Clinical trial NCT03745222
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Locally Advanced, Unresectable Non-Small Cell Lung Cancer Non-Small Cell Lung Cancer NSCLC Randomized BGB-A317 Tislelizumab PD-1
Sponsor: Celgene
Start date: 2019-05-22; Completion date: 2019-06-26
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed to compare the efficacy and safety of tislelizumab in combination with concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy versus cCRT alone, and tislelizumab given sequentially after cCRT versus cCRT alone, in newly diagnosed stage III subjects with locally advanced, unresectable non-small cell lung cancer (NSCLC). The primary endpoint is centrally-assessed progression free survival (PFS) in the intent-to-treat (ITT) population. .

Detailed description:

Arms: arm 1: Tislelizumab 200 mg is administered by intravenous (IV) administration and given together upfront with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by tislelizumab 200 mg by IV adminstration monotherapy. The standard platinum-based chemotherapy options include carboplatin/ paclitaxel and cisplatin/etoposide arm 2: Placebo is given with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by tislelizumab 200 mg by IV administration monotherapy. The standard platinum-based chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide. arm 3: Placebo is given with concurrent platinum-based chemoradiotherapy (cCRT) for the first 6 weeks, followed by placebo monotherapy. The standard platinum-based chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide.
Interventions: intervention 1: Tislelizumab intervention 2: Concurrent chemoradiotherapy (cCRT) intervention 3: Placebo
Intervention descriptions: intervention 1: PD-1 inhibitor (monoclonal antibody against PD-1) intervention 2: Chemotherapy options include carboplatin/paclitaxel and cisplatin/etoposide per standard of care. Radiotherapy will also be given concurrently with chemotherapy. intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
1
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
TITLE PAGE
A PHASE 3, RANDOMIZED, BLINDED, PLACEBO-
CONTROLLED STUDY OF TISLELIZUMAB (BGB-A317)
PLUS CHEMORADIOTHERAPY FOLLOWED BY 
TISLELIZUMAB MONOTHERAPY IN NEWLY 
DIAGNOSED, STAGE III SUBJECTS WITH LOCALLY 
ADVANCED, UNRESECTABLE NON-SMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
BGB-A317-NSCL-001
DATE FINAL:
21 May 2018
Amendment 1 FINAL:
20 Sep 2018
EudraCT NUMBER:
2018-001132-22
IND NUMBER:
138358
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
 
 
 
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
2
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: 86 Morris Avenue, Summit, NJ 07901
Phone:
Email:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
3
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
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Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
4
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
5
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
6
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
PROTOCOL SUMMARY
Study Title
A Phase 3, randomized, blinded, placebo-controlled study of tislelizumab (BGB-A317) plus 
chemoradiotherapy followed by tislelizumab monotherapy in newly diagnosed, stage III subjects 
with locally advanced, unresectable non-small cell lung cancer.
Indication
This trial will enroll treatment-naive subjects with locally advanced, unresectable stage III non-
small cell lung cancer (NSCLC).
 
 
The study protocols BGB-A317-NSCL-001 and 
BGB-A317-NSCL-001C have a total combined enrollment target of 840 subjects. The data from 
both study protocols will be collected into one database and the statistical analyses as described 
in Section 9 will be performed on the combined total number of subjects randomized into either 
the main protocol or the companion protocol. A single independent data monitoring committee 
(IDMC) and blinded independent central review will be utilized for these 2 study protocols.
Objectives
Primary Objective
The primary objective is to compare the progression free survival (PFS) of tislelizumab in 
combination with concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy
(Arm 1) versus cCRT alone (Arm 3); in addition, tislelizumab given sequentially after cCRT 
(Arm 2) will be compared with cCRT alone (Arm 3) in newly diagnosed stage III subjects with 
locally advanced unresectable non-small cell lung cancer (NSCLC).
Secondary Objective(s)
The secondary objectives are to: 
!
Compare overall survival (OS) (key secondary objective)
!
Compare OS at 24 months (key secondary objective)
!
Compare centrally-assessed objective response rate (ORR) (key secondary objective)
!
Compare centrally-assessed duration of response (DOR)
!
Compare proportion of subjects alive and progression-free at 12 and 18 months 
(APF12, APF18)
!
Compare time to death or distant metastasis (TTDM) 
!
Compare safety and tolerability of tislelizumab in combination with concurrent 
chemoradiotherapy (cCRT) followed by tislelizumab monotherapy versus cCRT 
alone, and tislelizumab given sequentially after cCRT versus cCRT alone
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
7
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
Compare impact on patient-reported lung cancer symptoms (appetite loss, cough, 
chest pain, dyspnea, and fatigue) assessed by European Organisation for Research 
and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30)
and its lung cancer module (EORTC QLQ-LC13).
!
Compare the proportion of subjects who received at least one dose of tislelizumab or 
placebo in the monotherapy phase before progression in Arm 1 versus Arm 2 and 3.
 
 
 
 
 
 
 
 
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study 
designed to compare the efficacy and safety of tislelizumab in combination with concurrent 
chemoradiotherapy (cCRT) followed by tislelizumab monotherapy versus cCRT alone, and 
tislelizumab given sequentially after cCRT versus cCRT alone, in newly diagnosed stage III 
subjects with locally advanced, unresectable NSCLC. 
The primary endpoint is centrally-assessed progression free survival (PFS) in the intent-to-treat 
(ITT) population. Newly diagnosed stage III subjects with histologically confirmed, locally 
advanced, unresectable NSCLC are eligible. 
Approximately 840 subjects will be randomized in a 1:1:1 ratio to receive the study drug
tislelizumab or placebo in the following 3 arms:  
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
8
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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The choice of chemotherapy regimen to be used as part of study treatment will be at the 
Investigator’s discretion, consisting of either 2 cycles of cisplatin plus etoposide or weekly 
carboplatin plus paclitaxel given during radiation therapy (RT) for 6 weeks.  Radiation therapy 
should start concurrently with chemotherapy in Cycle 1 of tislelizumab or placebo. If local 
technical or logistical circumstances do not allow for the start of RT at the beginning of Cycle 1, 
a 3-day administrative window to start RT will be allowed. Tislelizumab or placebo will be given 
starting from Cycle 1 Day 1 (C1D1) in the cCRT phase, and continued in the monotherapy phase 
for a duration of 12 months following the completion of cCRT, or until disease progression, 
unacceptable toxicity, or treatment discontinuation for another reason.
Randomization will be stratified by age 
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Safety and efficacy will be monitored by an IDMC.
 
 
 
 
 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms, leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the 
Investigator to reflect pseudoprogression, the subject may continue treatment until progressive 
disease is confirmed by repeated imaging at least 4 weeks later but not exceeding 6 to 8 weeks 
from the date of initial documentation of progressive disease, provided the following criteria are 
met:
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Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values). 
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Stable ECOG performance status (≤ 1).
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
9
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention.
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform subjects that this practice is not considered standard in the treatment of 
cancer. The decision to continue study drug(s) beyond initial Investigator-assessed progression 
must be discussed with the Sponsor medical monitor and documented in the study records.
The study conduct will be overseen by a Steering Committee (SC) composed of selected 
Investigators who are taking part in the study.  The SC will remain blinded to the study data by 
arm.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Adult subjects with newly diagnosed, histologically confirmed, locally advanced, unresectable 
stage III NSCLC for whom chemoradiotherapy is appropriate will be randomized.
Subjects with epidermal growth factor receptor (EGFR) sensitizing mutations or anaplastic 
lymphoma kinase (ALK) gene translocations may be randomized up to approximately 10% of 
the total randomized population.
Length of Study
Enrollment is expected to take approximately 28 months to complete. To reach final PFS 
analysis, 580 PFS events are expected across the 3 arms in approximately 35 months following 
randomization of the first subject.
The total study duration is estimated to be approximately 61 months from the randomization of 
the first subject to the final analysis, conducted when approximately 572 overall survival (OS)
events have occurred across the 3 arms. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
posttreatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Anti-PD-1 therapy/Placebo
Tislelizumab or placebo:  
 
Radiation therapy
Thoracic RT will be given 5 days per week for 6 weeks, in once daily fractions, 2 Gy per 
fraction, to a target dose of 60 Gy in 30 fractions. Please refer to Section 7.2.2 for RT 
administration.
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
10
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
Tislelizumab or placebo will be given starting from C1D1 in the cCRT phase, and will continue 
in the monotherapy phase for a duration of 12 months following the completion of cCRT, or 
until disease progression, unacceptable toxicity, or treatment discontinuation for another reason.
The total duration of tislelizumab (Arm 1), placebo followed by tislelizumab (Arm 2), or placebo 
alone (Arm 3) will be approximately 14 months, including the cCRT period.
Subjects may remain on treatment until disease progression, unacceptable toxicity, initiation of a 
subsequent anticancer therapy, withdrawal of consent, subject refusal, lost to follow-up, 
physician decision, or death.
Overview of Key Efficacy Assessments
All subjects will be evaluated for tumor response and progression by Investigator assessment for 
therapeutic decisions according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
guidelines, at screening and every 6 weeks (± 7 days) from randomization for the first 36 weeks, 
and every 9 weeks (± 7 days) from Week 36 onwards until documented disease progression, start 
of subsequent anticancer therapy, or withdrawal of consent. 
Response assessments will include computed tomography (CT) scan or magnetic resonance 
imaging (MRI). 
The primary endpoint of PFS will be based on response assessments evaluated by blinded 
independent central review.
In the follow-up phase, subsequent anticancer treatment administered following the last dose of 
investigational product (IP) and survival will be followed every 3 months (± 14 days) until death, 
withdrawal of consent, or lost to follow-up, whichever occurs first, or the End of Trial.
Overview of Key Safety Assessments
All subjects will be monitored for adverse events starting from the time the subject signs the 
informed consent form (ICF) until 30 days after the last dose of study treatment 
(tislelizumab/placebo, chemotherapy, or RT), as well as those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to study treatment. Subjects 
will also be monitored for immune related adverse events (serious or nonserious) starting from 
the time the subject signs the ICF until 90 days after the last dose of tislelizumab or placebo,
regardless of whether or not the subject starts a new anticancer therapy. All AEs and SAEs 
considered related to RT will be collected at any time after the first dose of RT, including late 
radiation toxicities. A thorough evaluation of medical conditions, including analysis of 
pulmonary function, left ventricular ejection fraction (LVEF), C-reactive protein, hepatitis B
virus and hepatitis C virus (HBV and HCV), will be conducted during screening. Documented 
physical examination (PE), vital signs, laboratory assessments (eg, serum chemistry, 
hematology, coagulation, thyroid function), 12-lead electrocardiogram (ECG), ophthalmologic 
examination, urinalysis, HBV and HCV (if positive at screening), and Eastern Cooperative 
Oncology Group (ECOG) performance status will be monitored regularly. Preventative measures 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
11
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
will be taken to avoid pregnancy in study subjects or their partners, and females of child-bearing 
potential will have pregnancy testing performed at screening and then throughout the study. The 
full schedule of assessments is described in Table 4 and Section 6.
Statistical Methods
The primary objective of the study is to assess the efficacy of either one of the tislelizumab arms 
(Arm 1 or Arm 2) compared with the control arm (Arm 3) in terms of PFS. There will be one 
interim and one final analysis for PFS, and one interim and one final analysis for OS, 
respectively. 
 
 
 
 
 
Efficacy Analyses
The primary efficacy analyses will be based on the ITT population. The primary and key 
secondary endpoints will also be analyzed using the per protocol population.
The primary endpoint, PFS, is defined as the time from randomization to the time of progression 
(based on blinded independent reviewer assessment using RECIST v1.1) or death, whichever is 
earlier. Subjects without progression or death will be censored according to censoring rules 
similar to those described by the Food and Drug Administration (FDA) in the FDA Guidance for 
Industry Clinical Trial Endpoints for Approval of Cancer Drugs and Biologics (FDA, 2007). The 
distribution of PFS will be estimated using the Kaplan-Meier method. The comparison of PFS 
between treatment arms (Arm 1 versus Arm 3 or Arm 2 versus Arm 3) will be conducted using a 
stratified log-rank test with age 
), chemotherapy regimen
), and region (
 as 
stratification factors. The hazard ratio (between Arm 1 or Arm 2 versus Arm 3) and the 
corresponding 95% confidence interval will also be provided based on a stratified Cox 
proportional hazard model. The median PFS (with 95% confidence interval) and estimation of 
PFS rate (with 95% confidence intervals) for specific time points (eg, 3 months, 6 months etc.) 
will be provided for each treatment arm.
The first key secondary endpoint, OS, is defined as the time from randomization to death due to 
any cause. Subjects without documented death at the time of analysis will be censored at the last-
known-to-be-alive date. The distribution of OS will be estimated using Kaplan-Meier method. A 
stratified log-rank test will be used to compare treatment groups in OS. The median OS (with 
95% confidence interval) and estimation of OS rate (with 95% confidence intervals) for different 
timepoints will be provided by treatment arm. The hazard ratio (between Arm 1 or Arm 2 versus 
Arm 3) and the corresponding 95% confidence interval will also be provided based on a 
stratified Cox regression model. 
The second key secondary endpoint, OS at 24 months (OS 24), is defined as the proportion of 
subjects alive at 24 months. The point estimate and the corresponding 95% confidence interval 
for each treatment arm will be estimated using the Kaplan-Meier method. The treatment
comparisons for OS 24 will be performed using an approach as described in Klein, 2007.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
12
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
The third key secondary endpoint, objective response rate (ORR), is defined as the percentage of 
subjects who achieve a complete response (CR) or partial response (PR) based on the blinded 
independent reviewer assessment using RECIST v1.1 criteria. The ORR for each treatment arm 
will be summarized using 95% Clopper-Pearson confidence interval. The difference in ORR 
between treatment arms and the associated 95% Wilson score confidence interval will be 
provided. A Cochran-Mantel-Haenszel (CMH) test will be used to compare ORR between 
treatment arms.
Safety Analyses
Safety analyses will be performed based on the safety population. Safety and tolerability will be 
monitored through continuous reporting of AEs and SAEs, laboratory abnormalities, and 
incidence of subjects experiencing dose modifications, dose interruptions, and/or premature 
discontinuation of IP. Descriptive statistics will be provided for summaries of adverse events, 
clinical laboratory data, and other safety assessments. Adverse events will be analyzed in terms 
of treatment-emergent adverse events (TEAEs), defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the first dose of study treatment up 
to 30 days following study treatment discontinuation or initiation of new anticancer therapy, 
whichever occurs first. Treatment-emergent AEs also include all immune-related AEs (irAEs) 
recorded up to 90 days after the last dose of tislelizumab or placebo, regardless of whether or not 
the subject starts a new anticancer therapy. All events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment-emergent AEs will be summarized per treatment 
arms by MedDRA system organ class and preferred terms. Grade 3 or higher TEAEs, SAEs, 
TEAEs leading to dose reduction and dose interruption, TEAEs leading to treatment 
discontinuation, and TEAEs with an outcome of death will be summarized per treatment arms by 
MedDRA system organ class and preferred terms. Additionally, adverse events of special interest 
for tislelizumab will be summarized in the same manner.
 
 
 
 
 
 
 
 
.
Power and Sample Size
There are 2 primary hypotheses to test in this study:
!
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!
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
13
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
A group sequential boundary based on Lan-Demets spending function that approximates the 
O’Brien-Fleming boundary is calculated for the comparison associated with each of the 2
primary hypotheses for the PFS endpoint. The key secondary endpoint of OS will be tested only 
if the hypothesis for the primary endpoint PFS is rejected at the interim or the final PFS analysis, 
in each pairwise comparison of treatment groups (Arm 1 versus Arm 3 or Arm 2 versus Arm 3). 
In addition, the other 2 key secondary endpoints, OS 24 and ORR, will also be tested if both the 
PFS and OS hypotheses in the same pairwise comparison of treatment groups are rejected. The 
overall type one error rate will be controlled using a graphic approach as described by Maurer 
and Bretz (Maurer, 2013).
Approximately 840 subjects will be randomized by 1:1:1 ratio to one of the treatment arms. 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
14
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................22
1.1.
Disease Background ...............................................................................................22
1.1.1.
Non-small Cell Lung Cancer ..................................................................................22
1.1.2.
First-line Concurrent Chemotherapy/ Radiation Therapy for Locally 
Advanced NSCLC ..................................................................................................22
1.1.3.
Anti-PD-1/PD-L1 Therapy for Locally Advanced or Metastatic Lung 
Cancers...................................................................................................................24
1.2.
Compound Background ..........................................................................................29
1.2.1.
Pharmacology.........................................................................................................29
1.3.
Rationale ................................................................................................................33
1.3.1.
Study Rationale and Purpose ..................................................................................33
1.3.2.
Rationale for the Study Design ...............................................................................34
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................36
1.3.3.1.
Rationale for Selection of Tislelizumab Dose .........................................................36
1.3.3.2.
Rationale for Selection of Chemotherapies .............................................................36
1.3.3.3.
Rationale for Selection of Radiotherapy Dose.........................................................37
1.3.5.
Rationale for Patient-Reported Outcomes and Quality of Life or Health 
Economics..............................................................................................................38
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................39
3.
OVERALL STUDY DESIGN ................................................................................44
3.1.
Study Design ..........................................................................................................44
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
15
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
3.2.
Study Duration for Subjects....................................................................................47
3.3.
End of Trial ............................................................................................................47
4.
STUDY POPULATION.........................................................................................48
4.1.
Number of Subjects ................................................................................................48
4.2.
Inclusion Criteria....................................................................................................48
4.3.
Exclusion Criteria...................................................................................................50
5.
TABLE OF EVENTS.............................................................................................53
6.
PROCEDURES......................................................................................................61
6.1.
Screening Period.....................................................................................................61
6.2.
Treatment Period ....................................................................................................64
6.2.1.
End of Treatment....................................................................................................65
6.3.
Follow-up Period....................................................................................................67
6.3.1.
Safety Follow-up ....................................................................................................67
6.3.2.
Efficacy Follow-up.................................................................................................68
6.3.3.
Survival Follow-up.................................................................................................68
6.4.
Efficacy Assessment...............................................................................................68
6.7.
Patient Reported Outcomes.....................................................................................70
6.7.1.
EORTC QLQ-C30..................................................................................................71
6.7.2.
EORTC QLQ-LC13 ...............................................................................................72
7.
DESCRIPTION OF STUDY TREATMENTS........................................................75
7.1.
Description of Investigational Product(s)................................................................75
7.1.1.
Tislelizumab (BGB-A317)......................................................................................75
7.1.2.
Placebo...................................................................................................................75
7.1.3.
Chemotherapy ........................................................................................................75
7.2.
Treatment Administration and Schedule .................................................................76
7.2.1.
Dosage, Administration, and Compliance ...............................................................76
7.2.1.1.
Tislelizumab or Placebo..........................................................................................79
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
16
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.2.1.2.
Chemotherapy ........................................................................................................80
7.2.2.
Radiation Therapy ..................................................................................................81
7.2.2.1.
Radiation Dose Specifications ................................................................................81
7.2.2.2.
Variations of Dose Prescription ..............................................................................82
7.2.2.3.
Localization, Simulation, and Immobilization.........................................................83
7.2.2.4.
Radiation Treatment Planning.................................................................................83
7.2.2.5.
Radiation Treatment Documentation.......................................................................83
7.2.2.6.
Organs at Risk ........................................................................................................84
7.2.2.7.
Quality Assurance and Compliance with Protocol-defined Radiation 
Prescription (Quality Control).................................................................................85
7.2.2.8.
Radiation Adverse Events and Interruption.............................................................85
7.2.3.
Supportive Care......................................................................................................88
7.2.4.
Overdose or Incorrect Administration.....................................................................88
7.2.5.
Dose Delay and Modification .................................................................................88
7.2.5.1.
General Guidance Regarding Dose Modifications...................................................88
7.2.5.2.
Dose Modification for Tislelizumab or Placebo ......................................................90
7.2.5.3.
Dose Modifications of Chemotherapy.....................................................................90
7.2.6.
Specific Considerations ..........................................................................................95
7.2.7.
Clinically Significant Effusions ..............................................................................96
7.2.8.
Creatinine Clearance...............................................................................................96
7.2.9.
Blinding..................................................................................................................96
7.3.
Method of Treatment Assignment...........................................................................97
7.4.
Packaging and Labeling..........................................................................................98
7.5.
Investigational Product Accountability and Disposal ..............................................98
7.6.
Investigational Product Compliance........................................................................98
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................99
8.1.
Permitted Concomitant Medications and Procedures...............................................99
8.2.
Prohibited Concomitant Medications and Procedures............................................100
8.3.
Required Concomitant Medications and Procedures..............................................101
8.3.1.
Management of Immune-related Adverse Events..................................................101
8.3.2.
Management of Infusion Reactions.......................................................................102
8.3.3.
Severe Hypersensitivity Reactions and Flu-Like Symptoms..................................104
8.3.4.
Treatment of Hepatitis B and Hepatitis C..............................................................104
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2


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
17
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.
STATISTICAL CONSIDERATIONS ..................................................................105
9.1.
Overview..............................................................................................................105
9.2.
Study Population Definition..................................................................................105
9.2.1.
Intent-to-treat Population......................................................................................105
9.2.2.
Safety Population..................................................................................................105
9.2.3.
Per Protocol Population ........................................................................................105
9.3.
Power and Sample Size Consideration..................................................................106
9.3.1.
Multiplicity Control Strategy................................................................................106
9.3.2.
Power and Sample Size.........................................................................................108
9.4.
Background and Demographic Characteristics......................................................109
9.5.
Subject Disposition...............................................................................................109
9.6.
Efficacy Analysis..................................................................................................109
9.6.1.
Primary Efficacy Endpoint....................................................................................110
9.6.2.
Secondary Efficacy Endpoints ..............................................................................110
9.6.2.1.
Overall Survival ...................................................................................................110
9.6.2.2.
OS at 24 Months...................................................................................................110
9.6.2.3.
Objective Response Rate ......................................................................................110
9.6.2.4.
Other Secondary Endpoints ..................................................................................110
9.7.
Safety Analysis.....................................................................................................111
9.9.
Other Topics.........................................................................................................112
9.9.1.
Data Monitoring Committee .................................................................................112
9.9.2.
Steering Committee ..............................................................................................113
10.
ADVERSE EVENTS............................................................................................115
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................115
10.2.
Evaluation of Adverse Events...............................................................................115
10.2.1.
Seriousness...........................................................................................................116
10.2.2.
Severity/Intensity..................................................................................................117
10.2.3.
Causality ..............................................................................................................117
10.2.4.
Duration ...............................................................................................................118
10.2.5.
Action Taken........................................................................................................118
10.2.6.
Outcome...............................................................................................................118
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35
235


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
18
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
10.3.
Abnormal Laboratory Values................................................................................118
10.4.
Pregnancy.............................................................................................................119
10.4.1.
Females of Childbearing Potential: .......................................................................119
10.4.2.
Male Subjects.......................................................................................................119
10.5.
Reporting of Serious Adverse Events....................................................................119
10.5.1.
Safety Queries ......................................................................................................120
10.6.
Expedited Reporting of Adverse Events................................................................120
11.
DISCONTINUATIONS .......................................................................................122
11.1.
Treatment Discontinuation....................................................................................122
11.2.
Study Discontinuation ..........................................................................................122
12.
EMERGENCY PROCEDURES...........................................................................123
12.1.
Emergency Contact...............................................................................................123
12.2.
Emergency Identification of Investigational Products ...........................................123
13.
REGULATORY CONSIDERATIONS.................................................................124
13.1.
Good Clinical Practice..........................................................................................124
13.2.
Investigator Responsibilities .................................................................................124
13.3.
Subject Information and Informed Consent...........................................................125
13.4.
Confidentiality......................................................................................................125
13.5.
Protocol Amendments...........................................................................................125
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................125
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............126
13.8.
Termination of the Study ......................................................................................126
14.
DATA HANDLING AND RECORDKEEPING...................................................127
14.1.
Data/Documents...................................................................................................127
14.2.
Data Management.................................................................................................127
14.3.
Record Retention..................................................................................................127
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................129
15.1.
Study Monitoring and Source Data Verification....................................................129
15.2.
Audits and Inspections..........................................................................................129
15.3.
Product Quality Complaint ...................................................................................129
16.
PUBLICATIONS .................................................................................................131
17.
REFERENCES.....................................................................................................132
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
19
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
18.
APPENDICES......................................................................................................140
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................140
APPENDIX B.
PATIENT REPORTED OUTCOMES: EORTC QLQ-C30 ..........................145
APPENDIX C.
PATIENT REPORTED OUTCOMES: EORTC QLQ - LC13......................147
APPENDIX D.
APPENDIX E.
APPENDIX F.
APPENDIX G.
CALCULATED CREATININE CLEARANCE (COCKCROFT AND 
GAULT 1976)......................................................................................................155
APPENDIX H.
IMMUNE-RELATED ADVERSE EVENT EVALUATION AND
MANAGEMENT .................................................................................................156
APPENDIX I.
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1.............................................................167
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
20
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
LIST OF TABLES
Table 1:
Approved Anti-PD-1 or Anti-PD-L1 Inhibitors for the Treatment of 
Advanced or Metastatic NSCLC.............................................................................27
Table 2:
Study Objectives.....................................................................................................39
Table 3:
Study Endpoints .....................................................................................................40
Table 4:
Table of Events.......................................................................................................53
Table 5:
Timing of Dose Administration of Tislelizumab or Placebo in Combination 
with Chemotherapy During cCRT...........................................................................77
Table 6:
Timing of Dose Administration of Tislelizumab or Placebo Monotherapy 
After Completion of cCRT .....................................................................................79
Table 7:
Summary of Dose Prescription Variations ..............................................................82
Table 8:
CTCAE Scale:  Acute Esophagitis Related to Radiation .........................................87
Table 9:
Dietary and Nutritional Support Recommendations for Acute Radiation 
Esophagitis .............................................................................................................87
Table 10:
Recommendations for Medication Management of Radiation Esophagitis ..............87
Table 11:
Lab parameters to Initiate Cisplatin and Etoposide Regimen...................................91
Table 12:
Dose Modifications for Cisplatin and Etoposide Based on Hematologic 
Nadir Values Prior to the Next Dose.......................................................................91
Table 13:
Dose Modifications for Cisplatin and Etoposide Based on Nonhematologic 
Toxicity..................................................................................................................92
Table 14:
Dose Modifications for Cisplatin Based on Renal Toxicity .....................................93
Table 15:
Parameters to Initiate Carboplatin and Paclitaxel Regimen......................................94
Table 16:
Dose Modifications for Carboplatin and Paclitaxel Based on Hematologic 
Toxicities................................................................................................................94
Table 17:
Dose Modifications for Carboplatin and Paclitaxel Based on 
Nonhematologic Toxicity .......................................................................................95
Table 18:
Immune-Related Adverse Events..........................................................................101
Table 19:
Management of Infusion Reactions.......................................................................103
Table 20:
Table 21:
Abbreviations and Specialist Terms......................................................................140
Table 22:
Recommended Diagnostic Tests in the Management of Possible Immune 
related Adverse Events .........................................................................................156
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
21
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................46
CCI


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
22
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
1.
INTRODUCTION 
1.1.
Disease Background 
1.1.1.
Non-small Cell Lung Cancer
Lung cancer is the most common cancer worldwide with approximately 1.8 million new 
diagnoses and 1.59 million deaths in 2012, which corresponds to the third highest incidence 
among cancers and the most common cancer-related mortality (Globocan, 2012). Globally, 
across all cancer types, lung cancer is more common in men (16.8%) compared to women 
(8.8%). As lung cancer can be asymptomatic at early stages, most lung cancers are diagnosed at 
an advanced stage which is not curable by surgery (American Joint Committee on Cancer 
[AJCC] Cancer Staging Manual, 2017), resulting in a poor prognosis. Non-small cell lung cancer 
(NSCLC) is the most common histological type of lung cancer, accounting for 80% to 85% of all 
lung cancers, and originates from the epithelial cells of the lung with the following major 
histological subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma 
(National Cancer Institute, 2018).
About one third of subjects with NSCLC present with locally advanced stage III disease, which 
includes subjects with involvement of locoregional mediastinal lymph nodes or mediastinal 
organs, with 5-year survival rates of 36% for stage IIIA, 26% for stage IIIB, and 13% for stage 
IIIC (American Cancer Society, 2018). Some patients with stage IIIA disease can undergo 
resection, and have improved survival compared to those that are unresectable.
1.1.2.
First-line Concurrent Chemotherapy/ Radiation Therapy for Locally Advanced 
NSCLC
Concurrent chemoradiotherapy (cCRT) has become the standard of care for subjects with locally 
advanced, unresectable stage III NSCLC (National Comprehensive Cancer Network [NCCN], 
2018) (European Society for Medical Oncology [ESMO] guidelines [Postmus, 2017]). Combined 
modality treatment with chemotherapy and radiation was shown to be superior to radiation 
therapy alone (Rolland, 2007). The positive outcomes for cCRT have been shown in multiple 
studies. A meta-analysis from the mid-1990s using updated data on individual subjects from 52 
randomized clinical trials (NSCLC Collaborative Group, 1995) and a subsequent meta-analysis 
of platinum-based chemotherapies from 1764 subjects (Aupérin, 2006) demonstrated that adding 
sequential or concurrent chemotherapy to radiotherapy improved survival in locally advanced 
NSCLC. When concurrent versus sequential chemoradiotherapy was compared directly in data 
for 1205 subjects from 6 clinical trials, there was a significant benefit of cCRT on overall 
survival (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.004), with an 
absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-
free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = 0.07). Concurrent treatment decreased 
locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = 0.01), although concurrent 
treatment was not different from sequential treatment on distant progression (HR, 1.04; 95% CI, 
0.86 to 1.25; P = 0.69). Concurrent chemoradiotherapy increased acute esophageal toxicity, but 
there was no significant difference regarding acute pulmonary toxicity (Aupérin, 2010). 
In order to improve outcomes for subjects with unresectable stage III NSCLC, induction and 
consolidation chemotherapy have also been studied.  There was more neutropenia observed with 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
23
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
induction chemotherapy with no improvement in overall survival (Vokes, 2007).  Consolidation 
chemotherapy has also not been shown to have any impact on overall survival compared to 
cCRT alone (Tsujino, 2013).  Therefore, cCRT is considered the standard of care for patients 
with locally advanced, unresectable stage III NSCLC. Of note, the standard of care for patients 
with stage III NSCLC remains cCRT regardless of epidermal growth factor receptor (EGFR) 
sensitizing mutations or anaplastic lymphoma kinase (ALK) gene translocations (NCCN, 2018; 
Postmus, 2017).  Epidermal growth factor receptor and ALK targeted agents are not utilized as 
upfront therapy and are still being investigated in trials such as the Radiation Thoracic Oncology 
Group (RTOG) 1306 study (Berman, 2016).
Multiple chemotherapy backbone regimens have also been found to be acceptable combination 
regimens in stage III NSCLC as part of the standard of care for cCRT.  Most regimens are 
combinations of cisplatin with either pemetrexed, etoposide, vinblastine, or vinorelbine.   Few 
studies have been conducted comparing these chemotherapy regimens, and no chemotherapy 
regimen has been clearly demonstrated to be better than others. Of the chemotherapy doublets 
that have comparative evidence, cisplatin in combination with either pemetrexed or etoposide 
has been studied in this stage III NSCLC treatment population.  The PROCLAIM multinational 
trial (Senan, 2016) endeavored to establish whether cisplatin/pemetrexed is superior to 
cisplatin/etoposide when given concurrently with standard radiation therapy (RT) at 60-66 Gray
(Gy), followed by a consolidation phase. Cisplatin/pemetrexed was not found to be superior in 
OS to cisplatin/etoposide (median overall survival [OS] 26.8 months versus 25.0 months; P = 
0.831).  Both arms had low incidences of Grades 3 or 4 pneumonitis (< 3%), with no significant 
differences between arms in treatment discontinuations due to drug-related adverse events (AEs)
or drug-related deaths.  The PROCLAIM study therefore establishes that outcomes with cisplatin 
with either pemetrexed or etoposide when used in cCRT with conventional radiation therapy are 
similar.
Carboplatin with paclitaxel given weekly during radiation is another acceptable cCRT option as 
recommended by the NCCN guidelines, with the 2 cycles of carboplatin and paclitaxel 
consolidation considered as optional (NCCN, 2018).  This regimen has been evaluated in several 
studies (Belani, 2005; Vokes, 2007; Yamamoto, 2010; Bradley, 2015) and is commonly used as 
a first-line treatment for locally advanced, unresectable stage III NSCLC in the US and other 
countries globally.  Weekly carboplatin/paclitaxel was used as part of the chemotherapy regimen 
backbone in the RTOG 0617 study that evaluated standard versus high doses of radiation to be 
given concurrently with chemotherapy (Bradley, 2015). A Phase 3 trial of concurrent thoracic 
radiation in unresectable stage III NSCLC found that weekly carboplatin/paclitaxel was superior 
to second-generation chemotherapy regimens such as mitomycin/vindesine, weekly 
irinotecan/carboplatin, or cisplatin or carboplatin as a single agent with radiation therapy 
(Yamamoto, 2010).  Of note, in the Phase 3 PACIFIC study, which evaluated the anti-
programmed cell death protein-ligand 1 (PD-L1) inhibitor durvalumab compared to placebo after 
cCRT, carboplatin with paclitaxel was the most common chemotherapy regimen chosen by 
investigators, administered to 33.9% of subjects in the intent-to-treat (ITT) population; 
consolidation chemotherapy after radiation was not permitted in this study (Antonia, 2017).
In an attempt to improve outcomes, higher doses of radiation have been studied in combination 
with chemotherapy.  Approximately 60 Gy in 1.8 to 2 Gy fractions has been previously 
established as the standard conventional radiation dose in stage III NSCLC in the RTOG 7301 
study (Bradley, 2015). Subsequently the RTOG 0617 study has shown that 74 Gy was not better 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
24
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
than 60 Gy (Bradley, 2015).  In fact, the median OS was 28.7 months for those subjects who 
received 60 Gy versus 20 months for those who received 74 Gy.  Local relapse rates were also 
lower in the 60 Gy cohort. Thus, the accepted standard of care is approximately 60 Gy in 2 Gy 
fractions (NCCN, 2018) (ESMO 2017 guidelines [Postmus, 2017]).
1.1.3.
Anti-PD-1/PD-L1 Therapy for Locally Advanced or Metastatic Lung Cancers
Anti-programmed cell death protein-1 (PD-1) therapy has emerged as an effective treatment for 
those expressing varying degrees of (PD-L1) (Hanna, 2017). Anti-PD-1 and anti-PD-L1 
therapies target the programmed death receptor pathway of T lymphocytes, and this checkpoint 
has been found to be activated in cancer allowing tumors to evade the host immune system.  In 
the US and other regions, multiple anti-PD-1 (eg, nivolumab and pembrolizumab) and anti-PD-
L1 (eg atezolizumab) therapies have been approved in lung cancer in the second line setting
(Table 1). In the first line setting, pembrolizumab has been approved by the US Food and Drug 
Administration (FDA) as monotherapy in subjects with metastatic NSCLC whose tumors express
a high level of PD-L1 (Tumor Prognostic Score ≥50%).  Pembrolizumab has also been granted 
accelerated approval by the FDA in the first-line setting in combination with pemetrexed and 
carboplatin in metastatic nonsquamous NSCLC (Table 1).
In the locally advanced, first-line NSCLC setting, the potential benefits of checkpoint blockade 
when given sequentially following completion of cCRT have been demonstrated by the 
PACIFIC trial (Antonia, 2017). This is a global Phase 3 trial of the anti-PD-L1 therapy, 
durvalumab, compared to placebo as consolidation therapy following 2 or more cycles of 
platinum-based chemotherapy administered concurrently with RT without progression in 
subjects with unresectable stage III NSCLC.  Subjects who were able to complete 
chemoradiotherapy, and who remained progression free at that time, were randomized within 1 
to 42 days after completing at least 2 cycles of platinum-based chemotherapy (containing 
etoposide, vinblastine, vinorelbine, a taxane, or pemetrexed) administered concurrently with 
definitive radiation therapy of 54 to 66 Gy. The trial demonstrated that median progression free 
survival (PFS) was significantly longer with durvalumab compared to placebo (median PFS 16.8 
months versus 5.6 months, stratified HR for disease progression or death = 0.52), with a similar 
safety profile in the 2 groups. Notably, enrollment was not restricted to any thresholds for the 
level of PD-L1 expression, and results showed that the PFS benefit was irrespective of baseline 
PD-L1 expression (HR 0.59 [95% CI, 0.43 to 0.82] for a PD-L1 expression level of < 25% and 
0.41 [95% CI, 0.26 to 0.65] for a PD-L1 expression level of ≥ 25%).  In February 2018, based on 
the results of the PACIFIC study, durvalumab was approved by the US FDA for the treatment of 
subjects with unresectable stage III NSCLC whose cancer had not progressed after 
chemoradiation (FDA News Release, 2018). This immunotherapy thus becomes the first 
treatment approved to reduce the risk of NSCLC progression in this setting, and may lead to a 
change in first line treatment for stage III subjects, with the potential recommendation that anti-
PD-L1 consolidation therapy be offered after concurrent chemoradiation therapy (NCCN, 2018). 
However, there are still some caveats to the PACIFIC study.  There is some uncertainty as to 
whether all subjects enrolled in this study underwent appropriate evaluations for optimal staging, 
and whether this trial included subjects with occult stage IV disease (Copur, 2018).  In addition, 
almost 30% of subjects enrolled did not proceed to randomization in the study, with the exact 
reasons for dropout not further specified beyond the majority of subjects not meeting eligibility 
criteria (Antonia, 2017).  It not clear whether these subjects were able to complete the cCRT 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
25
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
prior to randomization or the status of these subjects during the cCRT period.  Furthermore, OS
data is not yet available.  If an OS benefit is eventually shown, cCRT followed by anti-PD-L1 
therapy with durvalumab is anticipated to become an emerging standard of care for subjects with 
stage III NSCLC.
There are multiple ongoing studies evaluating anti-PD-1 or PD-L1 therapies in combination with 
radiation or chemoradiotherapy.  Based on the mechanism of action and biology of PD-1/PD-L1, 
it is not anticipated that the antibody will act as a direct radiation sensitizer for normal or 
malignant cells.  Emerging retrospective and prospective data suggests that anti-PD-1 therapy (at 
the established monotherapy dosing) in combination with radiation has similar toxicity to that 
anticipated with either treatment alone (Nomura, 2018; Fiorica, 2018).  This and other emerging 
data support that anti-PD-1 therapies can be safely added to standard of care chemotherapy 
regimens in NSCLC, with the potential for improved efficacy compared to chemotherapy alone. 
For example, the Phase 2 NICOLAS trial is evaluating the anti-PD-1 therapy, nivolumab, with 
cCRT in stage III NSCLC (Jabbour, 2017), and several ongoing trials are testing concurrent anti-
PD-1 or anti-PD-L1 therapies with cCRT in other solid tumor malignancies.
In the metastatic NSCLC setting, prior to the advent of immune checkpoint inhibitors (ICIs), the 
mainstay of treatment was chemotherapy involving platinum-containing doublets.  The 5-year 
survival rate for these subjects was low, ranging from 10% for stage IVA to less than 1% for 
stage IVB (American Cancer Society, 2018). Additional treatment for some patients is based on
tumor mutation status such as EGFR, ALK or proto-oncogene tyrosine-protein kinase ROS
(ROS-1) mutations, where tyrosine kinase inhibitors are primary treatment options.  In 2017, 
pembrolizumab in combination with pemetrexed and carboplatin was granted accelerated 
approval in the US in the first-line setting for all nonsquamous stage IV subjects based on the 
results of the Keynote-021 Phase 2 randomized study (Langer, 2016). Pembrolizumab is also 
approved for and recommended by the NCCN as a single-agent, first-line therapy in patients 
with advanced NSCLC who have PD-L1 expression levels of > 50% and EGFR mutation and 
ALK and ROS rearrangements negative or unknown based on the Keynote-024 study (Reck, 
2016) (Table 1). Most recently, the KEYNOTE-189 Phase 3 study showed that in subjects with 
previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the 
addition of pembrolizumab to standard chemotherapy (pemetrexed with a platinum-based drug) 
resulted in a significantly longer rate of OS at 12 months (69.2% versus 49.4% [HR 0.49; 95% 
CI, 0.38 to 0.64; P < 0.001]) and median PFS (8.8 months versus 4.9 months [HR 0.52; 95% CI, 
0.43 to 0.64; P < 0.001]) than chemotherapy alone (Gandhi, 2018).  In addition, the median PFS 
was significantly prolonged among subjects with stage IV or recurrent NSCLC who had high 
tumor mutational burden and were treated with nivolumab plus ipilimumab in the first-line 
setting compared to chemotherapy alone (7.2 months versus 5.5 months [HR 0.58; 97.5% CI, 
0.41 to 0.81; P < 0.001]) (Hellmann, 2018).
Targeted therapy is recommended for subjects with metastatic NSCLC with ALK or ROS1 
rearrangements or EGFR mutations, and subsequent targeted therapy can be used in subjects 
with EGFR mutations or ALK translocations upon progression (NCCN, 2018). For those 
subjects who do not have these genetic alterations, the NCCN recommends ICIs as preferred 
subsequent therapy based on improved OS, longer duration of response, and fewer AEs when 
compared to cytotoxic therapy.  Nivolumab has been FDA approved as subsequent therapy for 
patients with metastatic nonsquamous NSCLC (Checkmate-057) (Borghaei, 2015) and metastatic 
squamous NSCLC (Checkmate-017) (Brahmer, 2015) who have progressed on or after first-line 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
26
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
chemotherapy based on the Phase 3 randomized trial data.  Based on data from Keynote-010 
(Herbst, 2016) and Keynote-001(Garon, 2015) and FDA accelerated approval, the NCCN also 
recommends pembrolizumab as subsequent therapy for patients with metastatic NSCLC and PD-
L1 expression.  Atezolizumab has also been FDA approved for the treatment of patients with 
metastatic NSCLC whose disease progressed during or following platinum-containing 
chemotherapy. A summary of approved anti-PD-1 and anti-PD-L1 inhibitors for the treatment of 
advanced or metastatic NSCLC (not including durvalumab which was approved in Feb 2018 by 
US FDA for treatment of patients with unresectable stage III NSCLC whose disease has not 
progressed following concurrent platinum-based chemotherapy and radiation therapy) can be 
found in Table 1.
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
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BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 1:
Approved Anti-PD-1 or Anti-PD-L1 Inhibitors for the Treatment of Advanced or Metastatic NSCLC
Second-line treatment for advanced or metastatic lung cancer
First-line treatment for advanced NSCLC
Study
KEYNOTE10a
(Herbst, 2016)
CHECKMATE
057 (Borghaei, 
2015)
CHECKMATE
017 (Brahmer, 
2015)
OAK
(Rittmeyer, 
2017)
KEYNOTE24b
(Reck, 2016)
KEYNOTE021 Cohort G
(Langer, 2016;
Borghaei, 2017)
Subjects
N = 1034
N = 582
N = 272
N = 1225
N = 305
N = 123
Treatment
Pembro-
lizumab 
2 mg/kg 
(n = 345)
Pembro-
lizumab 
10 mg/kg
(n = 346)
Doce-
taxel 
(n = 
343)
Nivo-
lumab 
(n = 
287)
Doce-
taxel 
(n = 
268)
Nivo-
lumab 
(n = 
131)
Doce-
taxel 
(n = 
129)
Atezo-
lizumab 
(n = 
425)
Doce-
taxel 
(n = 
425)
Pembro-
lizumab 
mono-
therapy 
(n = 154)
Platinum-
based-
chemo-
therapy 
(n = 151)
Pembrolizumab 
plus pemetrexed/
carboplatin
(n = 60)
Chemo-
therapy 
only
(n = 63)
OS 
(months)
10.4
(9.4 -
11.9)
12.7  
(10.0 -
17.3)
8.5  
(7.5 -
9.8)
12.2
9.4
9.2
6
13.8 
(11.8 -
15.7)
9.6 
(8.6 -
11.2)
80.2
72.4
NR 
(22.8 - NR)
20.9 
(14.9 -
NR)
HR (95% 
CI)
0.71,
(0.58 -
0.88; p = 
0.0008)
0.61,
(0.49 -
0.75; p < 
0.0001)
NA
0.73,
(0.59 - 0.89; p = 
0.002)
0.59,
(0.44 - 0.79; p < 
0.001)
0.74,
(0.58 - 0.93; p = 
0.0102)
0.60
(0.41-0.89; p = 0.005)
0.59, 
(0.34-1.05; p = 0.03)
mPFS 
(months)
3.9 
(3.1 - 4.1)
4.0 
(2.7 - 4.3)
4.0 
(3.1 -
4.2)
2.3
4.2
3.5
2.8
2.8 
(2.6 -
3.0)
4.0 
(3.3 -
4.2)
10.3
6
19.0 
(8. 5 - NR)
8.9 
(6.2 -
11.8)
HR (95% 
CI)
0.88, 
(0.74 -
1.05; 
p = 0.068)
0.79, 
(0.66-
0.94;
p = 
0.004)
NA
0.92, 
(0.77-11; p = 0.39)
0.62, 
(0.47 - 0.81; p < 
0.001
0.95, 
(0.82-1.10)
0.50,
(0.37 - 0.68; p < 0.001)
0.54,
(0.33 - 0.88; p = 0.0067)
ORR (%)
18 
(14 - 23)
18 
(15 - 23)
9 
(7 - 13)
19
12
20,
9
14
13
44.8
27.8
55% (95% CI = 
42 – 68)
29% (95% 
CI = 18 –
41)
p-value
p < 0.001
p < 0.001
NA
p = 
0.021
NA
p = 
0.008
NA
NA
NA
NA
NA
NA
NA
TEAE ≥ 
Grade 3 
(%)
13
16
35
10
54
7
55
15
43
26.6
53.3
40
26
a FDA accelerated approval was granted for pembrolizumab in the metastatic NSCLC population with PD-L1 ≥1%
b FDA approval was granted for pembrolizumab as a single-agent, first-line therapy in patients with advanced NSCLC who have PD-L1 expression levels of >
50% and EGFR mutation and ALK and ROS rearrangements negative or unknown
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
28
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Abbreviations: CI = confidence interval; HR = hazard ratio; mPFS = median progression-free survival duration in months; NA = not available; NSCLC = non-
small cell lung cancer; NR = not reported; ORR = overall response rate; OS = overall survival; PD-1 = programmed cell death protein-1; PD-L1 = program cell 
death protein ligand-1; TEAE = treatment emergent adverse event
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&


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
29
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
1.2.
Compound Background 
1.2.1.
Pharmacology
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies. 
Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and affinity 
(KD = 0.15 nM). It competitively blocks the binding of both PD-L1 and programmed cell death 
ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T cells. In in vitro cell-
based assays, tislelizumab was observed to consistently and dose-dependently enhance the 
functional activity of human T cells and preactivated, primary peripheral blood mononuclear 
cells. In addition, tislelizumab has demonstrated antitumor activity in several human cancer 
allogeneic xenograft models, in which peripheral blood mononuclear cells were co-injected with 
human cancer cells (A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon 
cancer]) into immunocompromised mice. Robust antitumor activity of tislelizumab was also 
observed in human PD-1 transgenic mice transplanted with B16/F10 mouse melanoma cells 
overexpressing antimurine granulocyte-macrophage colony-stimulation factor.
The IgG4 variant antibody has very low binding affinity to FcγRIIIA and complement 1q, a 
subunit of complement 1, by in vitro assays, suggesting low or no antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity effects in humans (Labrijn, 2009). Unlike 
native IgG4 antibody, tislelizumab has no observable fragment antigen-binding-arm exchange 
activity in an in vitro assay, predicting the antibody would be stable in vivo and unlikely to form 
bispecific antibodies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
30
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
31
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
32
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
33
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
While cCRT has become the standard of care for the treatment of locally advanced, unresectable 
stage III NSCLC, as shown by the RTOG 9410 study which reported a significant improvement 
in overall survival with concurrent cisplatin-based chemoradiotherapy compared to sequential 
chemoradiotherapy (Curran, 2011), there has not been substantial improvement subsequently 
with cCRT alone despite exploration of different treatment options such as dose escalation of 
radiation, induction chemotherapy, and various regimens of consolidative chemotherapy 
following cCRT (Postmus, 2017). 
There is strong evidence that not only can there be synergy of ICIs with chemotherapy, this can 
occur with concurrent chemoradiotherapy as well. It is now known that both chemotherapy and 
RT can up-regulate the expression of PD-L1 (Zhang, 2008; Deng, 2014) due to the release of 
cytokines and other inflammatory molecules, which could make such tumors sensitive to a PD-
1/PD-L1 directed therapy. In this setting, chemotherapy and RT act as priming agents for 
immunotherapy; elimination of cancer cells by chemotherapy and/or RT triggers release of 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
34
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
antigens, which can turn poorly immunogenic or immunosuppressive tumors into an 
immunogenic environment (Vanneman, 2012). In addition, RT has an impact on the immune 
system by engaging both the innate and the adaptive arms, eliciting tumor-specific T-cells and 
establishing an immune memory against the tumor. This prolongs the effect of radiation,
improving locoregional control, decreasing metastatic spread, and increasing overall survival 
(Formenti, 2013). It is also anticipated that while chemotherapy has been shown to sensitize 
tumors to radiation therapy, immunotherapy with PD-1/PD-L1 therapies may be less directly 
interacting, and emerging data suggests that PD-1/PD-L1 antibodies can be given at full doses
with RT as they can be with chemotherapy (Fiorica, 2018).
As described earlier, the PD-L1 inhibitor, durvalumab, has demonstrated a PFS improvement in 
locally advanced, unresectable stage III NSCLC patients who were fully recovered and had not 
progressed following a full course of combined modality therapy.  A limitation of the PACIFIC 
study is that there was no requirement for fluorodeoxyglucose-positron emission tomography 
(FDG-PET) scans and/or brain imaging to rule out stage IV disease; this may have confounded 
the efficacy results in favor of the durvalumab arm and depressed the efficacy observed with 
combined modality alone in the control arm.  This study will require all subjects to be staged 
with FDG-PET and brain imaging to better establish that all randomized subjects are stage III.  
As only approximately 70% of subjects in the PACIFIC study who were enrolled were 
randomized, this trial will seek to determine if improved efficacy can be achieved to allow a 
higher proportion of subjects to complete the cCRT phase and enter the monotherapy phase.  In 
consideration of the limitations of the PACIFIC trial, this protocol will evaluate whether the 
addition of an anti-PD-1 therapy added to combined modality therapy can benefit subjects with 
definitive stage III unresectable NSCLC. In addition, the PACIFIC study subgroup analysis of 
PFS showed that subjects who started durvalumab closer to the last radiation therapy (last 
radiation to randomization < 14 days versus ≥ 14 days) seemed to trend towards greater PFS 
benefit with durvalumab.  Thus, the earlier introduction of tislelizumab given simultaneously 
with cCRT (Arm 1) may lead to further enhancement of immune mediated antitumor efficacy.
1.3.2.
Rationale for the Study Design
All randomized subjects on this trial will receive standard of care combined modality cCRT.  In 
order to minimize the heterogeneity of different chemotherapy backbones, this study will allow 
Investigators the option of cisplatin-etoposide as established by the PROCLAIM study.  This 
study will also allow weekly paclitaxel and carboplatin to give Investigators more than one 
chemotherapy option, as supported by the NCCN guidelines and the literature (NCCN, 2018; 
Yamamoto, 2010).  Radiotherapy will be given concurrently with chemotherapy for 5 days per 
week for 6 weeks, in once daily fractions, 2 Gy per fraction, to a target dose of 60 Gy in 30 
fractions.  As a pooled analysis of 41 Phase 2/3 trials did not show any evidence that 
consolidation after cCRT improves survival for stage III NSCLC and current guidelines continue 
to recommend cCRT alone (Bayman, 2014; Postmus, 2017), no consolidation chemotherapy will 
be given.  
Induction chemotherapy will not be allowed. All treatment will be initiated after randomization, 
and the study will be stratified according to the chemotherapy regimen chosen.
This study will employ a 3-arm design to evaluate the anti-PD-1 antibody, tislelizumab, in 
locally advanced unresectable stage III NSCLC. Subjects will be randomized 1:1:1 to receive 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
35
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
tislelizumab together with cCRT followed by tislelizumab monotherapy, or placebo together 
with cCRT followed by tislelizumab monotherapy, or placebo together with cCRT followed by 
placebo monotherapy. Subjects will be required to have EGFR mutation and ALK gene 
translocation results available prior to randomization; EGFR/ALK positive subjects will be 
allowed up to a maximum of 10% of the total number of subjects randomized.  The standard of 
care for patients with stage III NSCLC regardless of EGFR mutation or ALK gene translocation 
remains cCRT (NCCN, 2018; Postmus, 2017).  Targeted therapy is not utilized as upfront 
therapy for patients with EGFR mutations or ALK gene translocations and is still being 
investigated in trials such as RTOG 1306 (Berman, 2016).  A recent meta-analysis of 5 trials 
involving 3025 subjects with advanced second-line or later NSCLC randomized to receive a 
checkpoint inhibitor or docetaxel showed that there was prolonged survival in those who were 
EGFR wild type but not in those who were EGFR mutant (Lee, 2018), suggesting that there is no 
clear benefit from checkpoint inhibitor monotherapy for patients with EGFR mutations.  In 
contrast, in the PACIFIC study, subjects with EGFR mutation comprised 6% of the study 
population and the results in the subgroup analyses were consistent with the ITT population with 
a demonstrated PFS benefit from durvalumab, though a significant number of subjects (26%) did 
have unknown EGFR mutation status (Antonia, 2017). In the study IMpower150, where 
EGFR/ALK subjects represented 14% of the enrolled population, benefits have been observed 
(Reck, 2017). Thus, this study will include a limited number of subjects with EGFR mutation or 
ALK gene translocation, as this population warrants further investigation of anti-PD-1 therapy 
with cCRT in the first-line setting for stage III unresectable NSCLC. By requiring testing at 
screening, this study will better address the effect of anti-PD-1 therapy in patients with tumors 
expressing these gene alterations. In addition, this study will require all subjects be staged with 
FDG-PET CT and brain imaging to better establish that all randomized subjects are stage III.  
Prior studies of PD-1/PD-L1 therapy given concurrently with chemotherapy or with or in close 
proximity to radiation suggests a manageable safety profile (Samstein, 2017).  Furthermore, the 
PACIFIC study did not show any new safety signals when durvalumab was given after cCRT, 
with the safety profile consistent with other immunotherapies and monotherapy, with 
pneumonitis mostly low grade, and clinically important Grade 3 or 4 toxicities were balanced 
between the 2 groups.  However, the safety and tolerability of checkpoint inhibitors given 
concurrently with cCRT is still being evaluated. Preliminary data suggest that combining anti-
PD1 therapy and RT is safe (Liniker, 2016). Most recently, the early interim safety analysis of 
the NICOLAS study, a Phase 2 trial evaluating the addition of the anti-PD-1 therapy nivolumab 
to first-line cCRT in locally advanced, unresectable stage III NSCLC showed that this approach 
was safe and tolerable in that study, with no unexpected AEs or increased safety risks identified.  
At the time of this early interim safety analysis, 49 subjects had been recruited with a median 
follow-up of 6.6 months. The most frequently observed AEs were fatigue and anemia. For the 
first 21 patients, no pneumonitis grade ≥3 was observed by the end of the 3-month post-RT 
follow-up period (Peters, 2018). To address any potential toxicities of administering anti-PD-1 
treatment, particularly when given simultaneously with cCRT, a rigorous safety assessment will 
be implemented, with independent data monitoring committee (IDMC) safety reviews to assess 
for early safety signals.
 
 
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
Confidential and Proprietary
36
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 Enrollment may continue 
during these IDMC safety reviews.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
1.3.3.1.
Rationale for Selection of Tislelizumab Dose
The PK, safety, and efficacy data obtained from 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 
 was selected for further 
evaluation. Rates of treatment-related AEs and serious adverse events (SAEs) observed in 
patients receiving 
 were comparable, suggesting no clear 
dose-dependence across these regimens. Similarly, confirmed overall response rates (ORR) in 
subjects treated with tislelizumab 
 ranged between 10% and 15%, 
compared to a range of 15% to 38% for patients treated at
.
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 
 fell between serum exposure observed after 
 doses (dose 
range with comparable safety and efficacy rates). 
Additionally, no unexpected treatment related AEs occurred in the 
 cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable subjects treated (n = 13), 3 patients (23%) had a best overall response of PR, 4 subjects
(31%) had a best overall response of stable disease, and 6 subjects (46%) had a best overall 
response of progressive disease (PD). Therefore, clinical activity with a manageable and 
tolerable safety profile is expected to be maintained in subjects receiving tislelizumab 
 
.
1.3.3.2.
Rationale for Selection of Chemotherapies
Multiple chemotherapy backbone regimens, including combinations of cisplatin with either 
pemetrexed, etoposide, vinblastine, or vinorelbine, have been studied in stage III NSCLC and are 
acceptable combination regimens that can be utilized as standard of care in cCRT.  Few studies 
have been conducted comparing these chemotherapy regimens, and no chemotherapy regimen 
has been clearly demonstrated to be better than others. Of these chemotherapy doublets that have 
comparative evidence, cisplatin in combination with either pemetrexed or etoposide has been 
studied in this treatment population.  The PROCLAIM multinational trial endeavored to establish 
whether cisplatin-pemetrexed is superior to cisplatin-etoposide when given concurrently with 
standard radiotherapy at 60 to 66 Gy, followed by a consolidation phase; cisplatin-pemetrexed 
was not found to be superior in OS to cisplatin-etoposide (median OS 26.8 versus 25.0 months; P 
= 0.831).  Both arms had low incidences of Grades 3 or 4 pneumonitis (< 3%) and there were no 
significant differences between arms in treatment discontinuations due to drug-related AEs or 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
37
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
drug-related deaths (Senan, 2016). Carboplatin with paclitaxel given weekly during radiation is 
another acceptable cCRT option as recommended by the NCCN guidelines, with the 2 cycles of 
carboplatin and paclitaxel consolidation considered as optional (NCCN, 2018).  Weekly 
carboplatin/paclitaxel with RT has been evaluated in several studies (Belani, 2005; Vokes, 2007; 
Yamamoto, 2010; Bradley, 2015) and is often used as a first-line treatment for locally advanced, 
unresectable stage III NSCLC in the US and other countries globally.  Weekly 
carboplatin/paclitaxel was used as part of the chemotherapy regimen backbone in the RTOG 
0617 study that evaluated standard versus high doses of radiation to be given concurrently with 
chemotherapy (Bradley, 2015). A Phase 3 trial of concurrent thoracic radiation in unresectable 
stage III NSCLC found that weekly carboplatin/paclitaxel was superior to second-generation 
chemotherapy regimens such as mitomycin/vindesine, weekly irinotecan/carboplatin, or cisplatin 
or carboplatin as a single agent with radiation therapy (Yamamoto, 2010).  
For the chemotherapy backbone, this study will allow Investigators the choice of 
cisplatin/etoposide, given concurrently with RT based on the PROCLAIM study, or 
carboplatin/paclitaxel given weekly with RT; neither regimen will allow chemotherapy
consolidation.  
1.3.3.3.
Rationale for Selection of Radiotherapy Dose
The total dose of RT will be 60 Gy in 30 once-daily fractions of 2 Gy according to the standard 
dose recommended by the American Society of Radiation Oncology (Rodrigues, 2015), based on 
the dose for locally advanced, unresectable stage III NSLC established in the RTOG 0617 study 
(Bradley, 2015). The dose of 60 Gy is endorsed by ASCO (Bezjak, 2015), and is a dose 
supported by the NCCN and ESMO guidelines for cCRT (NCCN, 2018; Postmus, 2017). Dose 
escalation beyond 60 Gy in the context of combined modality concurrent chemoradiation has not 
been found to be associated with any clinical benefits (Rodrigues, 2015). 
Although other recent Phase 3 studies such as PROCLAIM had used a dose of 66 Gy (2 Gy per 
fraction), PROCLAIM was designed before the results of the RTOG 0617 study became 
available (Senan, 2016). As the present trial will involve administration of a PD-1 inhibitor with 
cCRT, it is critical for the radiation dosing to be standardized across the entire study globally, 
with the target dose of 60 Gy chosen as it is appropriate to eradicate the primary tumor and the 
involved lymph nodes, while minimizing toxicities such as acute radiation esophagitis and 
pneumonitis as much as possible.
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
38
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
1.3.5.
Rationale for Patient-Reported Outcomes and Quality of Life or Health 
Economics
It will be important to assess treatment effectiveness both in terms of objective outcomes (eg, 
PFS or OS) and subjective, patient reported outcomes (PROs) to ensure that the addition of 
tislelizumab to cCRT followed by tislelizumab monotherapy in newly-diagnosed, unresectable 
locally advanced NSCLC subjects, does not result in a detrimental impact on subjects’ health-
related quality of life (HRQoL) when compared to cCRT alone. This detailed information can 
help both clinicians and subjects to make informed and comprehensive decisions regarding the 
best available treatments. Patient reported outcomes are any information self-reported by the 
subject regarding their functioning or symptoms in relation to their health condition or therapy. 
Patient-reported HRQoL falls under the umbrella of PROs and covers physical symptoms and 
functioning domains, and usually provides an overall subject evaluation of their health and 
quality of life. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
39
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 2:
Study Objectives
Primary Objective
The primary objective is to compare the progression free survival (PFS) of tislelizumab in combination 
with concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy (Arm 1) versus cCRT 
alone (Arm 3); in addition, tislelizumab given sequentially after cCRT (Arm 2) will be compared with 
cCRT alone (Arm 3) in newly diagnosed stage III subjects with locally advanced unresectable non-small 
cell lung cancer (NSCLC).
Secondary Objective(s)
The secondary objectives are to: 
!
Compare overall survival (OS) (key secondary objective)
!
Compare OS at 24 months (key secondary objective)
!
Compare centrally assessed objective response rate (ORR) (key secondary objective)
!
Compare centrally assessed duration of response (DOR)
!
Compare proportion of subjects alive and progression-free at 12 and 18 months (APF12, APF18)
!
Compare time to death or distant metastasis (TTDM) 
!
Compare safety and tolerability of tislelizumab in combination cCRT followed by tislelizumab 
monotherapy versus cCRT alone, and tislelizumab given sequentially after cCRT versus cCRT 
alone
!
Compare impact on patient-reported lung cancer symptoms (appetite loss, cough, chest pain, 
dyspnea, and fatigue) assessed by the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and its lung cancer module (EORTC 
QLQ-LC13)
!
Compare the proportion of subjects who received at least one dose of tislelizumab or placebo in 
the monotherapy phase before progression in Arm 1 versus Arm 2 and 3.
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
40
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 3:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Progression free 
survival (PFS)
The time from the date of 
randomization to the date of the 
first objectively documented tumor 
progression as assessed by blinded 
independent central review per 
RECIST v1.1 or death from any 
cause, whichever occurs first
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until disease 
progression, new disease 
therapy, death or withdrawal 
of consent
Key 
Secondary
Overall survival 
(OS)
The time from the date of 
randomization to the date of death 
due to any cause 
Randomization to death
OS at 24 months
The proportion of subjects alive at 
24 months after randomization
Randomization to 24 months
Objective response 
rate (ORR)
The proportion of subjects in the 
ITT population who had complete 
response (CR) or partial response 
(PR) as assessed by blinded 
independent central review per 
RECIST v1.1
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until disease 
progression, new disease 
therapy, death or withdrawal 
of consent
Secondary
Duration of 
response (DoR)
The time from the first occurrence 
of a documented objective 
response to the time of relapse, as 
determined by blinded independent 
central review per RECIST v1.1, 
or death from any cause, 
whichever comes first
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until disease 
progression, new disease 
therapy, death or withdrawal 
of consent
Proportion of 
subjects alive and 
progression-free at 
12 months (APF12)
The proportion of subjects alive 
and progression free at 12 months 
(APF12) will be defined as the 
Kaplan-Meier estimate of PFS at 
12 months.
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until, disease 
progression, new disease 
therapy, death or withdrawal 
of consent
Proportion of 
subjects alive and 
progression-free at 
18 months (APF18)
The proportion of subjects alive 
and progression free at 18 months 
(APF18) 
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until disease 
progression, new disease 
therapy, death or withdrawal 
of consent
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
41
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 3:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Time to distant 
metastasis (TTDM)
TTDM will be defined as the time 
from the date of randomization 
until the first date of distant 
metastasis or death in the absence 
of distant metastasis. Distant 
metastasis is defined as any new 
lesion that is outside of the 
radiation field according to 
RECIST v1.1 or proven by biopsy.
Every 6 weeks post C1D1 for 
the first 36 weeks and then 
every 9 weeks until disease 
progression, new disease 
therapy, death or withdrawal 
of consent or death
Safety and 
tolerability
Safety and tolerability will be 
assessed from adverse events 
(using NCI CTCAE v5.0), 
laboratory tests, vital signs, ECOG 
performance status, physical 
exams, concomitant medications, 
and dose modifications.
Signature of informed 
consent through 90 days after 
the last dose of study 
treatment
Impact on the 
selected patient-
reported lung 
cancer symptoms 
(appetite loss, 
cough, chest pain, 
dyspnea, and 
fatigue) assessed by 
the corresponding 
domains in EORTC 
QLQ-C30 and its 
lung cancer module 
(EORTC QLQ-
LC13).
Differences between study arms, 
tests for within-group changes 
over time and tests for both 
deterioration and improvement 
will be performed on the selected 
lung cancer symptoms (appetite –
item 13 of EORTC QLQ-C30, 
cough – items 31 to 32 of EORTC 
QLQ-LC13, chest pain – item 40 
of EORTC QLQ-LC13, dyspnea –
items 33 to 35 of EORTC QLQ-
LC13, and fatigue – items 10, 12, 
18 of EORTC QLQ-C30)
Based on 
tislelizumab/placebo 21-day 
cycle: Screening, Day 1 of 
every cycle during study 
treatment, at discontinuation 
of the study treatment, and
30 days after the last dose of 
tislelizumab/placebo 
Proportion of 
subjects who 
continue to 
monotherapy phase
Proportion of subjects who receive 
at least one dose of tislelizumab or 
placebo in the monotherapy phase 
before progression as determined 
by blinded independent central 
review per RECIST v1.1
Randomization to the first 
dose in the monotherapy 
phase
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
42
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 3:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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*


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
43
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 3:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AEs = adverse events; C1D1 = Cycle 1 Day 1;
; ECOG = Eastern 
Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-C30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire lung cancer module; IHC = immunohistochemistry; ITT = intent-to-treat; NCI
CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events  version 5.0;
 
 
QoL = quality of life; RECIST v1.1 = 
Response Evaluation Criteria in Solid Tumors version 1.1; 
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
44
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study 
designed to compare the efficacy and safety of tislelizumab in combination with cCRT followed 
by tislelizumab monotherapy versus cCRT alone, and tislelizumab given sequentially after cCRT 
versus cCRT alone, in newly diagnosed stage III subjects with locally advanced, unresectable 
NSCLC. 
The primary endpoint is centrally-assessed PFS in the intent-to-treat (ITT) population. Newly 
diagnosed stage III subjects with histologically confirmed, locally advanced, unresectable 
NSCLC are eligible.
Approximately 840 subjects will be randomized in a 1:1:1 ratio to receive tislelizumab or 
placebo in the following 3 arms:  
!
 
 
 
The choice of chemotherapy regimen to be used as part of study treatment will be at the 
Investigator’s discretion, consisting of 2 cycles of cisplatin plus etoposide or weekly carboplatin 
plus paclitaxel given during RT for 6 weeks.  Radiation therapy should start concurrently with 
chemotherapy in Cycle 1 of tislelizumab or placebo. If local technical or logistical circumstances 
do not allow for the start of RT at the beginning of Cycle 1, a 3-day administrative window to 
start RT will be allowed. Tislelizumab or placebo will be given starting from Cycle 1 Day 1 
(C1D1) in the cCRT phase, and continued in the monotherapy phase for a duration of 12 months 
following the completion of cCRT, or until disease progression, unacceptable toxicity, or 
treatment discontinuation for another reason.
Subjects with EGFR sensitizing mutations or ALK gene translocations may be randomized up to 
approximately 10% of the total randomized population.
Randomization will be stratified by age 
), chemotherapy regimen 
), and region (
).
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
45
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the 
Investigator to reflect pseudoprogression, the subject may continue study treatment until 
progressive disease is confirmed by repeated imaging at least 4 weeks later but not exceeding 6 
to 8 weeks from the date of initial documentation of progressive disease, provided the following 
criteria are met:
!
Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values). 
!
Stable ECOG performance status (≤ 1).
!
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention.
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform subjects that this practice is not considered standard in the treatment of 
cancer. The decision to continue study drug(s) beyond initial Investigator-assessed progression 
must be discussed with the Sponsor medical monitor and documented in the study records.
The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, 
the Investigator may contact the medical monitor and forward appropriate supporting documents 
for review and discussion.
 
 
.
The blind should be maintained for persons responsible for the ongoing conduct of the study
through database lock and statistical analyses. Blinded persons may include but are not limited 
to: Clinical Research Physician, Clinical Research Scientist, Clinical Trial Manager, Study 
Statistician, Data Manager, Programmers, Clinical Research Associates. The study conduct will 
be overseen by a Steering Committee (SC) composed of selected Investigators who are taking 
part in the study.  The SC will remain blinded to the study data by arm.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
46
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
Figure 1:
Overall Study Design
                                                                                         
Randomization 1:1:1
N=840 (280 per Arm)
Stratification by age 
), chemotherapy regimen 
 
), and region (
)
 
 
Follow-Up
Safety until 90 days posttreatment (30 days posttreatment for AEs except for irAEs which require 90 days 
posttreatment follow up)
Response evaluation until progression, subsequent anticancer therapy, withdrawal of consent, lost to follow-up,
or death 
Survival follow-up until death, withdrawal of consent, lost to follow-up, or end of study
 
 
Screening
Eligibility Check
Collect tumor tissue and blood samples as applicable
Treat until progressive disease, death, 
unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 12 
months after cCRT phase.
 
 
Treat until progressive disease, 
death, unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 
12 months after cCRT phase.
Treat until progressive disease, death, 
unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 
12 months after cCRT phase.
IDMC safety check 
 
 
IDMC safety check 3 to 6 months after the first check, then approximately every 6 months thereafter
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
47
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Abbreviations:  C1D1 = Cycle 1 Day 1;
; IDMC = independent data 
monitoring committee; 
3.2.
Study Duration for Subjects 
Subjects may begin screening up to 28 days before randomization. Treatment must begin within 
3 days of randomization. Subjects will be treated for a maximum of approximately up to 6 weeks 
by cCRT plus either tislelizumab or placebo, followed by tislelizumab or placebo monotherapy
for a total of 12 months after completion of cCRT. Subjects will be followed in survival follow-
up until death, withdrawal of consent, lost to follow-up, or end of study. The total duration of 
tislelizumab (Arm 1), placebo followed by tislelizumab (Arm 2), or placebo alone (Arm 3) will 
be approximately 14 months, including the cCRT period.
Enrollment is expected to take approximately 28 months to complete. The total study duration is 
estimated to be approximately 61 months from the randomization of the first subject to the final 
analysis, conducted when approximately 572 OS events have occurred across the 3 arms. 
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
posttreatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol, 
whichever is the later date.
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
48
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 840 subjects with newly-diagnosed, locally advanced, stage III unresectable
NSCLC will be randomized worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject has newly diagnosed, histologically confirmed, locally advanced, stage III 
unresectable NSCLC.  
a.
Staging will be confirmed at screening by PET/CT and brain imaging by magnetic 
resonance imaging (MRI) or computed tomography (CT) with contrast.
b. FDG-PET/CT will be performed whole body, or sufficient to rule out distant 
metastases (eg, from skull base to knees), to exclude distant disease and confirm that 
subjects are in stage III. If the CT scan portion is with contrast and is of sufficiently
high quality, a separate CT scan at screening can be skipped.
c.
While centers are encouraged to obtain tissue confirmation of lymph node metastases 
in N2 or N3 disease, the tumor board/multidisciplinary team in individual cases may 
dispense with this procedure (AJCC Cancer Staging Manual, 2017).
4. Subject must have EGFR mutation and ALK gene translocation status available (testing 
using tumor tissue only) prior to randomization:
a.
If EGFR mutation and ALK gene translocation results are not available, subjects will 
be tested for EGFR sensitizing mutation or ALK translocation (using tumor tissue 
only). The test results verifying the presence or absence of both EGFR mutation and 
ALK gene translocation must be made available to the Sponsor for assessment before 
randomization. 
b. Subjects with EGFR mutation or ALK gene translocation will represent 
approximately 10% of the total randomized population. After this number is reached, 
subjects with EGFR mutation or ALK gene translocation will be excluded.
5. Subjects must be able to provide fresh or archival tumor tissues (formalin-fixed paraffin 
embedded [FFPE] blocks or at least 15 to 20 freshly cut unstained FFPE slides) with an 
associated pathological report (squamous or nonsquamous). In the absence of archival 
tumor tissues, a fresh biopsy (a minimum of 2 to 3 cores) of a tumor lesion at baseline is 
mandatory.  Subjects may be permitted to be enrolled on a case-by-case basis after 
discussion with the Sponsor medical monitor if fewer than 15 unstained slides can be
provided.
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
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d


Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
49
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7. Subject has adequate hematologic and end-organ function, as defined by the following 
laboratory results (obtained ≤ 2 weeks prior to randomization): 
a.
Absolute neutrophil count (ANC) ≥1.5 x 109/L 
b. Platelet count ≥100 x 109/L 
c.
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (≥ 28 days after growth factor support or 
transfusion) 
d. Calculated creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula) for 
subjects receiving cisplatin/etoposide, and ≥ 45 mL/min (Cockcroft-Gault formula)
for subjects receiving carboplatin/paclitaxel. 
e.
Total serum bilirubin ≤1.5 x upper limit of normal (ULN) (≤ 3 x ULN, if Gilbert’s 
syndrome or if indirect bilirubin concentrations are suggestive of extrahepatic source 
of the elevation)
f.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN 
8. A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at 
some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not 
been naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any time 
in the preceding 24 consecutive months) and must:
a.
Have 2 negative pregnancy tests as verified by the Investigator prior to starting study 
therapy. She must agree to ongoing pregnancy testing during the course of the study, 
and after end of study therapy. This applies even if the subject practices true 
abstinence* from heterosexual contact.
b. Agree to use 2 reliable forms of contraception simultaneously or to practice complete 
abstinence from heterosexual contact during the following time periods related to this 
study: 1) for at least 28 days before starting study treatment; 2) while taking study 
treatment; 3) during dose interruptions; and 4) for at least 120 days after the subject’s 
last dose of tislelizumab or placebo and 180 days after the subject’s last dose of 
chemotherapy. The 2 methods of reliable contraception must include one highly 
effective method and one additional effective (barrier) method. The following are 
examples of highly effective and additional effective methods of contraception:
!
Examples of highly effective methods:
∀
Intrauterine device
∀
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with the inhibition of ovulation (oral, intravaginal, or transdermal)
∀
Progestogen-only hormonal contraception associated with the inhibition of 
ovulation (oral, injectable, intrauterine, or implantable)
∀
Tubal ligation
∀
Vasectomized male partner, provided that the vasectomized partner is the sole 
sexual partner of the study participant and that the vasectomized partner has 
received medical assessment of surgical success.
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
50
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
Examples of additional effective methods:
∀
Male condom or female condom with or without spermicide
∀
Diaphragm
∀
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∀
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primary mode of action
9. Male subjects must:
a.
Practice true abstinence* (which must be reviewed on a monthly basis) or agree to 
use a condom during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and 
for at least 120 days after the subject’s last dose of tislelizumab or placebo and 180 
days after the subject’s last dose of chemotherapy, or longer if required by local 
regulations, even if he has undergone a successful vasectomy.
b. Agree to not donate sperm
10. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has received prior therapies targeting PD-1 or PD-L1. 
2. Subject has received chemotherapy, radiation, targeted therapy, biologic therapy, 
immunotherapy or investigational agent used to control NSCLC. 
3. Subject has a history of severe hypersensitivity reactions to other monoclonal antibodies. 
4. Subject has a history of interstitial lung disease or documented ongoing interstitial lung 
disease or history of pneumonitis that has required oral or intravenous steroids. 
5. Subject’s radiation treatment plans are likely to encompass a volume of whole lung 
receiving ≥ 20 Gy in total (V20) of more than 38% of lung volume. 
6. Subject has clinically significant pericardial effusion. 
7. Subject has clinically uncontrolled pleural effusion or ascites that requires pleurocentesis 
or paracentesis for drainage within 2 weeks prior to randomization. 
8. Subject has had a major surgical procedure, open biopsy, or significant traumatic injury ≤ 
14 days prior to randomization, or anticipation of need for major surgical procedure 
during the course of the study.  Note: Eligible patients for this study must have locally 
advanced, stage III NSCLC that is considered to be unresectable.  Any patient for whom 
the institutional practice would consider surgery to be a treatment option if disease 
                                               
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception].
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Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
51
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
downstaging is observed after completion of the chemoradiotherapy should be considered 
ineligible.
a.
Placement of vascular access device is not considered major surgery. 
9. Subject has any active malignancy ≤ 2 years before randomization, with the exception of 
NSCLC and any locally recurring cancer that has been treated curatively (eg, resected 
basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the 
cervix or breast).
10. Subject has severe chronic or active infections requiring systemic antibacterial, antifungal 
or antiviral therapy, including tuberculosis infection. 
11. Subject has known Human Immunodeficiency Virus (HIV) infection. 
12. Subject has untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with 
HBV deoxyribonucleic acid (DNA) > 500 IU/mL (2500 copies/mL), or active hepatitis C. 
a.
Subjects with inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable 
hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C can be enrolled.
13. Subject has active autoimmune diseases or history of autoimmune diseases that may 
relapse.  Subjects with the following diseases are allowed to be enrolled after further 
screening: type I diabetes, hypothyroidism managed with hormone replacement therapy 
only, skin diseases not requiring systemic treatment (such as vitiligo, psoriasis, or 
alopecia), or diseases not expected to recur in the absence of external triggering factors. 
14. Subject has medical conditions requiring systemic treatment with either corticosteroids (> 
10 mg daily prednisone or equivalent) or other immunosuppressive medications within 
14 days of randomization.  
a.
A brief (≤ 7 days) course of corticosteroids for prophylaxis (eg, contrast dye allergy) 
or for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted. 
b. Adrenal replacement steroid doses ≤ 10 mg daily prednisone or equivalent are 
permitted in the absence of active autoimmune disease. 
c.
Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption) are permitted. 
15. Subject has any of the following cardiovascular criteria: 
a.
Evidence of acute or ongoing cardiac ischemia 
b. Current symptomatic pulmonary embolism 
c.
Acute myocardial infarction ≤ 6 months prior to randomization 
d. Heart failure of New York Heart Association Classification III or IV ≤6 months prior 
to randomization 
e.
Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to randomization 
f.
Cerebral vascular accident or transient ischemic attack ≤6 months prior to 
randomization 
16. Subject has had prior allogeneic stem cell transplantation or organ transplantation. 
CCI
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f


Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
52
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
17. Subject has used any live vaccines against infectious diseases (eg, varicella, zoster, etc.) 
within 4 weeks (28 days) of randomization. Seasonal influenza vaccines that do not 
contain live virus are permitted.
18. Subject has used any herbal or patent medicines to control cancer or boost immunity 
within 14 days of the first study treatment administration.
19. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
20. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
21. Subject has any condition that confounds the ability to interpret data from the study.
22. Subject has a contraindication to the planned chemotherapy regimen to be administered 
on the study.
CCI
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
53
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
5.
TABLE OF EVENTS
Table 4:
Table of Events
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUc
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion 
criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
X
-
-
X
-
-
X
X
-
-
-
Complete medical 
history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior/concomitant 
medication evaluation
Continuous from ≤ 28 days prior to randomization until 30 days post last dose of study treatment
-
-
Prior/concomitant 
procedures evaluation
Continuous from ≤ 28 days prior to randomization until 30 days post last dose of study treatment
-
-
EGFR/ALK testing on 
tumor tissue (if status 
not available)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
&&,
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&


EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
54
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 4:
Table of Events (Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Confirmation of 
mediastinal nodal 
involvement, if 
applicable 
(Section 4.2)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Patient Reported 
Outcomes: EORTC 
QLQ-C30, LC13
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
SAFETY ASSESSMENTS
Adverse event 
evaluatione
Continuous from informed consent until 30 days post last dose of study treatment for AEs; 90 days post last dose of tislelizumab/placebo for 
irAEs
-
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital signs/weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Performance status 
ECOG
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
Height
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Body surface area 
calculation
-
X
X
X
X
X
X
-
-
-
-
-
-
-
-
Pulmonary function 
test
X
Only if clinically indicated
-
-
-
-
12-lead 
electrocardiogram
X
X
Only if clinically indicated
X
X
-
-
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
55
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 4:
Table of Events (Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Left ventricular 
ejection fraction
X
Only if clinically indicated
-
-
OCT (or equivalent 
diagnostic test) and 
visual acuity testsg
X
Approximately every 15 weeks (± 7 days) during study treatment
Xg
Hematology 
laboratoryfh
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Chemistry laboratoryfh
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Coagulation 
laboratory (PT, PTT, 
INR)h
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
Thyroid functionh
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
C-reactive protein
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HBV/ HCV testi
X
If clinically indicated. For subjects who have detectable HBV DNA or HCV RNA at screening or upon repeat 
testing, respective viral load test every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc.).
-
-
Urinalysis
X
If clinically indicated
-
-
Serum β-hCG 
pregnancy test
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Urine β-hCG 
pregnancy testj
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
&&,
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X
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52
35
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&


EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
56
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 4:
Table of Events (Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
EFFICACY ASSESSMENTS
Tumor assessment
CT/MRI
X
Every 6 weeks after randomization for the first 36 weeks (± 7 Days), and every 9 weeks from Week 36 (± 7 Days) onward until disease 
progression, start of a new anticancer therapy, or withdrawal of consent from the entire study
FDG-PET/CT
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CT scan, with 
contrast, of the head 
or brain MRI with 
contrast
X
Only if clinically indicated
 
 
 
 
 
 
 
 
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9 week
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
57
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 4:
Table of Events (Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
 
 
TREATMENT
Administer IP:
tislelizumab/placebo
-
X
-
-
X
-
-
Xn
-
-
X
-
-
-
-
 
Administer 
radiotherapyo
-
60 Gy in 30 fractions (2 Gy per day/5 days 
per week)
-
-
-
-
-
-
-
-
Accountability 
tislelizumab/placebo
-
X
-
-
X
-
-
X
-
-
X
-
-
-
-
Accountability 
etoposide/cisplatin
-
X
X
X
X
-
-
-
-
-
-
-
-
Administer IP: 
tislelizumab/placebo
-
X
X
Xn
X
&&,
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days 
-
35
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-
-
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35,


EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
58
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 4:
Table of Events (Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1d
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Administer 
appropriate 
chemotherapy  
premedications
-
X
X
X
X
X
X
-
-
-
-
-
-
-
-
Administer 
radiotherapyo
-
60 Gy in 30 fractions (2 Gy per day/5 days 
per week)
-
-
-
-
-
-
-
-
Accountability 
tislelizumab/placebo
-
X
-
-
X
-
X
-
-
X
-
-
-
-
FOLLOW-UP
Survival follow-up
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Every 3 
months 
(± 14 
days) 
until 
death
Disease therapy since 
IP discontinuation
-
-
-
-
-
-
-
-
-
-
-
-
X
X
At every 
survival 
follow-
up visit
&&,
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35
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235


EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
59
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase; β-hCG = beta human chorionic gonadotropin; CBC = complete blood count; cCRT = 
concurrent chemoradiotherapy; CK = creatine kinase; CK-MB = creatine kinase – cardiac muscle isoenzyme; CT = computed tomography; D = day; DNA = 
deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer – Quality of Life C30 questionnaire; EOT =  end of treatment; 
 
 FDG-PET = fluorodeoxyglucose - positron emission tomography; FU = follow-up; Gy = gray; HBcAb =
hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus HCV = hepatitis C virus; IP = 
investigational product; IRT = integrated response technology; MRI = magnetic resonance imaging; LC13 = Lung Cancer Module of EORTC QLQ-C30; OCT 
= optical coherence tomography; PD = progressive disease; 
 
 RNA = ribonucleic acid; RT = radiation therapy; SAE = serious adverse event; SOC = standard of care; 
 
a Screening evaluations must be completed within 28 days of randomization.
D1b Subjects should have Cycle 1 Day 1 (C1D1) dosing initiated within 3 days of randomization.
c End of treatment visit to be completed as soon as possible after IP discontinuation decision.
c The 90-Day Follow up Visit could be completed at the site or by telephone.
e All AEs and SAEs, regardless of relationship to study treatment, will be reported until 30 days after last dose of study treatment.  Immune-related AEs (serious 
or non-serious) should be reported until 90 days after the last dose of tislelizumab or placebo, regardless of whether or not the subject starts a new anticancer 
therapy.  All AEs and SAEs considered related to RT will be collected at any time after the first dose of RT, including late radiation toxicities. After a subject
has been discontinued from the study treatment, Investigators are not obligated to actively seek AEs or SAEs in former subjects.  However, if the Investigator 
learns of any AE related to radiation or any SAE, and he/she considers the SAE related to the study drug, the Investigator will notify the sponsor as described in
Section 10.
f Vitals, weight, hematology and chemistry will be collected weekly during Cycles 1, 2, and 3.
g Eye exam, visual acuity test, and optical coherence tomography (OCT) (or equivalent diagnostic test for retinal examination) captured as standard of care prior 
to obtaining written informed consent and within 28 days of randomization may be used rather than repeating tests. Eye exam, visual acuity test, and OCT (or 
equivalent diagnostic test) will be assessed at screening and then approximately every 15 weeks (± 7 days) during study treatment. The ophthalmologic 
assessments including eye exam, visual acuity test, and OCT (or equivalent diagnostic test) should only be performed once at either the EOT or during safety 
follow up, within 30 days of study treatment end.
h Hematology, serum chemistry, coagulation and thyroid function laboratory tests will be performed centrally. Local laboratory tests can be used for enrollment 
and dosing day. If screening laboratory tests are performed within 3 days of C1D1, these tests do not need to be repeated on C1D1. Before any administration 
of study treatment on each cycle, the results of CBC and serum chemistry should be available and reviewed by the Investigator. Of note, creatine kinase (CK) 
and creatine kinase – cardiac muscle isoenzyme (CK-MB) will be assessed as part of the serum chemistry panel (as per Section 6).  In case CK-MB 
fractionation is not available, please assess troponin (troponin I and/or T) instead.
i Testing will be performed by a central laboratory and/or the local laboratory at screening and will include at screening HBV/HCV serology (HBsAg, HBsAb, 
HBcAb, and HCV antibody) and viral load assessment (HBV DNA and HCV RNA). After screening, HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV 
antibody) and viral load assessment (HBV DNA and HCV RNA) may be performed if clinically indicated; for subjects who have detectable HBV DNA or 
HCV RNA at screening or upon repeat testing, respective viral load testing will be performed every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc).
j 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.
 
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
60
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
n Cycle 3 Day 1 dosing may be delayed up to 7 days in order to ensure that cCRT is completed prior to the start of monotherapy with tislelizumab or placebo.
o The schedule of radiotherapy and chemotherapy administrations is detailed in Table 5. Once commenced, radiotherapy should be given for 5 consecutive days 
weekly. Radiotherapy commences on Day 1 of chemotherapy, with a ± 3 days administrative window allowed for Day 1 of each cycle only.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
61
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
6.
PROCEDURES
 
 
 
 
 
 
 
 
 
 
6.1.
Screening Period
Screening evaluations including laboratory values must demonstrate subject eligibility, but may 
be repeated within the screening window, if necessary. These evaluations must be completed 
within 28 days of randomization unless noted otherwise below. 
Any questions regarding subject eligibility should be directed to the Sponsor or other Sponsor 
nominated representatives or designees for approval. Waivers to the protocol will not be granted 
during the conduct of this trial, under any circumstances.
The following will be performed at screening as specified in the Table of Events:
!
Informed consent: 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 
randomization may be used for screening assessments rather than repeating such tests.
!
Inclusion/exclusion criteria assessment
!
Interactive response technology (IRT) for subject number
!
Complete medical history (all relevant medical conditions diagnosed/occurring prior 
to screening should also be included)
!
Demographics (year of birth, sex, race, and ethnicity, if allowed by local regulations)
!
Disease history (including but not limited to specific information regarding diagnosis, 
staging, and histology)
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
62
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
randomization)
!
Prior and concomitant procedures (including all procedures occurring ≤ 28 days 
before randomization)
!
EGFR sensitizing mutation and ALK gene translocation testing. If EGFR mutation 
and ALK gene translocation results are not available, subjects will be tested for 
EGFR sensitizing mutation and ALK gene translocation. 
!
Cytological or histological confirmation of mediastinal nodal involvement (N2 and 
N3) if available
!
Pulmonary function tests: All subjects will undergo pulmonary function testing, 
which may include but is not limited to spirometry and assessment of diffusion 
capacity done during the screening period to assist the determination of suitability for
the study.
!
Adverse event assessment begins when the subject signs the informed consent form.
!
Physical examination (can be source documented only), height and weight
!
Vital signs: to include temperature and measurements of pulse rate, respiratory rate, 
and blood pressure
!
ECOG performance status
!
12-lead electrocardiogram (ECG)
!
Left ventricular ejection fraction (LVEF) assessment by echocardiogram or other 
medically appropriate method (eg, multiple-gated acquisition scan [MUGA])
!
Eye exam, visual acuity test, and optical coherence tomography (OCT) (or equivalent 
diagnostic test) will be assessed by an appropriate specialist at screening. Eye exam, 
visual acuity test, and OCT (or equivalent diagnostic test for retinal examination) 
captured as standard of care prior to obtaining written informed consent and within 28 
days of randomization may be used for the screening evaluation. 
!
Hematology panel including complete blood count (CBC), differential, absolute 
neutrophil count and platelet count. The results confirming study eligibility must be 
obtained ≤ 2 weeks prior to randomization.
!
Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, blood urea nitrogen (BUN), alkaline phosphatase, AST/SGOT, ALT/SGPT,
serum albumin, total bilirubin, creatinine, CK and CK-MB, and if needed, troponin I 
and/or T). The results confirming study eligibility must be obtained ≤ 2 weeks prior 
to randomization.
!
Coagulation studies including prothrombin time (PT), partial thromboplastin time
(PTT), international normalized ratio (INR).  Local lab results allowed to confirm 
subject eligibility.
!
Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4)
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
63
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
C-reactive protein 
!
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA) will be performed by the central laboratory 
and/or the local laboratory at screening and will include HBV/HCV serology 
(hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], hepatitis 
B core antibody [HBcAb], and HCV antibody) and viral load assessment (HBV DNA 
and HCV RNA). 
!
Urinalysis (including, but not limited to, specific gravity, pH, glucose, protein, 
ketones, blood)
!
Serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy test is required 
at screening for all female subjects of childbearing potential, including 
premenopausal women who have had a tubal ligation. A second confirmatory 
pregnancy test, either serum or urine, must be performed within 72 hours prior to the 
first administration of study treatment, if the initial serum pregnancy test did not 
already occur with 72 hours of dosing (negative results required for study treatment
administration). Counseling about pregnancy precautions and the potential risks of 
fetal exposure must be conducted.
!
Efficacy assessment/tumor evaluation (see Section 6.4).
!
Fluorodeoxyglucose - positron emission tomography (FDG-PET)/CT scan to be 
performed whole body, or sufficient to rule out distant metastases (eg, from skull base 
to knees). If the CT scan portion on the chest/abdomen/pelvis areas is with contrast 
and is of sufficient diagnostic quality, a separate repeat tumor CT scan at screening 
can be skipped. Subsequent tumor assessments will be done using CT scans (or MRI 
if CT scan cannot be done).
∀
Local assessment will be used for eligibility assessment
∀
Central reader will perform a retrospective assessment
!
Brain imaging by MRI with contrast or CT with contrast
∀
Local assessment will be used for eligibility assessment
∀
Central reader will perform a retrospective assessment
!
Patient Reported Outcomes: European Organization for Research and Treatment of 
Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30), Lung Cancer 
Module of EORTC QLQ-C30 (LC13),
 
 
 
!
Collect archival tumor tissues (formalin-fixed paraffin embedded [FFPE] blocks or 
slides) with an associated pathological report (squamous or nonsquamous). In the 
absence of archival tumor tissues, a fresh biopsy (2 or 3 cores) of a tumor lesion at 
baseline is mandatory.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
64
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
6.2.
Treatment Period
The subject may be randomized once all inclusion/exclusion criteria are verified and subject is 
deemed to be eligible; this must occur within 28 days of the subject signing the ICF.
For all tislelizumab/placebo dosing visits starting with Cycle 2, an administrative window of ±3 
days is permitted.
If screening assessments are performed within 72 hours of C1D1, safety laboratory and physical 
examinations need not be repeated at C1D1.  
If the Investigator suspects a drug-related toxicity, an unscheduled visit with additional
laboratory tests may be performed.
Duration of treatment cycles and schedule of study treatments administration are described in 
Section 7.2.
The following evaluations will be performed at the frequency specified in the Table of Events; 
see Table 4. The evaluations should be performed prior to dosing on the visit day, unless 
otherwise specified.
!
IRT registration for subject randomization and IP assignment
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Adverse event evaluation (continuously)
!
Physical examination (source documented only)
!
Vital signs (temperature, systolic and diastolic blood pressure, and pulse): on-
treatment vital sign measurements will be source documented only.  However, if an 
abnormal (out of range) value is reported at any given visit, that parameter should be 
collected in the electronic case report form (eCRF) at every subsequent scheduled 
visit until it returns to normal, and as an AE if appropriate.
!
Weight 
!
ECOG Performance status
!
Left ventricular ejection fraction (LVEF) assessment by echocardiogram or other 
medically appropriate method (eg, MUGA), if clinically indicated
!
Body surface area to be calculated and collected at chemotherapy dosing visits
!
12-lead ECG at Cycle 1 Day 1 and then as clinically indicated
!
Eye exam, visual acuity test, and OCT (or equivalent diagnostic test) assessed by an 
appropriate specialist approximately every 15 weeks (± 7 days) during study 
treatment and at a final assessment less than 30 days after the last dose of study 
treatment. In addition, Investigators should solicit subjects regarding changes in 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
65
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
vision, visual disturbance, or ocular inflammation at each scheduled study visit during 
study treatment. For any change in vision, referral to an appropriate specialist will be 
made for further management guidance.
!
Hematology panel including complete blood count, differential, absolute neutrophil 
count and platelet count
!
Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, BUN, alkaline phosphatase, AST/SGOT, ALT/SGPT, serum albumin, total 
bilirubin, creatinine, CK and CK-MB, and if needed, troponin I and/or T)
!
Coagulation panel (PT, PTT, INR)
!
Thyroid function testing (TSH, free T3, free T4)
!
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA) if clinically indicated; for subjects who have 
detectable HBV DNA or HCV RNA at screening or upon repeat testing, respective 
viral load test every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc).
!
Urinalysis (including, but not limited to, specific gravity, pH, glucose, protein, 
ketones, blood), if clinically indicated
!
Urine (or serum) β-hCG pregnancy test prior to dosing on Day 1 of each cycle for 
females of childbearing potential 
!
Efficacy assessment/tumor evaluation (see Section 6.4)
!
Brain imaging by MRI with contrast or CT with contrast, only if clinically indicated
!
Patient Reported Outcomes: EORTC QLQ-C30, LC13, 
,
 
and 
(see Section 6.7) on Day 1 of every cycle
!
Anti-tislelizumab antibodies assays: serum samples will be tested for the presence of 
anti-drug antibodies (ADAs) to BGB-A317 using a validated immunoassay
!
Blood (serum) for pharmacokinetics
!
 
!
Tislelizumab or placebo administration (see Section 7.2.1)
!
Tislelizumab or placebo accountability
!
Chemotherapy administration (see Section 7.2.1)
!
Chemotherapy accountability
!
Radiotherapy administration (see Section 7.2.2)
6.2.1.
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
tislelizumab/placebo treatment for any reason as soon as possible after the decision to 
permanently discontinue treatment has been made. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
66
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
The following evaluations will be performed as specified in the Table of Events:
!
IRT registration for subject treatment discontinuation 
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Adverse event evaluation (continuously)
!
Physical examination (source documented only)
!
Weight 
!
Vital signs (temperature, systolic and diastolic blood pressure, and pulse)
!
ECOG performance status
!
12-lead ECG
!
Left ventricular ejection fraction (LVEF) assessment by echocardiogram or other 
medically appropriate method (eg, MUGA), if clinically indicated
!
Eye exam, visual acuity test, and OCT (or equivalent diagnostic test) assessed by an 
appropriate specialist should only be performed once at either the EOT or during 
safety follow up, within 30 days after the last dose of study treatment.
!
Hematology panel including complete blood count, differential, absolute neutrophil 
count and platelet count
!
Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, BUN, alkaline phosphatase, AST/SGOT, ALT/SGPT, serum albumin, total 
bilirubin, creatinine, CK and CK-MB, and if needed, troponin I and/or T)
!
Coagulation panel (PT, PTT, INR)
!
Thyroid function testing (TSH, free T3, free T4)
!
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA) if clinically indicated; for subjects who have 
detectable HBV DNA or HCV RNA at screening or upon repeat testing, respective 
viral load test.
!
Urinalysis (including, but not limited to, specific gravity, pH, glucose, protein, 
ketones, blood), if clinically indicated
!
Urine β-hCG pregnancy test for females of childbearing potential
!
Efficacy assessment will be continued according to the schedule defined in the Table 
of Events, and does not need to be performed specifically for the EOT visit except as 
specified in Section 6.4) 
!
Patient Reported Outcomes: EORTC QLQ-C30, LC13, 
 
(see Section 6.7)
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
67
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
 
6.3.
Follow-up Period 
6.3.1.
Safety Follow-up
Subjects who discontinue tislelizumab/placebo treatment for any reason will be asked to return to 
the clinic for a Safety Follow-up Visit within 30 days (± 7 days) after the last study treatment or 
before the initiation of a new anticancer treatment, whichever comes first.
The following evaluations will be performed as specified in the Table of Events:
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Adverse event evaluation (continuously until 90 days after last dose of study 
treatment)
!
Physical examination (source documented only)
!
Weight 
!
Vital signs (temperature, systolic and diastolic blood pressure, and pulse)
!
ECOG performance status
!
12-lead electrocardiogram
!
Left ventricular ejection fraction (LVEF) assessment by echocardiogram or other 
medically appropriate method (eg, MUGA), if clinically indicated
!
Eye exam, visual acuity test, and OCT (or equivalent diagnostic test) assessed by an 
appropriate specialist should only be performed once at either the EOT or during 
safety follow up, within 30 days after the last dose of study treatment.
!
Hematology panel including complete blood count, differential, absolute neutrophil 
count and platelet count
!
Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, BUN, alkaline phosphatase, AST/SGOT, ALT/SGPT, serum albumin, total 
bilirubin, creatinine, CK and CK-MB, and if needed, troponin I and/or T)
!
Coagulation panel (PT, PTT, INR)
!
Thyroid function testing (TSH, free T3, free T4)
!
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA) if clinically indicated; for subjects who have 
detectable HBV DNA or HCV RNA at screening or upon repeat testing, respective 
viral load test.
!
Urinalysis (including, but not limited to, specific gravity, pH, glucose, protein, 
ketones, blood), if clinically indicated
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HB
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
68
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
Urine β-hCG pregnancy test for females of childbearing potential
!
Patient Reported Outcomes: EORTC QLQ-C30, LC13, 
 
and 
(see Section 6.7) at 30 days after the last study treatment.
!
!
 
!
Blood for pharmacokinetics 
!
 
!
Survival data
!
Disease therapy since IP discontinuation
All subjects will be monitored for adverse events starting from the time the subject signs the ICF 
until 30 days after the last dose of study treatment (tislelizumab/placebo, chemotherapy, or RT), 
as well as those SAEs made known to the Investigator at any time thereafter that are suspected of 
being related to study treatment, as described in Section 10.1. Subjects will also be monitored for 
immune related adverse events (serious or nonserious) starting from the time the subject signs 
the ICF until 90 days after the last dose of tislelizumab or placebo, regardless of whether or not 
the subject starts a new anticancer therapy. All AEs and SAEs considered related to RT will be 
collected at any time after the first dose of RT, including late radiation toxicities. The 90-Day 
Follow-up Visit could be conducted at site or by telephone, and will also include collection of 
survival data and disease therapy since IP discontinuation.
6.3.2.
Efficacy Follow-up
All subjects who discontinue treatment for reasons other than disease progression, start of a 
subsequent anticancer therapy, or withdrawal of consent from the entire study, will be followed 
for efficacy response assessments by CT scan or MRI and new disease therapies as specified in 
Section 6.4.
6.3.3.
Survival Follow-up
After the end of treatment visit, all subjects will be followed every 3 months (± 14 days) for 
survival until withdrawal of consent, death, or lost to follow-up, whichever occurs first, or until 
the End of Trial. Subsequent anticancer therapies should be collected at the same time schedule.
Subsequent anticancer therapy includes (but is not limited to) any systemic or local medication, 
surgery, radiation, or any other therapy intended to treat the subject’s cancer.
Survival follow-up may be conducted by record review (including public records) and/or
telephone contact with the subject, family, or the subject’s treating physician.
6.4.
Efficacy Assessment 
Tumor assessments by CT scan or MRI of the chest and abdomen/pelvis should be performed at 
screening within 28 days before randomization, and every 6 weeks (± 7 days) from 
randomization for the first 36 weeks, then every 9 weeks (± 7 days) thereafter until disease 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
69
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
progression, start of subsequent anticancer therapy, or withdrawal of consent from the entire 
study. The first 6-week tumor assessment after randomization should take place prior to initiation 
of monotherapy treatment (Cycle 3 Day 1). To ensure sufficient ability to assess tumor response, 
the same imaging procedure should be used throughout the study for each subject, and these 
imaging studies must include all lesions assessed at baseline. Tumor assessments by CT scan or 
MRI should also be performed at any time if clinically indicated. Subjects with historical tumor 
scans evaluable per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 performed ≤ 
28 days before randomization need not repeat scans for the purposes of screening, as use of 
historical tumor scans done within the 28-day screening window is permitted. Evaluation of 
response for therapeutic decisions should be performed using RECIST v1.1 guidelines 
(Appendix I) by Investigator assessment.
Central imaging reviewers blinded to treatment will provide independent review for disease 
progression and responses for all subjects enrolled into the study. Prospective collection of all 
on-study scans for all subjects enrolled in the study will be included as part of the review.
Films or electronic copies should be collected by the site and sent to the central imaging 
reviewer(s) and a copy of the file will be kept on site. Complete details regarding image handling 
and submission can be found in the Imaging Manual. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the 
Investigator to reflect pseudoprogression, the subject may continue treatment with tislelizumab 
until progressive disease is confirmed by repeated imaging at least 4 weeks later but not 
exceeding 6 to 8 weeks from the date of initial documentation of progressive disease, provided 
the following criteria are met:
!
Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values). 
!
Stable ECOG performance status (≤ 1).
!
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention.
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform subjects that this practice is not considered standard in the treatment of 
cancer. The decision to continue study drug(s) beyond initial Investigator-assessed progression 
must be discussed with the Sponsor medical monitor and documented in the study records.
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
70
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7.
Patient Reported Outcomes
The predominant patient-reported lung cancer symptoms (appetite loss, cough, chest pain, 
dyspnea, and fatigue) assessed by the EORTC QLQ-C30 and its lung cancer module LC13 will 
be a predefined secondary endpoint;
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
71
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
It will be important to assess treatment effectiveness both in terms of objective outcomes (eg, 
PFS or OS) and subjective, patient reported outcomes (PROs) to ensure that the addition of 
tislelizumab to cCRT followed by tislelizumab monotherapy in newly-diagnosed, unresectable 
locally advanced NSCLC subjects, does not result in a detrimental impact on subjects’ health-
related quality of life (HRQoL) when compared to cCRT alone. This detailed information can 
help both clinicians and subjects to make informed and comprehensive decisions regarding the 
best available treatments. Patient reported outcomes are any information self-reported by the 
subject regarding their functioning or symptoms in relation to their health condition or therapy. 
Patient-reported HRQoL falls under the umbrella of PROs and covers physical symptoms and 
functioning domains, and usually provides an overall subject evaluation of their health and 
quality of life.
Patient reported outcomes will be assessed in all randomized subjects using 2 European 
Organisation for Research and Treatment of Cancer (EORTC) Quality of Life instruments—the 
EORTC QLQ-C30 version 3 (Aaronson, 1993) and the lung cancer specific module (EORTC 
QLQ-LC13) (Bergman, 1994);
The EORTC QLQ-C30 and its lung cancer-specific module EORTC QLQ-LC13 are the most 
frequently used instruments in lung cancer subjects (Bouazza, 2017). The International 
Consortium for Health Outcomes Measurement (ICHOM) also recommends these instruments as 
PRO measures for monitoring lung cancer (Mak, 2016).
Patient-reported outcomes assessment will be performed electronically using a tablet at 
screening, on Day 1 of each treatment cycle, at the EOT visit and 30 days after EOT.
6.7.1.
EORTC QLQ-C30
The EORTC QLQ-C30, is a 30-item, psychometrically robust, cross-culturally accepted and 
internationally validated questionnaire designed to be applicable to a broad spectrum of cancer 
subjects as a core questionnaire, assessing QoL, psychosocial burden and physical symptoms. It 
is classified into 15 domains including 5 functional subscales (physical functioning, role 
functioning, emotional functioning, cognitive functioning, and social functioning); 3 multi-item 
symptom subscales (fatigue, nausea/vomiting, and pain); a global QoL subscale; and 6 single 
items addressing various symptoms and perceived financial impact. All EORTC QLQ-C30 items 
use a 4-point Likert scale (ie, “not at all,” “a little,” “quite a bit,” and “very much”), except the 2
items assessing global QOL (item 29 and item 30), which use a 7-point scale. The EORTC QLQ-
C30 uses a recall period of one week (Aaronson, 1993; Hjermstad, 1995; King, 1996; Osoba,
1997; Osoba, 1998). Each item from the EORTC QLQ-C30 questionnaires is measured on a 4-
point response scale; (not at all, a little, quite a bit, very much), with the exception of the 2 items 
measuring global health and QoL, which are measured on a 7-point response scale. The scale 
scores are linearly transformed to 0 to 100 scores (Aaronson, 1993). Scores vary from 0 (worst) 
to 100 (best) for the functional dimensions and GHS, and from 0 (best) to 100 (worst) for the 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
72
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
symptom dimensions; higher scores indicate better QoL, better functioning, or more severe 
symptoms, respectively. A copy of the questionnaire is presented in Appendix B.  
6.7.2.
EORTC QLQ-LC13
Subjects’ disease-related symptoms will be assessed using the EORTC Quality of Life 
Questionnaire-Lung Cancer 13 (QLQ-LC13; referred to here as the LC13) which is a lung-
cancer specific PRO and the first module to be used in conjunction with the EORTC QLQ-C30 
(Aaronson, 1993; Bergman, 1994). The LC13 covers 13 typical symptoms of lung cancer 
subjects, such as coughing, pain, dyspnea, sore mouth, peripheral neuropathy, and hair loss. 
Extensive field testing was conducted for validity, reliability, responsiveness (Bergman, 1994) as 
well as field studies to prove the validity of these instruments (Koller, 2015). In 2 international 
field studies, respectively, 883 and 735 lung cancer subjects (from Europe, North America, 
Australia, and Japan) completed the questionnaire pre- and on-treatment to assess the 
psychometric properties. The results demonstrated good reliability of the multi-item dyspnea 
scale. Validity was evaluated with an analysis of variance by disease stage and by performance 
status (Bergman, 1994). Overall, the EORTC QLQ-LC13 has undergone extensive testing and 
demonstrated good psychometric properties. A copy of the questionnaire is presented in
Appendix C.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
73
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
74
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
75
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.
DESCRIPTION OF STUDY TREATMENTS
Tislelizumab and placebo will be supplied by the Sponsor and labeled appropriately as 
investigational product for this study.  
Cisplatin, etoposide, carboplatin, and paclitaxel will be supplied or obtained according to local 
clinical study agreement and in accordance with local guidelines.  Please refer to local cisplatin, 
etoposide, carboplatin, and paclitaxel prescribing information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), the approved indications, known 
precautions, warnings, and adverse reactions of cisplatin, etoposide, carboplatin, and paclitaxel. 
The dosing schedules and dose adjustments to be followed for this study are described in 
Section 7.2.1, Section 7.2.2, and Section 7.2.5.
Additional information may be included on the label as needed or applicable.  Label(s) for 
investigational product (IP, also referred to as investigational medicinal product [IMP]) will 
contain information as required per local health authority.
7.1.
Description of Investigational Product(s)
7.1.1.
Tislelizumab (BGB-A317) 
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial containing 
a total of 100 mg antibody in 10 mL of isotonic solution. 
The study drug must be kept at the temperature condition as specified on the label. Tislelizumab 
must be stored at temperatures between 2oC and 8oC (36 to 46ºF) and protected from light.  
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal.  Please also refer to the Investigator’s Brochure for other details regarding tislelizumab.
7.1.2.
Placebo 
At the start of the study, placebo may not be available for distribution. Until placebo becomes 
available, sites that randomize subjects will be required to have an unblinded pharmacist (or 
designated site personnel) prepare a placebo IV bag until the Sponsor supplied placebo becomes 
available (please refer to Section 7.2.9 for further details).  The Sponsor supplied placebo is a 
sterile, preservative-free solution for infusion.
7.1.3.
Chemotherapy
Chemotherapy dosing durations are specified in Table 5. All other aspects of management (ie, 
handling, storage, administration, and disposal) of cisplatin, etoposide, carboplatin and paclitaxel
will be in accordance with the relevant local guidelines, package inserts and summaries of 
product characteristics (SmPC). For sites where the Sponsor is required to provide all study 
drugs including standard of care drugs, cisplatin, etoposide, carboplatin, and paclitaxel will either 
be supplied or reimbursed by the Sponsor or designee.
For the carboplatin/paclitaxel regimen supportive treatments are listed in Section 7.2.3.
For further details, refer to the Pharmacy Manual for the respective chemotherapies.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
76
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.2.
Treatment Administration and Schedule
7.2.1.
Dosage, Administration, and Compliance
Dosing schedules for tislelizumab or placebo and chemotherapy with RT are provided in
Table 5.
The dosing schedule for tislelizumab or placebo after completion of cCRT is provided in
Table 6.
All subjects will be monitored continuously for AEs. Treatment modifications (eg, dose delay, 
reduction, interruption or discontinuation) will be based on specific laboratory and adverse event 
criteria, as described in Section 7.2.5.
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
77
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 5:
Timing of Dose Administration of Tislelizumab or Placebo in Combination with Chemotherapy During cCRT
Order of 
administration 
on Day 1
Drug
Dose
Route
Days
Notes
1
Tislelizumab/Placebo
Concurrent with RT on 
Days 1
Day 1: infuse over 60 minutes (wait 1 hour 
before chemotherapy). If well tolerated, then can 
decrease infusion time as follows:
infuse over 30 minutesa (wait 1 hour 
before chemotherapy)
1
Tislelizumab/Placebo
Concurrent with RT on 
Days 1
Day 1: infuse over 60 minutes (wait 1 hour 
before chemotherapy) If well tolerated, then can 
decrease infusion time as follows:
: infuse over 30 minutesa (wait 1 hour 
before chemotherapy)
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EDMS Doc. Number: 
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
78
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 5:
Timing of Dose Administration of Tislelizumab or Placebo in Combination with Chemotherapy During cCRT
(Continued)
Order of 
administration 
on Day 1
Drug
Dose
Route
Days
Notes
Dexamethasonebc
20 mg 
PO or 
IV
Prior to paclitaxel on 
Days 1, 8, 15, 22, 29,
and 36
For oral administration: approximately 12 and 6 
hours, or for IV administration: 30 to 60 min
prior to paclitaxel
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50 mg
IV
Prior to paclitaxel on 
Days 1, 8, 15, 22, 29,
and 36
30 to 60 minutes prior to paclitaxel
Cimetidine or ranitidinebe
300 mg
50 mg
IV
Prior to paclitaxel on 
Days 1, 8, 15, 22, 29,
and 36
30 to 60 minutes prior to paclitaxel
AUC = area under the curve; BID = twice daily; cCRT = concurrent chemotherapy and radiotherapy; IM = intramuscular; IV = intravenous; PO = per oral; RT = 
radiation therapy.
a Reduction of tislelizumab or placebo infusion time from 60 minutes to 30 minutes is based on the 60-minute infusion being well tolerated. See Section 7.2.1.1.
b These products may be obtained by the investigational sites as local commercial products in certain countries if allowed by local regulations. These products 
should be prepared/stored/administered in accordance with the package inserts or summaries of product characteristics (SmPCs).
c Due to their immunomodulatory effects, premedication with steroids should be limited when clinically feasible. In addition, in the event of chemotherapeutic 
agent-related skin rash, topical steroid use is recommended as front-line treatment whenever is clinically feasible.
d Or equivalent antihistamine (eg, chlorpheniramine).
e Or equivalent histamine H2 receptor antagonist (eg, famotidine).
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
79
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
In the event that RT is interrupted to allow recovery from toxicities, the monotherapy 
administration of tislelizumab or placebo (starting with Cycle 3 Day 1) will not begin until 
completion of the full course of RT. In this case Cycle 3 Day 1 may be delayed up to 7 days. If a 
subject is unable to start Cycle 3 dosing within 7 days, then Cycle 3 will be considered “missed”, 
and dosing will resume at the scheduled Cycle 4 Day 1.
As monotherapy, tislelizumab or placebo will be administered for a duration of 12 months from 
the first dose of tislelizumab or placebo after completion of the cCRT period, or until disease 
progression, intolerable toxicity, or treatment discontinuation for another reason.
The total duration of tislelizumab (Arm 1), placebo and tislelizumab (Arm 2), and placebo (Arm 
3) will be approximately 14 months, including the cCRT period.
Table 6:
Timing of Dose Administration of Tislelizumab or Placebo Monotherapy 
After Completion of cCRT
Drug
Dose
Route
Days
Notes
Tislelizumab/Placebo
IV
 
Infuse over 30 minutes (with 
30 minutes monitoring)
cCRT = concurrent chemoradiotherapy; IV = intravenous
7.2.1.1.
Tislelizumab or Placebo
Tislelizumab or placebo will be administered on Day 1 
.
Tislelizumab or placebo will be administered, before chemotherapy, by IV infusion through an 
IV line containing a sterile, nonpyrogenic, 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.
As a routine precaution, after infusion of tislelizumab or placebo on Day 1 of Cycle 1 and Cycle 
2, subjects must be monitored for at least 1 hour (before chemotherapy administration) in an area 
with resuscitation equipment and emergency agents. From Cycle 3 onward, at least a 30-minute 
monitoring period is required in an area with resuscitation equipment and emergency agents.
The initial infusion (C1D1) will be delivered over 60 minutes; if this is well tolerated, then the 
subsequent infusions may be administered over 30 minutes, which is the shortest time period 
permissible for infusion. Tislelizumab or placebo must not be concurrently administered with 
any other drug (refer to Table 5).
Details of tislelizumab or placebo and chemotherapy dose administration are summarized in
Table 5.
As monotherapy, tislelizumab or placebo will be administered for a duration of 12 months from 
the first dose of tislelizumab or placebo after completion of the cCRT period, or until disease 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
80
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
progression, intolerable toxicity, or treatment discontinuation for another reason. Details of 
tislelizumab or placebo dose administration in monotherapy are summarized in Table 6.
Guidelines for dose delay, treatment interruption, or discontinuation and for the management of 
irAEs and infusion-related reactions are provided in detail in Section 7.2.5, Section 8.3, and 
Appendix H.
Refer to the Pharmacy Manual for detailed instructions on IP preparation, storage, and 
administration. 
7.2.1.2.
Chemotherapy
Chemotherapy regimens are administered after administration of tislelizumab or placebo.
 
 
 
 
 
. In addition, all subjects should receive the appropriate 
premedications as per the local approved label. Additional premedications should be 
administered as per standard practice. Due to their immunomodulatory effects, premedication 
with steroids should be limited when clinically feasible. In addition, in the event of 
chemotherapeutic agent-related skin rash, topical steroid use is recommended as front-line 
treatment whenever is clinically feasible. 
Needles or intravenous administration sets containing aluminum parts that may come in contact 
with carboplatin injection should not be used for the preparation and administration of the drug. 
Aluminum can react with carboplatin causing precipitate formation and loss of potency. 
Dosing of carboplatin will be based on the Calvert formula:
carboplatin dose (mg) = (Target AUC) x (GFR + 25). 
For the purposes of this protocol, the glomerular filtration rate (GFR) is considered to be 
equivalent to the creatinine clearance (calculated by the method of Cockcroft, 1976); see 
Appendix G. Carboplatin dose should be calculated prior to each dose using actual weight if the 
subject’s body weight changes by more than 10% from baseline (or the newly referred body 
weight) and current serum creatinine level according to local prescribing information and local
practice.
Each drug in the regimen should be administered sequentially. Details of tislelizumab or placebo 
and chemotherapy dose administration, including order of dosing and times between doses, are 
summarized in Table 5.
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 7.2.5.3. For commercially available drugs, please refer to the appropriate SmPC as a 
resource for guidelines. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
81
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Subjects will be monitored continuously for AEs and will be instructed to notify their physician 
immediately of any AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of each therapy.  
7.2.2.
Radiation Therapy
The chemotherapy should generally be delivered prior to the radiation therapy on the day of
treatment.  Chemotherapy doses that are missed during a weekly schedule concurrent with RT 
are not to be made up, but these should be documented.  Every effort should be made to continue 
the RT during the concurrent phase in an uninterrupted manner.  Should a subject develop severe 
esophagitis necessitating interruption of chemotherapy, the RT may continue, provided the 
Investigator believes supportive care will enable the subject to complete this part of the therapy 
without excess risk.
Prior to inclusion of any subject on this study, the radiation oncologist will evaluate the thoracic 
CT scan or MRI to ensure that the treatment volumes are unlikely to significantly exceed the 
specified normal tissue constraints. A subject will be excluded if the subject’s radiation treatment 
plans are likely to encompass a volume of whole lung receiving ≥ 20 Gy in total (V20) of more 
than 38% of lung volume.
All patients will receive RT using either a standardized 3-dimentional conformal radiotherapy
(3DCRT) technique, or an intensity modulated radiotherapy (IMRT) on a linear accelerator 
delivering a beam energy of ≥ 6 MV.  The total dose of RT will be 60 Gy in 30 once-daily 
fractions of 2 Gy (Bradley, 2015), prescribed at the International Commission on Radiation Units 
and Measurements (ICRU) 50 reference point, and given according to the recommendations for 
radiotherapy delivery of the European Organization for Research and Treatment of Cancer 
(EORTC)-Radiotherapy Group (De Ruysscher, 2017) and the International Commission on 
Radiation Units & Measurements Report 50 (ICRU Report 50, 1993).  
Weekly clinical assessments are required during the cCRT treatment.  While 60 Gy in 30 
fractions is the target dose of radiation, concern about patient tolerance discovered during 
treatment planning or delivery, for example, a V20 exceeding that recommended in the protocol, 
may dictate that a lower dose be administered.  Definitive radiation therapy will be considered as 
receiving a minimum of 56 Gy to the PTV.
7.2.2.1.
Radiation Dose Specifications
Subjects will receive treatment 5 days per week, in once daily fractions, 2 Gy per fraction, to a 
target dose of 60 Gy in 30 fractions. Normalization of the treatment plan will cover 95% of the 
planning target volume (PTV) with the prescription dose. The minimum PTV dose should ideally
not fall below 93% of the prescription dose. All radiation doses will be calculated with 
inhomogeneity corrections that take into account the density differences within the irradiated 
volume (that is, air in the lung and bone).  The maximum and minimum point doses (within the
PTV) will be reported. No field reductions will be permitted and the entire PTV must be treated 
daily. Radiation therapy commences on Day 1 of chemotherapy, with a ± 3 days administrative 
window allowed. When both chemotherapy and RT are administered at the same 
center/location, it is recommended that RT should follow within 30 to 60 minutes of the 
completion of chemotherapy or post-cisplatin hydration. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
82
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
When the RT is delivered at a separate location, logistic considerations may result in RT being 
delivered prior to the administration of chemotherapy or post-cisplatin hydration. On days where 
RT and/or chemotherapy are delayed for administrative reasons within the allowed protocol 
window of 3 days, this will not be considered a protocol violation, provided the full planned dose 
of RT is administered.
7.2.2.2.
Variations of Dose Prescription
The variations in dose prescription are described here, and summarized in Table 7 below.
No deviation:  ≥99% of the PTV receives at least 93% of the prescribed dose, and no volume
> 1 cm3 within the PTV receives > 110% of the prescribed dose, and no more than a contiguous 
volume of 1 cm3 outside the PTV receives a maximum of 110% of the prescribed dose, and the 
volume of both lungs (%) receiving a dose of 5Gy or higher (V5) is ≤65%.
Minor deviation:  Deviations of this magnitude are not desirable, but are acceptable. Between
< 99% but > 95% of the PTV receives at least 93% of the prescribed dose, or a contiguous 
volume of > 1 cm3 within the PTV receives > 110% but < 115% of the prescribed dose, or a 
contiguous volume of >1cm3 outside the PTV receives > 110% but < 115% of the prescribed 
dose, or V5 is > 65% but ≤80%.
Major deviation:  Doses in this region are not acceptable.  Less than 95% of the PTV is covered 
by 93% of the prescribed dose, or a contiguous volume of >1 cm3 within the PTV receives >
115% of the prescribed dose, or a contiguous volume of >1 cm3 outside the PTV receives >
115% of the prescribed dose, or V5 > 80%.
Table 7:
Summary of Dose Prescription Variations
No Deviation
Minor Deviation
Major Deviation
PTV volume coverage
≥99% of PTV receives
at least 93% of
prescribed dose
> 95% but <99% of
PTV receives at least
93% of prescribed dose
< 95% of PTV
receives 93% of
prescribed dose
Excessive dose within 
PTV
No contiguous volume
> 1 cm3 within the
PTV receives > 110%
of prescribed dose
> 1 cm3 contiguous
volume within PTV
receives > 110% but < 
115% of prescribed 
dose
> 1 cm3 contiguous 
volume within PTV 
receives
Excessive dose outside
PTV
No contiguous volume
> 1 cm3 outside PTV 
receives > 110% of 
prescribed dose
> 1 cm3 contiguous
volume outside PTV
receives > 110% but <
115% of prescribed 
dose
> 1 cm3 contiguous 
volume outside PTV 
receives > 115% of 
prescribed dose
Excessive V5 dose
V5 ≤65%
V5 > 65% but ≤80%
V5 > 80%
Abbreviations: PTV = planning target volume; V = volume.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
83
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.2.2.3.
Localization, Simulation, and Immobilization
Each subject will be positioned in an institutional specific immobilization device in the treatment 
position on a flat table. All planning CT scans should be performed in the treatment position 
using the same immobilization device for setup as is used at the linear accelerator. Optimal 
immobilization is critical for this protocol in order to ensure reproducibility of the daily setup. 
Either a conventional (non-4D CT) treatment planning CT study or a 4-dimensional computed 
tomography (4DCT) will be performed. Conventional CT scans will be performed during quiet, 
uncoached respiration while the subject undertakes a normal respiration, using at least 5-mm 
slices through the entire target volume.  The whole thorax (cricoid to L2) should be covered 
using < 1 cm slices in order to generate dose-volume histograms to be calculated of the lungs, 
spinal cord, heart, and esophagus.  A treatment planning FDG-PET/CT scan (or FDG-PET alone) 
with the subject in the treatment position can be used for treatment planning.  Where a PET/CT 
is obtained in the treatment position, the CT from this study may be used as the planning CT 
scan. 
The gross tumor volume (GTV), Internal Target Volume (ITV) and PTV will be defined on all 
appropriate slices (see definitions in Section 7.2.2.4). Intravenous contrast during the planning 
CT is optional, provided that a recent diagnostic chest CT was done with contrast to delineate the 
major blood vessels.  If not, intravenous contrast can be administered during the planning CT, if 
this is considered necessary in the view of the radiation oncologist.  If contrast is used, the 
densities can be overridden or the contrast scan could be registered to a noncontrast scan for 
planning purposes.  Acceptable methods of accounting for tumor motion include design of the 
PTV to cover the excursion of the lung primary cancer and nodes during breathing such as an 
ITV approach, breath-holds (eg, Eleckta ABC device), or respiratory gating (for example, Varian 
RPM system).
7.2.2.4.
Radiation Treatment Planning
Three-Dimensional Conformal Radiotherapy (3DCRT)
The PTV is to be treated with any combination of coplanar or noncoplanar 3D conformal fields 
shaped to deliver the specified dose while restricting the dose to the normal tissues.  The 
treatment plan used for each subject will be based on an analysis of the volumetric dose, 
including dose-volume histogram analyses of the PTV and critical normal structures. Each field 
is to be treated daily.
Intensity Modulated Radiation Therapy
The use of intensity modulated radiation therapy (IMRT) is permitted, provided that the 
institution has been using this technique for treating lung cancer for at least 6 months prior to 
study activations. As IMRT results in a greater proportion of out of target lung receiving 
radiation outside the PTV, it is recommended to maintain the total lung V5 level at 65% or less.  
7.2.2.5.
Radiation Treatment Documentation
Centers participating in this study will perform heterogeneity corrections for all study treatment 
planning.  It is recognized that differences between calculation algorithms in the different 
treatment planning systems may result in dose variations for individual subjects.  However, the 
clinical impact of this variation is likely to be limited when compared with other potential 
&(/*(1(35235,(7$5<,1)250$7,21
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7.2.2.5.
ntet


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
84
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
sources of variation that may arise in a multicenter trial, including interinstitutional and 
interclinician variations in contouring the GTV.
On the first day of therapy, and periodically thereafter in accordance with standard department 
protocols, one of the following verification procedures will be performed: a cone-beam CT scan, 
portal image of each field of 3DCRT or orthogonal images that localize the isocenter placement. 
These images should be compared to localization films and discrepancies corrected. These 
images will not be submitted for central review.  
Dose volume histograms will be generated for PTV, both lungs, lungs minus PTV, spinal cord, 
esophagus, and heart. The following dose values should be recorded:
!
Prescription point dose
!
Minimum, maximum, and mean dose in PTV
!
Maximum dose to spinal cord
!
V20 and V5
7.2.2.6.
Organs at Risk
Contouring of normal tissues and organs for radiotherapy planning will be in accordance with 
published guidelines (Kong, 2011). Normal tissue constraints shall be prioritized in the following 
order for treatment planning:
1 = spinal cord, 2 = lungs, 3 = heart, 4 = esophagus, and 5 = brachial plexus
Spinal cord: The spinal canal will be contoured and taken to represent the spinal cord.  The 
maximum cord dose will be limited to 46 Gy, but subjects who receive up to 48 Gy in order to 
ensure adequate tumor dose will be considered to have as a minor deviation. Subjects who 
receive more than 48 Gy to the cord will be counted as a major deviation.  
Lungs:  The dose-volume constraint to the lungs is the second highest priority and must be met, 
except if it conflicts with spinal cord dose constraints.  The volume of both lungs (total lung 
volume minus PTV) that receive more than 20 Gy (V20) should not exceed 35%.  All V20s up to
38% will be permitted and viewed as a minor deviation, provided the treating radiation 
oncologist believes this level of exposure is within subject tolerance.
Heart:  The heart will be contoured on all slices and detailed guidance for contouring is Feng, 
2011.  The cranial border will include the infundibulum of the right ventricle and the apex of 
both atria, and exclude the great vessels as much as possible.  The caudal border is defined as the 
lowest part of the left ventricle that is distinguishable from the liver.  The recommended dose 
limits are 60 Gy < 1/3; 45 Gy < 2/3; and 40 Gy < 100% of the heart.
Esophagus: Esophagitis is an expected side effect of concurrent therapy and has a relationship to
higher doses of radiation encompassing the entire esophageal circumference.  The outer wall of 
the esophagus will be contoured completely throughout the length of esophagus that is 
encompassed by a dose of radiation ≥46 Gy.
Brachial Plexus:  For tumors in close proximity to the brachial plexus, the plexus should be 
contoured to ensure that the maximal point dose to this structure is kept under 64 Gy.
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com


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
85
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Radiation toxicities will be assessed according to NCI CTCAE v5.0 criteria and reported per 
Section 10.1.  Note, radiation toxicities can arise more than 90 days after the completion of 
radiation therapy.  
7.2.2.7.
Quality Assurance and Compliance with Protocol-defined Radiation 
Prescription (Quality Control)
A formal radiotherapy quality assurance (QA) program will be a mandatory component of this 
study. Eligible radiotherapy facilities will complete a facility questionnaire in order to ensure that 
they are equipped to deliver radiation to the required quality. Prior to randomization of the first 
subject, sites will need to have undergone a “benchmarking” process where a 3-dimensional CT 
scan of an anonymized clinical case with stage III NSCLC will be electronically transmitted to 
participating sites by the QA program, and the local radiation oncologists from the sites will be 
required to contour target volumes and organs-at-risk volumes, in accordance with the quality 
assurance criteria specified for thoracic radiation therapy as defined in the approved RT QA 
program. This process will serve to ensure protocol-compliant contouring and radiotherapy 
planning. The radiotherapy plans will be reviewed by physicists and a radiation oncologist at the 
QA program, who will provide appropriate feedback to sites participating in this benchmarking.  
Early-treatment Subject Dosimetry Review:
An early-treatment subject dosimetry review of the treatment plan will be conducted for at least 
one case per center. The treatment plan feedback should be provided to the center by the time 5 
fractions (10 Gy) have been delivered to the first study subject. The objective of the review is to 
gain additional assurance that subjects treated at the site will conform to the protocol radiation 
requirements. Additional QA dosimetry reviews may be done subsequently in a sample of cases 
during the course of the study. Subjects may have their radiation field altered based on 
information obtained from these QA reviews. This should be sufficient to ensure adherence to 
the radiation prescription defined in the protocol.  
Post-treatment Subject Dosimetry Review:
All subjects treated by radiation in the study will have a retrospective radiation dosimetry review 
by the QA program, either during the course of the study or at the completion of the study, to 
correlate the degree of local control and toxicity with adherence to the protocol radiation 
prescription.  This will be a confirmation of the treatment delivered, and an overall assessment of 
compliance with protocol stipulations regarding radiation treatment.
7.2.2.8.
Radiation Adverse Events and Interruption
Investigators will be advised to suspend the use of chemotherapy given with radiation if they 
believe that continuing chemotherapy administration will compromise delivery of full-dose 
radiation in an uninterrupted manner.
Reversible or permanent alopecia, bone marrow toxicity, esophagitis and skin pigmentation are 
expected side effects of radiation therapy.  Radiation-induced myocarditis and spinal cord injury 
rarely occur at doses lower than 50 Gy.  Radiographic evidence of radiation-induced changes and 
subsequent fibrosis of the lung may occur within lung volumes receiving ≥20 Gy.  It is essential 
to spare as much normal lung as possible in order to avoid symptomatic lung injury.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
86
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
In case of interruptions due to machine breakdown or public holidays or any 
interruptions of radiation therapy up to 7 days, radiation should be completed to the 
prescribed doses.  Total number of fractions and elapsed days should be carefully 
reported.
!
During cCRT, esophagitis is managed according to Table 13 and Table 17 for the 
cisplatin/etoposide and carboplatin/paclitaxel regimens, respectively, and Table 9 and 
Table 10 in regard to RT. During this cCRT period, in case of Grade 3 esophagitis 
related to chemotherapies or tislelizumab or placebo, chemotherapies or tislelizumab 
or placebo should be held if the Investigator believes continued use will jeopardize 
the delivery of full-dose RT, and radiation is to be continued.  Retreatment with 
chemotherapies and/or tislelizumab or placebo is permitted if there is resolution of the 
esophagitis to ≤ Grade 2. 
If Grade 4 esophagitis related to RT, chemotherapies or tislelizumab or placebo
occurs, RT, chemotherapies, and/or tislelizumab or placebo should be held until 
resolution of the esophagitis to ≤ Grade 2.
!
During cCRT, in case of Grade 3 or Grade 4 radiation pneumonitis/lung infiltrates 
related to RT, the recommendation is to hold RT, chemotherapies and tislelizumab or 
placebo. Retreatment with RT, chemotherapies and tislelizumab or placebo is 
acceptable if symptoms resolve to ≤ Grade 1 or are controlled on prednisolone 
≤10 mg/day (or equivalent corticosteroids). Discontinue study treatment if symptoms 
persist with corticosteroid treatment.
Radiation toxicities will be assessed according to NCI CTCAE v5.0 criteria and reported per 
Section 10.1.  Note, radiation toxicities can arise more than 90 days after the completion of 
radiation therapy.
Esophagitis
The first symptoms of acute esophagitis usually start in the second or third week of RT, 
commonly at the dose of 18.0 to 21.0 Gy of standard fractionated RT (Wei, 2006), and include a 
sensation of difficult swallowing (dysphagia).  This may progress to painful swallowing of food 
and saliva (odynophagia) and later to constant pain not necessarily related to swallowing. In 
severe cases, subjects may not be able to swallow at all and may require intravenous hydration, 
feeding through a gastric tube and, in rare cases, parenteral nutrition.
Symptomatic esophagitis is common with combined modality therapy (Werner-Wasik, 2005)
and it does not constitute a reason to interrupt or delay radiotherapy or chemotherapy, provided 
oral intake is sufficient to maintain hydration. Symptoms of acute esophagitis may persist for 1 
to 3 weeks after completion of RT.  If CTCAE Grade 4 esophagitis occurs and treatment is 
interrupted, every effort should be made to limit the interruption to 3 treatment days or less.  
Subjects requiring hospitalization, placement of a feeding tube in the stomach, or intravenous 
feedings because of esophagitis may have their treatment interrupted in order to allow for healing 
of the esophageal mucosa.
Table 13 and Table 17 summarize the dose modifications of the chemotherapy regimens in cases 
of esophagitis Grade 3 or 4.
Table 8 lists esophagitis grading and clinical states according to the CTCAE v5.0.
&(/*(1(35235,(7$5<,1)250$7,21
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f


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
87
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 8:
CTCAE Scale:  Acute Esophagitis Related to Radiation
Grade
Clinical State
1
Asymptomatic; clinical or diagnostic observations only; intervention not indicated
2
Symptomatic; altered eating/swallowing; oral supplements indicated
3
Severely altered eating/swallowing; tube feeding, TPN, or hospitalization indicated
4
Life-threatening consequences; urgent operative intervention indicated
5
Death
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; TPN = total parenteral nutrition.
Acute esophageal toxicity should be managed with diet and medications, alone or in various 
combinations (Table 9 and Table 10), or comparable regimen, and intervention should be 
initiated at the first signs or symptoms of esophageal toxicity.
Table 9:
Dietary and Nutritional Support Recommendations for Acute Radiation 
Esophagitis
Supportive Measure
Recommendation
Dietary modification
!
Consider dietician referral
!
Avoid potentially irritant foods (tobacco, alcohol, coffee, and 
spicy foods)
!
Soft, bland diet
!
Small, frequent meals
Nutritional support
!
Liquid meal replacements/supplements
!
Intravenous hydration
!
Electrolyte correction
!
For prolonged symptoms, enteral feeding or total parenteral 
nutrition may be required, although former is preferred
!
Antiemetics may be beneficial
Modified from Baker, 2016
Table 10:
Recommendations for Medication Management of Radiation Esophagitis
Treatment 
Option
Management of Esophagitis
1
Ketoconazole 200 mg PO QD
2
Fluconazole 100 mg PO QD until the completion of radiation
3
Mixture of: viscous lidocaine 60 mL + Mylanta (or generic equivalent
antacid) 30 mL + sucralfate (1 gm/mL) 10 mL. Take 15 to 30 mL PO q3 to 4h PRN
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&


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
88
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 10:
Recommendations for Medication Management of Radiation Esophagitis
(Continued)
Treatment 
Option
Management of Esophagitis
4
Ranitidine 150 mg PO BID (or other histamine-2 [H2] receptor blocker or a proton 
pump inhibitor such as omeprazole) until completion of radiation
5
Grade 4 esophagitis: hold CRT until Grade 2 or less
Abbreviations: BID = twice daily; CRT = chemoradiotherapy; h = hour; PO = oral; PRN = when necessary; q = 
every; QD = every day.
7.2.3.
Supportive Care
Subjects should receive full supportive care, including epoetin and other hematopoietic growth 
factors (eg, colony-stimulating factors [CSFs]), transfusions of blood and blood products, 
antibiotics, antiemetics, other applicable medications, as needed according to local standard of 
care guidelines or practices.
Subjects on the carboplatin/paclitaxel regimen should receive supportive care including
dexamethasone, antihistamines and histamine H2 antagonists according to SmPCs, local standard 
of care guidelines, or practices; refer to Table 5.
7.2.4.
Overdose or Incorrect Administration
Any overdose (defined as ≥ 600 mg of tislelizumab or placebo in a 24-hour period, greater than 
10% of the calculated chemotherapy dose, or any dose over the protocol specified RT dose) or 
incorrect administration of study drug should be noted in the subject’s chart and on the 
appropriate eCRF. Adverse events associated with an overdose or incorrect administration of 
study drug will be recorded on the adverse event eCRF. If an overdose or incorrect 
administration of study treatment takes place and adverse events with significant safety influence 
are observed, the Sponsor or designee must be notified within 24 hours of awareness via the SAE 
reporting process as described in Section 10.5. Supportive care measures should be administered 
as appropriate.
7.2.5.
Dose Delay and Modification 
Every effort should be made to administer the study drugs according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided below. Reasons for dose modifications or delays, the supportive 
measures taken, and the outcome will be documented in the subject's chart and recorded in the 
eCRF.
7.2.5.1.
General Guidance Regarding Dose Modifications
Reasons for dose modifications or delays, the supportive measures taken, and the outcomes will 
be documented in the subject's chart and recorded in the eCRF. The severity of adverse events 
will be graded according to the NCI CTCAE v5.0 grading system.
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.2.5.1.
Reason
Reason


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
89
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Chemotherapy-related toxicities should be managed according to the prescribing information of 
the approved product combined with institutional standard practices. The details in this section 
are for reference:
!
Baseline body weight is used to calculate the required chemotherapy doses. Dose 
modifications are required if the subject’s body weight changes by more than 10% 
from baseline (or the newly referred body weight). Chemotherapy doses should not 
be modified for any body weight change of less than 10%, unless there is an ongoing 
toxicity requiring dose modification. When several toxicities with different grades of 
severity occur at the same time, the dose modifications should be according to the 
highest grade observed.
!
If any component of chemotherapy is temporarily interrupted, both chemotherapeutic 
agents will be delayed until doublet chemotherapy can be given as planned.
!
In case of chemotherapy related toxicity, chemotherapy will be delayed until it has 
resolved to baseline or ≤ Grade 1 prior to administering the next dose of 
chemotherapy, with the exception of toxicities of alopecia, Grade 2 fatigue, or other 
AEs which, in the opinion of the Investigator, would not affect the safety evaluation 
of tislelizumab or placebo, in which case chemotherapy should continue as scheduled. 
Chemotherapy treatment may be delayed from a planned administration date up to 2 
weeks for either chemotherapy regimen.
!
In case of tislelizumab or placebo related toxicity, tislelizumab or placebo will be 
delayed until it has resolved to baseline or ≤ Grade 1 prior to administering the next 
dose of tislelizumab or placebo, with the exception of alopecia, Grade 2 fatigue, or 
other AEs which, in the opinion of the Investigator, would not affect the safety 
evaluation of the study drugs. Chemotherapy should continue as scheduled. If the AE 
is resolved within 10 days, tislelizumab or placebo will be administered on the first 
available day. If the AE is not resolved within 10 days, tislelizumab or placebo will 
be omitted. If the AE is resolved within 21 days, tislelizumab or placebo and 
chemotherapy will be administered on Day 1 of the next planned cycle. 
!
The tumor assessment schedule will not be altered if chemotherapy and/or 
tislelizumab or placebo are delayed or discontinued. 
!
Every effort should be made to continue treatments in combination when the subject’s 
condition allows, also taking into consideration the subject’s convenience for the 
treatment schedule.
!
Following either completion of or discontinuation from chemotherapy, tislelizumab 
or placebo should be continued as scheduled, if clinically appropriate. 
!
If one component of chemotherapy is discontinued permanently during a cycle of 
treatment for reasons other than PD, the other component of chemotherapy could be 
continued per the study protocol or local practice.
!
If tislelizumab or placebo is discontinued permanently during a cycle of 
chemotherapy concurrent with RT, the subject may continue the cCRT per the study 
protocol or local practice. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
90
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.2.5.2.
Dose Modification for Tislelizumab or Placebo
There will be no dose reduction for tislelizumab or placebo in this study. 
Dose delays or interruptions of tislelizumab or placebo of less than 12 weeks will be permitted. 
Investigators should make every effort to maintain dose intensity in subjects. 
Subjects may temporarily suspend study drug (tislelizumab or placebo) if they experience 
toxicity that is considered related to tislelizumab or placebo and requires a dose to be withheld. If 
a dose of tislelizumab or placebo is delayed for ≤ 10 days for a planned dosing cycle (eg, Cycle 3 
Day 1), tislelizumab or placebo should be administered and all assessments should be conducted
on the first available day according to the original cycle (ie, Cycle 3). If the delay is more than 
10 days, the subject should skip the tislelizumab or placebo dose, and tislelizumab or placebo 
will be administered on Day 1 of the next planned cycle (ie, Cycle 4 Day 1, 42 days after the last 
dose given on Cycle 2 Day 1).
The subjects should resume tislelizumab or placebo treatment as soon as possible after the AEs 
recover to baseline or Grade 1 (whichever is more severe) within 12 weeks after last dose of 
tislelizumab or placebo. If the subject is unable to resume tislelizumab or placebo within 12 
weeks after the last dose of tislelizumab or placebo, then the subject should be discontinued from 
study treatment, unless approval to continue treatment is obtained from the Sponsor medical 
monitor.
If a scheduled dose coincides with a holiday that precludes dosing, dosing should commence on 
the nearest following date (≤ 3 days after scheduled dosing) and subsequent dosing can continue 
on a new 21-day schedule based on the infusion date. 
Subjects who discontinue treatment due to tislelizumab (or placebo) and/or chemotherapy 
toxicity in the absence of disease progression should continue with tumor assessments until 
disease progression.
Guidelines for dose modification, treatment interruption, or discontinuation, and for the 
management of irAEs and infusion-related reactions, are provided in detail in Section 7.2.5.2, 
Section 8.3, and Appendix H. 
7.2.5.3.
Dose Modifications of Chemotherapy
Toxicities related to chemotherapy must be resolved to baseline or ≤Grade 1 prior to 
administering the next dose of chemotherapy, with the exception of alopecia, Grade 2 fatigue, or 
other AEs which, in the opinion of the Investigator, would not affect the safety evaluation of the 
study drugs. A maximum of 2 dose reductions are permitted for cisplatin and etoposide. If 
additional reductions are required, that chemotherapeutic agent must be discontinued. Dose 
reductions of one chemotherapeutic agent do not require the same dose reductions of the other 
chemotherapeutic agent within the combination, unless the toxicities can reasonably be attributed 
to both agents. Once the dose has been decreased, it should remain reduced for all subsequent 
administrations, or further reduced if necessary. There will be no dose escalations in this study. 
Chemotherapy treatment may be delayed from a planned administration date up to 2 weeks for 
either chemotherapy regimen.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
&(/*(1(35235,(7$5<,1)250$7,21
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hem
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
91
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
holidays). Subjects should be placed back on study therapy within 2 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the subject's study record.
Dose modification guidelines for chemotherapy, depending on the severity of toxicity and an 
assessment of the risk versus benefit for the subject, with the goal of maximizing subject 
compliance and access to supportive care, are described in Section 7.2.5.3 and Section 8.3.
For toxicities not listed, dose modifications are permitted per local standards.
During the cCRT period, it is possible that abnormal liver function tests may arise as a result of 
radiation to the liver, as could occur with malignancies involving the lower part of the right lung. 
If the Investigator believes abnormal bilirubin or transaminase elevations are due to radiation and
not due to drug effects and that no dose modifications are necessary, continued full-dose 
chemotherapy may proceed after agreement with Sponsor.
7.2.5.3.1. Cisplatin and Etoposide
7.2.5.3.1.1. Hematologic Toxicity
Dose adjustments at the start of a subsequent cycle of study treatment will be based on platelet 
and neutrophil nadir (lowest value) counts from the preceding cycle.  Prior to treatment, the 
ANC must be ≥1.5 x 109/L and platelets must be ≥100 x 109/L (Table 11).
Table 11:
Lab parameters to Initiate Cisplatin and Etoposide Regimen
Laboratory Parameter
Value
ANC
≥1.5 X 109 cells/L
Platelets
≥100 X 109 cells/L
Abbreviations: ANC = absolute neutrophil count
Treatment may be delayed up to 2 weeks to allow sufficient time for recovery.  Upon recovery, 
treatment should be administered according to the guidelines in Table 12.
Table 12:
Dose Modifications for Cisplatin and Etoposide Based on Hematologic Nadir 
Values Prior to the Next Dose
ANC (x109L)
Platelet (x109L)
Dose for etoposide
(mg/m2)
Dose for Cisplatin
(mg/m2)
≥0.5
and
≥50
100% of previous dose
100% of previous dose
< 0.5
and
≥50
75% of previous dose
75% of previous dose
< 1.0 + fever of ≥
38.3ºCa
and
≥50
75% of previous dose
75% of previous dose
Any
and
< 50
75% of previous dose
50% of previous dose
Any
and
≤25 
50% of previous dose
50% of previous dose
&(/
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&


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
92
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 12:
Dose Modifications for Cisplatin and Etoposide Based on Hematologic Nadir 
Values Prior to the Next Dose (Continued)
ANC (x109L)
Platelet (x109L)
Dose for etoposide
(mg/m2)
Dose for Cisplatin
(mg/m2)
Any
and
< 50 with bleedingb
50% of previous dose
50% of previous dose
Recurrence of Grade 3 or 4 after 2 dose 
reductions (with either neutropenia or 
thrombocytopenia)
Discontinue subject from study treatment
Abbreviations: ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events.
a These criteria meet the CTCAE v5.0 definition of ≥ Grade 3 febrile neutropenia (NCI 2006).
b This criterion meets the CTCAE v5.0 definition of ≥ Grade 3 bleeding (NCI 2006).
7.2.5.3.1.2. Nonhematologic Toxicity
In general, for nonhematologic toxicities greater than or equal to Grade 3, treatment should be 
delayed until resolution to less than or equal to the subject’s baseline value before resuming 
treatment at a reduced dose.  However, exceptions may be made for Grade 3 neurotoxicity or 
esophagitis.  In the case of neurotoxicity, the Investigator and subject may decide to continue 
treatment at a reduced dose, with no delay required, as neurotoxicity may not resolve to baseline 
values.  Adjustments for esophagitis should follow dose modifications as described in Table 13,
which lists the relevant dose adjustments of etoposide and cisplatin for nonhematologic 
toxicities.
Table 13:
Dose Modifications for Cisplatin and Etoposide Based on Nonhematologic 
Toxicity
Eventa
Dose for Etoposide
(mg/m2)
Dose for Cisplatin
(mg/m2)
Other toxicity Grade 0 to 2
100% of previous dose
100% of previous dose
Diarrhea
Grade 0 to 2 requiring 
hospitalization
100% of previous dose
100% of previous dose
Mucositis
Grade 3 or 4
75% of previous dose
100% of previous dose 
Esophagitis
Grade 3b
Hold at the Investigator’s 
discretion
Hold at the Investigator’s 
discretion
Esophagitis
Grade 4c
Hold etoposide
Hold cisplatin
100% of p
100% of 
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or Grade 3 n
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ubject may
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odificat
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and cisplat
and cisplati
in and 
and Eto
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Dose for E
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23
5
100%
10
52
35
1(
tis
e 3
e 3b
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Esophagitis
Esophagitis
Grade 4
Grade 
(/
&


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
93
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 13:
Dose Modifications for Cisplatin and Etoposide Based on Nonhematologic 
Toxicity (Continued)
Eventa
Dose for Etoposide
(mg/m2)
Dose for Cisplatin
(mg/m2)
Hepatic toxicity
(transaminase elevation)
Grade 3 or 4
75% of previous dose
75% of previous dose
Neurotoxicity
Grade 2
100% of previous dose
50% of previous dose
Neurotoxicity
Grade 3d, e
75% of previous dose
discontinue cisplatin
Neurotoxicity
Grade 4
Discontinue etoposide
Discontinue cisplatin
Any Grade 3 or 4 not specified 
above
75% of previous dose 
75% of previous dose
Recurrence of any Grade 3 or 4 
toxicity after 2 dose reductions
Discontinue etoposide
Discontinue cisplatin
a Except nausea and/or vomiting.
b Grade 3 esophagitis will occur in a significant number of subjects toward the end of radiation therapy. For subjects 
who experience this event earlier in the course of their treatment than anticipated, the advice would be to hold 
chemotherapy and assess at weekly intervals. If symptoms do not progress at the time of assessment, 
chemotherapy can be resumed at 75% of previous dose for both drugs.
c Grade 4 esophagitis results in holding chemotherapy until toxicity resolves to ≤ Grade 2, and then chemotherapy 
may be resumed at 75% of previous dose for both drugs.
d Delay until resolution of toxicity to baseline value is not required for Grade 3 neurotoxicity.
e At the discretion of the attending physician, subjects experiencing Grade 3 neurologic toxicity as a transient 
ischemic attack that has completely resolved may not require dose reduction or discontinuation.
Table 14 lists dose modification for cisplatin based on renal toxicity.
Table 14:
Dose Modifications for Cisplatin Based on Renal Toxicity
Day
Calculated CrCl 
(mL/min)
Cisplatin dose (mg/m2)
On Days 1 and 8 of the subsequent 
cycle
≥ 60
100% of previous dose
On Days 1 and 8 of the subsequent 
cycle
< 60
Omit cisplatin dose, delay 1 week
If, after 1-week delay
≥ 60
75% of previous dose and increase 
pre- and post- cisplatin hydration
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cycle
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a
&


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
94
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 14:
Dose Modifications for Cisplatin Based on Renal Toxicity (Continued)
Day
Calculated CrCl 
(mL/min)
Cisplatin dose (mg/m2)
If, after 1-week delay
< 60
Notify Sponsor to determine if 
further chemotherapy is possible
Abbreviations: CrCl = creatinine clearance
7.2.5.3.2. Carboplatin and Paclitaxel
Before starting a new cycle of treatment, the creatinine clearance of the subject must be ≥ 45
mL/minute.
During the concurrent treatment, carboplatin (AUC = 2) and paclitaxel (40 to 50 mg/m2) are 
administered intravenously on Day 1 of a weekly cycle (Days 1, 8, 15, 22, 29, and 36, during 
cCRT period). Prior to treatment, ANC must be ≥ 1.5 X 109 cells/L, and platelets must be ≥ 100 
X 109 cells/L (Table 15). Chemotherapy treatment may be delayed up to 2 weeks from a planned 
administration date; if toxicities have not resolved to acceptable levels at that time notify the 
Sponsor’s medical monitor to determine if further chemotherapy is possible. Doses that are 
missed during the weekly schedule concurrent with radiation will not be made up but will be 
documented.
7.2.5.3.2.1. Hematologic Toxicity
Table 15:
Parameters to Initiate Carboplatin and Paclitaxel Regimen
Laboratory Parameter
Value
Creatinine clearance
≥ 45 mL/minute
ANC
≥ 1.5 X 109 cells/L
Platelets
≥ 100 X 109 cells/L
Abbreviations: ANC = absolute neutrophil count
Treatment may be delayed to allow sufficient time for recovery. Upon recovery, treatment 
should be administered according to the guidelines in Table 16 and Table 17 for hematologic 
toxicities and nonhematologic toxicities, respectively.
Table 16:
Dose Modifications for Carboplatin and Paclitaxel Based on Hematologic 
Toxicities
Adverse Event
Treatment
Febrile neutropenia; documented infection
Chemotherapy delay until recovered to ≤Grade 1 (ANC 
≥1.5 x 109/L)
Neutropenia
Grade 3 or 4
Chemotherapy delay until ≤Grade 1 (ANC ≥1.5 x 
109/L)
Thrombocytopenia
≥Grade 2 to 4
Chemotherapy delay until ≤Grade 1 (platelets < LLN -
75,000/mm3)
&(
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vent
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&(


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
95
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 16:
Dose Modifications for Carboplatin and Paclitaxel Based on Hematologic 
Toxicities (Continued)
Adverse Event
Treatment
Thrombocytopenia
≥Grade 3 associated 
with clinically 
significant bleeding
Discontinue chemotherapy
Abbreviations: ANC = absolute neutrophil count; LLN = Lower limit of normal
7.2.5.3.2.2. Nonhematologic Toxicity
For toxicities not listed in Table 17, dose modifications are permitted per local standards.
Table 17:
Dose Modifications for Carboplatin and Paclitaxel Based on Nonhematologic 
Toxicity
Event
Dose for Carboplatin 
(AUC)
Dose for Paclitaxel (mg/m2)
Ototoxicity Grade 3 to 4
Hold chemotherapy until ≤Grade 2
Neuropathy Grade 2
Continue carboplatin
Hold paclitaxel until ≤Grade 1
Neuropathy Grade 3
Continue carboplatin
Discontinue paclitaxel
Neuropathy Grade 4
Discontinue chemotherapy
Esophagitis Grade 3a or 4b
Hold chemotherapy until ≤Grade 2
Oral mucositis or stomatitis Grade 4
Discontinue chemotherapy
Diarrhea Grade 4
Discontinue chemotherapy
Other non-hematologic toxicity Grade 
3 to 4
Hold chemotherapy until ≤Grade 1 or baselinec
Any toxicity which recurs after 2 prior 
dose delays for the same drug-related 
AE
Discontinue chemotherapy
Abbreviations: AE = adverse event; AUC = are under the curve.
a Grade 3 esophagitis will occur in a significant number of subjects toward the end of radiation therapy. For subjects 
who experience this event earlier in the course of their treatment than anticipated, the advice would be to hold 
chemotherapy and assess at weekly intervals. If symptoms do not progress at the time of assessment, 
chemotherapy can be resumed.
b Grade 4 esophagitis results in holding chemotherapy until toxicity resolves to ≤ Grade 2, and then chemotherapy 
may be resumed.
c Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting or other AEs which, in the opinion of the 
Investigator, would not affect the safety evaluation of tislelizumab or placebo, may resolve to Grade 2 or baseline.
7.2.6.
Specific Considerations
Treatment may be delayed allowing a subject sufficient time to recover from treatment-related 
toxicity.
Any subject who has had 2 dose reductions and who experiences a toxicity that would cause a 
third dose reduction must be discontinued from chemotherapy treatment.
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7.2.6.
7.2.6
reatm
reatm


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
96
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.2.7.
Clinically Significant Effusions
If a subject develops clinically significant pleural or peritoneal effusions (on the basis of 
symptoms or clinical examination) and the Investigator determines that the effusion represents 
disease progression, it is recommended that the effusion be drained for cytologic evaluation for 
disease progression if clinically feasible.  If the effusion represents disease progression, the 
subject should be discontinued from study treatment and tumor assessment by imaging must be 
performed prior to initiation of subsequent anti-cancer therapy.  This imaging needs to be 
submitted for central review as for any other imaging for tumor assessment.
7.2.8.
Creatinine Clearance
Enrollment and dosing decisions should be based on calculated CrCl using the standard 
Cockcroft and Gault formula (Cockcroft, 1976; see Appendix G).
Local laboratory values used for serum creatinine may be used to calculate CrCl for enrollment 
or dosing decisions; however, if local laboratories are used to calculate CrCl, the same local 
laboratory must be used throughout the study.  In addition, a separate serum specimen must be 
collected before the initiation of treatment and whenever subsequent samples are collected for 
dosing decisions. These additional samples will be sent to a central laboratory and used for 
subsequent safety analyses.
For subjects receiving cisplatin/etoposide, the CrCl should be ≥60 mL/min prior to the start of 
any cycle; if a subject’s CrCl has not returned to ≥60 mL/min within 42 days after the last study 
therapy administration, the subject must be discontinued from the study treatment unless 
continuation is approved by the Sponsor. For subjects receiving carboplatin/paclitaxel, the CrCl 
should be ≥ 45 mL/min prior to the start of any cycle; if a subject’s CrCl has not returned to ≥ 45
mL/min within 42 days after the last study therapy administration, the subject must be 
discontinued from the study treatment unless continuation is approved by the Sponsor.
7.2.9.
Blinding
This is a randomized, double-blind, Phase 3 study. Subjects will be randomized to receive 
tislelizumab or placebo in a double-blind fashion.
At the start of the study, placebo may not be available for distribution. Until placebo becomes 
available, sites that randomize subjects will be required to have an unblinded pharmacist (or 
designated site personnel) prepare a placebo IV bag for subjects randomized to placebo identical 
in appearance to those provided to the infusion team for subjects randomized to tislelizumab. 
Once placebo becomes available, sites will use the Sponsor supplied placebo. All subjects, study 
site staff and Sponsor representatives, with the exception of designated individuals, will remain 
blinded to the subject’s randomized treatment arm.  
For sites that receive tislelizumab and placebo exclusively from the Sponsor (meaning, the site 
does not use institution-supplied placebo at any point in the trial), the subject, all study site staff 
and Sponsor representatives, with the exception of designated unblinded individuals, will be 
blinded to the subject’s randomized treatment arm.
!
Emergency unblinding 
Emergency unblinding for AEs may be performed through the study IRT.
rd 
rd 
Cl f
l or enro
or enro
f
l, the same
l, the same
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≥60 mL
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cycle
cycle; if a s
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nd, Phase 3
nd, Phase 
oubl
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Sponsor
to the subj
to the subj
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and 
nd Spon
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d


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
97
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
In case of an emergency, the Investigator or designated site personnel, as documented in the 
delegation of authority log, has the sole responsibility for determining if unblinding of a 
subject’s treatment assignment is warranted. Subject safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor medical monitor 
prior to unblinding a subject’s treatment assignment unless this could delay emergency treatment 
of the subject. If a subject’s treatment assignment is unblinded, the Sponsor must be notified 
immediately.
!
Inadvertent unblinding 
Every effort will be made to blind both the subject and the Investigator to the identity of 
tislelizumab or placebo, but the inadvertent unblinding of a subject may occur. If an Investigator, 
site personnel performing assessments, or subject is unblinded, the unblinding will not be 
sufficient cause (in and of itself) for that subject to be discontinued from study therapy or 
excluded from any safety or efficacy analyses.
Additionally, there may be ethical reasons to have the subject remain on tislelizumab or placebo. 
For subjects to continue on tislelizumab or placebo in the event of unblinding, the Investigator 
must obtain specific approval from the Sponsor’s medical monitor.
7.3.
Method of Treatment Assignment
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will be randomized by IRT via 1:1:1 ratio to either one of the following treatment 
groups:
 
 
 
The permuted block randomization method will be used to generate the randomization codes and 
the randomization will be performed by IRT to ensure a 1:1:1 treatment assignment ratio. The 
randomization schedule will be generated by the Sponsor or its designee. The randomization will 
be stratified by age 
), chemotherapy regimen (
 
), and region (
). 
If one of the tislelizumab arms (Arm 1 or Arm 2) is discontinued at study interim due to safety 
findings, and the Sponsor decides to continue the study with the remaining tislelizumab arm and 
the control arm (Arm 3), the newly recruited subjects will be randomized to the remaining 2
arms using a 1:1 randomization ratio, until the originally planned sample size of 560 in the 
remaining 2 arms is reached.  
C
C
I
&(/*(
the tisisleliz
leli
ngs, and the
ngs, and th
control
control ara
arm
rms using
using
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domizat
domizatioion
ll be perfor
ll be perf
edule will b
edule will 
age
age
5235,(7$5<,1)250$7,21
f
nvestigato
nvestigato
l not be
not be
therapy
therapy or
o
y
tislelizum
islelizu
nblinding, th
blinding, 
.
available su
available s
eit
either one 
her o
em
emaini
ain
(1
*(1
5,(
35,(
235
523
52
35


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
98
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
7.4.
Packaging and Labeling
The label(s) for IP will include the Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as
applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product receipt, return, disposal, and/or destruction including responsibilities 
for the site versus Celgene (or designee).
Accountability for study drug that is administrated during the course of the study is the
responsibility of the Investigator or designee. Investigational clinical supplies must be received
by a designated person at the clinical site and kept in a secure and temperature-controlled
location. The investigational site must maintain accurate records demonstrating dates and
amounts of study drug received, to whom it was administered (subject-by-subject accounting),
and accounts of any tislelizumab or placebo accidentally or deliberately destroyed or returned. 
Accurate recording of all IP administration will be made in the appropriate section of the 
subject’s eCRF and source documents. Unless otherwise notified, all vials of study drug, both 
used and unused, must be saved for drug accountability. The investigational product should be 
disposed of in accordance with the institutional/regional requirements after drug accountability 
has been completed by the monitor. The Investigator must return all unused vials of study drug 
to the Sponsor at the end of the study, or the study drug may be destroyed at the clinical site with 
the permission of the Sponsor. For either scenario, the outcome must be documented on the drug 
accountability log. The Sponsor will provide direction for the outcome of all unused vials.
7.6.
Investigational Product Compliance
Accurate recording of all IPs administered will be made in the appropriate section of the 
subject’s eCRF and source documents. The Investigator or designee is accountable for the 
compliance of all study-specific IPs either administered or in their custody during the course of 
the study.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
99
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from study treatments or disease progression. 
Supportive care, including but not limited to antiemetic medications, may be administered at the 
discretion of the Investigator. 
 
 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigator’s Brochure and/or local package 
insert.
8.1.
Permitted Concomitant Medications and Procedures
Most concomitant medications and therapies deemed necessary for supportive care (eg, 
antiemetics, antidiarrheal) and in a subject’s interest are allowed. All treatments that the 
Investigator considers necessary for a subject’s health and safety purpose may be administered at 
the discretion of the Investigator in keeping with the local standards of medical care. All 
concomitant medication including all prescription, over-the-counter, herbal supplements, and IV 
medications and fluids will be recorded on the eCRF. If changes (dose, stop, or start) in 
concomitant medication occur during the study, documentation of drug dosage, frequency, route, 
date, and reason for use will be recorded on the eCRF.
All concomitant medications received within 28 days before randomization and 30 days after the 
last infusion or dose of study treatment should be recorded.
Systemic corticosteroids required for the control of irAEs must be tapered over at least 1 month 
and be at nonimmunosuppressive doses (≤10 mg/day of prednisone or equivalent) before the 
next tislelizumab or placebo administration. The short-term use of steroids as prophylactic 
treatments (eg, subjects with contrast allergies to diagnostic imaging contrast dyes) is also 
permitted.
Subject may continue to receive hormone replacement therapy or supportive care if initiated 
prior to enrollment. 
Premedications and postmedications per the chemotherapy labels and per local guidelines are 
permitted.
The use of bisphosphonates during the trial for a nonmalignant indication is permitted.
Hematopoietic growth factors such as growth-colony stimulating factor (G-CSF) or granulocyte-
macrophage colony-stimulating factor (GM-CSF) may be used according to institutional or other 
specific guidelines (eg, country, regional, or oncology organizations, such as American Society 
of Clinical Oncology [ASCO], etc.) to treat febrile neutropenia and Grade 3 to 4 neutropenia, but 
should not be used as primary or secondary prophylaxis. The use of any growth factor support 
must be documented in the subject’s record and eCRF. Growth factors must be discontinued at 
least 48 hours prior to initiation of the next cycle of study drug.
According to the NCCN 2018 guidelines (NCCN, 2018), erythropoiesis-stimulating agents 
(ESAs) may be considered for the treatment of cancer-related anemia in subjects undergoing 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
100
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
palliative treatment. Erythropoietic therapy may be considered for treatment of study drug-
induced anemia in cases where hemoglobin is < 11 g/dL or a decrease of ≥2 g/dL from baseline, 
but only after the subject has been counseled about the risks and benefits of ESA use. 
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are prohibited or restricted at screening and during the study:
!
Immunosuppressive agents (except to treat a drug-related AE).
!
Systemic corticosteroids > 10 mg daily (prednisone or equivalent) within 14 days 
before randomization and during the study, except to treat or control a drug-related 
AE or for short-term use as prophylactic treatment (eg, antiemetic therapy for specific 
chemotherapy).
!
Any concurrent antineoplastic therapy (ie, chemotherapy, targeted therapy, hormonal 
therapy, immunotherapy, or standard or investigational agents [including Chinese 
herbal medicine and Chinese patent medicines] for the treatment of cancer).
!
Extensive radiation therapy during monotherapy (except for local, palliative 
radiotherapy provided that it does not compromise tumor assessments of target 
lesions).
!
Live vaccines within 28 days before randomization and 60 days following the last 
dose of study drugs. (NOTE: seasonal vaccines for influenza are generally inactivated 
vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.)
!
During cisplatin and carboplatin use, concurrent therapy with drugs having a potential 
ototoxic or nephrotoxic effect (eg, aminoglycosides, cefalotine, furosemide, 
amphotericin B) should be avoided or adequately monitored since this may lead to 
increased or exacerbated toxicity due to platin-induced changes in renal clearance of 
these substances.
!
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes 
CYP2C8 and CYP3A4. Therefore, in the absence of a PK drug-drug interaction 
study, caution should be exercised when administering paclitaxel concomitantly with 
medicines known to inhibit either CYP2C8 or CYP3A4 (eg ketoconazole and other 
imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, 
ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be 
increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly 
with medicines known to induce either CYP2C8 or CYP3A4 (eg, rifampicin, 
carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because 
efficacy may be compromised because of lower paclitaxel exposures.
!
Refer to the approved product labeling for complete information regarding drug-drug 
interactions.
!
The following are also excluded during the study: 
∀
Herbal remedies with immunostimulating properties (ie, mistletoe extract) or 
known to potentially interfere with major organ function (ie, hypericin) 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
101
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
∀
Subject should not abuse alcohol or other drugs during the study.
The following guideline should be also followed during the study:
!
With the exception of diagnostic biopsy of tumor tissue or placement of a venous 
access device, the Investigator should discuss with the medical monitor any 
individual subject requiring surgery during the study.
!
Eligible subjects for this study must have locally advanced, stage III NSCLC that is 
considered to be unresectable.  Any subject for whom the institutional practice would 
consider surgery to be a treatment option if disease downstaging is observed after 
completion of the chemoradiotherapy should have been considered ineligible for 
participation in the study.  Thus, surgical resection of NSCLC due to subsequent 
downstaging of the stage III NSCLC after chemoradiotherapy prior to progression is 
prohibited during the course of the study. 
8.3.
Required Concomitant Medications and Procedures
8.3.1.
Management of Immune-related Adverse Events
Immune-related AEs are of special interest in this study. If the events listed below or similar 
events occur, the Investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but are not limited to serologic, immunologic, 
and histologic (biopsy) data. If alternative causes have been ruled out and 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 18. All conditions similar to those listed should 
be evaluated in subjects receiving tislelizumab or placebo to determine whether they are 
immune-related. 
Recommendations for diagnostic evaluation and management of irAEs (see Appendix H) are
based on a recent ESMO guideline (Haanen, 2017). For any adverse events not included in 
Appendix H, please refer to the recent ESMO guideline for further guidance on diagnostic 
evaluation and management of immune-related toxicities. 
Table 18:
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
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
102
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 18:
Immune-Related Adverse Events (Continued)
Body System Affected
Events
Endocrine
Thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features 
of hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent 
diabetes mellitus; diabetic ketoacidosis; adrenal insufficiency
Respiratory
Pneumonitis/diffuse alveolitis
Eye
Episcleritis; conjunctivitis; iritis/uveitis
Neuromuscular
Arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis
Blood
Anemia; leukopenia; thrombocytopenia
Renal
Interstitial nephritis; glomerulonephritis; acute renal failure
Cardiac
Pericarditis; myocarditis; heart failure
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase
The management of irAEs is detailed in Appendix H.
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, tislelizumab or placebo should be 
discontinued after consultation with the Sponsor. Subjects who experience a recurrence of any 
event at the same or higher severity grade with rechallenge should permanently discontinue 
treatment.
8.3.2.
Management of Infusion Reactions
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Subjects should be closely monitored 
for such reactions. Immediate access to an intensive care unit 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 19. 
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9.


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
103
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 19:
Management of Infusion Reactions
NCI CTCAE Grade – severity
Guideline for Modification of Tislelizumab or Placebo 
Treatment
Grade 1 – mild
Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated.
Decrease tislelizumab or placebo infusion rate by 50% and 
closely monitor any worsening.
Manage medically as needed. Subsequent infusions should be 
given after premedication and at the reduced infusion rate.
Grade 2 – moderate
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hours.
Stop infusion. Infusion may be resumed at 50% of previous 
rate once infusion-related reactions have resolved or decreased 
to 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 discontinue the tislelizumab or placebo infusion.
Proper medical management should be instituted as described 
below. The subject should be withdrawn from tislelizumab or 
placebo treatment. 
Grade 4 – life threatening
Life threatening consequences; urgent 
intervention indicated.
Immediately and permanently discontinue tislelizumab or 
placebo treatment.
Proper medical management should be instituted as described 
below.
Abbreviations: IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAID = nonsteroidal anti-inflammatory drug.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
For further information, please refer to CTCAE v5.0.
Once the tislelizumab or placebo infusion rate has been decreased by 50% or suspended due to 
an infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the subject has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued, and the subject should be withdrawn from 
tislelizumab or placebo treatment.
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction.  This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen.  
In the next cycle, subjects should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
104
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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, antipyretic, glucocorticoids, epinephrine, bronchodilators, and 
oxygen.
8.3.3.
Severe Hypersensitivity Reactions and Flu-Like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar, 2008).
Subjects should be instructed to report any delayed reactions to the Investigator immediately.
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the subject 
discontinued from the study.
The subjects will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the subject 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 drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to subjects at the discretion of the 
Investigator.
8.3.4.
Treatment of Hepatitis B and Hepatitis C
Patients with active hepatitis B defined as either detectable HBsAg or HBV DNA at baseline 
must initiate treatment 2 weeks prior to randomization or first dose, and continue until 6 months 
after the last dose.  Patients should continue effective antiviral treatment during the study to 
decrease potential viral re-activation risk.  Peg-IFN, tenofovir, and entecavir are recommended in 
the American Association for the Study of Liver Disease guideline because they lack resistance 
with long-term use (Terrault, 2016).  The Investigator might use other antiviral agents, if 
appropriate, following local guidelines.  Management of antiviral therapy is at the discretion of 
the Investigator.
Patients with active hepatitis C should undergo treatment with antiviral therapy following the 
American Association for the Study of Liver Diseases guideline or the local guidelines as 
appropriate.  However, interferon-based therapy for either HBV or HCV is not permitted on 
study. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
105
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
 
 
 The study protocols BGB-A317-NSCL-001 and 
BGB-A317-NSCL-001C have a total combined enrollment target of 840 subjects.
 
 
The data from both study protocols will be 
collected into one database and the statistical analyses as described in Section 9 will be 
performed on the combined total of subjects randomized into either the main protocol or the 
companion protocol. A single IDMC and blinded independent central review will be utilized for 
these 2 study protocols.
This is a Phase 3, randomized, double-blind, placebo-controlled study designed to compare 
efficacy and safety in either tislelizumab concurrent with chemoradiotherapy followed by 
tislelizumab monotherapy (Arm 1), or placebo concurrent with chemoradiotherapy followed by 
tislelizumab (Arm 2), versus placebo concurrent with chemoradiotherapy followed by placebo 
(Arm 3), in subjects with locally advanced, unresectable non-small cell lung cancer. The primary 
treatment comparisons are the pairwise comparisons of either one of the tislelizumab arms (Arm 
1 or Arm 2) versus the control Arm (Arm 3). 
The sections below provide an overview of the proposed statistical considerations and analyses. 
The final statistical analysis methods will be documented in detail in the statistical analysis plan 
(SAP). 
9.2.
Study Population Definition 
9.2.1.
Intent-to-treat Population 
The intent-to-treat (ITT) population will consist of all randomized subjects regardless of whether 
the subjects receive any IP or have any efficacy assessment conducted. 
9.2.2.
Safety Population
The safety population will include any subjects who receive at least one dose of tislelizumab or 
placebo. In safety analyses, subjects will be included in treatment groups according to the actual 
treatment they receive, if the treatment received is different from the randomized treatment 
group. 
9.2.3.
Per Protocol Population
The per protocol population will include all subjects in the safety population who have met all 
the eligibility criteria and have no major protocol violation.  
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
106
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.3.
Power and Sample Size Consideration
9.3.1.
Multiplicity Control Strategy
There are 2 primary hypotheses in this study:
!
: PFS in Arm 1 ≤ Arm 3 versus PFS in Arm 1 > Arm 3
!
: PFS in Arm 2 ≤ Arm 3 versus PFS in Arm 2 > Arm 3
 
There will be one interim and one final analysis for PFS, and one interim and one final analysis 
for OS, respectively. The interim OS analysis will occur at the same as the final PFS analysis. 
Therefore, there will be 3 data cutoff time points in this study:
 
 
 
 
 
 
Although PFS is the primary endpoint of this study and the final PFS analysis will be completed 
at the second data cutoff time point, the study may continue to follow up for overall survival 
until a prespecified total number of OS events accumulates, if either of the PFS hypotheses are 
rejected at the interim or the final PFS analysis. 
A group sequential design is implemented based on Lan-Demets spending function that 
approximates the O’Brien-Fleming boundary for each of the primary hypotheses for the PFS 
endpoint. The hypotheses associated with the key secondary endpoint OS 
!
: OS in Arm 1 ≤ Arm 3 versus OS in Arm 1 > Arm 3
!
: OS in Arm 2 ≤ Arm 3 versus OS in Arm 2 > Arm 3
will be tested only if either one of the primary hypotheses for PFS is rejected at the interim or the 
final PFS analysis. In addition, the other 2 key secondary endpoints, OS at 24 months (OS 24) 
and ORR, will also be tested if both the PFS and OS hypotheses in the same pairwise comparison 
of treatment groups are rejected. 
The overall type one error rate control strategy here follows the graphic approach as described by
Maurer and Bretz (Maurer, 2013), and can be depicted by the following graph. The local alpha 
will be dynamically determined by given spending function of the group sequential design for 
each endpoint (Glimm, 2010; Maurer, 2013).
CCI
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
107
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Of note, if Arm 1 or Arm 2 is discontinued, and the study continues with one of the tislelizumab 
arms and the control arm, the graph will be simplified to the left (or right) half of the graph. The 
edges in between the 2 OS hypotheses will be removed, and the weight for edges from the OS 
endpoint to the OS 24 and ORR endpoint will be updated to 1/2, but other edges and the alpha 
allocation for each hypothesis in the remaining half graph will stay the same as in the initial 
graph.
 
 
 Additionally, to control the type 
one error due to multiple looks of OS data at the interim and the final OS analysis, a group 
sequential design based on an alpha spending function that approximates the O’Brien-Fleming 
boundary will also be implemented for either one of the OS hypotheses. The actual boundaries 
will depend on the number of OS events, or information time, at the time of second interim 
analysis. Similar alpha control approach will be implemented for the other key secondary 
endpoints OS 24 and ORR. Notably, if one or more hypotheses are rejected at the interim or final 
analysis, the superiority boundaries for the remaining unrejected hypotheses will be updated 
based on the alpha propagation strategy as described by Maurer and Bretz (Mauer, 2013) using 
the graph above. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
108
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.3.2.
Power and Sample Size
 
 
 
 
 
 Assuming a constant enrollment rate of 30 subjects per month, and a median 
PFS of 9 months in the placebo arm, it will take approximately 28 months to enroll 840 subjects, 
and 35 months to accumulate a total of 580 PFS events. 
 
 
 
 
 
 
 
 
 The time for the final OS analysis when approximately 572 
total OS events accumulates is projected to be 61 months.
The median PFS in the control arm (Arm 3) is based on data from historical trials with similar 
subjects. Ahn (2015) and Belderbos (2007) reported that the median PFS for inoperable 
(unresectable) stage III NSLC treated with concurrent chemoradiotherapy are 8.1 months and 8.5 
months, respectively. Factoring in potential improvements in best supportive care, a conservative 
estimate for median PFS of 9 months for the control arm is used for the sample size and power 
calculation. 
For the target PFS treatment effect, a hazard ratio of 0.7 is considered as a clinically meaningful 
improvement of PFS and is used for the sample size and power calculation. This target is 
considered reasonable based on the cross-trial evaluation of historical data for cCRT described 
above, including that from the recently published PACIFIC study results. T0 is considered as 
PFS from cCRT treatment and T1 as PFS from anti-PD-L1 consolidation (durvalumab) treatment 
for subjects who have stable disease or better following cCRT. Heuristically, the cCRT + anti-
PD-1 PFS is approximated as T = T0(T0 ≤2) + (2 + T1)(T0 > 2) for first line treatment. Fitting 
historical medians of T0 and T1 and conducting simulations, the median PFS is close to 14.6 
months, which corresponds to an approximately 38% improvement consistent with the target 
hazard ratio of 0.7.
A similar assessment was performed for overall survival. The median OS in the control arm is 
estimated at 22 months from Ahn (2015). The target hazard ratio of 0.7 is considered a clinically 
meaningful improvement.
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
109
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.
Background and Demographic Characteristics
Subjects age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race, region, and other categorical variables will be presented using 
frequency tabulation. Medical history data will be summarized using frequency tabulation by 
system organ class and preferred term. 
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency tabulation for both treatment and 
follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol deviations 
will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
The primary efficacy analysis will be conducted based on ITT population. The primary and key 
secondary endpoints will also be analyzed using per protocol population. While key analyses are 
described in this section, additional analyses, including subgroup analyses, will be specified in 
the statistical analysis plan (SAP).
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
110
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.6.1.
Primary Efficacy Endpoint
The primary endpoint of progression free survival is defined as the time from randomization to 
the time of progression based on blinded independent reviewer assessment using RECIST v1.1 
or death, whichever is earlier. Subjects without progression or death will be censored according 
to censoring rules similar to those described in the FDA Guidance for Industry Clinical Trial 
Endpoints for Approval of Cancer Drugs and Biologics (FDA, 2007). The distribution of PFS 
will be estimated using the Kaplan-Meier method. The comparison of PFS between treatment 
arms (Arm 1 versus Arm 3 or Arm 2 versus Arm 3) will be conducted using a stratified log-rank 
test with age
), chemotherapy regimen
 
), and region (
 as stratification factors. The hazard 
ratio (between Arm 1 or Arm 2 versus Arm 3) and the corresponding 95% confidence interval 
will also be provided based on a stratified Cox proportional hazard model. The median PFS (with 
95% confidence interval) and estimation of PFS rate (with 95% confidence intervals) for specific 
time points (eg, 3 months, 6 months etc.) will be provided for each treatment arm.
9.6.2.
Secondary Efficacy Endpoints
9.6.2.1.
Overall Survival
The key secondary endpoint of overall survival (OS) is defined as the time from randomization 
to death due to any cause. Subjects without documented death at the time of analysis will be 
censored at the last-known-to-be-alive date. The distribution of OS will be estimated using 
Kaplan-Meier method. A stratified log-rank test will be used to compare treatment groups in OS. 
The median OS (with 95% confidence interval) and estimation of OS rate (with 95% confidence 
intervals) for different timepoints will be provided by treatment arm. The hazard ratio (between 
Arm 1 or Arm 2 versus Arm 3) and the corresponding 95% confidence interval will also be 
provided based on a stratified Cox regression model.
9.6.2.2.
OS at 24 Months
The key secondary endpoint OS at 24 months is defined as the proportion of subjects alive at 24 
months (OS 24). The point estimate and the corresponding 95% confidence interval for each 
treatment arm will be estimated using Kaplan-Meier method. The treatment comparisons for OS 
24 will be performed using an approach as described in Klein, 2007.
9.6.2.3.
Objective Response Rate 
The key secondary endpoint of objective response rate (ORR) is defined as the percentage of 
subjects who achieve a CR or PR based on the independent reviewer assessment using RECIST 
v1.1 criteria. The ORR for each treatment arm will be summarized using 95% Clopper-Pearson 
confidence interval. The difference in ORR between treatment arms and the associated 95% 
Wilson score confidence interval will be provided. A Cochran-Mantel-Haenszel (CMH) test will 
be used to compare ORR between treatment arms.
9.6.2.4.
Other Secondary Endpoints
The proportion of subjects alive and progression free at 12 months (APF12) or 18 months 
(APF18) will be summarized (using the Kaplan-Meier curve) and presented by treatment arm. 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
111
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
For each treatment arm, the APF12 or APF18 based on the Kaplan-Meier method will be 
presented, along with its 95% confidence interval. Treatment comparisons for APF12 and APF18 
will be based on the approach as described in Klein, 2007.
Time to distant metastasis (TTDM) will be defined as the time from the date of randomization 
until the first date of distant metastasis or death in the absence of distant metastasis. Distant 
metastasis is defined as any new lesion that is outside of the radiation field according to RECIST 
v1.1 or proven by biopsy. Time to distant metastasis will be analyzed using similar methods as 
described for the analysis of PFS. 
The duration of response (DOR) is defined as the time from the first tumor assessment when the 
CR/PR response criterion is first met to the date of disease progression based on independent 
reviewers’ assessment following RECIST v1.1 criteria.
Patient reported outcome validated instruments (EORTC QLQ-C30 with the lung module LC13) 
will be used to assess the selected lung cancer symptoms: appetite (item 13 of QLQ-C30), cough 
(items 31 to 32 of LC13), chest pain (item 40 of LC13), dyspnea (items 33 to 35 of LC13), and 
fatigue (items 10, 12, 18 QLQ-C30). Baseline scores, postbaseline scores and change from 
baseline will be provided on global domain and subdomains (as applicable) per arm. Count and 
percent of subjects with minimal clinically important benefit from baseline scores will be 
summarized per arm. Count and percent of subjects improving, with no change and worsening 
their baseline score will be summarized per arm. Time to minimal clinically important 
improvement and decline in selected scores will be examined. Missing values will be addressed 
according to questionnaire guidelines. Analysis for selected efficacy variables versus change in 
selected EORTC QLQ-C30 and LC-13 scales will also be provided to explore the relationship 
between clinical response and HRQoL. The details will be provided in the separate SAP.
The proportion of subjects who received at least one dose of tislelizumab or placebo in the 
monotherapy phase before progression based on blinded independent reviewer assessment 
following RECIST v1.1 criteria, will be compared for Arm 1 versus Arm 2 and 3 combined. The 
proportion will be summarized using point estimate and 95% Clopper-Pearson confidence 
interval for Arm 1 versus Arm 2 and 3. The difference between treatment arms and the 
associated 95% Wilson score confidence interval will be provided. A Cochran-Mantel-Haenszel 
(CMH) test will be used to compare the proportion.
9.7.
Safety Analysis
Safety analysis will be performed based on the safety population. Safety and tolerability will be 
monitored through continuous reporting of AEs and serious adverse events (SAEs), laboratory 
abnormalities, and incidence of subjects requiring dose modifications, dose interruptions, and/or 
premature discontinuation of IP. The safety population will be the primary analysis population 
for safety analyses.  Descriptive statistics will be provided for summaries of adverse events, 
clinical laboratory data, and other safety assessments.
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs), 
defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) 
on or after the first dose of study drug up to 30 days following study drug discontinuation or 
initiation of new anticancer therapy, whichever occurs first. Treatment-emergent AEs also 
include all immune-related AEs (irAEs) recorded up to 90 days after the last dose of tislelizumab 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
112
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
or placebo, regardless of whether or not the subject starts a new anticancer therapy. All events 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent adverse events will be summarized per treatment arms by MedDRA system organ class 
and preferred terms. Grade 3 or higher TEAEs, SAEs, TEAEs leading to dose reduction and dose 
interruption, TEAEs leading to treatment discontinuation, and TEAEs with an outcome of death 
will be summarized per treatment arms by MedDRA system organ class and preferred terms. 
Additionally, adverse events of special interest for tislelizumab will be summarized in the same 
manner.
 
 
 
 
 
.
9.9.
Other Topics
9.9.1.
Data Monitoring Committee
An IDMC will be convened that will include medical oncologists with experience in treating 
subjects with lung cancer and a statistician, all of whom are not otherwise involved in the study 
conduct. During the study, the IDMC will review the safety and efficacy data in accordance with 
the guidelines for the preplanned interim analyses. There will be IDMC safety assessments 
during which the IDMC will examine unblinded safety data including but not limited to serious 
adverse events, adverse events, and other safety data individually and in aggregate and will 
provide recommendations on the continuation of the 3 arms based on safety and tolerability.
 
 
 
 
 
 
 Enrollment may
continue during these IDMC safety assessments.
An independent third party will prepare the reports of aggregate data summaries and individual 
subject data listings, as appropriate, to the IDMC members for each scheduled meeting. 
Operational details for the IDMC will be detailed in the IDMC charter.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
113
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
9.9.2.
Steering Committee
The conduct of this trial will be overseen by a steering committee (SC), presided over by the 
coordinating Principal Investigator and if possible the representative regional Investigators from 
regions participating in this study.  The SC will serve in an advisory capacity to the Sponsor.  
Operational details for the SC will be detailed in a separate SC charter.
Note: The SC is separate from the IDMC.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
114
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
 
 
 
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
115
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.2.4 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for tislelizumab,
cisplatin, carboplatin, etoposide, or paclitaxel overdose. Actual treatment should depend on the 
severity of the clinical situation and the judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All subjects will be monitored for adverse events starting from the time the subject signs the ICF 
until 30 days after the last dose of study treatment (tislelizumab/placebo, chemotherapy, or RT), 
as well as those SAEs made known to the Investigator at any time thereafter that are suspected of 
being related to study treatment. Subjects will also be monitored for immune related adverse 
events (serious or nonserious) starting from the time the subject signs the ICF until 90 days after 
the last dose of tislelizumab or placebo, regardless of whether or not the subject starts a new 
anticancer therapy. All AEs and SAEs considered related to RT will be collected at any time 
after the first dose of RT, including late radiation toxicities.
Adverse events and SAEs will be recorded on the AE page of the eCRF and in the subject’s 
source documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
116
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
117
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 5.0.
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
118
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP because of an AE or SAE, as applicable (eg, 
discontinuation, interruption, or dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
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part o
part o


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
119
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events. 
Study participants receiving chemotherapy have a potential risk of irreversible infertility. 
Patients should be advised to speak to their physician for further information about their locally 
available options for fertility preservation.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 120 days after the subject’s last dose of tislelizumab or placebo and 180 days 
after the subject’s last dose of chemotherapy, are considered immediately reportable events. 
Investigational product is to be discontinued immediately. The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to Celgene Drug Safety immediately by email, phone 
or facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.  
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
120
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 30 days after the last dose of study 
treatment; until 90 days after the last dose of tislelizumab or placebo for irSAEs regardless of 
whether or not the subject starts a new anticancer therapy) or any SAE made known to the 
Investigator at any time thereafter that is suspected of being related to IP.  All SAEs considered 
related to RT will be collected at any time after the first dose of RT, including late radiation 
toxicities. Serious adverse events occurring prior to treatment (after signing the ICF) will be 
captured.
 
 
  
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to tislelizumab based on the Investigator’s Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to non-Celgene IMP study drugs (cisplatin, 
etoposide, carboplatin, and paclitaxel) based on the following Reference Safety Information
documents:
!
Cisplatin- EU Summary of Product Characteristics (SmPC)
!
Etoposide- EU SmPC
!
Carboplatin- EU SmPC
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
121
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
Paclitaxel- EU SmPC
Celgene or its authorized representative shall notify the Investigator of the following information 
(In Japan, Celgene KK shall notify the Heads of the Institutes in addition to the Investigators):
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
!
Other important safety information and periodic reports according to the local 
regulations.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 14.3 for record retention 
information.)
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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pl
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
122
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
!
Adverse Event
!
Progressive disease
!
Symptomatic deterioration (global deterioration of health status)
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Study terminated by Sponsor
!
Other (to be specified on the eCRF)
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject from the investigational product, the Investigator may contact the Medical Monitor and 
forward appropriate supporting documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Study terminated by Sponsor
!
Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
123
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Sponsor Medical 
Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the IRT.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
124
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the study.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries.
 
 
 
 
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
125
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF, signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
126
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
127
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene Standard 
Operating Procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement.
 
 
 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
128
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
 
 
  
 
 
 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
ruction of 
uction of


EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
129
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, European Medicines 
Agency, Health Canada) and company authorized representatives.  The Investigator should make 
every effort to be available for the audits and/or inspections.  If the Investigator is contacted by 
any regulatory authority regarding an inspection, he/she should contact Celgene immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subjects.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified,
a 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
130
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing 
 or by contacting the Celgene Customer Care Center 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
131
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
16.
PUBLICATIONS
 
 
 
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
132
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
17.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
133
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
134
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
135
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
136
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
137
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 21:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
APF12
Alive and progression free at 12 months
APF18
Alive and progression free at 18 months
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BUN
Blood urea nitrogen
C1D1
Cycle 1 Day 1
CBC
Complete blood count
CMH
Cochran-Mantel-Haenszel
cCRT
Concurrent chemoradiotherapy
CI
Confidence interval
CR
Complete response
CrCl
Creatinine clearance
CRT
Chemoradiotherapy
CSF
Colony stimulating factor
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
3DCRT
Three-dimensional conformal radiotherapy
4DCT
4-dimensional computed tomography
DNA
Deoxyribonucleic acid
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EDMS Doc. Number:
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Table 21:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
DOR
Duration of response
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
EGFR
Epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer – Quality of 
Life C30 questionnaire
EORTC QLQ-LC13
European Organisation for Research and Treatment of Cancer – Quality of 
Life C30 questionnaire lung cancer module
EOT
End of treatment
ESA
Erythropoiesis-stimulating agents
ESMO
European Society for Medical Oncology
EuroQol
European Quality of Life
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose - positron emission tomography 
FFPE
Formalin-fixed paraffin embedded
GCP
Good clinical practice
G-CSF
Growth-colony stimulating factor
GFR
Glomerular filtration rate
GHS
Global health status
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GTV
Gross tumor volume
Gy
Gray
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
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EDMS Doc. Number:
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Celgene Corporation
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BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 21:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
HBV
Hepatitis B Virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICI
Immune checkpoint inhibitor
ICF
Informed consent form
ICH
International Council for Harmonisation
ICHOM
International Consortium for Health Outcomes Measurement
ICRU
International Commission on Radiation Units & Measurements
IDMC
Independent data monitoring committee
IFN-γ
Interferon- γ
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
IMP
Investigational medicinal product
IMRT
Intensity modulated radiation therapy
INR
International normalized ratio
IP
Investigational product
irAE
Immune related adverse event
irTEAE
Immune related treatment-emergent adverse event
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
ITV
Internal target volume
IV
Intravenous
LC13
Lung cancer module 13
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multiple-gated acquisition scan
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EDMS Doc. Number:
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Table 21:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OS 24
Overall survival at 24 months
OTC
Over the counter
PBMC
Peripheral blood mononuclear cells
PE
Physical examination
PD-1
Programmed cell death protein-1
PD-L1
Programmed cell death protein-ligand 1
PD-L2
Programmed cell death protein-ligand 2
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PQC
Product Quality Complaint
PR
Partial response
PRO
Patient reported outcome
 
PT
Prothrombin time
PTT
Partial thromboplastin time
PTV
Planning target volume
Q2W
Every two weeks
Q3W
Every three weeks
QA
Quality assurance
QoL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
ROS-1
Proto-oncogene tyrosine-protein kinase ROS
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Table 21:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
RT
Radiation therapy
RTOG
Radiation Thoracic Oncology Group
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering committee
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious AE
TSH
Thyroid stimulating hormone
TTDM
Time to death or distant metastasis
UK
United Kingdom
ULN
Upper limit of normal
US
United States
V5
Volume of both lungs (%) receiving a dose of 5Gy or higher
V20
Volume of whole lung minus Planning Target Volume receiving at least 20 
Gy of radiation in total expressed as a percent
WBC
White blood cell
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APPENDIX B. PATIENT REPORTED OUTCOMES: EORTC QLQ-C30
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APPENDIX C. PATIENT REPORTED OUTCOMES: EORTC QLQ - LC13
EORTC QLQ - LC13
Subjects sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you.
______________________________________________________________________________
EORTC QLQ - LC13
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you.
During the past week:                                                 Not at          A       Quite      Very
All          Little     a Bit      Much
31.    How much did you cough?                                                                1               2            3             4
32.    Did you cough up blood?                                                                   1               2            3             4
33.    Were you short of breath when you rested?                                     1               2            3             4
34.    Were you short of breath when you walked?                                   1               2            3             4
35.    Were you short of breath when you climbed stairs?                        1               2            3             4
36.    Have you had a sore mouth or tongue?                                             1               2            3             4
37.    Have you had trouble swallowing?                                                   1               2            3             4
38.    Have you had tingling hands or feet?                                                1               2            3             4
39.    Have you had hair loss?                                                                     1               2            3             4
40.    Have you had pain in your chest?                                                     1               2            3             4
41.    Have you had pain in your arm or shoulder?                                    1               2            3             4
42.    Have you had pain in other parts of your body?                              1               2            3             4
If yes, where
43.    Did you take any medicine for pain?
1             No                               2            Yes
If yes, how much did it help?                                                            1               2            3             4
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EDMS Doc. Number:
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EDMS Doc. Number:
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EDMS Doc. Number:
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BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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CCI
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CCI
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APPENDIX G. CALCULATED CREATININE CLEARANCE 
(COCKCROFT AND GAULT 1976)
This formula should be used for calculating creatinine clearance (CrCl) from local laboratory
results only. The central laboratory applies the formula and reports the value in its calculated
form.
(A). Weight-Based Formula for Calculated Creatinine Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl (mL/min) = [(140 – age*) X (weight in kg) X 1.0 ] X [72 X serum creatinine (mg/dL)]
For serum creatinine concentration in μmol/L:
CrCl(mL/min) = [(140 – age*) X (weight in kg) X 1.0]/[0.81 X serum creatinine (μmol/L)]
(B). Weight-Based Formula for Calculated Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl (mL/min) = [(140 – age*) X (weight in kg)] X 0.85] / [72 X serum creatinine (mg/dL)]
For serum creatinine concentration in μmol/L:
CrCl (mL/min) = [(140 – age*) X (weight in kg) X 0.85] / [0.81 X serum creatinine (μmol/L)]
* Age in years.
Source: (Cockcroft, 1976)
/dL)])]
e (
e (μmol/L
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APPENDIX H. IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT
The recommendations below for the diagnosis and management of any irAE are intended as 
guidance. This document should be used in conjunction with expert clinical judgment (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies.
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs. In addition to the results of these tests, the following 
factors should be considered when making an irAE diagnosis: 
!
What was the temporal relationship between initiation of tislelizumab/placebo and the 
adverse event?
!
How did the subject respond to withdrawal of tislelizumab/placebo?
!
Did the event recur when tislelizumab/placebo 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. 
Table 22:
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 subjects 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 subjects 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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Table 22:
Recommended Diagnostic Tests in the Management of Possible Immune 
related Adverse Events (Continued)
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 
subject experiences bleeding, pain or distension, consider colonoscopy with 
biopsy and surgical intervention, as appropriate. 
Eye Disorders
If subjects experience acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the subject 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 to 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: creatine 
kinase, erythrocyte sedimentation rate, CRP, troponin and consider a 
muscle biopsy.
Myocarditis
Perform ECG, CK/CK-MB, echocardiogram, troponin (troponin I and/or T),
and refer to a cardiologist.
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANA = antinuclear antibody; AST = aspartate 
aminotransferase; CK = creatine kinase; CK-MB = creatine kinase cardiac isoenzyme; CNS = central nervous 
system; CRP = C-reactive protein; CT = computed tomography; DLCO = diffusing capacity for carbon monoxide; 
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ECG = electrocardiogram; FBC = full blood count; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LCI = liver cystosolic antigen; LFT = liver function test; LKM = liver kidney microsomal 
antibody; LP = liver pancreas antigen; MRA = magnetic resonance angiogram; MRI = magnetic resonance 
imaging; PCR = polymerase chain reaction; SLA = soluble liver antigen; SMA = smooth muscle antibody; T4 =
thyroxine; TFT = thyroid function tests; TSH = thyroid-stimulating hormone; UEC = urea electrolytes and 
creatinine.
Treatment of Immune-related Adverse Events
!
Immune-related AEs can escalate quickly; study drug interruption, close monitoring, 
timely diagnostic work-up and treatment intervention, as appropriate, with subjects is 
required
!
Immune-related AEs should improve promptly after introduction of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice and contact the study medical monitor
!
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor
!
Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil)
!
Consider prophylactic antibiotics for opportunistic infections if the subject is 
receiving long-term immunosuppressive therapy
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EDMS Doc. Number:
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EDMS Doc. Number:
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Protocol BGB-A317-NSCL-001
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160
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
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Protocol BGB-A317-NSCL-001
Celgene Corporation
161
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
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162
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Table 23:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
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Protocol BGB-A317-NSCL-001
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163
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
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164
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
165
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
166
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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APPENDIX I.
THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1
The text below was obtained from 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 (v1.1).  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.
Nonmeasurable 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 nonmeasurable 
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
!
Blastic bone lesions are nonmeasurable
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Cystic lesions:
!
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts
!
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
Lesions with prior local treatment:
!
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional 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, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 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 nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological 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.
Nontarget 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 
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&


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progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
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 (CR) or surgical resection is an 
endpoint.
!
Tumor markers: Tumor markers alone cannot be used to assess objective tumor
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
170
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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 prostate-specific antigen 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.
!
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters
!
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note: the appearance 
of one or more new lesions is also considered progression).
!
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study
!
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR 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 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
171
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”. 
∀
When this occurs, it is important that a value be recorded on the eCRF.  If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned (Note: 
It is less likely that this rule will be used for lymph nodes since they usually have 
a definable size 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 Nontarget Lesions
While some nontarget 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.
!
CR: Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (<10 mm short axis).
!
PD: Unequivocal progression (as detailed below) of existing nontarget lesions.  
(Note: the appearance of one or more new lesions is also considered progression.)
!
Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits
!
When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget 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 nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in nontarget 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 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
172
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
same general concept applies here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). 
!
Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy”.  If “unequivocal progression” 
is seen, the 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 CR.  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 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
173
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
Evaluation of Best Overall Response
The BOR 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 BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and nontarget 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 BOR 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 BOR 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
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease.
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 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
174
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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.”
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 CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  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 nonrandomized 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 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks).
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Protocol BGB-A317-NSCL-001
Celgene Corporation
175
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
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 CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of 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 2 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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EDMS Doc. Number:
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Summary of Changes Protocol BGB-A317-NSCL-001
Celgene Corporation
3
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below.
 
 This 
includes the following revisions:
!
Additional Independent Data Monitoring Committee (IDMC) Assessment of the 
Safety and Tolerability of the Cisplatin Plus Etoposide Chemotherapy Regimen
An additional IDMC safety analysis with a minimum of 10 subjects who have completed 2 
cycles of tislelizumab, cisplatin/etoposide and radiation therapy and have been on study for at 
least 60 days will be conducted to provide additional safety information about this specific 
chemotherapy combination.
had concerns regarding the tolerability of cisplatin/etoposide administered in 
combination with tislelizumab and radiation therapy, since this regimen is known to have 
increased morbidity when compared to the regimen of carboplatin and paclitaxel (Santana-
Davila, 2014). Protocol Section 1.2.2.4 provides early data from Study BGB-A317-206, in which 
tislelizumab is administered in combination with 4 different platinum-containing doublet 
chemotherapy regimens (pemetrexed, paclitaxel, gemcitabine or etoposide combined with either 
cisplatin or carboplatin) in subjects with non-small cell lung cancer (NSCLC) or small cell lung 
cancer (SCLC). 
While there are no safety data for tislelizumab in combination with chemotherapy and radiation, 
data presented at ASCO 2018 regarding the use of immune checkpoint inhibitors in combination 
with chemotherapy and radiation in subjects with NSCLC have not identified any new safety 
concerns. The NICOLAS Phase 2 trial (Peters, 2018) is exploring the safety and feasibility of 
combined chemotherapy (which included cisplatin in combination with etoposide, vinorelbine or 
pemetrexed) and radiation with nivolumab in stage III NSCLC. At the time of an early interim 
analysis, 49 subjects were recruited with a median follow-up of 6.6 months. The most frequently 
observed AEs were fatigue and anemia. No unexpected AEs or increased safety risk were 
observed. For the first 21 subjects, no pneumonitis grade ≥3 was observed by the end of the 3-
month post radiotherapy (RT) follow-up period. The majority of these subjects (18 subjects) 
were on a concurrent chemotherapy and radiation schedule. This early interim safety analysis 
provides evidence that the addition of nivolumab to concurrent chemotherapy and radiation is 
safe and tolerable.
An early safety assessment across all the treatment arms in the current study would provide a 
meaningful basis for comparison of the relative safety of tislelizumab given concomitantly with 
chemotherapy and radiation. In the original protocol, 
 
 
 
 
 
. Therefore, the amendment 
includes an additional IDMC safety analysis with a minimum of 10 subjects who have completed 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Summary of Changes Protocol BGB-A317-NSCL-001
Celgene Corporation
4
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
2 cycles of tislelizumab, cisplatin/etoposide and radiation therapy and have been on study for at 
least 60 days, to provide additional safety information about this specific chemotherapy 
combination.
Revised sections: Protocol Summary, Section 1.3.2 (Rationale for the Study Design), Section 3.1 
(Study Design), Figure 1 (Overall Study Design), Section 9.9.1 (Data Monitoring Committee)
!
Increased Creatinine Clearance Eligibility and Dose Modification Requirements
for Subjects Receiving the Cisplatin Plus Etoposide Chemotherapy Regimen
Given the increased risk of renal injury with the combination of platinum-based chemotherapy
and tislelizumab and the absence of data characterizing the risks of renal toxicity with these 
regimens, the FDA had concerns that the creatinine clearance (CrCl) requirement of > 45 ml/min 
in inclusion criterion 7.d. in protocol Section 4.2 (Inclusion Criteria) was too low. The current 
amendment thus revises the required calculated creatinine clearance (CrCl) to ≥ 60 mL/min 
(Cockcroft-Gault formula) for subjects receiving cisplatin/etoposide. Since carboplatin dosing is 
based on area under the curve (AUC), which takes into consideration drug elimination through 
renal clearance, the requirement remains CrCl ≥ 45 mL/min for subjects receiving 
carboplatin/paclitaxel. 
In addition, Table 14 (Dose Modifications for Cisplatin Based on Renal Toxicity) is amended to 
reflect that resumption of cisplatin dosing following a delay due to renal toxicity, and the degree 
of dose reduction (if needed), depend upon the return of the subject’s CrCl to ≥ 60 mL/min rather 
than ≥ 45 mL/min.
Revised sections: Section 4.2 (Inclusion Criteria), Table 14 (Dose Modifications for Cisplatin 
Based on Renal Toxicity), Section 7.2.8 (Creatinine Clearance)
!
Clarification Regarding the East Asia Versus Other Stratification Factor 
As described in the protocol, this Phase 3 study will be conducted under 2 protocols. These 2 
protocols are as follows: 
1. Protocol BGB-A317-NSCL-001 is the main protocol 
 
2. Protocol BGB-A317-NSCL-001C is the companion protocol
 
The data from both study protocols will be collected into one database and the statistical analyses 
as described in protocol Section 9 will be performed on the combined total number of subjects 
randomized into either the main protocol or the companion study protocol. A single independent 
data monitoring committee (IDMC) and blinded independent central review will be utilized for 
these 2 study protocols. Randomization into the study will be stratified by age 
 
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Summary of Changes Protocol BGB-A317-NSCL-001
Celgene Corporation
5
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
Revised sections: Protocol Summary, Section 3.1 (Study Design), Section 9.1 (Statistical 
Considerations – Overview)
!
Addition of Rationale for Implementing the Statistical Assumptions of the 
Progression Free Survival (PFS) and Overall Survival (OS) Analyses
 requested that the analysis plan for the study provide a detailed description of the 
assumptions of the PFS and OS analyses, including the difference to be detected between arms 
and the estimated median PFS and OS in both arms. A justification for the assumptions of 
treatment effect has been added to the statistical assumptions in Section 9 of the amendment.
Revised sections: Section 9.3.2 (Statistical Considerations – Power and Sample Size)
In addition to the above changes 
 one significant change 
included in this amendment is summarized below:
!
Addition of timepoints for Patient Reported Outcomes Assessments
A secondary objective in the protocol is to compare the impact of study treatment on patient-
reported lung cancer symptoms (appetite loss, cough, chest pain, dyspnea, and fatigue) assessed 
by European Organisation for Research and Treatment of Cancer – Quality of Life C30 
questionnaire (EORTC QLQ-C30) and its lung cancer module (EORTC QLQ-LC13).
 
 
 
In the original protocol this data is collected at screening, Day 1 of Cycles 1 through 8, at 
discontinuation of the study treatment, and 30 days after the last dose of tislelizumab/placebo. To 
fully assess patient reported outcomes for the duration of study treatment, the amendment 
includes data collection at screening, Day 1 of every cycle during study treatment, at 
discontinuation of the study treatment, and 30 days after the last dose of tislelizumab/placebo.
Revised sections: Table 3 (Study Endpoints), Table 4 (Table of Events), Section 6.2 (Procedures 
– Treatment Period)
This amendment also includes several other minor clarifications and corrections:
!
!
Deletion of the statement that the wording of the 
 
will be replaced to adjust to the needs of the current study 
 
!
Change of Celgene Therapeutic Area Head
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EDMS Doc. Number:
Tislelizumab (BGB-A317)
Summary of Changes Protocol BGB-A317-NSCL-001
Celgene Corporation
6
BGB-A317-NSCL-001 Amendment 1 Final: 20 Sep 2018
!
 
 
!
Clarification that subjects who have detectable HBV DNA or HCV RNA either at 
screening or upon repeat testing during treatment (if clinically indicated) will have the
respective viral load test every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc.) (Table 4; 
Section 6.1, Procedures – Screening Period; Section 6.2, Procedures – Treatment Period; 
Section 6.2.1, Procedures – End of Treatment; Section 6.3.1, Procedures – Safety Follow-
Up)
!
Update the example of other medically appropriate methods of left ventricular ejection 
fraction (LVEF) assessment from MRI, CT and cardiac catheterization to multiple-gated 
acquisition scan (MUGA), and add the description of the assessment (if clinically 
indicated) to the End of Treatment and 30-Day Safety Follow-up visits in order to match 
the Table of Events (Procedures – Screening Period; Section 6.2, Procedures – Treatment 
Period; Section 6.2.1, Procedures – End of Treatment; Section 6.3.1, Procedures – Safety 
Follow-Up)
!
Clarify in a footnote that histamine H2 receptor antagonist premedications for paclitaxel 
can include not only cimetidine or ranitidine, but also other equivalent histamine H2 
receptor antagonists (eg, famotidine) (Table 5)
!
Minor formatting changes and corrections
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, RANDOMIZED, BLINDED, PLACEBO-CONTROLLED STUDY
OF TISLELIZUMAB (BGB-A317) PLUS CHEMORADIOTHERAPY 
FOLLOWED BY TISLELIZUMAB MONOTHERAPY IN NEWLY 
DIAGNOSED, STAGE III SUBJECTS WITH LOCALLY ADVANCED, 
UNRESECTABLE NON-SMALL CELL LUNG CANCER
STUDY DRUG:
TISLELIZUMAB (BGB-A317)
PROTOCOL NUMBER:
BGB-A317-NSCL-001 and BGB-A317-
NSCL-001C
DATE FINAL:
DRAFT 07 May 2019
Prepared by:
PPD, LLC
on behalf of
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
 
 
 
 
 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................12
3.1.
Primary Objective...................................................................................................12
3.2.
Secondary Objectives .............................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................14
4.1.
Overall Study Design and Plan ...............................................................................14
4.2.
Study Endpoints .....................................................................................................16
4.2.1.
Primary Efficacy Endpoint(s)..................................................................................16
4.2.2.
Secondary Endpoints ..............................................................................................16
4.2.2.1
Key Secondary Endpoints.......................................................................................16
4.2.2.2
Other Secondary Endpoints ....................................................................................16
4.3.
Stratification, Randomization, and Blinding............................................................17
4.3.1.
Randomization and Stratification............................................................................17
4.3.2.
Blinding..................................................................................................................18
4.4.
Sample Size Determination.....................................................................................18
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................20
5.1.
Reporting Conventions ...........................................................................................20
5.2.
Analysis Populations ..............................................................................................21
5.2.1.
Intent-to-Treat Population/Full Analysis Set ...........................................................21
5.2.2.
Safety Population....................................................................................................21
5.2.3.
Per-Protocol Population..........................................................................................21
5.2.5.
HRQoL evaluable Population .................................................................................21
6.
SUBJECT DISPOSITION......................................................................................22
7.
PROTOCOL DEVIATIONS ..................................................................................23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................24
8.1.
Demographics.........................................................................................................24
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
3
8.2.
Baseline Characteristics..........................................................................................24
8.3.
Cancer History and Baseline Lesion Status.............................................................24
8.4.
Medical History......................................................................................................25
8.5.
Prior and Concomitant Therapy ..............................................................................25
8.5.1.
Prior and Concomitant Anti-Cancer Therapy ..........................................................25
8.6.
Prior and Concomitant Medications........................................................................25
8.6.1.
Prior Medications ...................................................................................................25
8.6.2.
Concomitant Medications .......................................................................................25
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................26
9.1.
Treatment Duration.................................................................................................26
9.2.
Cumulative Dose ....................................................................................................26
9.3.
Dose Intensity.........................................................................................................26
9.4.
Relative Dose Intensity...........................................................................................27
9.5.
Dose Adjustment/Interruption.................................................................................27
10.
EFFICACY ANALYSIS ........................................................................................28
10.1.
Multiplicity.............................................................................................................28
10.2.
Analysis of Primary Efficacy Endpoint...................................................................30
10.3.
Analyses of Secondary Efficacy Endpoints.............................................................32
10.3.1.
Overall Survival .....................................................................................................32
10.3.2.
OS at 24 Months.....................................................................................................32
10.3.3.
Objective Response Rate ........................................................................................32
10.3.4.
Duration of Response .............................................................................................33
10.3.5.
Alive and Progression-Free at 12 or 18 Months ......................................................33
10.3.6.
Time to Distant Metastasis......................................................................................33
10.3.7.
Proportion of subjects who continue to monotherapy phase ....................................34
10.4.
Subgroup Analysis..................................................................................................34
11.
SAFETY ANALYSIS ............................................................................................35
11.1.
Adverse Events.......................................................................................................35
11.2.
Immune-related Adverse Events .............................................................................36
11.3.
Clinical Laboratory Evaluations..............................................................................36
11.3.1.
Hematology............................................................................................................37
11.3.2.
Clinical Chemistry..................................................................................................37
11.4.
Vital Sign Measurements........................................................................................37
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
4
11.5.
Physical Examination .............................................................................................38
11.6.
Electrocardiograms.................................................................................................38
11.7.
ECOG Performance Status......................................................................................38
11.8.
Ophthalmic Examinations.......................................................................................38
11.9.
Pregnancy test ........................................................................................................38
12.
QUALITY OF LIFE ANALYSIS...........................................................................39
12.1.
EORTC QLQ-C30 and LC13..................................................................................39
15.
INTERIM ANALYSIS...........................................................................................44
15.1.
General Information................................................................................................44
15.2.
Statistical Approaches for Control of Alpha............................................................44
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................46
17.
REFERENCES.......................................................................................................47
18.
APPENDICES........................................................................................................48
18.1.
Study Schematic and Study Events .........................................................................48
18.1.1.
Study Schematic .....................................................................................................48
18.1.2.
Table of Study Events.............................................................................................50
18.2.
Handling of Dates...................................................................................................57
18.2.1.
Calculation Using Dates .........................................................................................57
18.2.2.
Calculation of Cycles..............................................................................................58
18.3.
Date Imputation Guideline......................................................................................59
18.3.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications.......................59
18.3.2.
Prior/Concomitant Procedures ................................................................................60
18.3.3.
Medical History......................................................................................................60
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Censoring Rules for PFS.........................................................................................31
Table 3:
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EDMS Doc. Number: 24651554 - 23106086
PPD


Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
ADA
Antidrug antibodies
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
APF12
Alive and progression free at 12 months
APF18
Alive and progression free at 18 months
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
cCRT
Concurrent chemoradiotherapy
BMI
Body mass index
BSA
Body surface area
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CR
Complete response
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
EORTC QLQ-
C30
European organisation for research and treatment of cancer - quality of life C30 
questionnaire
EORTC QLQ-
LC13
European organisation for research and treatment of cancer - quality of life C30 
questionnaire lung cancer module
EOT
End of treatment
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
8
FDA
Food and Drug Administration
HR
Hazard ratio
HRQoL
Health-related quality of life
IDMC
Independent data monitoring committee
IFN-γ
Interferon- γ
IRT
Interactive response technology
ITT
Intent-to-treat
IV
Intravenous
LDH
Lactic dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NA
Not applicable
NCI
National Cancer Institute
NSCLC 
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-L1
Programmed cell death protein-ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
PP
Per protocol
PR
Partial response
PRO
Patient-reported outcome
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
9
STDEV
Standard deviation
Q3W
Every 3 weeks
SGOT
Serum glutamic oxaloacetic transaminase (AST)
TEAE
Treatment-emergent adverse events
TEirAE
Treatment-emergent immune-related adverse event
SGPT
Serum glutamic pyruvic transaminase (ALT)
TTDM
Time to death or distant metastasis
NE
Not-evaluable
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
10
2.
INTRODUCTION
This Phase 3 study will be conducted under 2 protocols as follows: 
1) Protocol BGB-A317-NSCL-001 is the main protocol 
 
 
2) Protocol BGB-A317-NSCL-001C is the companion protocol 
 
. 
 
 
 
The protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C have a total combined 
enrollment target of 840 subjects utilizing a virtually identical study design and patient 
population with regards to inclusion and exclusion criteria.  Both study protocols will utilize one 
IRT (Interactive Response Technology) for stratification and randomization and the data from 
two protocols will be collected into a single database. All the statistical analyses as described in 
this statistical analysis plan (SAP) will be performed on the combined total number of subjects 
randomized into either the main protocol or the companion protocol as one study. A single 
independent data monitoring committee (IDMC) and blinded independent central review will be 
utilized for these 2 protocols. There are minor differences, primarily administrative in nature, 
between the
This SAP describes the analyses and data presentations for Celgene’s protocols BGB-A317-
NSCL-001 and BGB-A317-NSCL-001C “A PHASE 3, RANDOMIZED, BLINDED, 
PLACEBO-CONTROLLED STUDY OF TISLELIZUMAB (BGB-A317) PLUS 
CHEMORADIOTHERAPY FOLLOWED BY TISLELIZUMAB MONOTHERAPY IN 
NEWLY DIAGNOSED, STAGE III SUBJECTS WITH LOCALLY ADVANCED, 
UNRESECTABLE NON-SMALL CELL LUNG CANCER”. Protocol BGB-A317-NSCL-001   
was originally issued on 21May2018 and subsequently amended on 20Sep2018 (Amendment 
No. 1). Protocol BGB-A317-NSCL-001C was originally issued on 03Oct2018. The two 
protocols contain the same definitions of analysis populations, derived variables and statistical 
methods for the analysis of efficacy and safety, which are defined in this SAP.
There will be one interim and one final analysis for progression-free survival (PFS), and one 
interim and one final analysis for overall survival (OS), respectively. The interim OS analysis 
will occur at the same as the final PFS analysis. Therefore, there will be 3 data cutoff time points 
in this study:
 
 
 
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
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Celgene anticipates accrual will be completed before the interim analysis of PFS is performed 
and the study is planned to continue until completion of the final PFS and OS analyses.
Throughout this SAP, the treatment arms will be referred to as the following 3 arms:
 
 
 
 
The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data prior to database lock and any data analysis for 
the interim analysis. This SAP will be finalized and signed prior to the clinical database lock for 
the interim analysis of PFS. All statistical analyses detailed in this SAP will be conducted using 
SAS® Version 9.4 or higher.
The decision of closing the study in very early stage is leading to the decision not to conduct any 
planned statistical analysis. As a consequence, the SAP is remaining in this draft version. The 
changes in the planned analysis are presented in section 16. 
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
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3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective is to compare the PFS of tislelizumab in combination with cCRT followed 
by tislelizumab monotherapy (Arm 1) versus cCRT alone (Arm 3); in addition, tislelizumab 
given sequentially after cCRT (Arm 2) will be compared with cCRT alone (Arm 3) in newly 
diagnosed stage III subjects with locally advanced unresectable non-small cell lung cancer 
(NSCLC).
3.2.
Secondary Objectives
The secondary objectives are to:
!
Compare OS (key secondary objective)
!
Compare OS at 24 months (key secondary objective)
!
Compare centrally-assessed objective response rate (ORR) (key secondary objective)
!
Compare centrally-assessed duration of response (DOR)
!
Compare proportion of subjects alive and progression-free at 12 and 18 months
(APF12, APF18)
!
Compare time to death or distant metastasis (TTDM)
!
Compare safety and tolerability of tislelizumab in combination with cCRT followed by 
tislelizumab monotherapy versus cCRT alone, and tislelizumab given sequentially after 
cCRT versus cCRT alone.
!
Compare impact on patient-reported lung cancer symptoms (appetite loss, cough, chest 
pain, dyspnea, and fatigue) assessed by European Organisation for Research and 
Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30) and its 
lung cancer module (EORTC QLQ-LC13).
!
Compare the proportion of subjects who received at least one dose of tislelizumab or 
placebo in the monotherapy phase before progression in Arm 1 versus Arm 2 and 3.
 
 
 
 
 
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This Phase 3 study will be conducted under 2 protocols as follows: 
1) Protocol BGB-A317-NSCL-001 is the main protocol 
 
 
2) Protocol BGB-A317-NSCL-001C is the companion protocol
 
It is important to note that these 2 protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C 
constitute a single global Phase 3, randomized, double-blind, placebo-controlled multicenter 
study designed to compare the efficacy and safety of tislelizumab in combination with
concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy versus cCRT 
alone, and tislelizumab given sequentially after cCRT versus cCRT alone, in newly diagnosed 
stage III subjects with locally advanced, unresectable NSCLC.
The primary endpoint is centrally-assessed PFS in the intent-to-treat (ITT) population. Newly 
diagnosed stage III subjects with histologically confirmed, locally advanced, unresectable 
NSCLC are eligible.
The two protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C have a total combined 
enrollment target of approximately 840 subjects who will be randomized in a 1:1:1 ratio to 
receive the study drug
tislelizumab or placebo in one of the following 3 treatment arms:
!
The choice of chemotherapy regimen to be used as part of study treatment will be at the
Investigator’s discretion, consisting of either 2 cycles of cisplatin plus etoposide or weekly
carboplatin plus paclitaxel given during radiation therapy (RT) for 6 weeks. Radiation therapy
should start concurrently with chemotherapy in Cycle 1 of tislelizumab or placebo. If local
technical or logistical circumstances do not allow for the start of RT at the beginning of Cycle 1,
a 3-day administrative window to start RT will be allowed. Tislelizumab or placebo will be given
starting from Cycle 1 Day 1 (C1D1) in the cCRT phase, and continued in the monotherapy phase
for a duration of 12 months following the completion of cCRT, or until disease progression,
unacceptable toxicity, or treatment discontinuation for another reason.
Randomization will be stratified by age 
), chemotherapy regimen
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, and region
 
 
Safety and efficacy will be monitored by an IDMC. There will be IDMC safety assessments 
during which the IDMC will examine unblinded safety data including but not limited to serious 
adverse events (SAEs), adverse events, and other safety data individually and in aggregate, and 
will provide recommendations on the continuation of the 3 arms based on safety and tolerability.
The first IDMC safety assessment will be conducted after approximately 30 subjects
 
 
. The second IDMC safety 
assessment will be conducted as determined by the IDMC but no later than 3 to 6 months after 
the first evaluation. Subsequent assessments will take place approximately every 6 months 
thereafter. 
 
Enrollment 
may continue during these IDMC safety reviews.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell
infiltration and other mechanisms, leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the
Investigator to reflect pseudoprogression, the subject may continue treatment until progressive 
disease is confirmed by repeated imaging at least 4 weeks later but not exceeding 6 to 8 weeks 
from the date of initial documentation of progressive disease, provided the following criteria are 
met:
!
Absence of clinical symptoms and signs of disease progression (including clinically
significant worsening of laboratory values).
!
Stable ECOG performance status (≤ 1).
!
Absence of rapid progression of disease or of progressive tumor at critical anatomical
sites (eg, cord compression) that requires urgent alternative medical intervention.
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform subjects that this practice is not considered standard in the treatment of 
cancer. The decision to continue study drug(s) beyond initial Investigator-assessed progression 
must be discussed with the Sponsor medical monitor and documented in the study records.
The study conduct will be overseen by a Steering Committee (SC) composed of selected
Investigators who are taking part in the study. The SC will remain blinded to the study data by 
arm.
The study will be conducted in compliance with International Council for Harmonisation (ICH)
Good Clinical Practices (GCPs).
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The study schematic is presented in 18.1.
4.2.
Study Endpoints
4.2.1.
Primary Efficacy Endpoint(s)
The primary endpoint is PFS, defined as the time from the date of randomization to the date of 
the first objectively documented tumor progression as assessed by blinded independent central 
review per RECIST v1.1 or death from any cause, whichever occurs first.
4.2.2.
Secondary Endpoints
4.2.2.1 Key Secondary Endpoints
!
OS, defined as the time from the date of randomization to the date of death due to any 
cause
!
OS at 24 months, defined as the proportion of subjects alive at 24 months after 
randomization.
!
ORR defined as the proportion of subjects who had complete response (CR) or partial
response (PR) as assessed by blinded independent central review per RECIST v1.1
4.2.2.2 Other Secondary Endpoints
!
The time from the first occurrence of a documented objective response to the time of 
relapse, as determined by blinded independent central review per RECIST v1.1, or death 
from any cause, whichever comes first
!
The proportion of subjects alive and progression free at 12 months (APF12) will be 
defined as the Kaplan-Meier estimate of PFS at 12 months
!
The proportion of subjects alive and progression free at 18 months (APF18)
!
TTDM will be defined as the time from the date of randomization until the first date of 
distant metastasis or death in the absence of distant metastasis. Distant metastasis is 
defined as any new lesion that is outside of the radiation field according to RECIST v1.1 
or proven by biopsy
!
Safety and tolerability will be assessed from adverse events (using NCI CTCAE v5.0),
laboratory tests, vital signs, ECOG performance status, physical exams, concomitant 
medications, and dose modifications
!
Differences between study arms, tests for within-group changes over time and tests for 
both deterioration and improvement will be performed on the selected lung cancer 
symptoms (appetite –item 13 of EORTC QLQ-C30, cough – items 31 of EORTC
QLQ-LC13, haemoptysis – item 32 of EORTC QLQ-LC13, chest pain – item 40 of 
EORTC QLQ-LC13, dyspnea –items 33 to 35 of EORTC QLQLC13, and fatigue – items
10, 12, 18 of EORTC QLQ-C30), and physical functioning – items 1 to 5 of EORTC 
QLQ-C30.
!
Proportion of subjects who receive at least one dose of tislelizumab or placebo in the 
monotherapy phase before progression as determined by blinded independent central
review per RECIST v1.1
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
17
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
4.3.1.
Randomization and Stratification
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will be randomized by IRT via 1:1:1 ratio to one of the following treatment arms:
 
 
The permuted block randomization method will be used to generate the randomization codes and 
the randomization will be performed by IRT to ensure a 1:1:1 treatment assignment ratio. The 
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randomization schedule will be generated by the Sponsor or its designee. The randomization will 
be stratified by age 
 chemotherapy regimen 
 
, and region
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4.3.2.
Blinding
This is a randomized, double-blind, Phase 3 study. Subjects will be randomized to receive
tislelizumab or placebo in a double-blind fashion.  Investigators, subjects, and researchers will be 
remaining in blinded throughout entire study until database lock.  An independent statistics and 
programming team will perform unblinding interim analyses and DMC data analysis.
4.4.
Sample Size Determination
There are 2 primary hypotheses in this study:
!
H1: PFS in Arm 1 ≤ Arm 3 versus PFS in Arm 1 > Arm 3
!
H2: PFS in Arm 2 ≤ Arm 3 versus PFS in Arm 2 > Arm 3
 
 
 
 
 
 
 
 
The median PFS in the control arm (Arm 3) was based on data from historical trials with similar 
patients. Ahn (2015) (Ahn, 2015) and Belderbos (2007) (Belderbos, 2007) reported that the 
median PFS for inoperable (unresectable) stage III NSCLC treated with concurrent chemo-
radiotherapy are 8.1 months and 8.5 months, respectively. Factoring in potential improvements 
in best supportive care, Celgene used a 
 estimate for median PFS of 9 months for the 
control arm for the sample size and power calculation. 
For the target PFS treatment effect, Celgene considered a hazard ratio of 0.7 as a clinically 
meaningful improvement of PFS and used that for the sample size and power calculation. This 
target is considered reasonable based on cross-trial evaluation of historical data for cCRT 
described above, including that from the recently published PACIFIC study results (Antonia, 
2017) . Celgene considers T0 as PFS from cCRT treatment and T1 as PFS from anti-PD-1 
consolidation (durvalumab) treatment for patients who have stable disease or better following 
cCRT. Heuristically, Celgene approximates the cCRT + anti-PD-1 PFS as T = T0(T0 ≤ 2) + (2 + 
T1) (T0 > 2) for first line treatment. Fitting historical medians of T0 and T1, 8 and 16.8 months 
respectively, and conducting simulations, the median PFS is close to 14.6 months, which 
corresponds to an approximately 38% improvement consistent with the target hazard ratio of 0.7.
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
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A similar assessment was performed for OS. The median OS in the control arm was estimated at 
22 months from Ahn (2015) (Aha, 2015). 
 
  
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
20
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
!
Data from all study centers in the main protocol BGB-A317-NSCL-001 and the 
companion protocol BGB-A317-NSCL-001C will be collected into a single database 
and analyzed;
!
All stratified efficacy analyses will use the stratification factors including age 
 
), chemotherapy regimen 
 
, and region 
 
!
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’; 
!
Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified 
differently in specific analysis;
!
Summary statistics will consist of the number and percentage of subjects (or cycles, if 
appropriate) in each category for discrete variables, and the sample size, mean, 
median, Standard Deviation (STDEV), minimum, and maximum for continuous 
variables;
!
All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value;
!
All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form XX (XX.X%), where the percentage is in the 
parentheses;
!
All listings will be sorted for presentation in order of treatment arm, study center, 
subject, and date of procedure or event;
!
All analysis and summary tables will have the analysis population sample size (ie, 
number of subjects);
!
The day of the first dose of any study drug will be defined as Day 1; 
!
Baseline value will be defined as the last value on or before the first dose of study 
drug is administered; if multiple values are present for the same time point, the 
average of these values will be used as the baseline. For subjects who were not 
treated, the baseline will be the assessment value taken on the visit of Cycle 1 Day 1 
if available; otherwise, the value on or prior to randomization date will be used. 
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
21
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population/Full Analysis Set
The intent-to-treat (ITT) population includes all randomized subjects regardless of whether the 
subjects receive any IP or have any efficacy assessment conducted. All efficacy analyses will be 
based on the ITT population, unless otherwise specified. The efficacy analyses will be performed 
according to treatment assigned at randomization.
5.2.2.
Safety Population
The safety population includes all subjects who receive at least one dose of tislelizumab or 
placebo. If a subject receives study drug other than the subject’s randomized treatment 
assignment, then the subject is assigned to the treatment arm reflecting the treatment that the 
subject actually received during the study. All safety analyses will be based on the Safety 
population, unless otherwise specified. 
5.2.3.
Per-Protocol Population
The per-protocol (PP) population includes all subjects in the safety population who have met all 
the eligibility criteria, and have no major protocol violation. The PP population will be used in 
sensitivity analyses of the primary and key secondary endpoints.
 
 
5.2.5.
HRQoL evaluable Population
The Health-Related Quality of Life (HRQoL) evaluable population will include all subjects
included in ITT population who completed the EORTC QLQ-C30 and EORTC QLQ-LC13
assessment at baseline (ie, Cycle 1 Day 1 Visit or Screening Visit if assessment at the Cycle 1 
Day 1 Visit was not completed, captured or available) and at least 1 postbaseline assessment 
visit.
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Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
22
6.
SUBJECT DISPOSITION
The total number of subjects screened will be presented, and subjects with screen failure and 
reasons for screen failure will be summarized by frequency and percentage.
Subject disposition (analysis of population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for treatment period 
during cCRT, treatment period after cCRT for ITT population. 
Reasons for treatment discontinuation will be summarized by treatment arm. The number and 
percentage of subjects who are in the survival follow-up, lost to survival follow-up, or died at the 
time of analysis will also be presented.
Reasons for study discontinuation will be summarized for all subjects who discontinue study.
Number of subjects randomized by strata and number of subjects randomized by region, country 
and site will be summarized. Listings will be provided for subjects who are screened but not 
enrolled, randomized but not treated, and for discontinued subjects with reason for treatment 
discontinuation.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
23
7.
PROTOCOL DEVIATIONS
The protocol deviations will be identified and assessed by clinical research physician or designee 
following company standard operational procedure. Protocol deviations and important protocol 
deviations will be reviewed before database lock to determine the PP population. Events that 
could trigger exclusion from the PP population include inclusion/exclusion criteria violations, 
failure to take any study drug as assigned, randomization errors, and prohibited concomitant 
medications and procedures. In this SAP, important protocol deviation is used interchangeably 
with major protocol violation. 
The important protocol deviations will be summarized separately by treatment arm for the ITT 
population. A by-subject listing of subjects with important protocol deviations in the ITT 
population will be provided. 
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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized for the ITT population. 
Individual subject listings will be provided to support the summary tables.
8.1.
Demographics
Subject’s age (years), height (cm), weight (kg), Body Mass Index (BMI) and Body Surface Area 
(BSA) at baseline will be summarized descriptively. Sex, race, ethnicity and reproductive status 
will be summarized by frequency counts.
Age will be calculated as follows: age = Integer of [(Date of informed consent – Date of Birth + 
1) / 365.25] or use derived age from eCRF. 
BMI will be calculated as follows: BMI (kg/m2) = weight in kg / (height in m)2.
BSA will be calculated as follows: BSA (m2) = 0.007184 × (Weight in kg)0.425 × (Height in 
cm)0.725.
8.2.
Baseline Characteristics
The following baseline characteristic will be summarized by frequency counts, by treatment arm 
and overall:
!
ECOG performance status at baseline (0, 1, ≥2);
!
Disease stage at diagnosis (IIIA, IIIB, IIIC);
!
Stage of cancer per blinded independent central review;
!
Histology subtype (Adenocarcinoma, Squamous cell carcinoma, Mixed adeno-squamous, 
Other); 
!
EGFR mutation (Positive, Negative); 
!
ALK rearrangement status (Positive, Negative); 
!
PDL1 result category (Positive, Negative); 
!
PDL1 scoring cut off (<1, 1 - 24, 25 – 49, >= 50, Not Available);
!
Pulmonary function results by tests;
!
Smoking status (Never, Current, Former).
8.3.
Cancer History and Baseline Lesion Status
The following items will be summarized for cancer diagnosis:
!
The time from the diagnosis date of the studied disease to first dose date in months, 
defined as (first dose date – diagnosis date + 1)/ 30.4375
!
Number of target/non-target lesions overall and by types of lesion;
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!
Method of assessment for target/non-target lesions
!
Sum of target lesion diameters
Subject listings will be provided for all of the above, as well as date of diagnosis.
8.4.
Medical History
A summary of medical and surgical history will be presented by MedDRA system and organ 
class (SOC) and preferred term (PT).
8.5.
Prior and Concomitant Therapy
8.5.1.
Prior and Concomitant Anti-Cancer Therapy
Prior and concomitant anti-cancer procedures will include radiation therapy for other disease,
stem cell transplants and surgeries for any diseases.  Prior and concomitant procedures will be 
tabulated separately. 
The number and percentage of subjects who had radiation therapy for other diseases will be 
presented. For subjects with radiation therapy, the number and percentage of subjects with each 
type of radiotherapy (External Beam Location, Radio-Immuno Therapy, Brachytherapy, Other) 
and each site of radiation therapy will be presented.
The number and percentage of subjects who had surgery for any diseases will be presented by 
study treatment group for overall and by anatomical location. 
Prior and concomitant procedures will be listed.
8.6.
Prior and Concomitant Medications
Medications reported on the Prior and Concomitant medications eCRF pages will be coded to 
therapeutic drug classes and generic drug names using the WHO drug dictionary. 
8.6.1.
Prior Medications
Prior medications are defined as all medications that were started before the first dose of study 
drug. A summary showing the number and percentage of subjects who took prior medications 
will be presented by WHO drug dictionary therapeutic drug class and generic drug name. This 
summary will be presented for the ITT population.
8.6.2.
Concomitant Medications
Concomitant medications for the Treatment Period are defined as medications that were initiated 
before the first dose of study drug and continued during the study treatment, or initiated on/after 
the date of the first dose of study drug and within 28 days after the date of treatment 
discontinuation. 
Summaries showing the number and percentage of subjects who took concomitant medications 
will be presented by WHO therapeutic drug class and generic drug name for the ITT population.
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the safety 
population. Descriptive statistics will be provided for treatment duration, number of cycles, 
cumulative dose, dose intensity, and relative dose intensity by treatment arm. Dose 
reduction/interruption will also be summarized.
9.1.
Treatment Duration
The treatment start date is the date of the first dose of study treatment. For subjects who 
discontinue early from study treatment, the treatment end date is the date of last dose recorded on 
the CRF. For subjects who are still on treatment at the time of study closure or clinical cutoff, the 
treatment end date will be the last treatment dose date or the cutoff date, whichever occurs first.
Treatment duration (in weeks) is calculated as (treatment end date – the date of the first dose of 
study drug + 1) / 7 and rounded to one decimal place. The treatment durations of a concomitant 
combination (e.g. tislelizumab + cCRT or placebo + cCRT) and each monotherapy (tislelizumab
or placebo), as well as overall treatment duration will be calculated and summarized 
respectively. Summary statistics for treatment duration (in weeks) as well as a frequency 
summary of treatment duration categories (<3 weeks, ≥ 3 to < 6 weeks, ≥ 6 to < 9 weeks, ≥ 9 to 
< 12 weeks, and every 3-week intervals so forth) will be provided. 
Descriptive statistics for the total number of treatment cycles subjects received and the number 
of doses administered for each study drug will be provided. A summary of the frequency of 
subjects dosed at each cycle will also be provided. 
9.2.
Cumulative Dose
Cumulative dose will be computed separately for each study drug. Cumulative dose for each 
study drug is defined as the sum of all actual doses, defined as the values entered on the actual 
dose administered field on the dosing eCRF, taken across the Treatment Period. Descriptive 
statistics will be presented for cumulative dose for the safety subjects. 
9.3.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose divided by the treatment 
duration in weeks. Dose intensity will be calculated separately for each study drug. 
Dose intensities will be calculated as follows:
!
 
 
 
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Dose intensity will be presented by each study drug for the Treatment Period of the study for the 
safety population.  
9.4.
Relative Dose Intensity
Relative dose intensity by week is the dose intensity divided by the protocol weekly dose, 
expressed as a percentage. Relative dose intensity will be calculated separately for each study 
treatment.
!
 
Percentage of protocol dose for each study treatment will be categorized into <70%, ≥70% to < 
80%, and ≥80 to <90% and ≥90%, and frequency counts will be provided for the safety 
population.
9.5.
Dose Adjustment/Interruption 
Dose adjustment for each study drug is defined as when dose administered after Cycle 1 Day 1 is 
different from the dose the subject receives at the previous dosing visit.
In addition, for each study drug, dose interruption is defined as the dose interruption collected 
from eCRF. 
Treatment exposure and dose adjustment or interruption will be summarized as follows 
(separately for each study drug):
!
Number of cycles and number of doses administered;
!
Number and percentage of subjects with at least 1 dose adjustment or interruption, 
and reasons (Adverse event, Per protocol, investigator decision, or other) for 
adjustment or reduction;
Number and percentage of subjects with at least one dose adjustment or interruption and number 
of dose adjustments or interruptions will be presented.
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10.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ITT population. In addition, the primary and 
key secondary efficacy endpoints will be analyzed using Per Protocol population. Statistical 
comparisons will be made between Arm 1 versus Arm 3 or Arm 2 versus Arm 3 stratified by age 
, chemotherapy regimen 
 
, and region 
 Efficacy results that will be 
considered statistically significant after consideration of the strategy for controlling the family-
wise Type 1 error rate are described in Section 10.1, Multiplicity. All statistical tests will be one-
sided and the corresponding p-values and two-sided confidence intervals (CIs) for intended point 
estimates will be reported.
10.1.
Multiplicity
There are 2 primary hypotheses in this study:
!
: PFS in Arm 1 ≤ Arm 3 versus PFS in Arm 1 > Arm 3
!
: PFS in Arm 2 ≤ Arm 3 versus PFS in Arm 2 > Arm 3
 
There will be one interim and one final analysis for PFS, and one interim and one final analysis 
for OS, respectively. The interim OS analysis will occur at the same as the final PFS analysis. 
Therefore, there will be 3 data cutoff time points in this study:
 
 
   
 
 
 
 
Although PFS is the primary endpoint of this study and the final PFS analysis will be completed 
at the second data cutoff time point, the study may continue to follow up for overall survival 
until a prespecified total number of OS events accumulates, if either of the PFS hypotheses are 
rejected at the interim or the final PFS analysis. 
A group sequential design is implemented based on Lan-Demets spending function that 
approximates the O’Brien-Fleming boundary for each of the primary hypotheses for the PFS 
endpoint. The hypotheses associated with the key secondary endpoint OS:
!
: OS in Arm 1 ≤ Arm 3 versus OS in Arm 1 > Arm 3
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!
: OS in Arm 2 ≤ Arm 3 versus OS in Arm 2 > Arm 3
will be tested only if either one of the primary hypotheses for PFS is rejected at the interim or the 
final PFS analysis. In addition, the other 2 key secondary endpoints, OS at 24 months (OS 24) 
and ORR, will also be tested if both the PFS and OS hypotheses in the same pairwise comparison 
of treatment groups are rejected. The hypotheses associated with OS 24 and ORR are: 
!
: OS 24 in Arm 1 ≤ Arm 3 versus OS 24 in Arm 1 > Arm 3
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!
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!
: ORR in Arm 2 ≤ Arm 3 versus ORR in Arm 2 > Arm 3
The overall type one error rate control strategy here follows the graphic approach as described by
Maurer and Bretz (Maurer, 2013), and can be depicted by the following graph. The local alpha 
will be dynamically determined by the given spending function of the group sequential design 
for each endpoint (Glimm, 2010; Maurer, 2013).
The alpha propagation strategy here allows passing alpha from one hypothesis to the other, 
provided that the hypothesis is rejected at the interim or final analysis. Therefore, depending on 
rejection or acceptance of other hypotheses, the significance level for testing each of the 
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hypotheses may be updated from the initially allocated alpha. Additionally, to control the type 
one error due to multiple looks of OS data at the interim and the final OS analysis, a group 
sequential design based on an alpha spending function that approximates the O’Brien-Fleming 
boundary will also be implemented for either one of the OS hypotheses. The actual boundaries 
will depend on the number of OS events, or information time, at the time of final PFS analysis. 
Similar alpha control approach will be implemented for the other key secondary endpoints OS 24 
and ORR. Notably, if one or more hypotheses are rejected at the interim or final analysis, the 
superiority boundaries for the remaining unrejected hypotheses will be updated based on the 
alpha propagation strategy as described by Maurer and Bretz (Mauer, 2013) using the graph 
above. 
The family-wise type one error rate will be 
 for the primary 
endpoint, PFS, and 3 key secondary endpoints, OS, OS 24 and ORR, for the comparisons of Arm 
1 vs Arm 3 and Arm 2 vs Arm 3.  
If both pairwise comparisons of Arm 1 and Arm 2 are statistically significantly better than Arm 3
for PFS or OS or OS 24 or ORR, comparison between Arm 1 and Arm 2 with estimates of 
hazard ratio or difference in rate and corresponding 95% CIs, will be provided as a supportive 
analysis.       
10.2.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint, PFS will be analyzed using the ITT and the PP Populations. The 
PFS is defined as the time in months from the date of randomization to the date of disease 
progression according to RECIST 1.1 criteria (documented by CT-scan result, not including 
symptomatic deterioration) or death (any cause) on or prior to the clinical cutoff date, whichever 
occurs earlier. 
PFS = (Date of Disease Progression or Death – Date of Randomization + 1) / 30.4375
Subjects who do not have disease progression or have not died as of the data cutoff date will be
censored at the time of the last radiologic assessment where the subject was documented to be 
progression-free prior to the data cutoff date.  In the event that a new anti-cancer therapy is 
initiated for a subject prior to documented progression (or death), the subject will be censored at 
the time of the last radiologic assessment where the subject was documented to be progression-
free prior to the new anti-cancer therapy. Subjects with a single missing radiologic assessment 
prior to a visit with documented disease progression (or death) will be analyzed as a PFS event at 
the time of the radiologic assessment that shows progression or death (whichever is earlier). 
Subjects with two or more consecutive missing radiologic assessments prior to a visit with 
documented disease progression (or death) will be censored at the time of the last radiologic 
assessment where the subject was documented to be progression-free prior to the first of the two 
or more consecutive missing visits. The PFS censoring rule is further illustrated in Table 2.
The distribution of PFS will be estimated using the Kaplan-Meier method. The comparison of 
PFS between treatment arms (Arm 1 versus Arm 3 or Arm 2 versus Arm 3) will be conducted 
using a stratified log-rank test with age 
, chemotherapy regimen 
(
), and region (
) as 
stratification factors. The hazard ratio (between Arm 1 versus Arm 3 or Arm 2 versus Arm 3) 
and the corresponding 95% confidence interval will also be provided based on a stratified Cox 
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proportional hazard model. The median PFS (with 95% confidence interval) and estimation of 
PFS rate (with 95% confidence intervals) for specific time points (eg, 3 months, 6 months etc.) 
will be provided for each treatment arm. The median differences with 95% CIs between each of 
a pair compared arms will be calculated using Kosorok’s method (Kosorok, 1999).
If both pairwise comparisons of Arm 1 and Arm 2 are statistically significantly better than Arm 3
for PFS, comparison between Arm 1 and Arm 2 with estimate of hazard ratio and corresponding 
95% CI, will be provided as a supportive analysis.
Table 2:
Censoring Rules for PFS
Value of Progression-
free Survival Date 
(ADT)
Censored 
(Y,N) 
Derivation
ADT = min(death date, 
progression date) 
N
If a subject died or had disease progression, and the 
time interval between the death date/progression date 
and the previous tumor assessment date with 
progression-free response or the randomization date is 
less than or equal to two scheduled tumor assessment 
visits (91 days in the first 36 weeks and 133 days after 
36 weeks from the first study dose). 
ADT = the last 
progression-free 
assessment date/ 
randomization date
Y
If a subject died or had disease progression, and the 
time interval between the death date/progression date 
and the previous tumor assessment date with 
progression-free response or the randomization date is 
greater than two scheduled tumor assessment visits (91 
days in the first 36 weeks and 133 days after 36 weeks 
from the first study dose). 
ADT = the last tumor 
assessment 
date/randomization date 
Y
If a subject did not die or have progression, and did not 
receive any subsequent anticancer chemotherapy. 
If there was no post-baseline tumor assessment, then 
ADT = the randomization date.
ADT = the last tumor 
assessment date on or 
prior to start of 
subsequent anticancer 
therapy/randomization 
date
Y
If a subject did not die or have progression on or prior 
to start of subsequent anticancer therapy, or a subject 
died/progressed after the start of sequent anticancer 
therapy. 
If there was no post-baseline tumor assessment, then 
ADT = the randomization date.
ADT = analysis date; N = no; Y = yes.
Note: Progression-free response refers to a response that was neither progressive disease (PD) nor not-evaluable 
(UE). 
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10.3.
Analyses of Secondary Efficacy Endpoints
The secondary efficacy endpoints will be analyzed based on ITT population. For the key 
secondary efficacy endpoints of OS, OS at 24 months and ORR, these will be analyzed using the 
ITT and the PP population respectively. Statistical analyses of Patient-Reported Outcomes 
relevant secondary endpoints will be described in Section 12 of this document.
10.3.1.
Overall Survival
The key secondary endpoint of OS is defined as the time from randomization to death due to any 
cause. Subjects without documented death at the time of analysis will be censored at the last-
known-to-be-alive date. OS is defined as the duration (in months) between randomization and 
death from any cause:
OS = (Date of Death – Date of Randomization + 1) / 30.4375
Subjects who are still alive at the end of the study or clinical data cut will be censored at the last-
known-to-be-alive date or clinical cutoff date, whichever is earlier.  
The distribution of OS will be estimated using Kaplan-Meier method. A stratified log-rank test 
will be used to compare treatment groups in OS. The median OS (with 95% confidence interval) 
and estimation of OS rate (with 95% confidence intervals) for different timepoints will be 
provided by treatment arm. The median differences with 95% CIs between each of a pair 
compared arms will be calculated using Kosorok’s method (Kosorok, 1999). The hazard ratio 
(between Arm 1 or Arm 2 versus Arm 3) and the corresponding 95% confidence interval will 
also be provided based on a stratified Cox regression model.
If both pairwise comparisons of Arm 1 and Arm 2 are statistically significantly better than Arm 3
for OS, comparison between Arm 1 and Arm 2 with estimate of hazard ratio and corresponding 
95% CI, will be provided as a supportive analysis.
10.3.2.
OS at 24 Months
The key secondary endpoint OS at 24 months is defined as the proportion of subjects alive at 24 
months (OS 24).   
The point estimate and the corresponding 95% confidence interval for each treatment arm will be 
estimated using Kaplan-Meier method. 
The treatment comparisons for OS 24 will be performed using the cloglog transform approach as 
described in Klein, 2007. The p-value of equality of the survival functions will be provided using
this approach.
If both pairwise comparisons of Arm 1 and Arm 2 are statistically significantly better than Arm 3
for OS 24, comparison between Arm 1 and Arm 2 with estimate of OS 24 difference and 
corresponding 95% CI, will be provided as a supportive analysis.
10.3.3.
Objective Response Rate 
The key secondary endpoint of ORR is defined as the percentage of subjects who achieve a CR 
or PR based on the independent reviewer assessment using RECIST v1.1 criteria. The number 
and percentage of those with a tumor response of partial response (PR), or complete response 
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(CR) will be presented, as well as the number and percentage with each of progressive disease 
(PD), SD, PR, CR, and Not-evaluable (NE). 
The ORR for each treatment arm will be summarized using 95% Clopper-Pearson confidence 
interval. The difference in ORR between treatment arms and the associated 95% confidence 
interval will be estimated using stratified Wilson score method. A Cochran-Mantel-Haenszel 
(CMH) test will be used to compare ORR between treatment arms.
If both pairwise comparisons of Arm 1 and Arm 2 are statistically significantly better than Arm 3
for ORR, comparison between Arm 1 and Arm 2 with estimate of ORR difference and 
corresponding 95% CI, will be provided as a supportive analysis.
10.3.4.
Duration of Response
The DOR is defined as the time from the first tumor assessment when the CR/PR response 
criterion is first met to the date of disease progression based on independent reviewers’ 
assessment following RECIST v1.1 criteria or death, whichever is earlier. 
For subjects who had a confirmed CR or PR, 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 progressive disease is radiologically documented (taking as reference for progressive 
disease the smallest measurements recorded on study) or death. 
Subjects who are non-responders (i.e., do not achieve at least a PR) will be excluded from this 
analysis. 
The duration of response will be analyzed using similar methods as described for the analysis of 
PFS.
10.3.5.
Alive and Progression-Free at 12 or 18 Months
The proportion of subjects alive and progression free at 12 months (APF12) or 18 months 
(APF18) will be summarized. The point estimate and the corresponding 95% confidence interval 
for each treatment arm will be estimated using Kaplan-Meier method. 
Treatment comparisons for APF12 and APF18 will be based on the cloglog transform approach 
as described in Klein, 2007. The p-value of equality of the survival functions will be provided 
using this approach.
10.3.6.
Time to Distant Metastasis
TTDM will be defined as the time from the date of randomization until the first date of distant 
metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new 
lesion that is outside of the radiation field according to RECIST v1.1 or proven by biopsy. 
Subjects who do not have documented new distant lesion or have not died as of the data cutoff 
date will be censored at the time of the last radiologic assessment or biopsy where the subject 
was documented to be distant lesion free prior to the data cutoff date.  
Time to distant metastasis will be analyzed using similar methods as described for the analysis of 
PFS. 
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34
10.3.7.
Proportion of subjects who continue to monotherapy phase
The proportion of subjects who received at least one dose of tislelizumab or placebo in the 
monotherapy phase before progression based on blinded independent reviewer assessment 
following RECIST v1.1 criteria, will be compared for Arm 1 versus Arm 2 and 3 combined. The 
proportion will be summarized using point estimate and 95% Clopper-Pearson confidence 
interval for Arm 1 versus Arm 2 and 3. The difference between treatment arms and the 
associated 95% Wilson score confidence interval will be provided. A Cochran-Mantel-Haenszel 
(CMH) test will be used to compare the proportion.
In addition, the proportion of subjects who are progression free at the end of cCRT will be 
compared for Arm 1 versus Arm 2 and 3 combined. Progression free at the end of cCRT is 
defined as CR or PR or SD based on blinded independent reviewer assessment following 
RECIST v1.1 criteria at week 6.
10.4.
Subgroup Analysis
The primary and key secondary efficacy endpoints will also be analyzed within the following 
subgroups, note that the age, chemotherapy regimen 
 
 region (
), baseline ECOG will be based on the 
clinical data instead of randomization data:
1.
1. Age 
); 
2. ECOG PS (0 vs 1);
3. Sex (male vs female); 
4. Stage at diagnosis (Stage IIIA vs Stage IIIB vs Stage IIIC);
5. Chemotherapy regimen 
);
6. Mutation (EGFR mutation or ALK rearrangement vs EFGR and ALK Wild-Type);
7. PD-L1 (positive (TPS >=1%) vs negative (TPS < 1%));
8. Smoking status (never vs current vs former);
9. Histology subtype (adenocarcinoma vs squamous cell carcinoma vs mixed adeno-
squamous vs other).
A forest plot will be provided based on the HRs or differences in rate for each subgroup. 
The consistency of the treatment effect will be assessed in the context of the primary efficacy 
analysis model with terms for treatment, stratum, its interaction with treatment, and the 
covariate. Treatment effects and nominal 95% confidence intervals by category for the 
classification variables listed above will be provided.  Formal statistical testing of these 
interactions will not be performed.
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Tislelizumab (BGB-A317)
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
35
11.
SAFETY ANALYSIS
The purpose of this section is to describe the safety analyses for the Treatment Period of the 
study. Adverse events and laboratory values will be analyzed based on the safety population, per 
treatment arm and for treatment-related TEAEs or TEAEs with action taken, also by specific 
drug. 
11.1.
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which 
are defined as any adverse events that had an onset date or a worsening in severity from baseline 
on or after the first dose of study drug up to 30 days following study drug discontinuation or 
initiation of new anticancer therapy, whichever occurs first. TEAEs also include all immune-
related AEs recorded up to 90 days after the last dose of tislelizumab or placebo, regardless of 
whether or not the subject starts a new anticancer therapy. In addition, any serious AE with an 
onset date more than 30 days after the last dose of study drug that is assessed by the investigator 
as related to study drug will be considered a TEAE. All AEs will be coded using the Medical 
Dictionary for Regulatory Affairs® (MedDRA). 
Treatment-related TEAE will be summarized for each treatment arm. If a subject experiences 
multiple occurrences of the same AE with different relationship to study medication categories, 
the subject will be counted once, as a relationship category of treatment-related. TEAEs with a 
missing relationship will be presented in the summary table as a relationship category of 
“treatment-related”.
The incidence of TEAEs will be summarized for each treatment arm by MedDRA SOC and PT 
in a descending order of frequency of SOC and PT within each SOC based on the combination 
arm. If a subject experiences multiple AEs under the same SOC or PT, then the subject will be 
counted only once for that SOC or PT.
The toxicity of AEs will be graded 1 to 5 according to the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0. For all other AEs not described in the CTCAE criteria, 
the toxicity will be assessed by the investigator as mild (grade 1), moderate (grade 2), severe 
(grade 3), life-threatening (grade 4) or death (grade 5). If a subject experiences the same AE 
more than once with different toxicity grade, then the event with the highest grade will be 
tabulated in “by grade” tables. If a subject experiences multiple AEs under the same preferred 
term (system organ class), then the subject will be counted only once for that preferred term 
(system organ class). In addition, AEs with a missing intensity will be presented in the summary 
table as an intensity category of “Missing.” 
Deaths during the study will be summarized by cause categories. AEs regarded as primary cause 
of deaths, as reported on CRF, will also be summarized by SOC and PT, For both types of 
summaries, on-treatment (within 30 days after the last dose of study treatment) and post-
treatment deaths will be summarized separately.
Tables summarizing the incidence of TEAEs will be generated for each of the following:
!
All TEAEs;
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
36
!
TEAEs reported as treatment-related; 
!
Serious TEAEs;
!
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!
All TEAEs with grade 3-4; 
!
Treatment-related grade 3-4 TEAEs;
!
TEAEs leading to death;
!
Treatment-related TEAEs leading to death;
!
TEAEs leading to drug discontinuation;
!
All TEAEs by CTCAE grade as well as grade 1-2 vs. grade 3-4;
!
All death within 30 days of last dose with cause of death.
Listings for the corresponding summary tables will be presented separately. Non-treatment-
emergent AEs will also be listed. 
11.2.
Immune-related Adverse Events
The treatment-emergent immune-related adverse event (TEirAE) will be summarized by 
treatment arm: 
!
Thyroid Disorders
!
Hypophysitis
!
Pneumonitis
!
Neurological Toxicity
!
Colitis
!
Eye Disorders
!
Hepatitis
!
Renal Toxicity
!
Dermatology
!
Joint or muscle inflammation
!
Myocarditis
11.3.
Clinical Laboratory Evaluations
Clinical laboratory values from the central laboratories will be graded according to NCI CTCAE 
version 5.0 for applicable tests. The worst grade during the treatment period will be summarized 
by treatment arm.  Frequency distributions for shift from baseline to the worst grade during 
treatment period will be presented by treatment arm. Normal ranges will be used to determine the 
categories of High, Low, and Normal for lab tests that have no severity grade. 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
37
Listings of clinical laboratory data from central laboratory with abnormal flags will be provided 
by subjects and tests. Listings will also be provided for the local laboratory data. 
11.3.1.
Hematology
Hemoglobin, hematocrit, red blood cell count and morphology, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count 
with absolute and differential and percent (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and bands), platelet count, reticulocytes, erythrocyte sedimentation rate, international 
normalized ratio, prothrombin time, partial thromboplastin time will be collected in hematology 
panel. Additional laboratory samples may be collected as clinically indicated.
In order to investigate the maximal degree of myelosuppression, the NCI CTCAE grade for 
hemoglobin, leukocytes, lymphocytes, neutrophils and platelets will be summarized by the worst 
grade in each treatment cycle and by the worst grade overall (i.e., any time after first dose of 
study drug). The number and percentage of subjects with each NCI CTCAE grade will be 
presented. A shift table representing the shift from the baseline grade to the worst grade will be 
provided for each of these laboratory tests.
Treatment group differences in each laboratory parameter with respect to the NCI CTCAE 
grades will be summarized by the frequency distribution of subjects with the grades.  
All laboratory parameters will be summarized by descriptive statistics within each treatment arm, 
as appropriate.
11.3.2.
Clinical Chemistry
Serum chemistry panel includes sodium, potassium, bicarbonate, calcium, magnesium, 
phosphorus, blood urea nitrogen, serum creatinine and clearance, uric acid, glucose, lactic 
dehydrogenase (LDH), total protein, albumin, alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, gamma glutamyl transferase, total, direct and indirect bilirubin, 
fibrinogen, ferritin. Additional laboratory samples may be collected as clinically indicated.
Hepatic and renal function will be summarized using the NCI CTCAE grade for ALT (SGPT), 
AST (SGOT), albumin, total bilirubin, creatinine, potassium, and sodium. The number and 
percentage of subjects that have each NCI CTCAE grade will be summarized using the worst 
grade for each cycle and overall. A shift table representing the shift from the baseline grade to 
the worst grade will be provided for each of these laboratory tests.
Treatment group differences in each laboratory parameter with respect to the NCI CTCAE 
grades will be summarized by the frequency distribution of subjects with the grades.  
All laboratory parameters will be summarized by descriptive statistics within each treatment arm, 
as appropriate.
11.4.
Vital Sign Measurements
Vital signs (Weight, Temperature, Systolic and Diastolic Blood Pressure, Pulse and Respiratory 
rate) will be recorded at screening and on Day 1 of each cycle and EOT. Vital sign data will be 
listed.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
38
11.5.
Physical Examination
Physical Examination will be recorded in source documentation (i.e. not collected on CRF) only 
and hence no table and listings will be produced.
11.6.
Electrocardiograms
Triplicate 12-lead ECGs will be recorded at screening and EOT and will be assessed locally. The 
12-lead ECGs (12-lead at 25 mm/sec reporting rhythm, ventricular rate, PR-interval, QRS 
complex, QT interval, and QTc interval) will be performed after the subject has been in the 
supine position for at least 5 minutes. Shift from baseline to most abnormal post-baseline 
qualitative assessment of ECG abnormality (i.e., ‘Normal’, ‘Abnormal, not clinically 
significant’, and ‘Abnormal, clinically significant’) will be displayed in cross–tabulations by 
treatment. 
11.7.
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) score runs from 0 to 5, with 0 denoting 
perfect health and 5 denoting death. ECOG performance status (PS) scores will be assessed and 
reported on the appropriate eCRF at screening, Day 1 of each cycle and at EOT. A shift table 
representing the shift from the baseline to the worst post-baseline ECOG PS scores will be 
provided for each treatment cycle and overall.
11.8.
Ophthalmic Examinations
The analysis of data from ophthalmic exams is under discussion; details will be provided in a 
subsequent SAP version.
11.9.
Pregnancy test
A by-subject listing of pregnancy test and results will be provided for all female subjects of 
childbearing potential.
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the safety population. 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
39
12.
QUALITY OF LIFE ANALYSIS
The predominant patient-reported lung cancer symptoms (appetite loss, cough, hemoptysis, chest 
pain, dyspnea, and fatigue) assessed by the EORTC QLQ-C30 and its lung cancer module LC13 
will be a predefined secondary endpoint;
 
 
 
 
 
12.1.
EORTC QLQ-C30 and LC13
Patient reported outcome validated instruments (EORTC QLQ-C30 with the lung module LC13) 
will be used to assess the selected lung cancer symptoms: appetite loss, cough, hemoptysis, chest 
pain, dyspnea, and fatigue, as secondary efficacy endpoints.
 
 
.
The EORTC QLQ-C30 and LC-13 scores will be calculated according to scoring algorithms 
defined by the authors. Missing response items will not be imputed. A domain with multiple 
items will be scored when 50% or more items in the domain have non-missing responses. Scores 
are transformed to a 0 to 100 scale, higher scores indicating better QoL, better functioning, or 
more severe symptoms.
To assess the extent of missing data at each assessment visit by treatment group, the PRO 
compliance rates for the EORTC QLQ-C30 and LC-13 will be estimated per treatment group on 
the ITT population. Subjects are considered compliant with completion of the EORTC QLQ-C30 
and LC-13 assessment if at least half of the items are non-missing at a given assessment visit.
To assess the effect of study treatments on HRQoL, the following analyses will be conducted for 
the selected symptoms identified as secondary efficacy endpoints based on the HRQoL evaluable 
population.
Baseline scores, post-baseline scores and change from baseline will be statistically described for 
all domains and symptoms (as applicable) by treatment arm. To interpret the difference in 
change score from baseline between treatment groups and change score at the individual level, 
values for clinically-meaningful change in EORTC QLQ-C30 domain scores reported in EORTC 
scoring manual (Osoba, 1998) will be considered. Other values defined according to cut-off 
values for clinically-meaningful change across different domains published by Cocks et al 
(Cocks, 2012) will also be considered for sensitivity analysis.
Count and percent of subjects with improvement and worsening in scores from their baseline 
score will be summarized by treatment group over study visit. Improvement and worsening will 
be defined based on values considered for clinically-meaningful change from baseline (Osoba, 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
40
1998; Cocks, 2012). Time to the first minimal clinically important improvement in scores will be 
examined using Kaplan-Meier method. 
Analysis for the following will be provided in a separate HRQoL statistical analysis plan. The 
HRQoL statistical analysis plan will be appended to the specific HRQoL report.
Descriptive statistics of the baseline HRQoL domain scores and key demographic and disease 
characteristics will be summarized by treatment group and overall for the HRQoL-evaluable and 
non-evaluable populations. The comparability of the HRQoL-evaluable and non-evaluable 
populations will be assessed to mitigate the potential selection bias. 
The relationship between selected clinical efficacy responses (PFS, OS, ORR) and selected 
symptoms defined as secondary endpoints will also be explored.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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41
 
 
 
  
 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
42
 
 
 
 
 
 
 
 
 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
44
15.
INTERIM ANALYSIS
15.1.
General Information
An independent Data Monitoring Committee will be established and will include medical 
oncologists and a statistician, all of whom are not otherwise involved in the study conduct. 
During the course of the study, the DMC will review the safety data regularly. The DMC will 
offer recommendations based on periodic evaluations of comparative safety data, in accordance 
with criteria outlined in the DMC Charter. An independent statistician will prepare the reports to 
the DMC members for each scheduled meeting. Details will be provided in the DMC charter. 
 
 
 
 
 
 
 
 
 
  Enrollment 
may continue during these IDMC safety reviews.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
15.2.
Statistical Approaches for Control of Alpha
One interim analysis for PFS and one interim analysis for OS are planned for this study. 
 
 
 
 
.
The approximate timeline for interim and final analyses, along with the superiority boundaries 
for the pairwise treatment comparison in PFS
 
 updated according to the actual number of events observed in the 2 treatment 
groups in the pairwise comparison, and the significance level updated due to rejection of other 
hypotheses as described in the protocol. Celgene anticipates accrual will be completed before an 
interim analysis of PFS is performed and the study is planned to continue until completion of the 
final PFS and OS analyses.  
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Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
45
Table 3:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
46
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
Per BeiGene press release excerpt from 17 June 2019:
BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage 
biopharmaceutical company focused on developing and commercializing innovative 
molecularly-targeted and immuno-oncology drugs for the treatment of cancer, today 
announced that it has entered into a mutual agreement with Celgene Corporation to 
terminate the parties’ global collaboration for tislelizumab, BeiGene’s investigational 
anti-PD-1 antibody.
Tislelizumab is the investigational agent in the BGB-A317-NSCL-001 (RATIONALE 001) 
study, which is being conducted in collaboration with BeiGene.  For the reasons noted above, 
Celgene is closing the BGB-A317-NSCL-001 (RATIONALE 001) study. 
Subject 
 is the only subject randomized and treated in BGB-A317-NSCL-001. Since the 
study is being closed no other subjects will be randomized or treated. The study treatment was 
unblinded at investigator request and the subject was randomized to treatment arm 2 (i.e. 
placebo+CRT for 2 cycles followed by tislelizumab monotherapy) and had received only one 
dose of placebo.
In this SAP the following subgroup analyses were added: Smoking status (never vs current vs 
former), Stage at diagnosis (Stage IIIA vs Stage IIIB vs Stage IIIC), Histology subtype 
(adenocarcinoma vs squamous cell carcinoma vs mixed adeno-squamous vs other). In Protocol 
Section 9 the above subgroup analyses are not described. These subgroup analyses will not be 
performed as result of the study closure. 
The decision of closing the study in very early stage is leading to the decision not to conduct any 
planned statistical analysis. As a consequence, the SAP is remaining in this stable draft version.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
47
17.
REFERENCES
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for interpreting change scores 
for the European Organisation for the Research and Treatment of Cancer Quality of Life 
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Glimm E, Maurer W, and Bretz F. Hierarchical Testing of Multiple Endpoints in Group 
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CTCAE. Am Soc Clin Oncol Educ Book. 2016;35:67-73.
Kosorok, Michael R. Two-Sample Quantile Tests under General Conditions. Biometrika, Vol. 
86, No. 4 (Dec., 1999), pp. 909-921
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches 
Statistics in Biopharmaceutical Research, 2013; 5:4, 311-320.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
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Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time.
Statist. Med. 2007;26:4505–4519.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al; PACIFIC Investigators.
Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med.
2017 Nov 16;377(20):1919-29.
Ahn JS, Ahn YC, Kim J-H, Lee CG, Cho EK, Lee KC, et al. Multinational Randomized Phase
III Trial With or Without Consolidation Chemotherapy Using Docetaxel and Cisplatin After
Concurrent Chemoradiation in Inoperable Stage III Non-Small-Cell Lung Cancer : KCSG-LU05-
04. J Clin Oncol 2015 Aug 20;33(24):2660-2670.
Belderbos J, Uitterhoeve L, van Zandwijk N, Belderbos H, Rodrigus P, van de Vaart P, et al, on
behalf of the EORTC LCG and RT Group. Randomised Trial of sequential versus concurrent
chemo-radiotherapy in patients with inoperable non-small cell lung cancer. Eur J Cancer.
2007;43:114-121.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
48
18.
APPENDICES
18.1.
Study Schematic and Study Events
18.1.1.
Study Schematic
                                                                                         
Randomization 1:1:1
N=840 (280 per Arm)
Stratification by age 
), chemotherapy regimen 
 
), and region (
)
 
Follow-Up
Safety until 90 days posttreatment (30 days posttreatment for AEs except for irAEs which require 90 days 
posttreatment follow up)
Response evaluation until progression, subsequent anticancer therapy, withdrawal of consent, lost to follow-up,
or death 
Survival follow-up until death, withdrawal of consent, lost to follow-up, or end of study
 
 
Screening
Eligibility Check
Collect tumor tissue and blood samples as applicable
Treat until progressive disease, death, 
unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 12 
months after cCRT phase.
 
 
Treat until progressive disease, 
death, unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 
12 months after cCRT phase.
Treat until progressive disease, death, 
unacceptable toxicity, 
subject/physician decision, 
withdrawal of consent, or a total of 
12 months after cCRT phase.
IDMC safety check 
 
 
IDMC safety check 3 to 6 months after the first check, then approximately every 6 months thereafter
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
49
Abbreviations:  C1D1 = Cycle 1 Day 1; cCRT = concurrent chemoradiotherapy; IDMC = independent data 
monitoring committee;
; 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
50
18.1.2.
Table of Study Events
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion 
criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
X
-
-
X
-
-
X
X
-
-
-
Complete medical 
history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior/concomitant 
medication evaluation
Continuous from ≤28 days prior to randomization until 30 days post last dose of study treatment
-
-
Prior/concomitant 
procedures evaluation
Continuous from ≤ 28 days prior to randomization until 30 days post last dose of study treatment
-
-
EGFR/ALK testing on 
tumor tissue (if status 
not available)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
51
(Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Confirmation of 
mediastinal nodal 
involvement, if 
applicable (the 
protocol Section 4.2)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Patient Reported 
Outcomes: EORTC 
QLQ-C30, LC13
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
SAFETY ASSESSMENTS
Adverse event 
evaluatione
Continuous from informed consent until 30 days post last dose of study treatment for AEs; 90 days post last dose of tislelizumab/placebo for 
irAEs
-
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Vital signs/weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Performance status 
ECOG
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
Height
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Body surface area 
calculation
-
X
X
X
X
X
X
-
-
-
-
-
-
-
-
Pulmonary function 
test
X
Only if clinically indicated
-
-
-
-
12-lead 
electrocardiogram
X
X
Only if clinically indicated
X
X
-
-
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
52
(Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Left ventricular 
ejection fraction
X
Only if clinically indicated
-
-
OCT (or equivalent 
diagnostic test) and 
visual acuity testsg
X
Approximately every 15 weeks (± 7 days) during study treatment
Xg
Hematology 
laboratoryfh
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Chemistry laboratoryfh
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
Coagulation 
laboratory (PT, PTT, 
INR)h
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
Thyroid functionh
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
C-reactive protein
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HBV/ HCV testi
X
If clinically indicated. For subjects who have detectable HBV DNA or HCV RNA at screening or upon repeat 
testing, respective viral load test every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc.).
-
-
Urinalysis
X
If clinically indicated
-
-
Serum β-hCG 
pregnancy test
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Urine β-hCG 
pregnancy testj
X
X
-
-
X
-
-
X
-
-
X
X
X
-
-
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
53
(Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
EFFICACY ASSESSMENTS
Tumor assessment
CT/MRI
X
Every 6 weeks after randomization for the first 36 weeks (± 7 Days), and every 9 weeks from Week 36 (± 7 Days) onward until disease 
progression, start of a new anticancer therapy, or withdrawal of consent from the entire study
FDG-PET/CT
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CT scan, with 
contrast, of the head 
or brain MRI with 
contrast
X
Only if clinically indicated
 
 
 
 
 
 
 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
54
(Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
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D1b
D8
D15
D22
D29
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±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
 
 
 
progression
TREATMENT
Administer IP: 
tislelizumab/placebo
-
X
-
-
X
-
-
Xn
-
-
X
-
-
-
-
Administer 
radiotherapyo
-
60 Gy in 30 fractions (2 Gy per day/5 days per 
week)
-
-
-
-
-
-
-
-
Accountability 
tislelizumab/placebo
-
X
-
-
X
-
-
X
-
-
X
-
-
-
-
Accountability 
etoposide/cisplatin
-
X
X
X
X
-
-
-
-
-
-
-
-
Administer IP: 
tislelizumab/placebo
-
X
X
X
Xn
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
55
(Continued)
Events
Screeninga
Treatment Period During cCRT
Treatment Period After cCRT
Up to 12 Months of Treatment
Follow-up Period
Day 
-28 to -1
D1b
D8
D15
D22
D29
D36
D43
D50
D57
Day 1 of each 21-
Day Cycle (starting 
D64)
EOTc
30-Day 
FU
90-Day 
FUd
PD/ 
Survival
Window (days)
-
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Administer 
appropriate 
chemotherapy
premedications
-
X
X
X
X
X
X
-
-
-
-
-
-
-
-
Administer 
radiotherapyo
-
60 Gy in 30 fractions (2 Gy per day/5 days per 
week)
-
-
-
-
-
-
-
-
Accountability 
tislelizumab/placebo
-
X
-
-
X
-
X
-
-
X
-
-
-
-
Accountability 
paclitaxel/carboplatin
-
X
X
X
X
X
X
-
-
-
-
-
-
-
-
FOLLOW-UP
Survival follow-up
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Every 3 
months 
(± 14 
days) 
until 
death
Disease therapy since 
IP discontinuation
-
-
-
-
-
-
-
-
-
-
-
-
X
X
At every 
survival 
follow-
up visit
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
56
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase; β-hCG = beta human chorionic gonadotropin; CBC = complete blood count; cCRT = concurrent 
chemoradiotherapy; CK = creatine kinase; CK-MB = creatine kinase – cardiac muscle isoenzyme; CT = computed tomography; D = day; DNA = deoxyribonucleic acid; ECOG = 
Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer – Quality of 
Life C30 questionnaire; EOT =  end of treatment; 
 FDG-PET = fluorodeoxyglucose -
positron emission tomography; FU = follow-up; Gy = gray; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg =  hepatitis B surface antigen;
HBV = hepatitis B virus HCV = hepatitis C virus; IP = investigational product; IRT = integrated response technology; MRI = magnetic resonance imaging; LC13 = Lung Cancer 
Module of EORTC QLQ-C30; OCT = optical coherence tomography; PD = progressive disease; 
 
; RNA = ribonucleic acid; RT = radiation therapy; SAE = serious adverse event; SOC = standard of care; T
 
.
a Screening evaluations must be completed within 28 days of randomization.
b Subjects should have Cycle 1 Day 1 (C1D1) dosing initiated within 3 days of randomization.
c End of treatment visit to be completed as soon as possible after IP discontinuation decision.
d The 90-Day Follow up Visit could be completed at the site or by telephone.
e All AEs and SAEs, regardless of relationship to study treatment, will be reported until 30 days after last dose of study treatment.  Immune-related AEs (serious or non-serious) 
should be reported until 90 days after the last dose of tislelizumab or placebo, regardless of whether or not the subject starts a new anticancer therapy.  All AEs and SAEs 
considered related to RT will be collected at any time after the first dose of RT, including late radiation toxicities. After a subject has been discontinued from the study treatment, 
Investigators are not obligated to actively seek AEs or SAEs in former subjects.  However, if the Investigator learns of any AE related to radiation or any SAE, and he/she 
considers the SAE related to the study drug, the Investigator will notify the sponsor as described in Section 10 of the protocol.
f Vitals, weight, hematology and chemistry will be collected weekly during Cycles 1, 2, and 3.
g Eye exam, visual acuity test, and optical coherence tomography (OCT) (or equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of randomization may be used rather than repeating tests. Eye exam, visual acuity test, and OCT (or equivalent diagnostic test) will be 
assessed at screening and then approximately every 15 weeks (± 7 days) during study treatment. The ophthalmologic assessments including eye exam, visual acuity test, and OCT 
(or equivalent diagnostic test) should only be performed once at either the EOT or during safety follow up, within 30 days of study treatment end.
h Hematology, serum chemistry, coagulation and thyroid function laboratory tests will be performed centrally. Local laboratory tests can be used for enrollment and dosing day. If 
screening laboratory tests are performed within 3 days of C1D1, these tests do not need to be repeated on C1D1. Before any administration of study treatment on each cycle, the 
results of CBC and serum chemistry should be available and reviewed by the Investigator. Of note, creatine kinase (CK) and creatine kinase – cardiac muscle isoenzyme (CK-MB) 
will be assessed as part of the serum chemistry panel (as per Section 6).  In case CK-MB fractionation is not available, please assess troponin (troponin I and/or T) instead.
i Testing will be performed by a central laboratory and/or the local laboratory at screening and will include at screening HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV 
antibody) and viral load assessment (HBV DNA and HCV RNA). After screening, HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) and viral load assessment 
(HBV DNA and HCV RNA) may be performed if clinically indicated; for subjects who have detectable HBV DNA or HCV RNA at screening or upon repeat testing, respective 
viral load testing will be performed every 4 cycles (ie, Day 1 of Cycles 5, 9, 13, etc).
j 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.
 
n Cycle 3 Day 1 dosing may be delayed up to 7 days in order to ensure that cCRT is completed prior to the start of monotherapy with tislelizumab or placebo.
o The schedule of radiotherapy and chemotherapy administrations is detailed in Table 5 of the protocol. Once commenced, radiotherapy should be given for 5 consecutive days 
weekly. Radiotherapy commences on Day 1 of chemotherapy, with a ± 3 days administrative window allowed for Day 1 of each cycle only.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
57
18.2.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed.  They include the dates of laboratory testing, physical examinations, 
tumor scans, etc.  They should be present whenever data for a protocol-specified 
procedure are present and should only be missing when a procedure are marked as 
NOT DONE in the database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures.  They should 
not be missing unless an event or medication is marked as ongoing in the database.  
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
16.3 (eg, for duration or cycle assignment, etc). However, in listings, log dates will be 
shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc.  They should not be 
missing if the milestone occurs for a subject.  They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine 
progression).  They may be subject to endpoint-specific censoring rules if the 
outcome did not occur, but are not otherwise subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth.  They may be subject to variable-specific censoring and imputation 
rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
18.2.1.
Calculation Using Dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference
between the date of interest and the first date of dosing of study drug (e.g,
tislelizumab or placebo) plus 1 day. The generalized calculation algorithm for relative 
day is the following: 
o
If TARGET DATE >= DRUG START DATE then STUDY DAY = 
(TARGET DATE – DRUG START DATE) + 1; 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
58
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Else use STUDY DAY = TARGET DATE – DRUG START DATE.
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period.  Note: 
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. 
!
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.
∀
Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used
∀
Partial birth date: impute missing day as 15th of the month; impute as 01-July for 
missing month; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4375
18.2.2.
Calculation of Cycles
In this study, subjects meeting inclusion criteria will be randomized 1:1:1 via IVRS into 1 of 3
treatment arms to receive one of following study drugs:
Every 3 treatment weeks consist of a treatment cycle.The start date of each cycle will be 
calculated as follows:
A qualified cycle is defined as a CRF cycle during which the subject receives at least one dose of 
study drug. All qualified cycles will be sorted as the calculated cycle excluding CRF cycles 
during which the subject did not receive any study drug dose. The earlier dosing date (whether 
for tislelizumab, cCRT or placebo) will be considered the start data of the cycle.
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
59
18.3.
Date Imputation Guideline
18.3.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications 
Incomplete Start Date:
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first doing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year
!
No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but is 
the same as the year of the first dosing date, then the first dosing date will be assigned 
to the missing date. 
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Tislelizumab (BGB-A317)
Celgene Corporation
Statistical Analysis Plan.              Protocols BGB-A317-NSCL-001 and BGB-A317-NSCL-001C
60
!
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
18.3.2.
Prior/Concomitant Procedures
Partially missing start dates for prior/concomitant procedures will be imputed in the ADaM 
dataset for prior/concomitant procedures. 
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
18.3.3.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history. The 16th of the month will be used to impute a partially missing start date that has only 
the day missing, and July 1st will be used to impute a partially missing start date that has both 
the month and day missing.
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