate 
032 
1/2 
Dako 
(28-8) 
78 (all patients) 
24.4 (15.3, 35.4) 
9.4 (5.7, 12.5) 
2.8 (1.5, 5.9) 
9.7 (7.3, 16.2) 
Sharma 
2016 
42 (PD-L1<1%) 
26.2 (13.9, 
42.0) 
2.8 (1.4, 
6.5) 
9.9 (7.0, 
NE) 
25 (PD-L1≥1%) 
24.0 (9.4, 
45.1) 
5.5 (1.4, 
11.2) 
16.2 (7.6, 
NE) 
CheckMate 
275 
2 
Dako 
(28-8) 
265 (all patients) 
19.6 (15.0, 24.9) 
NR 
2.0 (1.9, 2.6) 
8.7 (6.1, NE) 
Galsky 
2016 
 
143 (PD-L1<1%) 
16.1 (10.5, 
23.1) 
122 (PD-L1≥1%) 
23.8 (16.5, 
32.3) 
184 (PD-L1<5%) 
15.8 (10.8, 
21.8) 
81 (PD-L1≥5%) 
28.4 (18.9, 
39.5) 
Pembrolizumab 
KEYNOTE-
012 
1b 
Dako 
(22C3) 
29 (all patients) 
27.6 (12.7, 47.2) 
NR (2.0, 16.0+) 
2.0 (1.7, 4.0) 
12.7 (5.0, 
NR) 
Plimack, 
2015 
 
11 (PD-L1<1% in TC) 
9 (0, 41) 
18 (PD-L1≥1% in TC) 
33 (13, 59) 
4 (PD-L1<1% in TC and 
IC) 
0 (0, 60) 
24 (PD-L1≥1% in TC and 
IC) 
29 (13, 51) 
Abbreviations: Ab, antibody; CI, confidence interval; DOR, duration of response; IC, immune cell; NR, not reached; ORR, objective response rate; OS, overall 
survival; PD-1, programmed cell death-1; PD-L1, program death ligand-1; PFS, progression-free survival; TC, tumor cell.  
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1.5. 
Background Information on Tislelizumab 
1.5.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized immunoglobulin G4 (IgG4) variant 
monoclonal antibody against PD-1. It is being developed for the treatment of human 
malignancies.  
Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and affinity 
(dissociation constant [KD] = 0.15 nM) as demonstrated by receptor binding assays based on 
Surface Plasmon Resonance. It competitively blocks the binding of both PD-L1 and program 
death ligand-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 PBMCs (peripheral blood 
mononuclear cells). 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 non-small cell lung cancer 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 Fc (fragment crystallizable region) 
gamma receptor (FcR) IIIA and complement 1q (C1q) by in vitro assays, suggesting a low or no 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effect in 
humans (Labrijn et al 2009). 
Please refer to the tislelizumab investigator’s brochure (IB) (BeiGene Investigator’s Brochure, 
BGB-A317) for additional details regarding nonclinical studies of tislelizumab. 
1.5.2. 
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 and 
PBMC. The pivotal studies were conducted following good laboratory practices regulations. The 
single dosing levels were spanning from the intended human doses to 10 folds higher than the 
maximum of the intended human doses, and the repeat dosing levels 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 or target organs were noted or identified in mice or monkeys. No specific 
tissue cross reactivity was found in both human and monkey tissues, nor effect on cytokine 
release was observed in human whole blood assay or PBMC assay. Toxicokinetic profile was 
well characterized with dose proportional increases in systemic exposure without apparent 
accumulation or sex difference. Immunogenicity was observed without apparent effect on the 
systemic exposure. The No Observed Adverse Effect Level 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 the current study BGB-A317-204. 
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Please refer to the tislelizumab IB (BeiGene Investigator’s Brochure, BGB-A317) for more 
detailed information on the toxicology of tislelizumab.  
1.5.3. 
Clinical Pharmacology 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim pharmacokinetics 
(PK) analysis (data cutoff date 28 August 2017) was conducted using noncompartmental 
methods, using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, and 10 
mg/kg once every 2 weeks, and 2.0 mg/kg, 5.0 mg/kg, and 200 mg once every 3 weeks (Phase 1a 
Parts 1, 2, and 3, and Phase 1b in BGB-A317_Study_001), and patients who received doses of 
200 mg once every 3 weeks in Phase 1 of Study BGB-A317-102 (n=19). The maximum 
observed plasma concentration and the area under the plasma or serum concentration-time curve 
increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both after single-
dose administration at steady state. Preliminary PK data from 27 patients who were administered 
1 dose of 200 mg once every 3 weeks (Phase 1a, Part 3 and Study BGB-A317-102) showed 
tislelizumab concentrations between the range of concentrations observed for patients who were 
administered 2 mg/kg and 5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first-order elimination 
shows a systemic plasma clearance of tislelizumab of 0.173 L/day, volume of distribution in the 
central and peripheral compartments of 2.89 L and 1.76 L, respectively, and half-life of 
approximately 19 days. Race, gender, and body weight were not significant covariates on the 
clearance of tislelizumab, which supports fixed-dosing across different ethnic groups. 
1.5.4. 
Prior Clinical Experience of Tislelizumab 
As of 28 February 2018, there are 13 ongoing studies with tislelizumab, including monotherapy 
and combination studies in solid tumors and hematological malignancies. Of the ongoing 
monotherapy studies in solid tumors, available data from BGB-A317_Study_001 and BGB-
A317-102 are summarized below (with a data cutoff date of 28 August 2017). 
Please refer to the tislelizumab IB (BeiGene Investigator’s Brochure, BGB-A317) for more 
detailed information on efficacy and safety of tislelizumab. 
1.5.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017) 
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts to establish the maximum tolerated dose, if any, a 
recommended Phase 2 dose for the Phase 1b, and a flat dose (fixed dose) followed by a Phase 1b 
component to investigate efficacy in select tumor types in indication expansion arms and to 
further evaluate safety and tolerability of tislelizumab.  
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens 
including 0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg once every 2 weeks; 2 mg/kg or 5 mg/kg 
once every 3 weeks; and 200 mg once every 3 weeks. In Phase 1b, 323 patients had received 
tislelizumab in Phase 1b across 9 indication-expansion cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the 
population was male, and 65.6% of patients were white. The median number of prior anticancer 
therapy regimens was 2 (range: 0 to 12). The median treatment exposure duration was 
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2.50 months (range: 0 to 23.0), and the median study follow-up duration was 5.56 months 
(range: 0.0 to 26.9). As of 28 August 2017, there were 210 patients (47.8%) remaining on study 
in Study BGB-A317_Study_001.   
Preliminary Safety 
Of the 439 total patients in the Safety analysis set for BGB-A317_Study_001, 240 (54.7%) 
experienced at least 1 treatment-emergent adverse event (TEAE) assessed as related to 
tislelizumab by the investigator and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE. 
The most commonly occurring related TEAEs for patients treated with the tislelizumab 
monotherapy in BGB-A317_Study_001 were fatigue (12.8%), rash (7.7%), nausea (6.8%), 
diarrhoea (6.6%), and hypothyroidism (4.8%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 
patients were pneumonitis (6 patients, 1.4%); colitis and alanine aminotransferase (ALT) 
increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate 
aminotransferase (AST) increased (3 patients each, 0.7%); and diarrhoea, 
gamma-glutamyltransferase increased, and diabetic ketoacidosis (2 patients each, 0.5%). All 
other events occurred in single patients. Lastly, 18 patients (4.1%) experienced an infusion-
related reaction; all were mild/moderate in severity.  
Preliminary Efficacy 
For patients in Phase 1a (n=116, evaluable), there were 20 patients with a confirmed response 
and 42 patients with a best overall response (BOR) of stable disease (SD).  
For patients in Phase 1b (n=286 evaluable), a total of 26 patients had a confirmed response. 
Additionally, there were 101 patients with a BOR of SD.  
1.5.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017) 
This Phase 1/2 study was a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.  
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of 
the population was male, and 100% of patients were Asian (Chinese). The median number of 
prior anti-cancer therapy regimens was 2 (range: 0 to 9). The median treatment exposure 
duration was 1.78 months (range: 0 to 8.0), and the median study follow-up duration was also 
1.78 months (range: 0.0 to 8.0). As of 28 August 2017, there were 113 patients (91.9%) 
remaining on study in Study BGB-A317-102. 
Preliminary Safety 
Of the 123 total patients in the Safety analysis set for Study BGB-A317-102, 69 (56.1%) 
experienced at least 1 TEAE assessed as related to tislelizumab by the investigator and 10 (8.1%) 
were ≥ Grade 3 in severity. The most commonly occurring related TEAEs were AST increased 
(20 patients, 16.3%), ALT increased (17 patients, 13.8%), and blood bilirubin increased and 
anaemia (13 patients each, 10.6%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 patients were 
AST increased (3 patients, 2.4%) and ALT increased (2 patients, 1.6%). All other events 
occurred in single patients, including a case of retinal detachment (Grade 4). 
Preliminary efficacy data are not yet available. 
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1.5.4.3. 
Immune-Related Reactions 
In patients treated with tislelizumab monotherapy, the following immune-related adverse events 
(irAEs) were observed: 
• Acute hepatitis and abnormal liver function have been reported, including 1 patient 
with fatal hepatitis. Additionally, 3.2% of patients experienced treatment-related 
abnormal liver function tests, and 1.4% of patients experienced immune-related 
hepatitis or hyperbilirubinaemia. 
• Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal 
pneumonitis.   
• Colitis has been reported in approximately 2% of patients treated. Diarrhoea has been 
reported in 6.6% of patients.  
• Endocrinopathies have been reported including diabetes mellitus (hyperglycemia and 
ketoacidosis). In addition, thyroiditis, including thyrotoxicosis and hypothyroidism 
has been reported. Furthermore, hypophysitis has been reported in < 1% of patients 
treated.  
• Other immune-related events (< 1% of patients with tislelizumab monotherapy except 
where noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); 
haemolytic anaemia, nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, 
pancreatitis, stomatitis, uveitis, and dry eye (1.4%).   
Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in 
combination with paclitaxel and cisplatin. The patient’s initial symptoms were dyspnea and tea-
colored urine 2 weeks after starting treatment. Elevated urine and serum cardiac and skeletal 
muscle enzymes were reported. The patient died of multi-organ failure 6 days later. 
1.6. 
Study Rationale and Benefit-Risk Assessment 
Comparing with currently available therapies, anti-PD-1/PD-L1 antibodies approved or currently 
under clinical trials have already demonstrated significant clinical benefit in the population of 
patients with metastatic or unresectable UBC. Reported data of anti-PD-1/PD-L1 antibodies, 
such as atezolizumab, nivolumab and pembrolizumab, has demonstrated favorable efficacy (See 
Section 1.4). In addition, data has been reported that PD-L1 could be employed as a biomarker to 
predict better efficacy among 2nd-line patients with UBC (Table 1). Also, PD-L1 expression has 
been detected in UBC with high mutation rate, which is another factor considered to be related to 
better response to the immune checkpoint inhibitors. 
According to the latest data collected from BGB-A317_Study_001, the early anti-tumor activity 
of tislelizumab, including in UBC, has been observed. Preliminary data from the ongoing Phase 
1 and Phase 2 studies show the safety profile of tislelizumab is largely consistent with that of 
other anti-PD-1 antibodies and included mostly mild/moderate AEs. Very few Grade 3/4 irAEs 
have been observed, and they have been generally reversible and manageable with study drug 
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interruption and/or steroid treatment. For further information on the safety profile of 
tislelizumab, please refer to the IB (BeiGene Investigator’s Brochure, BGB-A317). 
Given the lack of standard of care for the 2nd-line patients with UBC in Asia, as well as the low 
ORR and short PFS/OS provided by therapies currently available, the benefit/risk assessment of 
this study, ie, tislelizumab treating patients with previously treated, program death ligand-1 
positive (PD-L1+) locally advanced or metastatic UBC, is considered as acceptable to support 
further clinical study. 
 
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2. 
OBJECTIVES 
2.1. 
Primary Objective 
• To determine the efficacy of tislelizumab in patients with previously treated, PD-L1+, 
locally advanced or metastatic UBC, as measured by the ORR according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 assessed by independent 
review committee (IRC)  
2.2. 
Secondary Objectives 
• To evaluate the efficacy of tislelizumab as measured by DOR, PFS, and disease control 
rate (DCR) according to RECIST version 1.1 assessed by IRC 
• To evaluate the efficacy of tislelizumab as measured by OS 
• To evaluate the efficacy of tislelizumab as measured by ORR, DOR, PFS and DCR 
according to RECIST version 1.1 and immune-related RECIST (irRECIST) assessed 
by investigators  
• To evaluate the safety and tolerability of tislelizumab as determined by the frequency 
and severity of adverse events (AEs) according to National Cancer Institute Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) version 4.03, and the rate of 
discontinuation of treatment due to AEs   
2.3. 
Exploratory Objectives 
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3. 
STUDY DESIGN  
3.1. 
Description of Study 
3.1.1. 
Initial Treatment Stage  
This is a single-arm, multicenter Phase 2 study to evaluate the efficacy and safety of the anti-PD-
1 monoclonal antibody tislelizumab in participants with PD-L1+ locally advanced or metastatic 
UBC who have progressed during or following a platinum-containing regimen. The study is 
composed of an initial screening phase (up to 28 days), a treatment phase (until disease 
progression, intolerable toxicity, or treatment withdrawal for other reasons), safety follow up 
phase, and survival follow-up phase.  
Approximately 110 patients will be allocated to receive tislelizumab 200 mg IV every 3 weeks. 
Radiological assessment of tumor-response status should be performed every 9 weeks (±1 week). 
Tumor response will be assessed by IRC based on the RECIST version 1.1, and by investigators 
based on RECIST version 1.1 and irRECIST. Pseudo-progression may occur due to IC 
infiltration and other mechanisms as manifested by apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, for progressive disease (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. 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 clinically significant worsening 
laboratory values). b. Stable ECOG performance status. c. Absence of rapid progression of 
disease or of progressive tumor at critical anatomical sites (eg, cord compression) that 
necessitates urgent alternative medical intervention. 
Patients will be evaluated for AEs (all grades, according to NCI-CTCAE version 4.03), serious 
adverse events (SAEs), and any AE that leads to treatment discontinuation will be followed up to 
30 days after the last dose of study treatment or until the initiation of another anticancer therapy, 
whichever occurs first. Patients who have an ongoing study treatment-related AE upon study 
completion or at discontinuation from the study will be followed until the event has resolved to 
baseline or ≤ Grade 1, the investigator assesses the event as stable; the patient is lost to follow-
up, the patient withdraws consent, or it has been determined that study treatment or participation 
is not the cause of AE. Immune-related adverse events will be recorded until up to 90 days after 
the last dose of study treatment, regardless of whether or not the patient starts a new anticancer 
therapy. Telephone contacts with patients should be conducted to assess irAEs and concomitant 
medications (if appropriate, ie, associated with an irAE or is a new anticancer therapy) at 
60 days, and 90 days (± 14 days) after the last dose of study drug, 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.  
If a patient discontinues study treatment due to the reason other than disease progression or 
death, then tumor assessments should continue to be performed following the scheduled 
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assessment plan until the start of new anti-cancer therapy, disease progression, death, lost to 
follow-up or withdrawn consent. 
3.1.2. 
Independent Review Committee  
An IRC will be established to perform an independent review of all radiological scans for the 
efficacy analysis and to determine the response and disease progression on the basis of the 
RECIST version 1.1 in addition to the local investigator’s review of radiographs. Only the results 
from the investigator’s review of radiographs will be used to determine whether patients should 
be enrolled or should remain in the study. The IRC’s assessment will only be used in the efficacy 
analysis. All decisions made during the performance of the study will be on the basis of the local 
investigator’s review and assessment of radiographs. Sites will submit radiological files to the 
centrally located IRC’s data review facility during the study on an ongoing basis or at the 
sponsor’s request for efficacy analysis. Detail rules and guidelines on IRC tumor assessments are 
outlined separately in an IRC Charter.  
Because the China National Medical Products Administration (NMPA) approved the urothelial 
carcinoma indication for tislelizumab on 09 April 2020, and the Center for Drug Evaluation 
(CDE) of the NMPA had agreed that “IRC tumor assessment will not be required after 
16 September 2019," tumor responses are not assessed by the IRC after 16 September 2019. 
3.2. 
End of Study 
The end of study is defined as the date of the last follow-up visit. Primary efficacy analysis of 
ORR will be conducted no later than 6 months after the first dose of the last patient. The study 
will continue until the last data point from the last patient (OS) is received. The survival 
information of each patient will be collected until death, loss to follow up, withdrawal of 
consent, or study termination by the sponsor. The sponsor may terminate the study at any time.  
3.3. 
Rationale for Study Design 
3.3.1. 
Rationale for PD-L1 Selection in Urothelial Bladder Cancer  
Despite recent improvements in treatment, the prognosis for patients with advanced UBC 
remains dismal, with median OS of approximately 15 months (Garcia 2006). Patients who 
receive 2nd-line treatment for their disease have an even more limited prognosis, with median 
survival duration of approximately 7-9 months (Sonpavde 2010). Approved therapies are 
associated with significant toxicities (eg, neuropathy, febrile neutropenia, myelosuppression, and 
alopecia) that negatively impact quality of life. Therefore, there is a continuing need for more 
efficacious, better-tolerated treatments for patients with advanced UBC.  
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in some 
patients. Expression of PD-L1 by TCs in several tumor types has been shown to correlate with 
response to therapy (Topalian 2012). Published results suggest in bladder cancer that expression 
of PD-L1 in tumors correlates with response to anti-PD-1 or anti-PD-L1 therapy (Balar 2016; 
Galsky 2016; Loriot 2016; Massard 2016; Rosenberg 2016).    
On the basis of these observations, this study will select PD-L1 high patients to achieve greater 
clinical benefit. The PD-L1 expression status will be measured by immunohistochemistry assay 
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in a central laboratory and using Ventena PD-L1 (SP263) antibody. According to published data 
from duvalumab using the same antibody (Massard 2016), PD-L1 is defined as high if ICs 
involve >1% of the tumor area, either ≥25% of TCs or ≥25% of ICs express PD-L1; if ICs 
involve ≤1% of the tumor area, TCs ≥25% or ICs=100%. And PD-L1 is defined as low/negative 
if did not meet criterion for PD-L1 high. Meanwhile, the relationship between PD-L1 status (as 
determined by immunohistochemistry) and efficacy in patients with UBC is still being 
investigated in other ongoing studies of tislelizumab. Criteria of PD-L1 positivity might be 
adjusted based on further findings.   
3.3.2. 
Rationale for Tislelizumab Dosage  
The PK, safety, and efficacy data obtained from the first-in-human study BGB-
A317_Study_001, as well as other clinical study data, were analyzed in aggregate to determine 
the recommended dose for pivotal studies of tislelizumab. The flat dose of 200 mg IV once every 
3 weeks was selected for further evaluation. 
Simulations do not suggest any clinically meaningful differences in exposure following fixed 
dose or dose adjusted for weight (Bai 2012). On the basis of this analysis, a fixed dose of 200 mg 
is selected (equivalent to a body weight−based dose of 3.3 mg/kg, calculated with 60 kg). 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear dose-
dependence across these regimens. Similarly, confirmed objective response rates (ORRs) in 
patients treated with tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% 
and 15%, compared to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once 
every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the clearance of tislelizumab was 
found to be independent of body weight, ethnicity, and gender, and the observed serum exposure 
of a 200-mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose 
range with comparable safety and efficacy rates).  
Additionally, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n=13), 3 patients (23%) had a BOR of partial response (PR), 
4 patients (31%) had a BOR of SD, and 6 patients (46%) had a BOR of PD. Therefore, clinical 
activity with a manageable and tolerable safety profile is expected to be maintained in patients 
receiving tislelizumab 200 mg once every 3 weeks. 
In conclusion, tislelizumab 200 mg once every 3 weeks is the recommended dose for pivotal 
studies. 
3.3.3. 
Rationale for Pharmacokinetic Evaluation Schedule  
The proposed sampling scheme for tislelizumab concentration assessments will contribute to the 
characterization of tislelizumab PK. The tislelizumab concentration results may be compared 
with available data from other tislelizumab clinical studies and correlated with safety events in 
this study as appropriate.  
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3.3.4. 
Rationale for the Use of Modified Response Criteria (Immune-Based)  
Cancer immunotherapies may result in early apparent radiographic progression (pseudo-
progression/tumor immune infiltration), including the appearance of new lesions, followed by 
delayed response (Wolchok 2009). Additionally, responding tumors may appear to increase in 
size because of the influx of ICs (Hoos 2010). Unconventional response patterns have been 
described in patients treated with anti-cytotoxic T lymphocyte-associated antigen 4 (Wolchok 
2009). Therefore, irRECIST will be used in this study to accommodate the possible appearance 
of new lesions and to allow the apparent increase in tumor burden to be confirmed at a 
subsequent assessment prior to designation of PD. This study is designed to characterize these 
different patterns of response and will provide supportive clinical evidence.  
3.4. 
Study Endpoints 
3.4.1. 
Primary Endpoints  
• ORR – defined as the proportion of patients who had confirmed complete response 
(CR) or PR assessed by IRC using RECIST version 1.1 
3.4.2. 
Secondary Endpoints  
Efficacy: 
• DOR – defined as the time from the first determination of a confirmed objective 
response by IRC according to RECIST version 1.1 until the first documentation of 
progression or death, whichever comes first  
• PFS – defined as the time from date of first dose of study drug to date of first 
documentation of disease progression assessed by IRC using RECIST version 1.1 or 
death, whichever occurs first  
• DCR – defined as the proportion of patients who achieve CR, PR, and SD assessed by 
IRC using RECIST version 1.1 
• OS – defined as the time from the date of first dose of study drug until date of death 
from any cause 
• ORR, DOR, PFS and DCR assessed by investigator per RECIST version 1.1 and 
irRECIST respectively 
Safety: 
To evaluate the safety and tolerability of tislelizumab, as defined by: 
• The incidence and severity of AEs according to NCI-CTCAE version 4.03 
• Changes in vital signs, physical findings, and clinical laboratory results 
3.4.3. 
Exploratory Endpoints  
•
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4. 
MATERIALS AND METHODS 
4.1. 
Study Population 
4.1.1. 
Inclusion Criteria  
1. Patients with histologically or cytologically documented locally advanced (T4b, any N; 
or any T, N2-3) or metastatic (M1, Stage IV) TCC of the urothelium (including renal 
pelvis, ureters, urinary bladder, urethra) 
2. Disease progression during or following treatment with at least one platinum-containing 
regimen for inoperable locally advanced or metastatic urothelial carcinoma or disease 
recurrence  
a. Patients who received prior neoadjuvant or adjuvant chemotherapy and progressed 
within 12 months of treatment with platinum-containing regimen will be considered 
as second-line patients  
b. Patients intolerant to platinum-containing regimen due to Grade 4 hematologic 
toxicity or Grade 3 or 4 non-hematologic toxicity may also be eligible 
Note: No more than 2 prior lines of systemic therapy for metastatic UBC  
3. Patients must submit archival tumor tissue (formalin-fixed paraffin-embedded block 
containing tumor [preferred] or at least 5 unstained slides) with an associated pathology 
report, or agree to a tumor biopsy for determination of PD-L1 expression and other 
biomarker analyses (fresh tumor biopsies are strongly recommended at baseline in 
patients with readily accessible tumor lesions and who consent to the biopsies). PD-L1 
expression will be assessed centrally, and patients who are tested as PD-L1 high are 
eligible  
PD-L1 expression is defined as high:  
• If ICs involve >1% of the tumor area, either ≥ 25% of TCs or ≥ 25% of ICs express 
PD-L1  
• If ICs involve ≤ 1% of the tumor area, TCs ≥25% or ICs=100%  
And PD-L1 expression is defined as low/negative if it did not meet the criterion for PD-
L1 high. 
Note: Tumor tissue should be of good quality based on total and viable tumor content. 
4. Patients must have at least one measurable lesion as defined per RECIST version 1.1 
assessed by the investigator (Imaging report must be submitted to the sponsor medical 
monitor to permit review of measurable disease at baseline)  
5. Male or female, aged ≥ 18 years on day of signing informed consent 
6. Patients have voluntarily agreed to participate by giving written informed consent 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 
8. Life expectancy ≥ 12 weeks 
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9. Patient must have adequate organ function as indicated by the following screening 
laboratory values obtained within 7 days prior to the first study treatment 
a. Absolute neutrophil count (ANC) ≥1.5×109/L 
b. Platelets ≥100×109/L 
c. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (Note: Criteria must be met without a 
transfusion within 14 days of obtaining the sample) 
d. Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula, see 
Appendix 5)  
e. Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (total bilirubin must be <4 
X ULN for patients with Gilbert’s syndrome) 
f. Aspartate aminotransferase (AST) and ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for patients 
with liver metastases 
10. Female patients 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 agree to remain abstinent (refrain from heterosexual intercourse) or uses adequate 
contraceptive methods that result in a failure rate of <1% per year before study entry 
and throughout the study until 120 days after the last investigational product 
administration  
Note: Examples of contraceptive methods with a failure rate of < 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices 
11. Male patients are eligible to participate in the study if they are vasectomized or agree to 
use contraception during the study treatment period and for at least 120 days after the last 
dose of study drug 
4.1.2. 
Exclusion Criteria  
1. History of severe hypersensitivity reactions to other humanized monoclonal antibodies 
2. Prior active malignancy within 2 years prior to Cycle 1 Day 1, exceptions include the 
tumor under investigation in this study, localized prostate cancer treated with curative 
intent and absence of prostate-specific antigen (PSA) relapse, and locally recurring 
cancers that have undergone curative intent treatment, such as resected basal or squamous 
cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast 
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3. Prior therapies targeting PD-1 or PD-L1 
4. Active brain or leptomeningeal metastases as determined by computed tomography (CT) 
or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments. Patients with brain metastases are permitted if they are asymptomatic, eg, 
diagnosed incidentally at screening by brain MRI, or patients with previously treated 
brain metastases that is asymptomatic, radiographically stable and not requiring steroid 
medications for at least 4 weeks prior to Cycle 1 Day 1  
5. Patients with active autoimmune diseases or history of autoimmune diseases that may 
relapse should be excluded (see Appendix 4 for a more comprehensive list of 
autoimmune diseases). Patients with the following diseases are allowed to be enrolled for 
further screening: type I diabetes, hypothyroidism managed with hormone replacement 
therapy only, skin diseases not requiring systemic treatment (such as vitiligo, psoriasis or 
alopecia), controlled celiac disease, or diseases not expected to recur in the absence of 
external triggering factors 
6. Patients 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; patients 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. With severe chronic or active infections (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal or antiviral therapy within 14 days prior to first dose of 
study drug. 
9. With uncontrollable pleural effusion, pericardial effusion or ascites requiring 
pleurocentesis or abdominal tapping less than 4 weeks 
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac 
disease (Class II or greater), myocardial infarction within the previous 3 months, unstable 
arrhythmias, or unstable angina 
Note: Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate 
11. Known history of Human Immunodeficiency Virus (HIV) 
12. Patients with untreated chronic hepatitis B or chronic HBV carrier with HBV DNA ≥500 
IU/mL (or 2.5 × 103 cps/mL), or active hepatitis C should be excluded. Patient with 
inactive HBsAg carrier, active HBV infection with sustained anti-HBV suppression 
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(HBV DNA <500 IU/mL or 2.5 × 103 cps/mL) and patients whose hepatitis C has been 
cured (HCV RNA is lower than detection limit) can be enrolled 
13. 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 
14. Prior chemotherapy, radiotherapy, immunotherapy or any investigational therapies 
(including Chinese herbal medicine and Chinese patent medicines) used to control cancer 
within 2 weeks of Cycle 1 Day 1. AEs associated with these therapies must be Grade 0-1, 
baseline or stabilized (except for alopecia)  
15. Prior allogeneic stem cell or solid organ transplant 
16. Administration of a live or attenuated vaccine within 4 weeks prior to study drug 
administration 
17. Major surgical procedure other than for diagnosis within 28 days prior to study drug 
administration 
4.2. 
Method of Treatment Assignment and Blinding 
This is a single-arm Phase 2 study.  
Each patient enrolled in this study will receive a unique patient number after signing the 
informed consent. Each patient receiving tislelizumab will be identified by this unique number. 
Once this unique patient number has been assigned to a patient, it cannot be reassigned to any 
other patient. 
4.3. 
Study Treatment 
4.3.1. 
Formulation, Packaging, and Handling  
Tislelizumab is a monoclonal antibody drug which is formulated for IV injection in a sterile, 
single-use vial containing a total of 100 mg antibody in 10 mL of isotonic solution.  
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 
carton.  
The contents of the label will be in accordance with all applicable regulatory requirements. 
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. 
The investigational product must be kept at the temperature condition as specified on the label.  
Refer to the pharmacy manual for details regarding IV administration, accountability, and 
disposal. Please also refer to the IB (BeiGene Investigator’s Brochure, BGB-A317) for other 
details regarding tislelizumab. 
4.3.2. 
Dosage, Administration, and Compliance  
The dose level of tislelizumab in this study is 200 mg administered every 3 weeks (Q3W).  
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Tislelizumab will be administered by IV infusion, using a volumetric pump through an IV line 
containing a sterile, non-pyrogenic, low-protein binding 0.2 or 0.22 micron in-line or add-on 
filter. Specific instructions for product preparation and administration are provided in the 
pharmacy manual. The initial infusion will be delivered over 60 min; if well-tolerated, second 
infusion and each subsequent infusion may be administered over 30 min, which is the shortest 
time period permissible for infusion. Tislelizumab must not be concurrently administered with 
any other drug (refer to Section 4.4). Use of a volumetric pump was recommended to control the 
infusion speed and to avoid potential infusion reactions associated with too rapid administration. 
The pump may not be needed if the infusion speed is controlled through alternative means and 
consistent with approved institutional procedures. However, tislelizumab drug solution must still 
be infused at the speed ≥ 60 minutes for the 1st infusion time or ≥ 30 minutes in the 2nd time of 
infusion and thereafter. As well, the IV administration line must be equipped with a sterile, non-
pyrogenic, low-protein binding 0.2 or 0.22 micron in-line or add-on filter as described in the 
coincident protocol. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterward in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a ≥ 30-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents. 
Guidelines for dosage modification, treatment interruption or discontinuation and for the 
management of irAEs and infusion-related reactions are provided in Section 5.3.1, Section 5.3.2, 
and Appendix 6.  
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF). AEs associated with an overdose or 
incorrect administration of study drug should be recorded on the AE eCRF.  
Refer to the Pharmacy Manual and IB for detailed instructions on drug preparation, storage, and 
administration.  
4.4. 
Concomitant Therapy 
4.4.1. 
Permitted Therapy  
In general, concomitant medications and therapies deemed necessary for the supportive care (eg, 
such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. 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 (OTC), 
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. In addition, telephone 
contacts with patients should be conducted to assess irAEs and concomitant medications (if 
appropriate, ie, associated with an irAE or is a new anticancer therapy) at 60 and 90 days (± 14 
days) after the last dose of study drug regardless of whether or not the patient starts a new 
anticancer therapy.  
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The eCRF entry must include the dose, regimen, route, indication, and start and stop dates of use 
of the prior and concomitant medication.  
Systemic corticosteroids required for the control of infusion reactions or irAEs must be tapered 
gradually (see Appendix 6) 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 patients with contrast allergies to diagnostic imaging contrast dyes will be 
permitted. 
Patients may continue to receive hormone replacement if initiated prior to enrollment. 
Bisphosphonates and RANK-L inhibitors are allowed for bone metastases if initiated prior to 
enrollment. 
Whole brain radiation therapy and/or stereotactic radiosurgery are permitted for patients with 
progressive central nervous system (CNS) metastasis, but only for patients who have clinical 
benefit outside the brain. Palliative (limited-field) radiation therapy is permitted, but only for 
pain control or prophylaxis of bone fracture to sites of bone disease present at baseline and only 
if all of the following criteria are met: 
• Repeat imaging demonstrates no new sites of bone metastases 
• The lesion being considered for palliative radiation is not a target lesion 
• The case is discussed with the sponsor medical monitor, and the medical monitor 
agrees that the conditions required to receive palliative radiation are met 
4.4.2. 
Prohibited Concomitant Medications/Procedures 
The following medications and procedures are prohibited during the study: 
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
Country) herbal medicine and Chinese patent medicines] for treatment of cancer). 
• Live or attenuated vaccines within 28 days prior to the first dose of study therapy and 
60 days of last dose. Examples of live or attenuated 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. 
• Major surgery (excluding prior diagnostic biopsy or placement of a venous access 
device).  
• Herbal remedies with immune-stimulating properties (ie, mistletoe extract) or known 
to potentially interfere with major organ function (ie, hypericin). Patients must notify 
the investigator of all herbal remedies used during the study. 
4.4.3. 
Restricted Concomitant Medications/Procedures 
The following medications are restricted during the study: 
• Immunosuppressive agents (except to treat a drug-related AE). 
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• Systemic corticosteroids > 10 mg daily (prednisone equivalent), except to treat a 
drug-related AE (per protocol) or for short-term use as prophylactic treatment. 
• Patients should not abuse alcohol or other drugs during the study.  
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 4.4.1. 
4.5. 
Study Assessments  
Flowcharts of scheduled study assessments are provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented for each patient.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable.  
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend that 
precludes the visit, the visit should be scheduled on the nearest following feasible date, with 
subsequent visits rescheduled accordingly.  
4.5.1. 
Informed Consent Forms and Screening Log  
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations.  
Informed Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
Re-screening under limited conditions should be allowed after consultation with the sponsor, eg, 
when a patient narrowly misses a laboratory criterion and it’s correctable and not due to rapidly 
deteriorating condition or PD. PD-L1 expression assessed by central laboratory during screening 
visit may be used rather than repeating tests. Multiple attempts should not be allowed for re-
screening.   
4.5.2. 
Medical History and Demographic Data  
Medical history includes clinically significant diseases, surgeries, cancer history (including prior 
cancer therapies and procedures), reproductive status, smoking history, and all medications (eg, 
prescription drugs, OCT drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 30 days before the first dose.  
Demographic data will include age, ECOG performance status, gender, and self-reported 
race/ethnicity.  
Cancer history will include an assessment of prior platinum-containing treatment regimens, 
including start and stop dates, best response and reason for discontinuation.  
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4.5.3. 
Physical Examinations  
During the screening visit, a complete physical examination should include an evaluation of the 
head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems. Any abnormality identified during 
screening will be graded according to NCI-CTCAE version 4.03 and recorded on the Medical 
History eCRF with appropriate disease/condition terms. Height and weight should be measured 
and recorded in the eCRF. Body mass index (in kg/m2) should also be captured in the eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be recorded in 
patient notes. New or worsened clinically significant abnormalities should be recorded as AEs on 
the AE eCRF.  
4.5.4. 
Eastern Cooperative Oncology Group Performance Status  
ECOG performance status (Table 2) will be assessed at the screening visit, prior to Day 1 of each 
treatment cycle, End of Treatment visit, and safety follow-up visit. If the screening laboratory 
assessment is performed ≤ 96 hours prior to the first administration of tislelizumab, they do not 
have to be repeated on Day 1 of Cycle 1 and will be used as baseline.   
Table 2: ECOG Performance Status 
Grade 
Performance 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair 
5 
Dead 
  
4.5.5. 
Vital Signs  
Vital signs will include measurements of temperature, heart rate, and systolic and diastolic blood 
pressures while the patient is in a seated position after resting for 10 minutes.  
The patient’s vital signs should be determined within 60 minutes before the infusion, and if 
clinically indicated during and 30 minutes after the infusion. Patients will be informed about the 
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possibility of delayed post-infusion symptoms and instructed to contact their study physician if 
they develop such symptoms.  
4.5.6. 
Tumor and Response Evaluations  
Screening assessments must include CT scans (with oral/IV contrast unless contraindicated) or 
MRI of the chest, abdomen, and pelvis. A spiral CT scan of the chest may be obtained but is not 
a requirement.  
A MRI or CT (with contrast if not contraindicated) scan of the brain must be done at screening to 
exclude CNS metastasis. An MRI scan of the brain is required to confirm or refute the diagnosis 
of CNS metastases at baseline in the event of an equivocal scan. Patients with CNS metastases if 
they are asymptomatic may be eligible for the study (see Section 4.1.2).  
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast diagnostic 
CT scan.  
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at screening if clinically indicated. If bone metastases are present at screening and 
cannot be seen on CT or MRI scans, or if clinically indicated, TC-99m or NaF-PET bone scans 
should be repeated when CR is identified in target disease or when progression in bone is 
suspected.  
CT scans of the neck or extremities should also be performed if clinically indicated and followed 
throughout the study if there is evidence of disease at screening. At the investigator’s discretion, 
other methods of assessment of measurable disease as per RECIST version 1.1 may be used. 
Results of standard of care tests or examinations performed prior to obtaining informed consent 
and ≤28 days prior to study entry may be used for the purposes of screening rather than repeating 
such tests.  
For subsequent tumor assessments, the same radiographic procedure used to assess disease sites 
at screening should be used throughout the study (eg, the same contrast protocol for CT scans). 
All known sites of disease must be documented at screening and reassessed at each subsequent 
tumor evaluation. Response will be assessed by the investigator using RECIST version 1.1 and 
irRECIST (see Appendix 3 and Appendix 2, respectively). The same evaluator should perform 
assessments if possible to ensure internal consistency across visits. An objective response should 
be confirmed by repeat assessments ≥4 weeks after initial documentation. It is recommended that 
the confirmatory tumor assessment is not left until the next scheduled CT scan, but be performed 
as soon as possible following the 28 days interval from the initial documentation of response. 
Tumor assessment will need to follow the original schedule after the confirmation scan. 
At the investigator’s discretion, radiographic scans should be repeated at any time if PD is 
suspected.  
Patients who discontinue study treatment early during the initial treatment stage for reasons other 
than disease progression (eg, toxicity) should continue to undergo scheduled tumor assessments 
(every 9 weeks) until the patient begins a subsequent treatment, experiences disease progression, 
withdraws consent, dies, or until the study closes, whichever occurs first.  
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Patients who continue treatment beyond radiographic disease progression (see Section 4.6.2) will 
be monitored with a follow-up scan at least 4 weeks later or at the next scheduled tumor 
assessment (not exceed 12 weeks) before discontinuation of study treatment.  
Scans will be submitted to an IRC for central review.  
4.5.7. 
Laboratory, Biomarker, and Other Biological Samples 
Local laboratory assessments will include the following:  
• Hematology (complete blood count, including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, lymphocytes, monocytes, and basophils], and platelet count)  
• Serum chemistries (glucose, blood urea nitrogen or urea, creatinine, sodium, 
potassium, magnesium, chloride, bicarbonate [optional], calcium, phosphorus, total 
bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase [LDH], amylase, 
total protein, albumin, creatine kinase [CK], and creatine kinase cardiac muscle 
isoenzyme [CK-MB]). 
• Note: In the event that CK-MB fractionation is not available, serum troponins 
(troponin I and/or T) measurements will be performed instead; if only either troponin 
is assessed per local standards that same should be evaluated throughout. 
• Coagulation panel (activated Partial Thromboplastin Time (aPTT) and prothrombin 
time (PT)/ international normalized ratio [INR])  
• Urine or serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation)  
• Urinalysis (specific gravity, pH, glucose, protein, ketones, blood, and microscopic 
examination including WBC/high power field (HPF), RBC/HPF, and any additional 
findings)  
• Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4)  
• HBV serology (HBsAg, antibodies against HBsAg, antibodies against hepatitis B 
core antigen [HBcAb])  
• Patients who are HBsAg positive at screening must not be enrolled until further 
definite testing with HBV DNA titres can fulfill the criteria in Section 4.1.2.  
• HCV serology (anti-HCV)  
• Patients positive for HCV antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA. 
Central laboratories will coordinate the collection of archival tumor, fresh tumor, and leftover 
tumor tissue and blood samples for the assessment of tislelizumab PK, biomarkers and ADA 
assays. Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  
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The following assessments will be performed at a central laboratory:  
• ADA assays  
Serum samples will be assayed for the presence of ADAs to tislelizumab with use of 
validated immunoassays.  
• PK assay  
Serum samples will be assayed for tislelizumab concentration with use of a validated 
immunoassay.  
4.5.8. 
Tumor Tissue Samples and Biomarkers Assessment 
Archival tumor tissues (formalin-fixed paraffin-embedded block with tumor tissue [preferred] or 
around 15 unstained slides (at least 5 slides are required), or fresh biopsy need to be sent to 
central laboratory for PD-L1 status determination prospectively during screening (fresh tumor 
biopsies are strongly recommended at baseline or paired for biomarker analysis in patients with 
readily accessible tumor lesions and who consent to the biopsies). Tumor tissue samples will be 
assessed centrally for PD-L1 expression by immunohistochemistry with the Ventana SP263 
assay optimized for use on the automated Bench Mark ULTRA platform (Ventana). PD-L1 
expression for both TCs and ICs in the tumor microenvironment was determined by the 
percentage of cells expressing PD-L1 at any intensity above background staining. PD-L1 is 
defined as high:  
• If ICs involve >1% of the tumor area, either ≥25% of TCs or ≥25% of ICs expressed 
PD-L1  
• If ICs involve ≤1% of the tumor area, TCs ≥25% or ICs=100%  
And PD-L1 is defined as low/negative if did not meet criterion for PD-L1 high, and patients are 
excluded if tested low/negative. 
 
Tumor tissue should be of good quality based on total and viable tumor content (sites will be 
informed if the quality of the submitted specimen is inadequate to determine tumor PD-L1 
status). Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable. Specimens from transurethral resection of bladder tumors without a muscle 
invasive component (ie, T2 or greater) are not acceptable; these patients will be required to 
submit an additional specimen obtained at the time of cystectomy/nephronureterectomy or 
metastatic spread (eg, sample from a metastatic lesion).   
For fresh biopsy specimens, acceptable samples include core needle biopsies for deep tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions.  
Refer to the laboratory manual for additional details on laboratory assessments and sample 
handling.  
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4.5.9. 
Cardiac and Pulmonary Function Tests  
4.5.9.1. 
Electrocardiograms  
A twelve-lead electrocardiogram (ECG) is required at screening, safety follow-up and as 
clinically indicated. ECGs should be obtained on the same machine whenever possible. Lead 
placement should be as consistent as possible. ECG recordings should be performed after the 
patient has been resting in a supine position for at least 10 minutes.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. Any clinically significant morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF.  
4.5.9.2. 
Pulmonary Function Tests  
Patients who are suspected or known to have serious respiratory concurrent illness or exhibit 
significant respiratory symptoms unrelated to underlying cancer should take a pulmonary 
function test (refer to Appendix 1 for details). 
4.5.10. 
Anti-Drug Antibody Testing  
Tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response to tislelizumab will be closely monitored. 
 
 
 
 
 
 
 
  
4.5.11. 
Assessments during Treatment  
All visits must occur within ± 3 days from the scheduled date unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless a time 
window is specified. Assessments scheduled on the day of study treatment administration (Day 
1) of each cycle should be performed prior to study treatment infusion unless otherwise noted.  
See the study flowchart provided in Appendix 1 for the schedule of treatment period 
assessments.  
The following assessments may be performed ≤ 96 hours before Day 1 of each cycle: ECOG 
performance status, limited physical examination, local/central laboratory tests, AE evaluation, 
and concomitant medication evaluation.  
If scheduled dosing and study assessments are precluded because of a holiday, weekend, or other 
event, then dosing may be postponed to the soonest following date, with subsequent dosing 
continuing on a 21-day schedule. If treatment was postponed for fewer than 2 days, the patient 
can resume the original schedule.  
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Blood samples for PK will be obtained according to the schedule in Appendix 1.  
The End of Treatment visit is conducted when the investigator determines that tislelizumab will 
no longer be used. If routine laboratory tests (eg, hematology, serum chemistry) are completed 
within 7 days before the End of Treatment visit, these tests need not be repeated. Tumor 
assessment is not required at the End of Treatment visit provided that fewer than 6 weeks have 
passed since the last assessment. 
4.5.12. 
Safety Follow-up Visit  
Patients who discontinue from treatment for disease progression will be asked to return to the 
clinic around 30 days after the last treatment for a safety follow-up visit, or before the initiation 
of a new anticancer treatment, whichever occurs first. In addition, telephone contacts with 
patients should be conducted to assess irAEs and concomitant medications (if appropriate, ie, 
associated with an irAE or is a new anticancer therapy) at 60 days, and 90 days (±14 days) after 
the last dose of study drug, regardless of whether or not the patient starts a new anticancer 
therapy. The End of Treatment visit at which a response assessment showed PD that results in 
patient discontinuation, may be used as the safety follow-up visit, if it occurred 30 days (± 
7 days) after the last study treatment. Patients who discontinue study treatment prior to disease 
progression will have their tumors assessed as outlined in Section 4.5.6. 
See the study flowcharts provided in Appendix 1 for assessments to be performed at the safety 
follow-up visit.  
4.5.12.1. Adverse Events  
All AEs (including SAEs [see Section 5.2.2] regardless of attribution, will be recorded until 30 
days following their last dose of study treatment or until they receive another anti-cancer 
therapy, whichever comes first. Ongoing AEs thought to be related to study treatment will be 
followed until the event has resolved to baseline or ≤ Grade 1, the event is assessed by the 
investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it has 
been determined that study treatment or participation is not the cause of the AE. Immune-related 
adverse events will be recorded until up to 90 days after the last dose of study treatment, 
regardless of whether or not the patient starts a new anticancer therapy. All drug-related SAEs 
will be recorded by investigator after treatment discontinuation until patient death, withdrawal of 
consent, or loss to follow-up, whichever occurs first. 
4.5.13. 
Survival Follow-Up 
Following discontinuation of the treatment, all patients will be followed for survival status 
beginning 3 months after safety follow-up visit or as directed by sponsor. Survival follow-up 
information will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study 
termination by the sponsor.  
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4.6. 
Patient, Treatment, Study, and Site Discontinuation 
4.6.1. 
Patient Discontinuation  
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. Reasons 
for withdrawal from the study may include but are not limited to the following:  
• Patient withdrawal of consent at any time  
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study  
• Investigator or sponsor determines it is in the best interest of the patient  
• Patient non-compliance  
Every effort should be made to obtain information on patients who withdraw from the study. The 
primary reason for withdrawal from the study should be documented on the appropriate eCRF. 
Patients who withdraw from the study will not be replaced.  
4.6.2. 
Study Treatment Discontinuation  
Patients must discontinue study treatment if they experience any of the following:  
• Clinical deterioration (eg, uncontrollable pain secondary to disease or unmanageable 
ascites, etc.) attributed to disease progression as determined by the investigator after 
integrated assessment of radiographic data, biopsy results, and clinical status  
• Intolerable toxicity related to tislelizumab, including development of an immune-
mediated AE determined by the investigator to be unacceptable given the individual 
patient’s potential response to therapy and severity of the event  
• Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment  
• Use of another non-protocol anti-cancer therapy (see Section 4.4.2)  
• Pregnancy  
Patients will be permitted to continue study treatment after RECIST version 1.1 criteria for PD 
are met if they meet all of the following criteria:  
• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening laboratory values)  
• 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 
Patients in whom radiographic disease progression is confirmed at a subsequent tumor 
assessment may be considered for continued study treatment at the discretion of the investigator 
if they continue to meet the criteria above and have evidence of clinical benefit.  
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The primary reason for study treatment discontinuation must be documented in the eCRF. 
4.6.3. 
Study and Site Discontinuation  
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include but are not limited to the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients  
• Patient enrollment is unsatisfactory  
The sponsor will notify the investigator if the sponsor decides to discontinue the study. The 
sponsor has the right to close a site at any time. At the time of a site’s closure, patients who are 
still on treatment may transfer to a long-term extension study for continuous treatment and 
monitoring when a long-term extension study becomes available. Reasons for closing a site may 
include but are not limited to the following:  
• Excessively slow recruitment  
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• Non-compliance with the International Conference on Harmonization (ICH) guideline 
for Good Clinical Practice  
• No study activity (ie, all patients have completed and all obligations have been 
fulfilled)  
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5. 
ASSESSMENT OF SAFETY  
5.1. 
Safety Plan 
Tislelizumab is not approved and is currently in clinical development. Human experience is 
currently limited and the entire safety profile is not known at this time. The following 
information is based on results from nonclinical and clinical studies and published data on 
similar molecules.  
Measures will be taken to ensure the safety of patients participating in this trial, including the use 
of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2, respectively) and close 
monitoring (as indicated below and in Section 4.5). See Section 5.2 for complete details 
regarding safety reporting for this study.  
Administration of tislelizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. All AEs and SAEs 
will be recorded during the trial and for up to 30 days after the last dose of study treatment or 
until the initiation of another anti-cancer therapy, whichever occurs first. Immune-related AEs 
should be reported for 90 days after the last dose of study treatment, regardless of whether or not 
the patient starts a new anticancer therapy. All drug related SAE will be recorded by the 
investigator after treatment discontinuation until patient death, withdrawal of consent, or lost to 
follow up, whichever occurs first. Investigators are instructed to report all events (AEs, 
pregnancy-related AEs). The potential safety issues anticipated in this trial, as well as measures 
intended to avoid or minimize such toxicities, are outlined in the following sections.  
5.1.1. 
Risks Associated with Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. Limited safety 
data are available in patients and the full safety profile has not been characterized. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of irAEs, specifically the induction or enhancement of autoimmune conditions. 
AEs observed with anti PD-1 therapy are presented in Section 5.3.1.   
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, 
such events should be recognized early and treated promptly to avoid potential major 
complications. Suggested workup procedures for suspected irAEs are provided in Appendix 6.  
5.1.2. 
General Plan to Manage Safety Concerns  
5.1.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this trial. Results from the 
nonclinical toxicology studies with tislelizumab, as well as the nonclinical/clinical data from 
other PD-L1/PD-1 inhibitors, were taken into account. Specifically, patients at risk for study-
emergent autoimmune conditions or with history of autoimmune disease that may relapse, and 
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patients who have received a live viral vaccine within 4 weeks before Cycle 1 Day 1 are 
excluded from the study (see Section 4.1).  
5.1.2.2. 
Safety Data Review  
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI-CTCAE v4.03. Patients will be assessed for safety 
(including laboratory values) according to the schedule in Appendix 1. Laboratory values must 
be reviewed prior to each infusion.  
General safety assessments will include serial interval histories, physical examinations, and 
specific laboratory studies, including serum chemistries and blood counts (see Appendix 1 for 
the list and timing of study assessments).  
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.  
All SAEs will be reported in an expedited fashion (see Section 5.2.7 and 5.2.9). In addition, the 
Medical Monitor will review and evaluate observed AEs on a regular basis. 
All AEs will be recorded during the study (non-serious AE information will be collected from 
the time of the first dose of study drug and information on SAEs will be collected from the time 
of signed informed consent), and for up to 30 days after the last dose of study treatment or until 
the initiation of another anticancer therapy, whichever occurs first. 
Immune-related AEs will be recorded until up to 90 days after the last dose of study treatment, 
regardless of whether or not the patient starts a new anticancer therapy. All drug-related SAEs 
will be recorded by the investigator after treatment discontinuation until patient death, 
withdrawal of consent, or loss to follow up, whichever occurs first. 
Patients who have an ongoing study treatment-related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline or ≤ 
Grade 1, the event is assessed by the investigator as stable, the patient is lost to follow-up, the 
patient withdraws consent, or it has been determined that study treatment or participation is not 
the cause of the AE.  
5.1.3. 
Dose Interruption  
There will be no dose reduction for tislelizumab in this study.  
Dose delays or interruptions less than 12 weeks will be permitted. Investigators should make 
every effort to maintain dose intensity in patients. 
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to study drug and requires a dose to be withheld. The patients should resume tislelizumab 
treatment as soon as possible after the AEs recover to normal or Grade 1 within 12 weeks after 
last dose of study treatment. Two dosing delays due to toxicity will be permitted. In case a 
patient is benefiting from the study treatment while meeting the discontinuation criteria, 
discussion between the sponsor and investigator will be conducted to make a decision that will 
be in the best interest of the patient. 
The tumor assessment schedule will not be altered if tislelizumab is delayed. 
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Management of tislelizumab irAEs is presented in Section 5.3.1. See Section 5.3.2 for guidelines 
for the management of infusion-related reactions.  
5.2. 
Safety Parameters and Definitions 
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol.  
5.2.1. 
Definition of an Adverse Event 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of an 
investigational product, whether considered related to investigational product or not.  
Examples of an AE include:  
• Worsening of a chronic or intermittent pre-existing condition including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome   
• 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)  
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. However, there may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this instance, all patient identifiers will be blinded on the copies of 
the medical records prior to submission to the sponsor. 
5.2.2. 
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 patient 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 patient has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
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treatment that would not have been appropriate in the physician’s office or out-patient 
setting.  
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and 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  
• Is considered a significant medical event by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to present one of the outcomes listed above).  
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
5.2.3. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction, the specificity or severity of which is not 
consistent with those noted in the IB. 
5.2.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events 
5.2.4.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of its relationship to study drug, will 
be reported until 30 days following their last dose of study treatment or initiation of new 
anticancer therapy, whichever comes first. Immune-related adverse events should be reported for 
90 days after the last dose of tislelizumab, regardless of whether or not the patient starts a new 
anticancer therapy. After treatment discontinuation, the investigator should report any SAEs that 
are believed to be related to tislelizumab treatment.  
5.2.4.2. 
Following Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
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All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
post-mortem findings, including histopathology. 
New or updated information will be recorded on the originally completed SAE report, with all 
changes signed and dated by the investigator. The updated SAE report should be re-sent to the 
sponsor within the time frames outlined in Section 5.2.7.1. 
5.2.4.3. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, vital signs) 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 5.2.1) or an SAE (as defined in Section 5.2.2). This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and significantly worsen during the study. The definition of clinically significant is 
left to the judgment of the investigator. In general, these are the laboratory test abnormalities or 
other abnormal assessment that: 
• are associated with clinical signs or symptoms, or 
• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or 
• further diagnostic investigation. 
5.2.4.4. 
Eliciting Adverse Events 
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?  
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5.2.5. 
Evaluating Adverse Events and Serious Adverse Events  
5.2.5.1. 
Assessment of Severity 
The investigator will make assessment of severity for each AE and SAE reported during the 
study. When applicable, AEs and SAEs should be assessed and graded based upon the NCI-
CTCAE Version 4.03. Toxicities that are not specified in the NCI-CTCAE will be defined as 
follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 5.2.2. 
5.2.5.2. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab IB in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always makes assessment of causality for every SAE prior to transmission of the 
SAE report to the sponsor, since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE report accordingly.  
Investigators must also systematically assess the causal relationship of AEs to study drug 
(including any other non-study drugs, radiation therapy, etc.) using the following definitions:  
• Definitely related: There is clear evidence to suggest a causal relationship to the study 
drug, and there is reasonable temporal relationship; the occurrence of AE is definitely 
attributed to the pharmacological effect of study treatment.  
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• Probably related: There is a reasonable temporal relationship to suggest a causal 
relationship to the study drug; the occurrence of AE could not be explained by the 
patient’s medical history, concurrent medical condition, or other the patient’s signs or 
symptoms.  
• Possibly related: There is some evidence to suggest a causal relationship to the study 
drug (eg, the AE occurred within a reasonable time after administration of the study 
drug). However, the influence of other factors may have contributed to the AE such 
as the patient’s clinical condition, other concomitant AEs.  
• Unlikely related: There is little evidence to suggest there is a causal relationship to the 
study drug. There is another reasonable explanation for the AE such as disease or 
other drugs.  
• Unrelated: An AE will be considered “not related” to the use of the study drug if any 
of the following criteria are met:  
− An unreasonable temporal relationship between administration of the drug and the 
onset on the AE (eg, the AE occurred either before, or too long after 
administration of the drug for it to be considered drug-related);  
− A causal relationship between the drug and the AE is biologically implausible (eg, 
death as a passenger in an automobile accident);  
− A clearly more likely alternative explanation for the AE is present (eg, typical 
adverse reaction to a concomitant drug and/or typical disease-related AE). 
The causality for cases assessed with 5-point scale will be mapped to 2-point scale during 
aggregate safety data analysis according to the BeiGene latest mapping rule. 
5.2.6. 
Specific Instructions for Recording Adverse Events and Serious Adverse Events  
5.2.6.1. 
Disease Progression  
Disease progression, which is expected in this study population and measured as an efficacy 
endpoint, should not be recorded as an AE term. Similarly, nonserious AEs that are clearly 
consistent with the pattern of progression of the underlying disease and are considered 
unequivocally due to disease progression should not be recorded. However, if there is any 
uncertainty as to whether a nonserious AE is due to disease progression, it should be recorded as 
an AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded 
and reported (see Section 5.2.7).  
5.2.6.2. 
Death 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death”, 
“death of unknown cause”, or “death unexplained”.  
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5.2.7. 
Reporting Serious Adverse Events  
5.2.7.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 3. 
Table 3: Timeframe and Documentation Methods for Reporting Serious Adverse Events to the 
Sponsor or Designee  
Type of SAE  Timeframe 
for Making 
Initial Report 
Documentation 
Method  
Timeframe 
for Making 
Follow-up 
Report  
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24 
hours of first 
knowledge of 
the event  
SAE report 
As 
expeditiously 
as possible 
SAE report 
 
Email or fax 
SAE form or 
Pregnancy 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
5.2.7.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the sponsor within 24 hours as outlined in Section 5.2.7.1. The SAE report will 
always be completed as thoroughly as possible with all available details of the event, and 
forwarded to the sponsor within the designated timeframes. If the investigator does not have all 
information regarding an SAE, he/she is not to wait to receive additional information before 
notifying the sponsor of the SAE 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 5.2.5.2. 
The sponsor will provide a list of project contacts for SAE receipt. 
5.2.7.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 5.2.7.2. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
All SUSARs (as defined in Section 5.2.3), will be submitted to all applicable regulatory 
authorities and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised IB) from the sponsor, the responsible person according to local requirements is required 
to promptly notify his/her IRB or IEC. The investigator should place copies of safety reports 
from the sponsor in the investigator site file. 
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5.2.8. 
Pregnancy Reporting 
If a female patient or the partner of a male patient becomes pregnancy while receiving 
investigational therapy or within 120 days after the completion of the last dose of study drug, a 
pregnancy report form should be completed and expeditiously submitted to the sponsor to 
facilitate outcome follow-up. Information on the status of the mother and child will be forwarded 
to the sponsor. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
investigational product should be recorded and reported as an SAE.  
5.2.9. 
Post-study Adverse Event 
A post-study AE or SAE is defined as any event that occurs outside of the AE/SAE reporting 
period, defined in Section 5.2.4.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient 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. 
5.2.10. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
• tislelizumab IB  
5.3. 
Management of Adverse Events of Special Interest 
As a routine precaution, after infusion of tislelizumab on day 1 of cycle 1 and cycle 2, patients 
must be monitored for at least 1 hour afterwards in an area with resuscitation equipment and 
emergency agents. From cycle 3 onward, a minimum of a 30-minute monitoring period is 
required in an area with resuscitation equipment and emergency agents.  
The management for infusion-related reactions, severe hypersensitivity reactions and irAEs 
according to the NCI-CTCAE criteria are outlined below. 
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5.3.1. 
Immune-related Adverse Events  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related should be classified as irAEs and identified as such in the 
eCRF AE page until Day 90, after treatment discontinuation. 
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 6. 
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 4. 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 American 
Society of Clinical Oncology (ASCO) guidelines (Brahmer et al 2018) and common immune-
related toxicities are detailed in Appendix 6. For any AEs not included in Appendix 6, please 
refer to the ASCO Clinical Practice Guideline (Brahmer et al 2018) for further guidance on 
diagnostic evaluation and management of immune-related toxicities. 
Table 4: 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 
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Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Dose modification and management for irAEs are detailed in Appendix 6. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the Sponsor. Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
5.3.2. 
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. Patients should be closely monitored 
for such reactions. 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.   
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 5. 
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Table 5 Treatment Modification for Symptoms of Infusion-Related Reactions 
Due to Study Drug(s) 
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 hrs 
Stop infusion.  Infusion may be resumed at 50% 
of previous rate once infusion-related reactions 
has resolved or decreased to at least Grade 1 in 
severity.  Any worsening is closely monitored.  
Proper medical management should be instituted 
as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology 
Criteria for Adverse Event; 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 
patient has a second infusion-related reaction (≥ Grade 2) on the slower infusion rate, infusion 
should be discontinued and the patient should be withdrawn from tislelizumab treatment.  
NCI-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, brochodilators, and oxygen. 
In the next cycle, patients 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. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
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5.3.3. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al, 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the patient 
discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the patient should be placed on monitor 
immediately and ICU should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
5.3.4. 
Renal Function Abnormalities 
Patients with moderate renal dysfunction (estimated glomerular filtration rate > 30 mL/min/1.73 
m2 and < 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation) 
may be enrolled into the study. The following algorithm is proposed for the use of steroid 
treatment in the management of irAEs: 
• If the serum creatinine is normal at baseline, please see Section 5.3.1 and refer to 
Appendix 6 for diagnosis and management of patients with abnormal renal laboratory 
values.  
• If the serum creatinine is Grade 1 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with 
tislelizumab, refer to Appendix 6 for diagnosis and management of patients with 
abnormal renal laboratory values. Check the estimated glomerular filtration rate 
(GFR) using Appendix 7 and the estimated GFR calculator link. In the setting of a 
Grade 2 serum creatinine increase only, study treatment can continue unless the 
serum creatinine increases by at least 50% from the baseline value OR the estimated 
GFR falls below 20 mL/min/1.73 m2.  
• If the serum creatinine is Grade 2 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with 
tislelizumab, refer to Appendix 6 for diagnosis and management of patients with 
abnormal renal laboratory values. In the setting of a Grade 3 serum creatinine 
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increase only, study treatment will be held until serum creatinine improves to baseline 
and treatment may resume only after discussion with the sponsor medical monitor.   
 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
The statistical analyses will be performed by the sponsor or designee after the data collection for 
the primary efficacy analyses is completed and the database is locked and released. Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP). 
6.1. 
Statistical Analysis 
6.1.1. 
Analysis Sets  
The Safety analysis set includes all patients who received any dose of tislelizumab.  
The Efficacy Evaluable analysis set includes all patients who have received any dose of 
tislelizumab and had measurable disease per IRC according to RECIST version 1.1 at baseline. 
This will be the primary analysis set for the efficacy analyses. 
The Per-Protocol (PP) analysis set includes patients in the Efficacy Evaluable analysis set who 
had no major protocol deviations. Criteria for exclusion from the PP will be determined and 
documented before the database lock for the primary analysis. This will be the secondary 
analysis set for efficacy analysis when there are over 15% patients, ie, 17 patients, who had 
major protocol deviations. 
6.1.2. 
Patient Disposition 
The number of patients enrolled, treated, prematurely discontinued from study drug and those 
with major protocol deviations will be counted. The primary reason for study drug discontinued 
will be summarized according to the categories in the eCRF. The end of study status (alive, dead, 
withdrew consent or lost to follow-up) at the data cutoff date will be summarized using the data 
from the eCRF. 
Protocol deviations will be summarized and listed by each category (major or minor). 
6.1.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety analysis set 
using descriptive statistics. Continuous variables include age, weight, vital signs and time since 
initial UBC diagnosis; categorical variables include number of previous systemic regimens in the 
metastatic setting, gender, ECOG, country, race, smoking status, TNM staging, metastatic site, 
site of primary tumor and previous therapy with platinum-based regimen. 
6.1.4. 
Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes. Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior and 
concomitant medications will be summarized and listed by drug and drug class in the Clinical 
Study Report (CSR) for this protocol. Prior medications will be defined as medications that 
stopped before the first dose of study drug. Concomitant medications will be defined as 
medications that (1) started before the first dose of study drug and were continuing at the time of 
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the first dose of study drug, or (2) started on or after the date of the first dose of study drug up to 
30 days after the patient’s last dose. In addition, telephone contacts with patients should be 
conducted to assess irAEs and concomitant medications (if appropriate, ie, associated with an 
irAE or is a new anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of study 
drug regardless of whether or not the patient starts a new anticancer therapy. A listing of prior 
and concomitant medications will be included in the CSR of this protocol. 
6.2. 
Efficacy Analyses 
6.2.1. 
Primary Efficacy Analysis  
The primary efficacy endpoint is ORR as determined by IRC using the RECIST version 1.1. 
ORR is defined as the proportion of patients achieving a best overall response of CR or PR. 
The ORR in this study is estimated as 25%, which is deemed a clinically meaningful 
improvement based on a historical control of 10%. Hence, the null and alternative hypotheses are 
set as follows: 
H0: ORR=10% 
Ha: ORR ≥25% 
A binomial exact test will be performed for hypothesis testing among the evaluable patients (ie, 
patients with measurable disease at baseline) in the Efficacy Evaluable analysis set. If the 
obtained one-sided p-value is ≤ 0.025, it will be concluded that the single agent tislelizumab 
statistically significantly increases ORR compared with historical control. Therefore, the 
superiority of single agent tislelizumab as measured by ORR will be demonstrated. 
Clopper-Pearson 95% confidence interval (CI) of ORR will be constructed to assess the 
precision of the rate estimate.  
The primary efficacy analysis will be conducted no later than 6 months after the first dose of the 
last patient, and will be based on the Efficacy Evaluable analysis set. In case if patients without 
measurable disease per IRC who have been enrolled and treated, they will be excluded from the 
primary efficacy analysis.     
6.2.2. 
Secondary Efficacy Analysis  
DOR will be estimated using the Kaplan-Meier method. Its 95% CI will be constructed using 
Greenwood’s formula. DOR censoring rule will follow US FDA Guidance for Industry Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (FDA Guidance 2007). Only 
patients who have achieved an objective response will be included in the analysis of DOR. 
PFS and OS will be analyzed similarly as DOR in the Efficacy Evaluable analysis set. PFS at 
12m and OS at 12m will be calculated based on KM method.  
DCR will be summarized similarly as ORR in the Efficacy Evaluable analysis set.  
Efficacy outcomes based on tumor assessment (ORR, DOR, PFS and DCR) per investigator 
review according to RECIST version 1.1 and irRECIST, respectively, will be summarized in the 
secondary efficacy analyses.   
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6.3. 
Safety Analysis 
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (eg, hematology, clinical chemistry, urinalysis), vital signs, ECGs, and 
physical examinations, will also be used in determining safety. Descriptive statistics will be used 
to analyze all safety data in the Safety analysis set. 
6.3.1. 
Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity (mg/day) and relative dose intensity. 
The number (percentage) of patients requiring dose interruption, dose delay, and drug 
discontinuation due to AEs will be summarized. The cycle in which the first dose interruption 
occurred will be summarized using descriptive statistics. Frequency of dose interruption/delay 
will be summarized by categories.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
6.3.2. 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA). AEs will be coded to MedDRA (Version 18.1 or higher) lower level term closest to 
the verbatim term. The linked MedDRA preferred term (PT) and primary System Organ Class 
(SOC) are also captured in the database. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pre-treatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation. 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. Only those AEs that were treatment emergent will be included in summary 
tables. All AEs, treatment emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and Preferred Term. A patient will be counted only once by the highest severity grade per 
CTCAE v.4.03 within an SOC and Preferred Term, even if the patient experienced more than 1 
TEAE within a specific SOC and Preferred Term. The number (percentage) of patients with 
TEAEs will also be summarized by relationship to the study drug. Treatment-related AEs include 
those events considered by the investigator to be definitely, possibly or probably related to study 
treatment or with missing assessment of the causal relationship. SAEs, deaths, TEAE with ≥ 
Grade 3 severity, irAE, treatment-related TEAEs and TEAEs that led to treatment 
discontinuation, dose interruption, dose reduction, or dose delay will be summarized. 
6.3.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated as 
appropriate. Abnormal laboratory values will be flagged and identified as those outside (above or 
below) the normal range. Reference (normal) ranges for laboratory parameters will be included 
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in the CSR for this protocol. Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, maximum for continuous variables; n [%] for categorical variables) for 
laboratory parameters and their changes from baseline will be calculated. Laboratory values will 
be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded using CTCAE v.4.03 will be summarized by CTCAE 
grade. In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low ranges (eg, calcium, glucose, magnesium, potassium, sodium) will 
be summarized separately. 
6.3.4. 
Vital Signs 
Specific vital signs (eg, blood pressure and temperature) will be summarized and listed. The 
change from baseline will also be displayed.  
6.4. 
Exploratory Analyses 
6.5. 
Determination of Sample Size 
The sample size calculation was based on the power of the comparison between estimated ORR 
in the study and the historical rate. It is assumed an ORR of 25% in the study as compared to 
10% in the historical control. Using a binomial exact text, the power is 0.986 with 110 patients to 
demonstrate statistical significance at a 1-sided alpha of 0.025. 
6.6. 
Interim Analyses  
No interim analysis for anti-tumor activity or efficacy is planned for this study. 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1. 
Data Quality Assurance 
The sponsor will be responsible for the data management of this study, including quality 
checking of the data. Data entered manually will be collected via electronic data capture (EDC) 
through use of eCRFs. Sites will be responsible for data entry into the EDC system. In the event 
of discrepant data, sponsor or delegated contract research organization (CRO) will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system.  
The sponsor will perform oversight of the data management of this study. The sponsor or 
delegated CRO will produce an EDC study specification document that describes the quality 
review process to be performed on the data. Other electronic data will be sent directly to the 
sponsor or delegated CRO, using the sponsor’s or delegated CRO’s standard procedures to 
handle and process the electronic transfer of these data.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. System 
backups for data stored by the sponsor and records retention for the study data will be consistent 
with the sponsor’s standard procedures.  
7.2. 
Electronic Case Report Forms 
eCRFs are to be completed using a sponsor-designated EDC system a validated data 
management system that is compliant with all regulatory requirements. Sites will receive training 
and help text for appropriate eCRF completion. eCRFs should be handled in accordance with 
instructions from the sponsor.  
All eCRFs should be completed by designated, trained site staff. The investigator has ultimate 
responsibility for the collection and reporting of all clinical data entered on the eCRF. eCRFs 
should be reviewed and electronically signed and dated by the investigator or designated sub- 
investigator to attest to its accuracy, authenticity, and completeness.  
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format on a compact disc that must be kept with the study records. Acknowledgement of receipt 
of the compact disc is required.  
Completed, eCRFs are the sole property of sponsor and should not be made available in any 
form to third parties without written permission from sponsor, except for authorized 
representatives of sponsor or appropriate regulatory authorities. 
7.3. 
Source Data Documentation 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (ie, source data) entered into the eCRFs by authorized site personnel are accurate, complete, 
and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include but are not limited to hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies of transcriptions that are certified after 
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verification as being accurate and complete, microfiche, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at pharmacies, laboratories, and medico-
technical departments involved in a clinical trial.  
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the study monitoring plan. This includes any protocol data to be entered directly into 
the eCRFs (ie, no prior written or electronic record of the data) and considered source data.  
Source documents that are required to verify the validity and completeness of data entered into 
the eCRFs must not be obliterated or destroyed and must be retained per the policy for retention 
of records described in Section 7.5.  
To facilitate source data verification, the investigator s and institutions must provide the sponsor 
and authorized study monitor direct access to applicable source documents and reports for trial-
related monitoring, sponsor or delegated third party audits, and IRB/IEC review. The 
investigational site must also allow inspection by applicable health authorities.  
7.4. 
Use of Computerized Systems 
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (ie, in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research. An acceptable 
computerized data collection system allows preservation of the original entry of data. If original 
data are modified, the system should maintain a viewable audit trail that shows the original data, 
as well as the reason for the change, name of the person making the change, and date of the 
change.  
7.5. 
Retention of Records 
Records and documents pertaining to the conduct of this study and the distribution of 
investigational medicinal product including eCRFs, electronic patient-reported outcome data (if 
applicable), Informed Consent Forms, laboratory test results, and medication inventory records, 
must be retained by the principal investigator for at least 15 years after completion or 
discontinuation of the study. 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 or for the length of 
time required by relevant national or local health authorities, whichever is longer. After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the sponsor. Written notification 
should be provided to the sponsor prior to transferring any records to another party or moving 
them to another location.  
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8. 
ETHICAL CONSIDERATIONS 
8.1. 
Compliance with Laws and Regulations 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting).   
8.2. 
Informed Consent 
The sponsor’s sample Informed Consent Form will be provided to each site. If applicable, it will 
be provided in a certified translation of the local language. The final IRB/IEC-approved Consent 
Forms must be provided to the sponsor for health authority submission purposes according to 
local requirements.  
The Consent Forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.  
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate. 
The final revised IRB/IEC-approved Consent Forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/IEC 
policy) during their participation in the study. For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent process and 
that written informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study.  
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any time.  
8.3. 
Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/IEC by the principal investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB/IEC.  
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
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informing the IRB/IEC of any protocol amendments (see Section 9.5). In addition to the 
requirements for reporting all AEs to the sponsor, investigators must comply with requirements 
for reporting SAEs to the local health authority and IRB/IEC. Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file.  
In addition to the requirements for reporting all AEs to the sponsor, investigators must comply 
with requirements for reporting SAEs to the local health authority and IRB/IEC. Investigators 
may receive written IND safety reports or other safety-related communications from the sponsor. 
Investigators are responsible for ensuring that such reports are reviewed and processed in 
accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file.  
8.4. 
Confidentiality 
The sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names are 
not included in data sets that are transmitted to any sponsor location.  
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law.  
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated by this study must be available for inspection upon request by representatives of 
the FDA, the China NMPA and other national and local health authorities, sponsor monitors, 
representatives, and collaborators, and the IRB/IEC for each study site, as appropriate.  
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from sponsor, including but not limited to the IB, this protocol, CRFs, the 
investigational new drug, and any other study information, remain the sole and exclusive 
property of sponsor during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of the 
study or as required by law) without prior written consent from sponsor. The Investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain. 
8.5. 
Financial Disclosure 
Investigators will provide the sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. Investigators are 
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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study (ie, last patient, last visit). 
                                             
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1. 
Study Documentation 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including but not limited to the protocol, protocol amendments, 
Informed Consent Forms, and documentation of IRB/IEC and governmental approval. In 
addition, at the end of the study, the investigator will receive the patient data, which include an 
audit trail containing a complete record of all changes to data.  
9.2. 
Protocol Violations 
The investigator should document and explain any violations from the approved protocol. The 
investigator should promptly report any violations that might impact patient safety and data 
integrity to the sponsor and to the IRB/IEC in accordance with established IRB/IEC policies and 
procedures.  
9.3. 
Site Inspections 
Site visits will be conducted by the sponsor or an authorized representative for inspection of 
study data, patients’ medical records, and eCRFs. The investigator will permit national and local 
health authorities; sponsor study monitors, representatives, and collaborators; and the IRBs/ECs 
to inspect facilities and records relevant to this study.  
9.4. 
Administrative Structure 
This trial will be sponsored and managed by BeiGene (Shanghai) Co., Ltd. Sponsor will provide 
clinical operations management, data management, and medical monitoring. 
Approximately 30 sites in China and other Asian countries will participate to enroll 
approximately 110 patients.  
Enrollment will occur through an IxRS system. Central facilities will be used for certain study 
assessments throughout the study (eg, specified laboratory tests, biomarker analyses, and PK 
analyses, and tumor imaging assessment) as specified in Section 4.5. Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.  
9.5. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. Protocol amendments will be 
submitted to the IRB/IEC and to regulatory authorities in accordance with local regulatory 
requirements.  
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an immediate 
hazard to patients or changes that involve logistical or administrative aspects only (eg, change in 
medical monitor or contact information).  
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9.6. 
Publication and Data Sharing Policy 
A CSR will be prepared and provided to the regulatory agency(ies). BeiGene will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of CSRs (ICH 
E3). Note that an abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the trial. The data generated in this clinical trial are the exclusive 
property of the sponsor and are confidential. As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors, 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The processes of 
reviewing manuscripts and presentations that are based on the data from this study is detailed in 
the investigator’s clinical study agreement. Each investigator agrees that, in accordance with the 
terms of clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings in advance of the publication/presentation. 
 
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10. 
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BeiGene Investigator’s Brochure, BGB-A317. Edition 4.1, May 2017. 
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Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-
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Chinese Urological Association (CUA). Guidelines for the diagnosis and treatment of diseases in Urology 
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Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on eligibility for adjuvant cisplatin 
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Galsky MD, Retz M, Siefker-Radtke A, et al. Efficacy and safety of nivolumab monotherapy in patients 
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#LBA31_PR. 
Garcia JA, Dreicer R. Systemic chemotherapy for advanced bladder cancer: update and controversies. J 
Clin Oncol. 2006; 24:5545-51 
GLOBOCAN 2012. Estimated incidence, mortality and 5-year prevalence: men/women. Available at: 
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed 29 December 2016 
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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. 
Han S-J, Zhang S-W, Chen W-Q et al. Analysis of the status and trends of bladder cancer incidence in 
China. Oncology Progress. 2013. Available at: http://en.cnki.com.cn/Article_en/CJFDTOTAL-
AZJZ201301026.htm. Accessed 11 August 2017. 
Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for 
cancer immunotherapy. Semin Oncol. 2010;37:533-46. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, Reporting, 
Editing, and Publication of Scholarly Work in Medical Journals. 2016. Available online: 
http://www.icmje.org. Accessed 08 August 2017. 
Immune Related Adverse Reactions Management Guide of Nivolumab.  Available at: 
http://www.opdivohcp.com/servlet/servlet.FileDownload?file=00Pi000000ijs1vEAA.  Accessed 11 Aug 
2017. 
Koren E, Smith HW, Shores E, et al. Recommendations on risk-based strategies for detection and 
characterization of antibodies against biotechnology products. J Immuno Methods. 2008; 333:1-9. 
Labrijn AF, Buijsse AO, van den Bremer ET, et al. Therapeutic IgG4 antibodies engage in Fab-arm 
exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009;27(8):767-71. 
Li K, Lin T, Xue W, et al. Current status of diagnosis and treatment of bladder cancer in China – analyses 
of Chinese bladder cancer consortium database. Asian Journal of Urology. 2015;2(2):63-69. 
Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in 
combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial 
carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066-73 
Loriot Y, Rosenberg JE, Powles T, et al. Atezolizumab in platinum-treated locally advanced or metastatic 
urothelial carcinoma (mUC): Updated OS, safety and biomarkers from the phase 2 IMvigor210 study. 
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Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (medi4736), an anti-
programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial 
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National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer.  Available at: 
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National Comprehensive Cancer Network Clinical Practice Guideline in Oncology: Bladder Cancer, Asia 
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National Comprehensive Cancer Network Clinical Practice Guideline in Oncology: Bladder Cancer. 
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Sheng X. Understanding of immunotherapy and its markers in advanced bladder cancer, CSCO 2016: 
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Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid 
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Worobec AS and Rosenberg AS. A Risk-Based Approach to Immunogenicity Concerns of Therapeutic 
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based-approach-immunogenicity-concerns-therapeutic-protein-products-part-2-considering-host-spe. 
Accessed 01 August 2017. 
 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screening 1 
Treatment Cycles 
Safety Follow-
up 3 
Survival 
Follow-up 4 
Cycles 1 to 3 
(Every 21 days) 
Cycle 4 and 
Subsequent Cycles 
(Every 21 Days) 
End of 
Treatment 
Visit2 
Days (Window) 
-28 to ~-1 
1 
8 
15 
1 (± 3) 
0 to 7 Days 
30 ± 7 Days 
After Last 
Dose 
Every 3 
Months 
Informed consent 1 
x 
  
  
  
  
  
  
  
Inclusion/Exclusion criteria 
x 
  
  
  
  
  
  
  
Demographic/Medical 
history/Prior medications 5 
x 
  
  
  
  
  
  
  
Concomitant medications 6 
x 
x 
x 
x 
x 
x 
x 
  
Adverse events 7 
x 
x 
x 
x 
x 
x 
x 
 x 
Complete physical examination 
8 
x 
  
  
  
  
  
x 
  
Limited physical examination 8, 
9 
  
x 
 
 
x 
x 
  
  
ECOG performance status 9 
x 
x 
 
 
x 
x 
x 
  
Vital signs 10 
x 
x 
x 
x 
x 
x 
x 
  
12-lead ECG 11 
x 
As clinically indicated  
x 
  
HBV and HCV serology 12 
x 
As clinically indicated  
 
Hematology 9,13 
x 13 
x 
x 
x 
x 
x 
x 
  
Serum chemistry 9,14 
x 14 
x 
x 
x 
x 
x 
x 
  
Coagulation parameters 15 
x 
 As clinically indicated 
x 
  
Urinalysis 9,16 
x 
x 
 
 
x 
 
x 
  
Pregnancy test 17 
x 
x 
 
 
x 
x 
x 
  
Thyroid function 9,18 
x 
x 
 
 
x  
 
x 
  
Anti-tislelizumab antibodies 19 
  
x 
 
 
x 
 
x 
  
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Assessment 
Screening 1 
Treatment Cycles 
Safety Follow-
up 3 
Survival 
Follow-up 4 
Cycles 1 to 3 
(Every 21 days) 
Cycle 4 and 
Subsequent Cycles 
(Every 21 Days) 
End of 
Treatment 
Visit2 
Days (Window) 
-28 to ~-1 
1 
8 
15 
1 (± 3) 
0 to 7 Days 
30 ± 7 Days 
After Last 
Dose 
Every 3 
Months 
Pharmacokinetics 20 
  
x 
 
 
x 
 
x 
  
Tumor assessment 21 
x 
 
 
 
x 
x 
 
  
Brain MRI/CT with contrast 
x 
 As clinically indicated 
  
  
Study drug administration 22 
  
x 
 
 
x 
 
  
  
Screening tumor tissue 23 
x 
  
  
  
  
  
  
  
Survival status 4 
  
  
  
  
  
  
 x 
x 
Pulmonary function tests 24 
x 
 
 
 
 
 
 
 
Abbreviations: x, to be performed; ECOG, Eastern Cooperative Oncology Group; ECHO, echocardiography; HBV, hepatitis B virus; HCV, hepatitis C virus; 
MRI, magnetic resonance imaging; TURBT, transurethral resection of bladder tumor  
1. Written informed consent must be obtained before performing any study-specific tests or procedures. Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to study entry may be used for screening assessments rather than repeating such 
tests. 
2. The End of Treatment visit is conducted when the investigator determines that tislelizumab will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End of Treatment visit, these tests need not be repeated. Tumor assessment is not 
required at the End of Treatment visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The mandatory safety follow-up visit is required to be conducted 30 days (±7 days) after the last dose of study therapy, or until initiation of a new anti-
cancer therapy, whichever occurs first. Patients who are discontinued from the treatment due to an unacceptable drug-related adverse event will be 
followed until the resolution of the adverse event (AE) to baseline or ≤ Grade 1, the event is assessed by the investigator as stable, the patient is lost to 
follow-up, the patient withdraws consent, or it has been determined that study treatment or participation is not the cause of the adverse event. The TEAE 
classification also applies to severe irAEs (≥ Grade 3 in severity by NCI-CTCAE) that are recorded up to 90 days after discontinuation from 
tislelizumab, regardless of whether or not the patient starts a new anticancer therapy. 
4. Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits beginning 3 months after safety follow-
up visit or as directed by sponsor and approximately every 3 months for the subsequent follow-ups until death, loss to follow-up, withdrawal of consent, 
or study termination by sponsor. All patients will be followed for survival and new anticancer therapy information unless the patient requests to be 
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withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator. If the patient withdraws from study 
treatment but not from follow-up, the study staff may use a public information source (eg, county records) to obtain information about survival status 
only. 
5. 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.  
6. Concomitant medications include any prescription medications or over-the-counter medications. 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. At subsequent visits, changes to 
current medications or medications used since the last documentation of medications will be recorded. In addition, telephone contacts with patients 
should be conducted to assess immune-related adverse events (irAEs) and concomitant medications (if appropriate, ie, associated with an irAE or is a 
new anticancer therapy) at 60 days, and 90 days (± 14 days) after the last dose of study drug, regardless of whether or not the patient starts a new 
anticancer therapy. 
7. Adverse events and laboratory safety measurements will be graded per NCI-CTCAE version 4.03. All adverse experiences, whether gradable by 
CTCAE or not, will also be evaluated for seriousness. 
8. Complete and limited physical examinations are defined in Section 4.5.3. 
9. ECOG performance status, limited physical examination, and local laboratory assessments may be obtained ≤ 96 hours before Day 1 of each cycle. 
10. Vital signs to include temperature, heart rate, and systolic and diastolic blood pressure. The patient’s vital signs should be determined within 60 minutes 
before the infusion, and if clinically indicated during and 30 minutes after the infusion. 
11. Electrocardiogram (ECG) recordings will be obtained during screening, safety follow-up and as clinically indicated at other timepoints. Patients should 
be resting and in a supine position for at least 10 minutes prior to ECG collection. 
12. Testing will be performed by the local laboratory at screening and as clinically indicated. Include HBsAg, HBcAb and HCV antibody. Patients who are 
HBsAg positive or HCV antibody positive at screening must not be enrolled until further definite testing with HBV DNA titres < 500 IU/mL (or 2500 
cps/mL), or HCV RNA polymerase chain reaction test is negative (lower than detection limit) respectively. 
13. Hematology consists of complete blood count, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, 
lymphocytes, eosinophils, monocytes, and basophils), and platelet count and will be analyzed by the local study site laboratory. A manual differential 
can be done if clinically indicated. Refer to Section 4.5.7 for a list of laboratory results obtained with 7 days prior to the first study treatment. 
14. Serum chemistry includes blood urea nitrogen or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate (optional), calcium, 
phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, amylase, total protein, albumin, creatine kinase [CK], and 
creatine kinase cardiac muscle isoenzyme [CK-MB], and will be analyzed by the local study site laboratory. Refer to Section 4.5.7 for a list of 
laboratory results obtained with 7 days prior to the first study treatment. In the event that CK-MB fractionation is not available, serum troponins 
(troponin I and/or T) measurements will be performed instead; if only either troponin is assessed per local standards that same should be evaluated 
throughout. 
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15. 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. 
16. Specific gravity, pH, glucose, protein, ketones, blood, and microscopic examination including WBC/HPF, RBC/HPF, and any additional findings. 
17. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days prior to Cycle 1 Day 1. Urine pregnancy tests will be performed at each visit prior to dosing. A serum pregnancy test must be 
performed if the urine pregnancy test is positive or equivocal. 
18. Analysis of free T3, free T4 and TSH will be performed by the local study site laboratory. Thyroid function tests will be performed on Day 1 of Cycle 1 
and every three cycles thereafter (eg, Cycles 1, 4, 7, 10, etc.), and at the mandatory safety follow-up visit.  
19. Blood for anti-tislelizumab antibodies should be collected within 60 min before start of Day 1 infusion of Cycle 1, 2, 5, 9 and 17, 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. 
20. Procedures for collection of PK samples are described in the laboratory manual. Predose (within 60 min before start infusion) samples should be 
collected at Day 1 of Cycle 1, 2, 5, 9 and 17; a postdose (within 30 min after the end of infusion) sample should be collected at Day 1 of Cycle 1 and 
Cycle 5; additional PK samples should be collected at the mandatory safety follow-up visit. Should a patient present with any Grade 3 or above 
immune-related adverse event, additional blood PK samples may be taken to determine the plasma concentration of tislelizumab. 
21. Examinations performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1 Day 1 may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. The same radiographic procedure must be used 
throughout the study for each patient. The investigator must review results before dosing at the next cycle. Patients will undergo tumor assessments 
every 9 weeks. Patients who discontinue from treatment for reasons other than disease progression (eg, toxicity) will continue scheduled tumor 
assessments until disease progression, withdrawal of consent, or death. Investigators may perform additional scans or more frequent assessments if 
clinically indicated. An objective response should be confirmed by repeat assessments ≥4 weeks after initial documentation. It is recommended that the 
confirmatory tumor assessment is not left until the next scheduled CT scan, but be performed as soon as possible following the 28 days interval from the 
initial documentation of response. Tumor assessment will need to follow the original schedule after the confirmation scan. Patients who continue 
treatment beyond radiographic disease progression (see Section 4.6.2) will be monitored with a follow-up scan at least 4 weeks later or at the next 
regularly scheduled time point (not exceed 12 weeks) before discontinuation of study treatment.  
22. The initial infusion will be delivered over 60 min; if well-tolerated, second infusion and each subsequent infusion may be administered over 30 min, 
which is the shortest time period permissible for infusion. 
23. Representative tumor specimens in paraffin blocks (preferred) or around 15 unstained slides (at least 5 slides are required), with an associated pathology 
report, must be submitted for determination of sufficient viable tumor content prior to study enrollment; tumor specimens will be evaluated for PD-L1 
expression and other biomarkers. Tumor tissue should be of good quality based on total and viable tumor content (sites will be informed if the quality of 
the submitted specimen is inadequate to determine tumor PD-L1 status). Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage 
samples are not acceptable. After signing of the Informed Consent Form, tumor tissue must be submitted up to 28 days prior to study entry for 
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evaluation. Patients who submit TURBT specimens that do not contain a muscle invasive component will be required to submit an additional specimen 
obtained at the time of cystectomy/nephroureterectomy or metastatic spread (ie, sample from a metastatic lesion). 
24. Patients who are suspected or known to have serious/severe respiratory condition or exhibit significant respiratory symptoms unrelated to underlying 
cancer will have pulmonary function testing which may including but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period, to assist the determination of suitability for enrollment on the study. 
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APPENDIX 2. IMMUNE-RELATED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (IRRECIST)  
RECIST v1.1 has its shortcomings for targeted immunotherapy in oncology. Using RECIST v1.1 
in immunotherapy trials would lead to declaration of progressive disease (PD) too early, when 
the treatment effect is not yet fully evident. RECIST also neglects the importance of the ‘flare 
effect’ - pseudo-progression effect within the so-called flare time window. 
Immune related Response Criteria (irRC) based on WHO criteria were published with an aim to 
provide better assessment of the effect of immunotherapeutic agents. With this poster we 
introduce irRECIST based on RECIST v1.1, irRC and Nishino 2013 findings. Our aim is to define 
criteria that better capture antitumor activity and reduce irRC criteria ambiguity (Bohnsack 2014).  
The major differences between RECIST v1.1 (Eisenhauer 2009) and irRECIST are highlighted 
in table below: 
 
Summary of Key Changes 
RECIST v1.1 
irRECIST 
New lesion after 
baseline 
PD 
New measurable lesions* are 
added to total measured tumor 
burden (TMTB)† and followed 
Non-target 
lesions 
May contribute to the designation 
of overall progression 
Contribute mostly in the 
assessment of CR; only massive 
and unequivocal progression 
contributes to the assessments of 
other overall responses besides CR 
Radiographic 
progression 
≥20% increase in the sum of 
diameters; ≥1 new lesion; or 
unequivocal progression in 
non-target disease 
≥20% increase in TMTB relative 
to baseline; or with massive and 
unequivocal progression of non-
target lesions, even without 
progress in the TMTB 
* Up to a maximum of five new lesions in total and a maximum of two new lesions per organ. 
† Total Measured Tumor Burden of all target lesions 
 
A guideline of irRECIST overall tumor assessment is summarized in table below:  
% Change 
in TMTB 
Relative to 
Baseline 
Target 
Lesion 
Response 
Non-Target 
Lesion1 
Response 
New 
Measurable 
Lesions2 
New Non- 
Measurable 
Lesions3 
Overall 
Response 
100%↓4 
CR 
CR 
No 
No 
irCR 
100%↓4 
CR 
Non-CR or 
not all 
evaluated 
No 
No 
irPR 
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% Change 
in TMTB 
Relative to 
Baseline 
Target 
Lesion 
Response 
Non-Target 
Lesion1 
Response 
New 
Measurable 
Lesions2 
New Non- 
Measurable 
Lesions3 
Overall 
Response 
>30%↓ 
PR 
Non-PD5 
Yes/No 
Yes/No 
irPR 
Between 
30%↓and 
20%↑ 
SD 
Non-PD5 
Yes/No 
Yes/No 
irSD 
N/A in this study 
irNN 
≥20%↑ 
PD 
Any 
Yes/No 
Yes/No 
irPD 
Not all 
evaluated 
NE 
Non-PD5 
Yes/No 
Yes/No 
irNE 
N/A in this study 
irND 
1. Non-target lesions do not affect irPR and irSD assessments. Only a massive and unequivocal worsening of non-
target lesions alone, even without progress in the TMTB is indicative of irPD. 
2. ≤ 2 lesions per organ, ≤ 5 lesions total, per timepoint. 
3. Only a massive and unequivocal progression of new non-measurable lesions leads to an overall assessment of 
irPD for the timepoint. Persisting new non-measurable lesions prevent irCR. 
4. When lymph nodes are included as target lesions, the % change in the sum of the diameters may not be 100% 
even if complete response criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm 
in order to meet the definition of CR. 
5. PD indicates a massive and unequivocal progression of non-target lesions. 
 
The text below was obtained from the reference: Bohnsack O, Hoos A, and Ludajic K. 
Adaptation of the immune related response criteria: irRECIST. Annals of Oncology. 2014.25 
(suppl_4): iv361-iv372 (Bohnsack 2014)  
Original irRC Including 
WHO Criteria References 
irRECIST Modifications and Clarifications 
Rationale for Modification 
At the baseline tumor 
assessment, the sum of the 
products of the two largest 
perpendicular diameters (SPD) 
of all index lesions (five 
lesions per organ, up to 10 
visceral lesions and five 
cutaneous index lesions) is 
calculated. 
1. 0 Baseline: Measurable Lesion 
Definitions and Target Lesion 
Selection 
Follow the definitions from RECIST v1.1. 
Measurable lesions must be accurately measured in 
at least one dimension with a minimum size of: 
• 10 mm in the longest diameter by CT or MRI 
scan (or no less than double the slice thickness) for 
nonnodal lesions and ≥15 mm in short axis for 
nodal lesions 
• 10 mm caliper measurement by clinical exam 
• 20 mm by chest X-ray 
Up to 5 target lesions may be 
selected at baseline. Lesions will be 
measured unidimensionally. The 
minimum target lesion size at 
baseline in irRECIST is aligned 
with RECIST v1.1, as outlined in 
Nishino 2013. 
WHO 5.1.2 
Unmeasurable Disease 
There are many forms of 
unmeasurable disease, and 
only a few are mentioned as 
1.1. Baseline: Non-measurable 
Lesion Definitions 
Follow the definitions from RECIST v1.1 Non-
target lesions will include: 
• Measurable lesions not selected as target lesions 
Although irRC does not specifically 
define non-target lesions, irRC is 
derived from WHO criteria and 
indicates accordance with the same 
for the purposes of definitions of 
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Original irRC Including 
WHO Criteria References 
irRECIST Modifications and Clarifications 
Rationale for Modification 
examples: 
1. Lymphangitic pulmonary 
metastases. 
2. Skin involvement in breast 
cancer. 
3. Abdominal masses that can 
be palpated but not measured. 
• All sites of non-measurable disease, such as 
neoplastic masses that are too small to measure 
because their longest uninterrupted diameter is < 10 
mm (or < two times the axial slice thickness), ie. 
the longest per-pendicular diameter is≥10 and < 15 
mm. 
• Other types of lesions that are confidently felt to 
represent neoplastic tissue, but are difficult to 
measure in a reproducible manner. These include 
bone metastases, leptomeningeal metastases, 
malignant ascites, pleural or pericardial effusions, 
ascites, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, skin lesions, etc. 
non-target lesions. Further 
clarifications in alignment with 
RECIST v1.1 are provided. 
Not specified. 
1.2 Baseline: Target and Non-Target Lymph 
Node Lesion Definitions 
Follow the definitions from RECIST v1.1 
No change in definition of target 
and non-target lymph nodes from 
RECIST v1.1. 
Not specified. 
1.3 Baseline: Non-Target Lesion Selection 
All lesions or sites of disease not recorded as target 
lesions should be recorded as non-target lesions at 
baseline. There is no limit to the number of non-
target lesions that can be recorded at baseline. 
In alignment with RECIST v1.1, all 
malignant lesions have to be 
selected at baseline. The excess of 
measurable lesions and all true non-
measurable lesions will be selected 
as non-target lesions at baseline and 
followed at subsequent timepoints. 
Not specified. 
1.4 Baseline: Bone Lesions 
Follow the definitions from RECIST v1.1.  
Regardless of the imaging modality blastic bone 
lesions will not be selected as target lesions. Lytic 
or mixed lytic-blastic lesions with a measurable 
soft tissue component ≥10 mm can be selected as 
target lesions. 
Bone lesions are to be handled the 
same as in RECIST v1.1. 
Not specified. 
1.5 Baseline: Brain Lesions  
Brain Lesions detected on brain scans can be 
considered as both target or non-target lesions. 
Brain lesions can be selected as 
target or non-target lesions at 
baseline, depending on the protocol 
definition, indication, and study 
design. 
Not specified. 
1.6 Baseline: Cystic and Necrotic Lesions as 
Target Lesions 
Lesions that are partially cystic or necrotic can be 
selected as target lesions. The longest diameter of 
such a lesion will be added to the Total Measured 
Tumor Burden (TMTB) of all target lesions at 
baseline. If other lesions with a non-liquid/non-
necrotic component are present, those should be 
preferred. 
RECIST v1.1 does not integrate 
viability of tumor tissue into the 
assessment, and that is carried over 
into irRECIST. 
Not specified. 
1.7 Baseline: Lesions with Prior Local 
Treatment 
During target lesion selection the radiologist will 
consider information on the anatomical sites of 
previous intervention (eg, previous irradiation, RF-
ablation, TACE, surgery, etc.). Lesions undergoing 
prior intervention will not be selected as target 
lesions unless there has been a demonstration of 
progress in the lesion. 
In order to minimize site vs. central 
discrepancy information about prior 
intervention needs to be available 
to both the Investigators and 
independent reviewers. 
Not specified. 
1.8 Baseline: No Disease at Baseline 
If a patient has no measurable and no non-
measurable disease at baseline the radiologist will 
irND is a valid assessment in 
studies with adjuvant setting where 
the protocol and study design allow 
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Original irRC Including 
WHO Criteria References 
irRECIST Modifications and Clarifications 
Rationale for Modification 
assign‘No Disease’ (irND) as the overall tumor 
assessment for any available follow-up timepoints 
unless new measurable lesions are identified and 
contribute to the TMTB. 
to include patients with no visible 
disease. This had not been 
addressed at all in any prior 
immune-response related criteria 
but needs to be included to also 
allow for these patients to be 
assessed accurately. 
At each subsequent tumor 
assessment, the SPD of the 
index lesions and of new, 
measurable lesions (≥5×5 mm; 
up to 5 new lesions per organ: 
5 new cutaneous lesions and 
10 visceral lesions) are added 
together to provide the total 
tumor burden.  
2.0 Follow-up: Recording of Target and New 
Measureable Lesion Measurements 
The longest diameters of non-nodal target and new 
non-nodal measurable lesions, and short axes of 
nodal target and new nodal measurable lesions will 
be recorded. Together they determine the Total 
Measured Tumor Burden (TMTB) at follow-up. 
In alignment with Nishino et al 
2013, unidimensional 
measurements are used. 
Measurements of all measured 
lesions (baseline-selected target 
lesions and new measurable lesions) 
are combined into TMTB at follow-
up. 
 
2.1 Follow-up: Definition of Measurable New 
Lesions 
In order to be selected as new measurable lesions 
(≤2 lesions per organ, ≤5 lesions total, per 
timepoint), new lesions must meet criteria as 
defined for baseline target lesion selection and meet 
the same minimum size requirements of 10 mm in 
long diameter and minimum 15 mm in short axis 
for new measurable lymph nodes. New measurable 
lesions shall be prioritized according to size, and 
the largest lesions shall be selected as new 
measured lesions. 
Proposed selection of up to 5 new 
measurable lesions of at least 10 
mm each verus 10 new measurable 
lesions as suggested in the irRC 
criteria is due to the following: 5 
new measurable lesions add up at 
least 50 mm to the TMTB. Since 
PD is determined by at least a 20% 
increase in TMTB compared to 
nadir, this would mean that for irPD 
assessment the nadir TMTB had to 
be 25 cm, or 10 cm for 2 lesions in 
one organ, which is a significant 
tumor burden already for any cancer 
patient. That is why measuring up 
to 5 new lesions in total is sufficient 
and will not obstruct an irPD 
assessment. Measuring more than 5 
new lesons is not needed. 
Larger lesions must be preferred as 
new measurable over smaller 
lesions, because there will be a 
greater impact of the TMTB %-
increase by these larger lesions for 
irPD, to support a most 
conservative approach. 
Non-index lesions at follow-
up timepoints contribute to 
defining irCR (complete 
disappearance required). 
2.2 Follow-up: Non-Target Lesion Assessment 
The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. 
The response of non-target lesions primarily 
contributes to the overall response assessments of 
irCR and irNon-CR/Non-PD (irNN). Non-target 
lesions do not affect irPR and irSD assessments. 
Only a massive and unequivocal worsening of non-
target lesions alone, even without progress in the 
TMTB is indicative of irPD. 
Non-target lesions have a 
subordinate function. In the event 
that non-target lesions massively 
progress one cannot ignore such 
worsening and in these rare cases 
irPD based only on non-target 
lesions will be a valid assessment 
option. 
New, non-measurable lesions 
at follow-up timepoints do not 
define progression, they only 
preclude irCR. 
2.3 Follow-up: New Non-Measurable Lesions 
Definition and Assessment 
All new lesions not selected as new measurable 
lesions are considered new non-measurable lesions 
and are followed qualitatively. Only a massive and 
When new non-measurable lesions 
substantially worsen in these rare 
cases irPD based only on new non-
measurable lesions will be an 
assessment option. 
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Original irRC Including 
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Rationale for Modification 
unequivocal progression of new non-measurable 
lesions leads to an overall assessment of irPD for 
the timepoint. Persisting new nonmeasurable 
lesions prevent irCR. 
irRC Overall Tumor 
Assessments 
irCR, complete disappearance 
of all lesions (whether 
measurable or not, and no new 
lesions) 
• Confirmation by a repeat, 
consecutive assessment no 
less than 4 weeks from the 
date first documented 
irPR, decrease in tumor 
burden ≥50% relative to 
baseline 
• Confirmed by a consecutive 
assessment at least 4 weeks 
after first documentation 
irSD, not meeting criteria for 
irCR or irPR, in absence of 
irPD irPD, increase in tumor 
burden ≥25% 
relative to nadir (minimum 
recorded tumor burden) 
• Confirmation by a repeat, 
consecutive assessment no 
less than 4 weeks from the 
2.4 irRC Overall Tumor Assessments  
irCR, complete disappearance of all measurable 
and non-measurable lesions. Lymph nodes must 
decrease to < 10 mm in short axis. Confirmation of 
response is not mandatory. 
irPR, decrease of ≥30% in TMTB relative to 
baseline, non-target lesions are irNN, and no 
unequivocal progression of new non-measurable 
lesions. 
irSD, failure to meet criteria for irCR or irPR in the 
absence of irPD. 
irNN, no target disease was identified at baseline 
and at follow-up the patient fails to meet criteria for 
irCR or irPD. 
irPD, minimum 20% increase and minimum 5 mm 
absolute increase in TMTB compared to nadir, or 
irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended 
minimum 4 weeks after the first irPD assessment. 
irNE, used in exceptional cases where insufficient 
data exists. 
irND, in adjuvant setting when no disease is 
detected. 
The irRECIST overall tumor 
assessment is based on TMTB of 
measured target and new lesions, 
non-target lesion assessment and 
new non-measurable lesions. 
 
The thresholds for irPR and irPD 
assessment are aligned with 
RECIST v1.1, and confirmation of 
response is not required. 
 
An irPD confirmation scan may be 
recommended for patients with a 
minimal TMTB%-increase over 
20% and especially during the flare 
time-window of the first 12 weeks 
of treatment, depending on the 
compound efficacy expectations, to 
account for expected delayed 
response. 
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APPENDIX 3. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES 
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts 
J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009; 45:228 24729 (Eisenhauer 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. 
Bone lesions: 
• Bone scan, 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 
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• Blastic bone lesions are non-measurable 
• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if 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 patented 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 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 has 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. 
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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 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 complete response or 
surgical resection is an endpoint. 
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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 patient 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 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. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.   
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
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 
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“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 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 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 
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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 
patient 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 patient 
who has visceral disease at baseline and while on trial has a CT or MRI brain ordered which 
reveals metastases. The patient’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 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 
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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 patient’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 
patient 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 patient’s best response depends on the subsequent 
assessments. For example, a patient 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 patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
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. 
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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 patients 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 patient 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 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 2 or 3) 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 
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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). 
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 randomised 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 patients 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 4. PRE-EXISTING AUTOIMMUNE DISEASES  
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease. Patients with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study. 
Possible exceptions to this exclusion could be patients with a medical history of such entities as 
atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease is 
low. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible for this study. In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the infectious agent 
are not excluded (eg, acute Lyme arthritis). Please contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions.  
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigold 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Diabetes mellitus Type 1 
Dysautonomia 
Epidermolysis bullosa acquista 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture’s syndrome 
Graves’ disease 
Guillain-Barré syndrome 
Hashimoto’s disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord’s thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodusa 
Polyarthritis 
Polyglandular autoimmune 
syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter’s syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovanagi-Harada disease 
Granulomatosis with polyangiitis 
 
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APPENDIX 5. COCKCROFT-GAULT FORMULA  
 
 
 
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APPENDIX 6. IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE are intended as a 
guidance. This document should be used in conjunction with expert clinical judgement (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies. 
• Criteria used to diagnose irAEs include blood tests, diagnostic imaging, 
histopathology, and microbiology assessments to exclude alternative causes such as 
infection, disease progression, and adverse effects of concomitant drugs. In addition 
to the results of these tests, the following factors should be considered when making 
an irAE diagnosis:  
• 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.  
Radiographic appearance is often nonspecific.  Depending on the 
location of the abnormality, bronchoscopy and bronchoalveolar lavage 
or lung biopsy may be considered.  Consult with a respiratory medicine 
physician for cases of uncertain cause.  
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Recommended Diagnostic Tests in the Management of  
Possible Immune-related Adverse Events 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
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 a patient experiences acute, new onset, or worsening of eye 
inflammation, blurred vision, or other visual disturbances, refer the 
patient urgently to an ophthalmologist for evaluation and management.   
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 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 muscle 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 
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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. 
 
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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 (IV) 
(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 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
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 co-morbidities, 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  
Initiate pulse IV methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation.  Convert to 
oral prednisolone and taper over at 
least 1 month.  Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
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 empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day.  Taper over at least 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 stools 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 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
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. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
symptoms 
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. 
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 judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 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. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
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; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 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.  
Hold study treatment 
until improved to 
baseline Grade; 
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 > 1.5X-3X 
baseline or > 1.5X-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. 
3 
Creatinine > 3X baseline 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
Hold study treatment 
until the cause is 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
or > 3X-6X ULN 
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. 
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 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 
Initiate IV (methyl)prednisolone 
Discontinue study 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Blindness (at least 
20/200) in the affected 
eyes 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
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. 
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 guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
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 
Admit to hospital for emergency 
care.  Consider IV corticosteroids if 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
complications or 
dehydration 
not contraindicated by infection. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1 
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 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
 
 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
3 
Severe symptoms with 
mild 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. 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, chronic heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle 
isoenzyme; INR, international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate 
mofetil; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, 
thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
 
 
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APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating GFR from serum creatinine are the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1 and the 
Modification of Diet in Renal Disease (MDRD) Study equation. The National Kidney Disease 
Education Program (NKDEP) calculators rely on creatinine determinations which are isotope 
dilution mass spectrometry (IDMS) traceable. All laboratories should be using creatinine 
methods calibrated to be IDMS traceable. Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL. This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-
calculators.aspx 
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STATISTICAL ANALYSIS PLAN 
ADDENDUM 
 
Study Protocol 
Number: 
BGB-A317-204 
Study Protocol 
Title: 
A Single-Arm, Multicenter Phase 2 Study of BGB-A317 in Patients with 
Previously Treated PD-L1+ Locally Advanced or Metastatic Urothelial 
Bladder Cancer  
 
Date: 
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Version: 
Addendum 1.0 
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SIGNATURE PAGE 
Author: 
 
               Sr. Principal Statistician 
                
 
 
 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vice President, Biometrics 
 
 
 
Executive Director, Clinical 
Development I/O 
 
 
 
 
Medical Director, Clinical Development 
 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
5 
2 
ANALYSIS OF ORR, DOR, PFS AND DCR ASSESSED BY 
INVESTIGATORS PER irRECIST 
5 
3 
CHANGE OF THE DEFINITION OF DOSE MODIFICATION 
5 
4 
REFERENCES 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RATIONALE FOR ADDENDUM 
This addendum describes the analyses of secondary efficacy endpoints of ORR, DOR, PFS and 
DCR assessed by investigators per irRECIST, which was not included in the Statistical Analysis 
Plan (SAP) Version 1.1. 
Other notable modifications include: 
• Change of the definition of dose modification 
 
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1 
INTRODUCTION 
The original analyses of Protocol BGB-A317-204 “A Single-Arm, Multicenter Phase 2 Study of 
BGB-A317 in Patients with Previously Treated PD-L1+ Locally Advanced or Metastatic 
Urothelial Bladder Cancer” were described in the Statistical Analysis Plan Version 1.1 
(03/04/2019). The purpose of this addendum is to describe the statistical analysis methods that 
will be used to analyze ORR, DOR, PFS and DCR assessed by investigators per irRECIST 
which was not included in the original SAP. This addendum also describes the change of the 
definition of dose modification. 
2 
ANALYSIS OF ORR, DOR, PFS AND DCR ASSESSED BY INVESTIGATORS PER 
irRECIST 
The analysis methods of IRC-assessed ORR, DOR, PFS and DCR as well as ORR, DOR, PFS and 
DCR per investigator review according to RECIST version 1.1 were described in the Section 6.4.1 
and Section 6.4.2 in the original SAP. 
ORR, DOR, PFS and DCR per investigator review according to irRECIST, will be analyzed using 
the same analysis methods as corresponding IRC-assessed efficacy endpoints. 
3 
CHANGE OF THE DEFINITION OF DOSE MODIFICATION 
Dose modification was defined to include dose delay, infusion rate decreased and infusion 
interruption in the original SAP. This addendum changes the definition of dose modification to 
include dose delay and infusion interruption. 
This change of the definition of dose modification will also change the summaries of patients with 
any TEAE leading to dose modification as well as patients with any treatment-related TEAE 
leading to dose modification described in the original SAP. 
4 
REFERENCES 
Bohnsack O, Hoos A, and Ludajic K. Adaptation of the immune related response criteria: 
irRECIST. Annals of Oncology. 2014;25 (suppl_4): iv361-iv372. 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-A317-204 
Study Protocol 
Title: 
A Single-Arm, Multicenter Phase 2 Study of BGB-A317 in Patients with 
Previously Treated PD-L1+ Locally Advanced or Metastatic Urothelial 
Bladder Cancer  
 
Date: 
Mar 4, 2019 
Version: 
1.1 
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SIGNATURE PAGE 
Author: 
 
               Sr. Statistician I 
                
 
 
Date:  ______________ 
 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vice President, Biometrics 
 
 
Date: ________________ 
 
Chief Medical Officer, I/O 
 
 
Date: ________________ 
 
 
Medical Director, Clinical Development
 
Date: ________________ 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
3 
STUDY OBJECTIVES 
8 
3.1 
Primary Objectives 
8 
3.2 
Secondary Objectives 
8 
3.3 
Exploratory Objectives 
8 
4 
STUDY ENDPOINTS 
8 
4.1 
Primary Endpoints 
8 
4.2 
Secondary Endpoints 
9 
4.3 
Exploratory Endpoints 
9 
5 
SAMPLE SIZE CONSIDERATIONS 
9 
6 
STATISTICAL METHODS 
9 
6.1 
Analysis Sets 
9 
6.2 
Data Analysis General Considerations 
10 
6.2.1 
Definitions and Computations 
10 
6.2.2 
Conventions 
10 
6.2.3 
Handling of Missing Data 
11 
6.2.4 
Adjustment for Covariates 
11 
6.2.5 
Multiplicity Adjustment 
11 
6.3 
Patient Characteristics 
11 
6.3.1 
Patient Disposition 
11 
6.3.2 
Protocol Deviations 
11 
6.3.3 
Demographic and Other Baseline Characteristics 
11 
6.3.4 
Disease History 
12 
6.3.5 
Prior Anti-Cancer Drug Therapies,  Radiotherapy and 
Surgeries 
12 
6.3.6 
Prior and Concomitant Medications 
12 
6.3.7 
Medical History 
12 
6.4 
Efficacy Analysis 
12 
6.4.1 
Primary Efficacy Endpoints 
13 
6.4.2 
Secondary Efficacy Endpoints 
13 
6.4.3 
Subgroup Analyses 
14 
6.4.4 
Exploratory Efficacy Endpoints 
14 
6.5 
Safety Analyses 
14 
6.5.1 
Extent of Exposure 
14 
6.5.2 
Adverse Events 
15 
6.5.3 
Laboratory Values 
17 
6.5.4 
Vital Signs 
19 
6.5.5 
Electrocardiograms (ECG) 
19 
6.5.6 
ECOG 
19 
6.6 
Pharmacokinetic Analyses 
19 
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6.7 
Immunogenic Analyses 
19 
7 
INTERIM ANALYSIS 
19 
8 
CHANGES IN THE PLANNED ANALYSIS 
19 
9 
REFERENCES 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
AE 
adverse event 
BOR 
best overall response 
BP 
blood pressure 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
Ctrough 
minimum observed plasma concentration 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GEP 
gene expression profiling 
IC 
immune cell 
IRC 
independent review committee 
irRECIST 
Immune-related RECIST 
KM 
Kaplan-Meier 
MedDRA® 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1+ 
Program Death Ligand-1 positive 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse events 
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SAF 
Safety analysis set 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TC 
tumor cell 
TEAE 
treatment-emergent adverse event 
TLG 
table listing and graph 
TMB 
tumor mutation burden 
UBC 
urothelial bladder cancer 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Protocol BGB-A317-204 “A Single-
Arm, Multicenter Phase 2 Study of BGB-A317 in Patients with Previously Treated PD-L1+ 
Locally Advanced or Metastatic Urothelial Bladder Cancer”. The focus of this SAP is for the 
planned primary, secondary 
 analysis specified in the study protocol. 
 
Reference materials for this statistical plan include the protocol BGB-A317-204 (version 4.0, dated 
11 July 2018). If the protocol or case report forms are amended or updated then appropriate 
adjustments to the SAP may be made if they are related to the planned analyses. 
The SAP described hereafter is an a priori plan. This is an open label study and the SAP will be 
finalized and approved before database lock. Statistical programming may occur as study data 
accumulate in order to have analysis programs ready at the time the study finishes. 
2 
STUDY OVERVIEW 
Study Design 
This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the anti-PD-
1 monoclonal antibody tislelizumab in participants with PD-L1+ locally advanced or metastatic 
urothelial bladder cancer (UBC) who have progressed during or following a platinum-containing 
regimen. The study is composed of an initial screening phase (up to 28 days), a treatment phase 
(until disease progression, intolerable toxicity, or withdrawal for other reasons), safety follow-up 
phase (around 30 days), and survival follow-up phase.  
Approximately 110 patients will be allocated to receive tislelizumab 200 mg intravenously every 
3 weeks. Radiological assessment of tumor-response status should be performed every 9 weeks 
(±1 week). Tumor response will be assessed by independent review committee (IRC) based on the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and by investigators based 
on RECIST version 1.1 and immune-related RECIST (irRECIST). 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. Thus, for progressive disease (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. 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 ECOG performance status. c. Absence of rapid progression of disease or of progressive 
tumor at critical anatomical sites (e.g. cord compression) that necessitates urgent alternative 
medical intervention. 
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Patients will be evaluated for adverse events (AEs) (all grades, according to National Cancer 
Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) version 4.03). All AEs 
and serious adverse events (SAEs) will be recorded during the trial and for up to 30 days after the 
last dose of study treatment or until the initiation of another anticancer therapy, whichever occurs 
first. Immune-related AEs should be reported for 90 days after the last dose of study treatment, 
regardless of whether or not the patient starts a new anticancer therapy. Patients who have an 
ongoing study treatment-related AE upon study completion or at discontinuation from the study 
will be followed until the event has resolved to baseline or ≤ Grade 1, the investigator assesses the 
event as stable; the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of AE. If a patient discontinues 
study treatment due to the reason other than disease progression or death, then tumor assessments 
should continue to be performed following the scheduled assessment plan until the start of new 
anti-cancer therapy, disease progression, death, lost to follow-up or withdrawn consent. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
• 
To determine the efficacy of tislelizumab in patients with previously treated, PD-L1+, 
locally advanced or metastatic UBC, as measured by the Objective Response Rate 
(ORR) according to RECIST Version 1.1 assessed by IRC 
3.2 
SECONDARY OBJECTIVES  
• 
To evaluate the efficacy of tislelizumab as measured by duration of response (DOR), 
progression-free survival (PFS), and disease control rate (DCR) according to RECIST 
version 1.1 assessed by IRC  
• 
To evaluate the efficacy of tislelizumab as measured by overall survival (OS)  
• 
To evaluate the efficacy of tislelizumab as measured by ORR, DOR, PFS and DCR 
according to RECIST version 1.1 and irRECIST assessed by investigators 
• 
To evaluate the safety and tolerability of tislelizumab as determined by the frequency 
and severity of AEs according to NCI-CTCAE version 4.03, and the rate of 
discontinuation of treatment due to AEs 
3.3 
EXPLORATORY OBJECTIVES 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
  ORR defined as the proportion of patients who achieved confirmed best overall 
response (BOR) of complete response (CR) or partial response (PR) assessed by IRC 
using RECIST version 1.1 
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4.2 
SECONDARY ENDPOINTS 
Efficacy: 
• 
DOR– defined as the time from the first determination of a confirmed objective 
response by IRC according to RECIST version 1.1 until the first documentation of 
progression or death, whichever comes first. 
• 
PFS– defined as the time from date of first dose of study drug to date of first 
documentation of disease progression assessed by IRC or death, whichever occurs 
first using RECIST version 1.1 
• 
DCR– defined as the proportion of patients who achieved a confirmed BOR of CR, 
PR, or SD assessed by IRC using RECIST version 1.1 
• 
OS – defined as the time from the date of first dose of study drug until date of death 
from any cause. 
• 
ORR, DOR, PFS and DCR assessed by investigator per RECIST version 1.1 are 
defined similarly as ORR, DOR, PFS and DCR by IRC 
Safety: 
To evaluate the safety and tolerability of tislelizumab, as defined by: 
• 
The incidence and severity of AEs according to NCI-CTCAE version 4.03 
• 
Changes in vital signs, physical findings, and clinical laboratory results 
4.3 
EXPLORATORY ENDPOINTS 
5 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation was based on the power of the comparison between estimated ORR in the 
study and the historical rate. It is assumed an ORR of 25% in the study as compared to 10% in the 
historical control. Using a binomial exact text, the power is 0.986 with 110 patients to demonstrate 
statistical significance at a 1-sided alpha of 0.025. 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
Safety analysis set (SAF) includes all patients who received any dose of tislelizumab. The SAF 
analysis set will be used for all safety summaries.  
Efficacy Evaluable analysis set (EE) includes all patients who have received any dose of 
tislelizumab and had measurable disease per IRC according to RECIST version 1.1 at baseline. This 
will be the primary analysis set population for the efficacy analyses. 
 
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Per-Protocol analysis set (PP) includes patients in the Efficacy Evaluable analysis set who had no 
important protocol deviations. Important protocol deviations are a subset of major protocol 
deviations impacting efficacy analysis. Criteria for exclusion from the PP will be determined and 
documented before the database lock for the primary analysis. This will be the secondary 
analysis set for efficacy analysis when there are over 15% patients who had important protocol 
deviations.    
The PK analysis set (PK) includes all patients who receive at least 1 dose of tislelizumab per the 
protocol, for whom any post dose tislelizumab PK data are available. 
ADA analysis set includes all patients who have non-missing baseline ADA and at least one non-
missing post-baseline ADA results.   
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA), version 9.3 or higher, and/or other validated statistical software as required. 
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median,  minimum (Min), maximum (Max) and n.  Categorical variables will be summarized 
as number (percentage) of patients.  
 
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs in detail. 
6.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first dose of study drug.  
For assessments conducted on or after the date of the first dose of study drug, study day will be 
calculated as (assessment date – date of first dose of study drug + 1).  For assessments conducted 
before the date of the first dose of study drug, study day is calculated as (assessment date – date 
of first dose of study drug). There is no study day 0.  
Treatment duration (day): The treatment duration will be calculated as (date of the last dose of 
study drug – date of first dose of study drug + 21 days). 
Baseline: Baseline is defined as the last non-missing value collected before or at the time of first 
dose date. 
Unscheduled Visits: Unscheduled measurements will not be included in by-visit table summaries 
and graphs, but will contribute to best/ worst case value where required (e.g. shift table). Listings 
will include scheduled and unscheduled data. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 
 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
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significant digit. 
 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 significant digit. 
 Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
 P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and concomitant 
medications.   
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For observed 
data analyses, missing data will not be imputed and only the observed records will be included. 
6.2.4 Adjustment for Covariates 
No adjustments for covariates are planned for primary, secondary and exploratory analyses in the 
study. 
6.2.5 Multiplicity Adjustment 
No multiplicity adjustments will be made in this trial. 
6.3 
PATIENT CHARACTERISTICS 
6.3.1 Patient Disposition 
The number and percentage of patients treated, permanently discontinued from study treatment, 
remained in treatment, discontinued from study, and remained in study will be summarized in the 
SAF.  The primary reasons for study treatment discontinuation and study discontinuation will be 
summarized according to the categories in the CRF. Study follow-up time and primary reason for 
screen failure will be summarized.   
6.3.2 Protocol Deviations 
Important protocol deviation criteria will be established and patients with important protocol 
deviations will be identified and documented before the database lock.  
 
Important protocol deviations will be summarized by category in the SAF. Important protocol 
deviations will be listed. 
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the SAF using descriptive 
statistics.   
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Continuous demographic and baseline variables include age, BMI (in kg/m2) and body weight 
(in kg) ; categorical variables include gender, age group (<65 years, ≥65 years), country, ECOG 
performance status at baseline, smoking status, and PD-L1 expression. 
6.3.4 Disease History 
UBC history characteristics will be summarized in the SAF.  Categorical disease characteristics 
variables include site of primary tumor, histology/cytology, histology grade, tumor staging, and 
known metastasis. Continuous disease history variables include time from initial UBC diagnosis. 
6.3.5 Prior Anti-Cancer Drug Therapies,  Radiotherapy and Surgeries 
The number and percentage of patients with prior anti-cancer drug therapies, with any prior 
platinum-containing treatment regimen, number of prior regimen, time from end of last therapy to 
study entry and intent of therapy for last therapy will be summarized in the SAF. 
The number and percentage of patients with any prior anti-cancer radiotherapy, anatomical site, 
time from end of last radiotherapy to study entry will be summarized in the SAF.  
The number and percentage of patients with any prior anti-cancer surgeries, surgery and location, 
and time from last surgery to study entry will be summarized in the SAF.   
6.3.6 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) of the version currently in effect at BeiGene at the time of database lock, 
and will be further classified to the appropriate Anatomical Therapeutic Chemical (ATC) code. 
The number and percentage of patients who took prior and concomitant medications will be 
summarized respectively by ATC medication class and WHO DD preferred term (PT) in the 
SAF. Prior medications are defined as medications that stopped before the first dose of study 
drug.  Concomitant medications are defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the patient’s last dose.    
 
6.3.7 Medical History 
Medical history will be coded using MedDRA version currently in effect at BeiGene at the time 
of database lock. The number and percentage of patients reporting a history of any relevant medical 
condition (including surgical and allergy history) will be summarized by System Organ Class 
(SOC) and PT in the SAF. 
6.4 
EFFICACY ANALYSIS 
Efficacy analyses will be based on the EE analysis set with the exception that OS will be analyzed 
in the SAF.  
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6.4.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is ORR as determined by IRC using the RECIST version 1.1. ORR 
is defined as the proportion of patients achieved confirmed BOR of CR or PR. Patients with no 
post-baseline response assessment (due to any reason) will be considered non-responders for ORR 
analysis.  
The ORR in this study is estimated as 25%, which is deemed a clinical meaningful improvement 
from historical control of 10%. Hence, the null and alternative hypotheses are set as follows: 
H0: ORR=10% 
Ha: ORR ≥25% 
The primary efficacy analysis will be conducted no later than 6 months after the first dose of the 
last patient, and will be based on EE analysis set. The number and percentage of ORR as 
determined by IRC using the RECIST version 1.1 will be summarized. Clopper-Pearson 95% 
confidence interval (CI) of ORR will be provided to assess the precision of estimation.  
For hypothesis testing, one-sided p-value from the binomial exact test will be provided. If the 
obtained one-sided p-value is ≤ 0.025, it will be concluded that the single agent tislelizumab 
statistically significantly increases ORR compared with historical control. Therefore, the 
superiority of single agent tislelizumab as measured by ORR will be demonstrated. 
In addition, the number and percentage of patients for each of the BOR categories will be 
presented. Time to confirmed response will also be summarized. 
A waterfall plot of best percent change in sum of target lesion diameters from baseline will be 
provided. The patients will be ordered by the percentage, patients with the largest percentage will 
be presented on the right.  
6.4.2 Secondary Efficacy Endpoints 
IRC-assessed DCR is defined as the proportion of patients achieved BOR of CR, PR or SD by 
IRC in accordance with RECIST version 1.1 criteria. DCR as assessed by IRC per RECIST 
version 1.1 and Clopper-Pearson 95% CI will be provided.  
 
IRC-assessed PFS is defined as the time from the date of first study dose of study drug to the date 
of first documentation of disease progression assessed by IRC using RECIST version 1.1 or death 
(whichever occurs first). Kaplan-Meier method will be used to estimate median and other quartiles 
of PFS along with its 95% confidence interval (constructed using Brookmeyer and Crowley 
method). Kaplan-Meier curves will be constructed to provide a visual description of the PFS 
change over time. Event free rate at selected timepoints will be estimated with 95% confidence 
interval using Greenwood formula. Follow-up time will be estimated by the reverse Kaplan-Meier 
method.  
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OS is defined as the date of first dose of study drug until date of death from any cause. Patients 
who remained alive before data cutoff or discontinuation of the study (discontinued study due to 
reasons other than ‘Death’) will be censored at the time of data cutoff or the last date the patient 
was known to be alive. OS will be analyzed similarly as PFS.   
DOR for responders (IRC-assessed CR or PR) is defined as the time from the first determination 
of a confirmed objective response by IRC according to RECIST version 1.1 until the first 
documentation of progression or death, whichever comes first. Only patients in EE who have 
achieved an objective response will be included in the analysis of DOR. Censoring rule for DOR will 
follow PFS censoring rule. DOR will be analyzed similarly as PFS.   
A swimmer plot of duration of treatment, with indicators for the start and end of each disease 
response episode assessed by IRC, will also be provided. The patients will be ordered by the 
duration of exposure. Patients with the longest duration will be presented at the top of the plot. 
 
ORR, DOR, PFS and DCR per investigator review according to RECIST version 1.1, will be analyzed 
using the same analysis methods as corresponding IRC-assessed efficacy endpoints above.  
6.4.3 Subgroup Analyses 
Primary endpoint will be summarized based on following baseline characteristics and prognostic 
subgroups including age group <65 years vs. ≥65 years; country (China vs Korea); smoking status 
(never vs current vs former); ECOG performance status 0 vs. 1; PD-L1(TC <50% and IC<50% vs. 
TC≥50% or IC≥50%); lymph node only  (Yes vs. No);visceral metastasis (Yes vs. No); Liver 
metastasis (Yes vs. No); most recent prior anti-cancer therapy received, if deemed necessary and 
when there is sufficient number of patients in the subgroup, otherwise relevant subgroups may be 
combined.    
Within each selected subgroup, ORR and corresponding 95% CI will be displayed using forest 
plot. 
6.4.4    Exploratory Efficacy Endpoints 
Not applicable.  
6.5 
SAFETY ANALYSES 
All safety analyses will be based on SAF.  The incidence of treatment-emergent adverse events 
(TEAEs, Section 6.5.2) and SAEs will be summarized. Laboratory test results, vital signs, ECG,  
ECOG and their changes from baseline will be summarized using descriptive statistics. Abnormal 
values will be flagged. 
6.5.1 Extent of Exposure 
The tislelizumab dose information of each patient will be assessed by the following variables:  
 Number of treatment cycles equals to the count of cycles with tislelizumab  
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 Duration of exposure (weeks) is defined as:  
(date of last dose of tislelizumab + 21 days – date of first dose of tislelizumab)/7 
 Cumulative dose (mg): the sum of all actual doses of tislelizumab, given from first to last 
administration 
 Actual dose intensity (ADI) in mg/cycle is defined as:  
Cumulative dose (mg) / Duration of exposure (cycle) 
 Relative dose intensity (RDI) in % is defined as:  
100 ×
ADI (mg/cycle)
Planned Dose Intensity (mg/cycle) 
Where Planned dose intensity equals to 200 mg/cycle. 
Number of treatment cycles by patient as a quantitative variable and by category (ie, number (%) 
of patient receiving at least 1 cycle, at least 2 cycles etc), duration of exposure, cumulative dose, 
ADI and RDI will be summarized by descriptive statistics. 
The following analyses will be performed to describe tislelizumab dose delay/infusion change, 
where infusion change includes infusion rate decrease, infusion interrupted, and infusion 
discontinued.  The number (percentage) of patients requiring dose delay/ infusion change will be 
summarized. The cycle in which the first dose delay/ infusion change occurred will be 
summarized using descriptive statistics. Frequency of dose delay/ infusion change will be 
summarized by categories. 
6.5.2 Adverse Events  
AEs will be graded by the investigators using CTCAE version 4.03 and coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) currently in effect at BeiGene at the time of 
database lock. 
A treatment-emergent AE (TEAE) is defined as an AE that had an onset date or a worsening in 
severity from baseline (pre-treatment) on or after the first dose of study drug up to 30 days 
following the last dose of study drug. The TEAE classification also applies to immune related AEs 
(irAE) that are recorded up to 90 days after the last dose of   tislelizumab, regardless of whether 
or not the patient starts a new anticancer therapy. Only those AEs that are treatment emergent will 
be included in summary tables.  All AEs, treatment emergent or otherwise, will be presented in 
patient data listings. 
An overview table of patients with at least one TEAE will be presented with the incidence of: 
 patients with any TEAE 
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 patients with any TEAE with grade 3 or higher  
 patients with any serious TEAEs 
 patients with any TEAE leading to death  
 patient with any TEAE leading to treatment discontinuation 
 patients with any TEAE leading to dose modification, including dose delay, infusion rate 
decreased and infusion interruption  
 patients with any treatment-related TEAE 
 patients with any treatment-related TEAE with grade 3 or higher  
 patients with any treatment-related serious TEAEs 
 patients with any treatment-related TEAE leading to death  
 patient with any treatment-related TEAE leading to treatment discontinuation 
 patients with any treatment-related TEAE leading to dose modification, including dose 
delay, infusion rate decreased and infusion interruption  
 patients with any irTEAE 
 patients with any infusion-related TEAE 
 
Treatment-related TEAEs include those events considered by the investigator to be definitely, 
possibly or probably related or possibly unrelated to study treatment or with missing assessment 
of the causal relationship. For patients with multiple occurrences of the same event will be counted 
only once, and the maximum grade per CTCAE v4.03 will be used. 
If the grade is missing for one of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences with the same preferred term of the same patient 
will be used. If the patient has no other TEAE with the same preferred term, then impute as the 
maximum severity on all TEAE with the same preferred term; If the severity is missing for all 
the occurrences, do not impute, a “missing” category will be added in the summary table. 
The incidence of following TEAEs will be reported by SOC and PT, sorted by decreasing order of 
the frequency of the SOC first and then by decreasing order of the frequency of the PT within the 
SOC: 
 TEAE (any grade) 
 TEAE by maximum severity 
 TEAE leading to treatment discontinuation  
 TEAE leading to dose modification  
 TEAE leading to death 
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 TEAE with grade 3 or higher   
 Treatment-related TEAE   
 Serious TEAE   
 Treatment-related Serious TEAE   
 Infusion related TEAE 
 
All deaths and cause of death will be summarized, including those occurred during the study 
treatment period and those reported during the survival follow-up period after treatment 
discontinuation. 
6.5.3 Laboratory Values 
Laboratory results will be summarized for selected parameters described in Table 1.  
For all parameters listed in Table 1 the actual value and the change from baseline will be 
summarized by visit using descriptive statistics.   
Laboratory parameters that are graded according to CTCAE v4.03 will be summarized by shifts 
from baseline CTCAE grades to the worst post-baseline grades. In the summary of laboratory 
parameters by CTCAE grade, parameters with CTCAE grading in both high and low directions 
will be summarized separately.  
 
Table 1 
Clinical Laboratory Tests 
 
Serum Chemistry 
Hematology 
Urinalysis 
Thyroid Function 
Alkaline phosphatase (ALP) 
Red blood cell (RBC) count 
Specific gravity Free Triiodothyronine 
(FT3) 
Alanine aminotransferase 
(ALT) 
Hemoglobin 
Hematocrit 
pH 
  
Free Thyroxine (FT4) 
Thyroid Stimulating 
Hormone (TSH) 
Aspartate aminotransferase 
(AST) 
White blood cell (WBC) 
count 
 
 
Albumin 
Neutrophil (Absolute) 
 
 
Amylase 
Lymphocyte (Absolute) 
RBC 
 
bilirubin 
Monocyte (Absolute) 
WBC 
 
Blood Urea Nitrogen 
Urea 
Basophil (Absolute) 
Eosinophil (Absolute) 
Platelet count 
 
 
Creatinine 
 
 
 
Calcium 
 
 
 
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Phosphate 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total Protein 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium  
 
 
 
Chloride 
CK 
CK-MB 
Troponin T 
Troponin I 
 
 
 
ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferases, WBC = white 
blood cell 
 
 
 
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6.5.4 Vital Signs 
Descriptive statistics for vital signs parameters (i.e., diastolic and systolic BP, heart rate, pulse 
rate, temperature) and changes from baseline will be summarized by visit. 
6.5.5 Electrocardiograms (ECG) 
ECG will be performed during screening, safety follow-up and as clinically indicated at other 
timepoints. ECG abnormality by visit will be summarized.  
6.5.6 ECOG 
A shift table from baseline to worst post-baseline in ECOG performance score will be summarized.   
6.6 
PHARMACOKINETIC ANALYSES 
Tislelizumab trough serum concentration (Ctrough) will be tabulated and summarized for each cycle 
at which PK is to be measured. Descriptive statistics will include means, medians, ranges, standard 
deviation, coefficient of variation (CV%), Geometric mean and geometric CV%, as appropriate.  
Additional PK analyses may be conducted as appropriate. 
6.7 
IMMUNOGENIC ANALYSES 
Immunogenic response to tislelizumab will be summarized descriptively.  
7 
INTERIM ANALYSIS 
No interim analysis for anti-tumor activity or efficacy is planned.   
8 
CHANGES IN THE PLANNED ANALYSIS 
ORR, DOR, PFS and DCR assessed per irRECIST will not be analyzed. Besides, predictive 
biomarkers, including TMB and GEP will not be analyzed.  
9 
REFERENCES 
Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics. 1982; 
38: 29-41. 
Clopper, C. and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial, Biometrika 1934; 26: 404-413.  
Collett D. Modelling survival data in medical research. New York: Chapman & Hall; 1994.  
Common Terminology Criteria for Adverse Events (CTCAE).  Version 4.0.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 
Washington, DC, USA, May 28, 2009. 
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Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 2009; 
45:228-47. 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research. FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, 2007. 
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical Patients 
(London: Her Majesty’s Stationery Office). 1926; 33:1-26. 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.  
Washington, DC: United States Food and Drug Administration; 2007. 
Kaplan E, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 
1958; 53:457-81. 
 
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